Difference between revisions of "Staging page"

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[[#top|Back to Top]]
 
[[#top|Back to Top]]
 
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{| class="wikitable" style="text-align:center; width:50%;"
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{{#lst:Section editor transclusions|aml}}
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! colspan="2" align="center" style="color:white; font-size:125%; background-color:#4a1486" |'''Section editor'''
 
−
|-
 
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| style="background-color:#F0F0F0" |[[File:Hilal.jpg|frameless|upright=0.3|center]]
 
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|<big>Talal Hilal, MD<br>University of Mississippi<br>Jackson, MS</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/THilalMD THilalMD]
 
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|-
 
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Unlike the other chemotherapy regimen pages, this one is not disease-specific. Rather, this is a gathering point for all allogeneic hematopoietic stem cell transplant (HSCT) conditioning regimens. Unless otherwise specified, the day before HSCT is day -1, the day of HSCT is day 0, and the day after HSCT is day +1.
 
 
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
|}
 
|}
 +
''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Acute promyelocytic leukemia - null regimens|this page]]. If you still can't find it, please let us know so we can add it.''
 
{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
 
=Guidelines=
 
=Guidelines=
−
=="How I Treat"==
+
==ELN==
−
*'''2020:''' Puerta-Alcalde et al. [https://doi.org/10.1182/blood.2020005884 How I perform hematopoietic stem cell transplantation on patients with a history of invasive fungal disease]
+
*'''2019:''' Sanz et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509567/ Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet]
−
*'''2019:''' McCurdy & Luznik [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6872960/ How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide]
+
===Older===
−
=Myeloablative regimens, all lines of therapy=
+
*'''2009:''' Sanz et al. [http://www.bloodjournal.org/content/113/9/1875.long Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet]
−
==BuCyTBI {{#subobject:44b691|Regimen=1}}==
+
==[http://www.esmo.org/ ESMO]==
−
BuCyTBI: '''<u>Bu</u>'''sulfan, '''<u>Cy</u>'''clophosphamide, '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
+
*'''2013:''' Fey et al. [http://annonc.oxfordjournals.org/content/24/suppl_6/vi138.full.pdf+html Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/23970018 PubMed]
 +
==[https://www.nccn.org/ NCCN]==
 +
*[https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf NCCN Guidelines - Acute Myeloid Leukemia]
 +
=Upfront induction therapy=
 +
==ADE & ATRA {{#subobject:e221d7|Regimen=1}}==
 +
ADE & ATRA: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide, '''<u>A</u>'''ll-'''<u>T</u>'''rans '''<u>R</u>'''etinoic '''<u>A</u>'''cid
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:ab84cb|Variant=1}}===
+
===Regimen {{#subobject:386fd2|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 20%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[http://www.bloodjournal.org/content/93/12/4131.long Burnett et al. 1999 (UK MRC AML12)]
 +
|1993-1997
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#ADE_.26_ATRA|ADE & ATRA]], shorter duration
 +
| style="background-color:#1a9850" |Superior OS
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJM197902153000702 Fefer et al. 1979]
+
|[https://doi.org/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
−
| style="background-color:#ffffbe" |Pilot, <20 pts
+
|2002-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ATRA_.26_Idarubicin|"Spanish therapy"]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoints of RR/OS
 
|-
 
|-
 
|}
 
|}
−
<section begin="ab84cb" />
+
''Note: this is included for historic purposes. Efficacy for UK MRC AML15 is based on the 2012 update, which was specifically pertinent to APL.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Busulfan (Myleran)]]
+
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV once every 12 hours on days 1 to 10 (total dose: 2000 mg/m<sup>2</sup>)
−
*[[Cyclophosphamide (Cytoxan)]]
+
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
−
====Radiotherapy====
+
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
*[[External beam radiotherapy|TBI]]
+
====Targeted therapy====
−
</div>
+
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO, starting on day 1 and continuing until remission or maximum of 60 days
−
<section end="ab84cb" />
+
'''One course'''
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*UK MRC AML15: [[#ADE_.26_ATRA_88|ADE 8-3-5 + ATRA]] consolidation
 +
</div></div>
 
===References===
 
===References===
−
#Fefer A, Cheever MA, Thomas ED, Boyd C, Ramberg R, Glucksberg H, Buckner CD, Storb R. Disappearance of Ph1-positive cells in four patients with chronic granulocytic leukemia after chemotherapy, irradiation and marrow transplantation from an identical twin. N Engl J Med. 1979 Feb 15;300(7):333-7. [https://doi.org/10.1056/NEJM197902153000702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/366408 PubMed]
+
# '''UK MRC AML12:''' Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the randomized MRC trial. Blood. 1999 Jun 15;93(12):4131-43. [http://www.bloodjournal.org/content/93/12/4131.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/10361110 PubMed] NCT00002658
−
==Busulfan & Cyclophosphamide {{#subobject:83e07a|Regimen=1}}==
+
## '''Update:''' Burnett AK, Hills RK, Milligan DW, Goldstone AH, Prentice AG, McMullin MF, Duncombe A, Gibson B, Wheatley K. Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol. 2010 Feb 1;28(4):586-95. Epub 2009 Dec 28. [https://doi.org/10.1200/JCO.2009.22.9088 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20038732 PubMed]
−
BuCy: '''<u>Bu</u>'''sulfan & '''<u>Cy</u>'''clophosphamide
+
# '''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [https://doi.org/10.1200/JCO.2010.31.4310 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21172891 PubMed] ISRCTN17161961
 +
## '''Update:''' Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. [https://www.nature.com/articles/leu2012360 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23222369 PubMed]
 +
## '''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [https://doi.org/10.1200/jco.2012.47.4874 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23940227 PubMed]
 +
==Arsenic trioxide monotherapy {{#subobject:bdedf2|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 9.6/120 {{#subobject:5a23a8|Variant=1}}===
+
===Regimen variant #1, 0.15 mg/kg (pediatric dosing) {{#subobject:359bzc|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 33%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.bbmt.org/article/S1083-8791(02)50049-5 Andersson et al. 2002]
+
|[https://doi.org/10.1182/blood-2005-08-3532 Mathews et al. 2006]
−
| style="background-color:#91cf61" |Phase 2
+
|1998-2004
 +
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
<section begin="5a23a8" />
+
''Note: the maximum duration was decreased from 75 to 60 days after 2001.''
−
''Note: abstract is limited in detail including which days the treatments are given.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy====
−
*[[Busulfan (Myleran)]] 0.6 mg/kg IV every 6 hours for 16 doses (total dose: 9.6 mg/kg)
+
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 to 3 hours once per day  
−
*[[Cyclophosphamide (Cytoxan)]] 60 mg/kg IV once per day for 2 days (total dose: 120 mg/kg)
+
'''Continued until CR or up to 60 days'''
 
</div>
 
</div>
−
<section end="5a23a8" />
+
<div class="toccolours" style="background-color:#cbd5e7">
−
</div><br>
+
====Subsequent treatment====
 +
*Patients in CR: [[#Arsenic_trioxide_monotherapy_2|Arsenic trioxide]] consolidation
 +
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, 12.8/120 {{#subobject:eeaff3|Variant=1}}===
+
===Regimen variant #2, 0.16 mg/kg {{#subobject:31ae8c|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 76: Line 97:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2011.40.2362 Lee et al. 2013 (COSAH C-005)]
+
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC397380/ Shen et al. 2004]
−
|2005-2009
+
|rowspan=2|2001-2003
−
| style="background-color:#1a9851" |Phase 3 (C)
+
| rowspan="2" style="background-color:#1a9851" |Randomized (C)
−
|[[#Busulfan_.26_Fludarabine|Busulfan & Fludarabine]]
+
|1. [[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]]
−
| style="background-color:#91cf60" |Seems to have superior OS
+
| style="background-color:#fc8d59" |Seems to have inferior DFS
 
|-
 
|-
−
|[https://doi.org/10.1016/S1470-2045(15)00200-4 Rambaldi et al. 2015 (GITMO-AMLR2)]
+
|2. [[#ATRA_monotherapy|ATRA]]
−
|2008-2012
+
| style="background-color:#d3d3d3" |Not reported
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Busulfan_.26_Fludarabine|Busulfan & Fludarabine]]
 
−
| style="background-color:#fc8d59" |Seems to have inferior 1-year non-relapse mortality
 
 
|-
 
|-
 
|}
 
|}
−
<section begin="eeaff3" />
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy====
−
*[[Busulfan (Myleran)]] 3.2 mg/kg IV once per day on days -7 to -4 (total dose: 12.8 mg/kg)
+
*[[Arsenic trioxide (Trisenox)]] 0.16 mg/kg IV once per day  
−
*[[Cyclophosphamide (Cytoxan)]] 60 mg/kg IV once per day on days -3 and -2 (total dose: 120 mg/kg)
+
'''Continued until CR'''
−
====GVHD prophylaxis====
 
−
*[[Cyclosporine]]
 
−
*[[Methotrexate (MTX)]] "according to the discretion of the attending physician"
 
−
====Supportive therapy====
 
−
*[[Filgrastim (Neupogen)]] 450 mcg SC once per day, starting on day +5 and continued until ANC greater than 3000/uL
 
 
</div>
 
</div>
−
<section end="eeaff3" />
+
<div class="toccolours" style="background-color:#cbd5e7">
−
</div><br>
+
====Subsequent treatment====
 +
*Patients in CR: Consolidation, see text for details
 +
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #3, 16/200 {{#subobject:334af6|Variant=1}}===
+
===Regimen variant #3, 10 mg (flat dose) {{#subobject:35af8c|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 33%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJM198312013092202 Santos et al. 1983]
+
|[https://doi.org/10.1182/blood-2005-08-3532 Mathews et al. 2006]
 +
|1998-2004
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
<section begin="334af6" />
+
''Note: the maximum duration was decreased from 75 to 60 days after 2001.''
−
''Note: the day of allogeneic stem cell transplant is not specified in the protocol.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy====
−
*[[Busulfan (Myleran)]] 1 mg/kg IV every 6 hours on days 1 to 4 (total dose: 16 mg/kg)
+
*[[Arsenic trioxide (Trisenox)]] 10 mg IV over 2 to 3 hours once per day  
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg/kg IV once per day on days 5 to 8 (total dose: 200 mg/kg)
+
'''Continued until CR or up to 60 days'''
−
</div>
 
−
<section end="334af6" />
 
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Patients in CR: [[#Arsenic_trioxide_monotherapy_2|Arsenic trioxide]] consolidation
 +
</div></div>
 
===References===
 
===References===
−
#Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, Braine HG, Burns WH, Elfenbein GJ, Kaizer H, Mellits D, Sensenbrenner LL, Stuart RK, Yeager AM. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med. 1983 Dec 1;309(22):1347-53. [https://doi.org/10.1056/NEJM198312013092202 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/6355849 PubMed]
+
# Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De Thé H, Wang ZY, Chen SJ, Chen Z. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5328-35. Epub 2004 Mar 24. [http://www.pnas.org/content/101/15/5328.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC397380/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/15044693 PubMed]
−
#Andersson BS, Kashyap A, Gian V, Wingard JR, Fernandez H, Cagnoni PJ, Jones RB, Tarantolo S, Hu WW, Blume KG, Forman SJ, Champlin RE. Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant. 2002;8(3):145-54. [https://www.bbmt.org/article/S1083-8791(02)50049-5 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/11939604 PubMed]
+
# Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006 Apr 1;107(7):2627-32. Epub 2005 Dec 13. [https://doi.org/10.1182/blood-2005-08-3532 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16352810 PubMed]
−
#'''COSAH C-005:''' Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, Lee JH, Lee WS, Park JH, Bae SH, Hyun MS, Kim DY, Kim SD, Min YJ, Lee KH. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013 Feb 20;31(6):701-9. Epub 2012 Nov 5. [https://doi.org/10.1200/jco.2011.40.2362 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23129746 PubMed] NCT00774280
+
## '''Update:''' Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, Viswabandya A, Thirugnanam R, Abraham A, Shaji RV, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010 Aug 20;28(24):3866-71. Epub 2010 Jul 19. [https://doi.org/10.1200/jco.2010.28.5031 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20644086 PubMed]
−
#'''GITMO-AMLR2:''' Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. [https://doi.org/10.1016/S1470-2045(15)00200-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26429297 PubMed] NCT01191957
+
==Arsenic trioxide & ATRA {{#subobject:2b304d|Regimen=1}}==
−
==Busulfan & Fludarabine {{#subobject:576283|Regimen=1}}==
 
−
BuFlu: '''<u>Bu</u>'''sulfan & '''<u>Flu</u>'''darabine
 
−
<br>Flu/Bu: '''<u>Flu</u>'''darabine & '''<u>Bu</u>'''sulfan
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1 {{#subobject:d415a|Variant=1}}===
+
===Regimen variant #1, 0.15/45 {{#subobject:a85b5f|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 138: Line 152:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
 +
|[http://www.bloodjournal.org/content/107/9/3469.long Estey et al. 2005]
 +
|2002-2005
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://doi.org/10.1016/S1470-2045(15)00200-4 Rambaldi et al. 2015 (GITMO-AMLR2)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ Ravandi et al. 2008]
−
|2008-2012
+
|2002-2007
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+
| style="background-color:#91cf61" |Phase 2
−
|[[#Busulfan_.26_Cyclophosphamide|Busulfan & Cyclophosphamide]]
+
| style="background-color:#d3d3d3" |
−
| style="background-color:#fc8d59" |Seems to improve 1 & 2 year NRM, similar OS
+
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1300874 Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)]
 +
|2007-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 +
|[[#ATRA_.26_Idarubicin|ATRA & Idarubicin]]
 +
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> <br>(HR 0.15, 95% CI 0.03-0.67)
 
|-
 
|-
 
|}
 
|}
−
'''Diseases Studied: [[Acute myeloid leukemia]]'''
+
''<sup>1</sup>Reported efficacy for GIMEMA/DSIL APL0406 is based on the 2019 update.''<br>
−
'''Graft types studied''': Bone Marrow, Mobilized Peripheral Blood Stem Cells
+
''Note: In Estey et al. 2005, arsenic trioxide was started on day 11, but was later modified to start on day 1 after a death due to hyperleukocytosis and intracranial hemorrhage during induction. GIMEMA/DSIL APL0406: Patients with <u>low-</u> or <u>intermediate-risk</u> APL (white blood cell count at presentation less than or equal to 10 x 10<sup>9</sup>/L) were eligible.''
−
<section begin="d415a" />
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy====
−
*[[Busulfan (Myleran)]] 0.8 mg/kg IV four times per day for 2 hour infusions on days -6 to -3
+
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days.
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -6 to -3
+
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days (GIMEMA/DSIL APL0406) or 90 days (Estey et al. 2005 & Ravandi et al. 2008).
−
====Immunosuppressive therapy====
+
====Supportive therapy====
−
*[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]] by the following criteria:
+
*''As described in GIMEMA/DSIL APL0406:''
−
**Unrelated donors, identical: 0.5 mg/kg IV once on day -3, then 2 mg/kg IV once on day -2, then 2.5 mg/kg IV once on day -1
+
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day from days 1 until the end of induction or the onset of differentiation syndrome
−
**If donor mismatched total ATG dose could be increased to 7.5 mg/kg
+
**Patients who develop differentiation syndrome then received: [[Dexamethasone (Decadron)]] 10 mg IV every 12 hours until signs and symptoms resolve, and for a minimum of 3 days
−
====GVHD prophylaxis====
+
*Hemostatic support: Transfusions to keep platelet count greater than 30 x 10<sup>9</sup>/L for the first 10 days of induction and greater than 20 x 10<sup>9</sup>/L for the remainder of induction
−
*[[Cyclosporine]]
+
*[[Hydroxyurea (Hydrea)]] by the following criteria:
−
*[[Methotrexate (MTX)]]
+
**Patients with WBC count greater than 10 x 10<sup>9</sup>/L and less than 50 x 10<sup>9</sup>/L after the start of therapy: 500 mg PO four times per day, given until WBC count is less than 10 x 10<sup>9</sup>/L
 +
**Patients with WBC count greater than 50 x 10<sup>9</sup>/L after the start of therapy: 1000 mg PO four times per day, given until WBC count is less than 10 x 10<sup>9</sup>/L
 +
'''Up to 60- to 90-day course'''
 
</div>
 
</div>
−
<section end="d415a" />
+
<div class="toccolours" style="background-color:#cbd5e7">
−
</div><br>
+
====Subsequent treatment====
 +
*[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation
 +
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2 {{#subobject:d415b|Variant=1}}===
+
===Regimen variant #2, 0.16/25 {{#subobject:9c8a05|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 172: Line 200:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230823/ Andersson et al. 2008]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC397380/ Shen et al. 2004]
−
|1997-2005
+
|2001-2003
−
| style="background-color:#91cf61" |Non-randomized
+
| style="background-color:#1a9851" |Randomized (E-esc)
−
| style="background-color:#d3d3d3" |
+
|1. [[#Arsenic_trioxide_monotherapy|Arsenic trioxide]]<br>2. [[#ATRA_monotherapy|ATRA]]
−
| style="background-color:#91cf60" |Suggested improved outcomes, but shorter follow up
+
| style="background-color:#91cf60" |Seems to have superior DFS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2013.48.8312 Zhu et al. 2013]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Stub#Realgar-Indigo_naturalis_formula_monotherapy|Realgar-Indigo naturalis formula]]
 +
| style="background-color:#eeee01" |Non-inferior DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 0.16 mg/kg IV once per day, starting day 1 and continuing until remission
 +
*[[All-trans retinoic acid (ATRA)]] 12.5 mg/m<sup>2</sup> PO twice per day, starting day 1 and continuing until remission or maximum of 90 days.
 +
'''Up to 90-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Patients achieving CR: chemotherapy-based consolidation and maintenance. These details are available in the original paper but are omitted here.
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 0.3/45 {{#subobject:e391b9|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Years of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)00193-X Burnett et al. 2015 (UK NCRI AML17)]
 +
|2009-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 +
|[[#ATRA_.26_Idarubicin|ATRA & Idarubicin]]
 +
|
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL
 +
|-
 +
|}
 +
''Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 0.3 mg/kg IV once per day on days 1 to 5, then 0.25 mg/kg IV twice per week on weeks 2 to 8
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation
 +
</div></div>
 +
===References===
 +
# Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De Thé H, Wang ZY, Chen SJ, Chen Z. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5328-35. Epub 2004 Mar 24. [http://www.pnas.org/content/101/15/5328.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC397380/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/15044693 PubMed]
 +
## '''Update:''' Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WL, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3342-7. Epub 2009 Feb 18. [http://www.pnas.org/content/106/9/3342.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651325/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19225113 PubMed] content property of [http://hemonc.org HemOnc.org]
 +
# Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. [http://www.bloodjournal.org/content/107/9/3469.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16373661 PubMed]
 +
# Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009 Feb 1;27(4):504-10. Epub 2008 Dec 15. [https://doi.org/10.1200/jco.2008.18.6130 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19075265 PubMed]
 +
## '''Update:''' Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. [http://www.bloodjournal.org/content/129/10/1275 link to full article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5413297/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28003274 PubMed]
 +
# '''GIMEMA/DSIL APL0406:''' Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. [https://doi.org/10.1056/NEJMoa1300874 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23841729 PubMed] NCT00482833
 +
## '''HRQoL analysis:''' Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. [https://doi.org/10.1200/JCO.2014.55.3453 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25245446 PubMed]
 +
## '''Update:''' Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. [https://doi.org/10.1200/JCO.2016.67.1982 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27400939  PubMed]
 +
## '''Update:''' Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. [https://doi.org/10.1038/s41375-019-0589-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31611624 PubMed]
 +
# Zhu HH, Wu DP, Jin J, Li JY, Ma J, Wang JX, Jiang H, Chen SJ, Huang XJ. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial. J Clin Oncol. 2013 Nov 20;31(33):4215-21. Epub 2013 Oct 14. [https://doi.org/10.1200/JCO.2013.48.8312 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24127444 PubMed] ChiCTR-TRC-12002151
 +
# '''UK NCRI AML17:''' Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. [https://doi.org/10.1016/S1470-2045(15)00193-X link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26384238 PubMed] ISRCTN55675535
 +
## '''Update:''' Russell N, Burnett A, Hills R, Betteridge S, Dennis M, Jovanovic J, Dillon R, Grimwade D; NCRI AML Working Group. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood. 2018 Sep 27;132(13):1452-1454. Epub 2018 Aug 10. [https://doi.org/10.1182/blood-2018-05-851824 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6225356/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30097508 PubMed]
 +
== Arsenic trioxide, ATRA, Gemtuzumab ozogamicin {{#subobject:533ccc|Regimen=1}} ==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, GO 6 mg/m<sup>2</sup> {{#subobject:d00673|Variant=2}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Years of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)00193-X Burnett et al. 2015 (UK NCRI AML17)]
 +
|2009-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#ATRA_.26_Idarubicin|ATRA & Idarubicin]]
 +
|
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 0.3 mg/kg IV once per day on days 1 to 5, then 0.25 mg/kg IV twice per week on weeks 2 to 8
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days
 +
====Antibody-drug conjugate therapy====
 +
*[[Gemtuzumab ozogamicin (Mylotarg)]] by the following criteria:
 +
**WBC count greater than 10 x 10<sup>9</sup>/L: 6 mg/m<sup>2</sup> IV once on day 1
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, GO 9 mg/m<sup>2</sup> {{#subobject:7f2ac1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/107/9/3469.long Estey et al. 2005]
 +
|2002-2005
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209101/ Kanakry et al. 2014 (J0844)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ Ravandi et al. 2008]
−
|2009-2011
+
|2002-2007
 
| style="background-color:#91cf61" |Phase 2
 
| style="background-color:#91cf61" |Phase 2
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4797026/ Mielcarek et al. 2016 (FHCC 2541.00)]
+
|}
−
|2011-2013
+
''Note: in some protocols, if GO was unavailable, Idarubicin 12mg/m<sup>2</sup> given instead. The original protocol was modified between Estey et al. 2005 and Ravandi et al. 2008. Estey et al. 2005 covered part of the whole cohort. In the initial protocol, arsenic trioxide was started on day 11, and gemtuzumab ozogamicin was only used for high risk patients. After a death due to hyperleukocytosis and intracranial hemorrhage during induction, the protocol was modified as described in Ravandi et al. 2008 so arsenic trioxide was started on day 1, and gemtuzumab ozogamicin was given if WBC count went greater than 30 x 10<sup>9</sup>/L for any patient in the first four weeks of therapy.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day on days 1 to 28, or until CR
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 28, or until CR
 +
====Antibody-drug conjugate therapy====
 +
*[[Gemtuzumab ozogamicin (Mylotarg)]] by the following criteria:
 +
**WBC count greater than 10 x 10<sup>9</sup>/L: 9 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy====
 +
*"Prophylactic and therapeutic antibiotics and transfusion of blood products to maintain platelet counts more than 30 x 10<sup>9</sup>/L, fibrinogen more than 150 mg/dL, and the international normalized ratio for prothrombin time less than 1.5" per institutional guidelines
 +
*[[Unfractionated heparin (UFH)]] or [[Tranexamic acid (Cyklokapron)]] used if clinically indicated
 +
*[[Methylprednisolone (Solumedrol)]] by the following study-specific criteria:
 +
**Estey et al. 2005: 20 mg PO once per day for 10 days to decrease risk of differentiation syndrome
 +
**Ravandi et al. 2008: 50 mg PO once per day for 5 days to decrease risk of differentiation syndrome
 +
'''28-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation
 +
=== References ===
 +
# Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. [http://www.bloodjournal.org/content/107/9/3469.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16373661 PubMed]
 +
## '''Update:''' Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. [http://www.bloodjournal.org/content/129/10/1275 link to full article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5413297/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28003274 PubMed]
 +
# Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009 Feb 1;27(4):504-10. Epub 2008 Dec 15. [https://doi.org/10.1200/jco.2008.18.6130 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19075265 PubMed]
 +
## '''Update:''' Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. [http://www.bloodjournal.org/content/129/10/1275 link to full article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5413297/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28003274 PubMed]
 +
# '''UK NCRI AML17:''' Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. [https://doi.org/10.1016/S1470-2045(15)00193-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/26384238 PubMed] ISRCTN55675535
 +
## '''Update:''' Russell N, Burnett A, Hills R, Betteridge S, Dennis M, Jovanovic J, Dillon R, Grimwade D; NCRI AML Working Group. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood. 2018 Sep 27;132(13):1452-1454. Epub 2018 Aug 10. [https://doi.org/10.1182/blood-2018-05-851824 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6225356/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30097508 PubMed]
 +
==Arsenic trioxide, ATRA, Idarubicin {{#subobject:e30b39|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:50c777|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1182/blood-2012-02-410746 Iland et al. 2012 (ALLG APML4)]
 +
|2004-2009
 
| style="background-color:#91cf61" |Phase 2
 
| style="background-color:#91cf61" |Phase 2
−
| style="background-color:#d3d3d3" |
+
|-
−
| style="background-color:#d3d3d3" |
 
 
|}
 
|}
−
'''Diseases Studied: [[Acute myeloid leukemia]], [[Myelodysplastic syndrome]], [[Acute lymphocytic leukemia]], [[Chronic myeloid leukemia]], [[Non-Hodgkin lymphoma]]'''
 
−
'''Graft types studied''': Matched Related / Unrelated Donor Bone Marrow, Mobilized Peripheral Blood Stem Cells
 
−
<section begin="d415b" />
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day on days 9 to 36
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 36
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Busulfan (Myleran)]] 130 mg/m<sup>2</sup> IV over 3 hours once per day on days -6 to -3
+
*[[Idarubicin (Idamycin)]] by the following criteria:
−
**Dosing targeted for optimal pharmacokinetics but different parameters each institution, please consult the original publication for optimal levels
+
**Patients up to age 61: 12 mg/m<sup>2</sup> IV once per day on days 2, 4, 6, 8
−
*[[Fludarabine (Fludara)]] 40 mg/m<sup>2</sup> IV over 60 minutes once per day on days -6 to -3, '''given first'''
+
**Patients 61 to 70 years old: 9 mg/m<sup>2</sup> IV once per day on days 2, 4, 6, 8
−
====Immunosuppressive therapy====
+
**Patients older than 70: 6 mg/m<sup>2</sup> IV once per day on days 2, 4, 6, 8
−
*''For unrelated or mismatched donors'': [[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]] 0.5 mg/kg IV once on day -3, then 1.5 mg/kg IV once on day -2, then 2 mg/kg IV once on day -1
 
−
====GVHD prophylaxis====
 
−
<nowiki>#</nowiki>1 Tacrolimus & methotrexate based (Andersson et al.)
 
−
*[[Tacrolimus (Prograf)]]
 
−
*[[Methotrexate (MTX)]]
 
 
====Supportive therapy====
 
====Supportive therapy====
−
*All patients received [[Filgrastim (Neupogen)]] SC once per day from day +7 until achieving an absolute neutrophil count (ANC) ≥1.5 × 10<sup>9</sup>/L for three days
+
*[[Prednisone (Sterapred)]] 1 mg/kg PO once per day on days 1 to 10, or until WBC count falls below 1 x 10<sup>9</sup>/L, or until resolution of differentiation syndrome (whichever occurs last)
−
*[[Phenytoin (Dilantin)]] prophylaxis used during and for one day after IV busulfan
+
*Hemostatic support : Values checked and products transfused once or twice per day to keep platelet count greater than 30 x 10<sup>9</sup>/L, fibrinogen greater than 1.5 g/L (150 mg/dL), normal PT and PTT
−
<nowiki>#</nowiki>2 Post-Transplant Cy based (Kanakry et al. and FHCC 2541.00)
+
*Electrolyte support while on [[Arsenic trioxide (Trisenox)]]: supplemental potassium and magnesium given to keep levels in the upper half of their normal ranges
−
====GVHD prophylaxis====
+
'''36-day course'''
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg/kg IV once per day on days +3 & +4 (used alone in Kanakry et al. when all patients received bone marrow grafts)
+
</div>
−
*± [[Cyclosporine]] intravenous loading dose of CSP was given on day 5, followed by subsequent twice daily dosing adjusted to maintain whole blood trough at 120 to 360 ng/mL. In abscence of GVHD Cyclosporine was tapered from day +56 through day +126 (used in FHCC 2541.00 with PBSCT grafts)
+
<div class="toccolours" style="background-color:#cbd5e7">
−
====Supportive therapy====
+
====Subsequent treatment====
−
*[[Mesna (Mesnex)]] given with cyclophosphamide
+
*[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation, in 3 to 4 weeks
 +
</div></div>
 +
===References===
 +
# '''ALLG APML4:''' Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. [https://doi.org/10.1182/blood-2012-02-410746 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22715121 PubMed] ACTRN12605000070639
 +
==ATRA monotherapy {{#subobject:45c33c|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:430573|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM199105163242002 Warrell et al. 1991]
 +
|NR
 +
| style="background-color:#ffffbe" |Pilot, <20 pts
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[http://www.bloodjournal.org/content/82/11/3241.long Fenaux et al. 1993 (EAPLG APL 91)]
 +
|1991-1992
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 +
|7+3d
 +
| style="background-color:#1a9850" |Superior EFS
 +
|-
 +
|[https://doi.org/10.1056/NEJM199710093371501 Tallman et al. 1997 (ECOG E2491)]
 +
|1992-1995
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 +
|Cytarabine & Daunorubicin
 +
| style="background-color:#1a9850" |Superior OS
 +
|-
 +
|}
 +
''These obsolete regimens are here for historical reference; ATRA is no longer used as monotherapy for induction; some patients in EAPLG APL 91 received concurrent chemotherapy (see paper for details)''
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day, starting day 1 and continuing until remission or maximum of 90 days
 
</div>
 
</div>
−
<section end="d415b" />
+
<div class="toccolours" style="background-color:#cbd5e7">
−
</div><br>
+
====Subsequent treatment====
 +
*EAPLG APL 91: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation
 +
*ECOG E2491: ATRA consolidation, then [[#Cytarabine_.26_Daunorubicin|cytarabine & daunorubicin]] consolidation
 +
</div></div>
 +
===References===
 +
# Warrell RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri LM, Hittelman WN, Vyas R, Andreeff M, Tafuri A, Jakubowski A, Gabrilove J, Gordon MS, Dmitrovsky E. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991 May 16;324(20):1385-93. [https://doi.org/10.1056/NEJM199105163242002 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1850498 PubMed]
 +
# '''EAPLG APL 91:''' Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D, Huebner G, Bauters F, Fegueux N, Fey M, Sanz M, Lowenberg B, Maloisel F, Auzanneau G, Sadoun A, Gardin C, Bastion Y, Ganser A, Jacky E, Dombret H, Chastang C, Degos L; European APL Group. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. Blood. 1993 Dec 1;82(11):3241-9. [http://www.bloodjournal.org/content/82/11/3241.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8241496 PubMed]
 +
## '''Update:''' Fenaux P, Chevret S, Guerci A, Fegueux N, Dombret H, Thomas X, Sanz M, Link H, Maloisel F, Gardin C, Bordessoule D, Stoppa AM, Sadoun A, Muus P, Wandt H, Mineur P, Whittaker JA, Fey M, Daniel MT, Castaigne S, Degos L; European APL Group. Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. Leukemia. 2000 Aug;14(8):1371-7. [https://doi.org/10.1038/sj.leu.2401859 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10942231 PubMed]
 +
<!-- Presented in part at the 36th meeting of the American Society of Hematology, Seattle, December 1–5, 1995. -->
 +
# '''ECOG E2491:''' Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997 Oct 9;337(15):1021-8. Erratum in: N Engl J Med 1997 Nov 27;337(22):1639. [https://doi.org/10.1056/NEJM199710093371501 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9321529 PubMed]
 +
## '''Update:''' Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, Ogden A, Weinstein H, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002 Dec 15;100(13):4298-302. Epub 2002 Aug 15. [http://www.bloodjournal.org/content/100/13/4298.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/12393590 PubMed]
 +
==ATRA, Cytarabine, Daunorubicin {{#subobject:dade93|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #3 {{#subobject:d415c|Variant=1}}===
+
===Regimen variant #1, 45/1400/180 {{#subobject:c7080e|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 225: Line 426:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2011.40.2362 Lee et al. 2013 (COSAH C-005)]
+
|[https://doi.org/10.1200/jco.2006.08.1596 Adès et al. 2006 (EAPLG APL 2000)]
−
|2005-2009
+
|2000-2004
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Busulfan_.26_Cyclophosphamide|Busulfan & Cyclophosphamide]]
+
|[[#ATRA_.26_Daunorubicin|ATRA & Daunorubicin]]
−
| style="background-color:#fc8d59" |Seems to have inferior OS
+
| style="background-color:#1a9850" |Superior OS
 +
|-
 +
|}
 +
''This induction arm was a randomization for young (less than 60), low-risk (WBC count less than 10 x 10<sup>9</sup>/L) patients. High-risk (WBC count greater than 10 x 10<sup>9</sup>/L) patients received this regimen in a non-randomized fashion, along with intrathecal therapy during consolidation.''
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day, starting day 1 and continuing until remission or maximum of 90 days
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 3 (total dose: 1400 mg/m<sup>2</sup>)
 +
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 3 to 5
 +
'''One course of up to 90 days'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 45/1400/200 {{#subobject:8ee9d6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ Powell et al. 2010 (C9710)]
 +
|1999-2004
 +
| style="background-color:#91cf61" |Non-randomized portion of phase 3 RCT
 
|-
 
|-
 
|}
 
|}
−
'''Diseases Studied: [[Acute myeloid leukemia]], [[Myelodysplastic syndrome]], [[Acute lymphocytic leukemia]], [[Chronic myeloid leukemia]], [[Myelofibrosis]]'''
 
−
'''Graft types studied''': Matched Related / Unrelated Donor Bone Marrow, Mobilized Peripheral Blood Stem Cells
 
−
<section begin="d415c" />
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day, starting day 1 and continuing until remission or maximum of 90 days
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Busulfan (Myleran)]] 3.2 mg/kg IV once per day on days -7 to -4, '''given first on days overlapping with fludarabine''' (total dose: 12.8 mg/kg)
+
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 3 (total dose: 1400 mg/m<sup>2</sup>)
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -6 to -2, '''given second on days overlapping with busulfan'''
+
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 3 to 6
−
====GVHD prophylaxis====
+
'''One course of up to 90 days'''
−
*"[[Cyclosporine]]
 
−
*[[Methotrexate (MTX)]] "according to the discretion of the attending physician"
 
−
====Supportive therapy====
 
−
*[[Filgrastim (Neupogen)]] 450 mcg SC once per day, starting on day +5 and continued until ANC greater than 3000/uL
 
 
</div>
 
</div>
−
<section end="d415c" />
+
<div class="toccolours" style="background-color:#cbd5e7">
−
</div><br>
+
====Subsequent treatment====
 +
*[[#Arsenic_trioxide.2C_then_ATRA_.26_Daunorubicin|Arsenic trioxide, then ATRA & daunorubicin]] consolidation versus [[#ATRA_.26_Daunorubicin|ATRA & daunorubicin]] consolidation
 +
</div></div>
 +
===References===
 +
# '''EAPLG APL 2000:''' Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; EAPLG. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. [https://doi.org/10.1200/jco.2006.08.1596 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17116939 PubMed] NCT00591526
 +
## '''Pooled subgroup analysis:''' Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. [http://www.bloodjournal.org/content/111/3/1078.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017 PubMed]
 +
# '''C9710:''' Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. [http://www.bloodjournal.org/content/116/19/3751.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20705755 PubMed] NCT00003934
 +
==ATRA, Cytarabine, Idarubicin {{#subobject:e4a23d|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #4 {{#subobject:6eb66d|Variant=1}}===
+
===Regimen {{#subobject:124ac5|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 254: Line 481:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1053/bbmt.2002.v8.pm12374451 Russell et al. 2002]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6269295/ Adès et al. 2018 (APL 2006)]
−
|1999-2001
+
|2006-2013
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized portion of phase 3 RCT
 
|-
 
|-
 
|}
 
|}
−
'''Diseases Studied: [[Acute myeloid leukemia]], [[Myelodysplastic syndrome]], [[Chronic myeloid leukemia]], [[Chronic lymphocytic leukemia]], [[Non-Hodgkin lymphoma]], [[Hypereosinophilic syndrome]]'''
 
−
'''Graft types studied''': Matched Related / Unrelated Donor Bone Marrow or Mobilized Peripheral Blood Stem Cells
 
−
<section begin="6eb66d" />
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day, starting on day 1 and continuing until complete remission
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Busulfan (Myleran)]] 3.2 mg/kg (ideal body weight) IV over 3 hours once per day on days -5 to -2
+
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 3 (total dose: 1400 mg/m<sup>2</sup>)
−
*[[Fludarabine (Fludara)]] 50 mg/m<sup>2</sup> IV once per day on days -6 to -2
+
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once per day on days 3 to 5
−
====Immunosuppressive therapy====
+
'''One course until CR'''
−
*[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]] 0.5 mg/kg IV once on day -2, then 2 mg/kg IV once per day on days -1 & 0 (total dose of 4.5 mg/kg)
 
−
====GVHD prophylaxis====
 
−
*[[Cyclosporine]] IV or PO twice per day, with doses adjusted to maintain cyclosporine levels of 150 to 400 umol/L
 
−
*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> (route not specified) once on day 1, then 10 mg/m<sup>2</sup> (route not specified) once per day on days 3, 6, 11
 
−
====Supportive therapy====
 
−
*[[Folinic acid (Leucovorin)]] 5 mg started 24 hours after each dose of methotrexate and continued every 6 hours until 12 hours before the next dose of methotrexate
 
−
*[[Phenytoin (Dilantin)]] "loading" PO/IV, dosed to maintain therapeutic levels of 40 to 80 umol/L on days -5 to -2
 
 
</div>
 
</div>
−
<section end="6eb66d" />
+
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Patients with baseline WBC less than 10 x 10<sup>9</sup>/L: [[#Cytarabine_.26_Idarubicin|Cytarabine & Idarubicin]] versus Arsenic trioxide & Idarubicin versus ATRA & Idarubicin consolidation
 +
*Patients with baseline WBC greater than 10 x 10<sup>9</sup>/L: [[#Cytarabine_.26_Idarubicin|Cytarabine & Idarubicin]] versus Arsenic trioxide, Cytarabine, Idarubicin consolidation
 +
</div></div>
 +
===References===
 +
# '''APL 2006:''' Adès L, Thomas X, Guerci Bresler A, Raffoux E, Spertini O, Vey N, Marchand T, Récher C, Pigneux A, Girault S, Deconinck E, Gardin C, Tournilhac O, Lambert JF, Chevallier P, de Botton S, Lejeune J, Dombret H, Chevret S, Fenaux P; French Belgian Swiss APL group. Arsenic trioxide is required in the treatment of newly diagnosed acute promyelocytic leukemia: analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL group. Haematologica. 2018 Dec;103(12):2033-9. Epub 2018 Jul 19. [http://www.haematologica.org/content/103/12/2033 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6269295/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30026341 PubMed] NCT00378365
 +
==ATRA & Daunorubicin {{#subobject:6c0f66|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:aa790b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2006.08.1596 Adès et al. 2006 (EAPLG APL 2000)]
 +
|2000-2004
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, Cytarabine, Daunorubicin]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
''This induction arm was a randomization for young (less than 60), low-risk (WBC count less than 10 x 10<sup>9</sup>/L) patients. Low-risk (WBC count less than 10 x 10<sup>9</sup>/L) older (greater than 60) patients received this regimen in a non-randomized fashion.''
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day, starting on day 1 and continuing until remission or maximum of 90 days
 +
====Chemotherapy====
 +
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 3 to 5
 +
'''One course of up to 90 days'''
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Daunorubicin_monotherapy|Daunorubicin]] consolidation
 +
</div></div>
 
===References===
 
===References===
−
#Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Brown C, Stewart D, Ruether JD, Morris D, Glick S, Gyonyor E, Andersson BS. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant. 2002;8(9):468-76. [https://doi.org/10.1053/bbmt.2002.v8.pm12374451 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12374451 PubMed]
+
# '''EAPLG APL 2000:''' Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; EAPLG. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. [https://doi.org/10.1200/jco.2006.08.1596 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17116939 PubMed] NCT00591526
−
#de Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R, Shpall EJ, Shahjahan M, Pierre B, Giralt S, Korbling M, Russell JA, Champlin RE, Andersson BS. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004 Aug 1;104(3):857-64. Epub 2004 Apr 8. [https://doi.org/10.1182/blood-2004-02-0414 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15073038/ PubMed]
+
## '''Pooled subgroup analysis:''' Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. [http://www.bloodjournal.org/content/111/3/1078.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017 PubMed]
−
#Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M, Roberson S, Giralt S, Pierre B, Russell JA, Shpall EJ, Jones RB, Champlin RE. Once daily IV busulfan and fludarabine (IV Bu-Flu) compares favorably with IV busulfan and cyclophosphamide (IV BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant. 2008;14(6):672-84. [http://www.bbmt.org/article/S1083-8791(08)00118-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230823/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18489993 Pubmed]
+
==ATRA & Idarubicin {{#subobject:772861|Regimen=1}}==
−
#'''COSAH C-005:''' Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, Lee JH, Lee WS, Park JH, Bae SH, Hyun MS, Kim DY, Kim SD, Min YJ, Lee KH. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013 Feb 20;31(6):701-9. Epub 2012 Nov 5. [https://doi.org/10.1200/jco.2011.40.2362 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23129746 PubMed] NCT00774280
+
AIDA: '''<u>A</u>'''TRA, '''<u>IDA</u>'''rubicin
−
#'''J0844:''' Kanakry CG, O'Donnell PV, Furlong T, de Lima MJ, Wei W, Medeot M, Mielcarek M, Champlin RE, Jones RJ, Thall PF, Andersson BS, Luznik L. Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol. 2014; 32(31):3497-505. Epub 2014 Sep 29. [https://doi.org/10.1200/JCO.2013.54.0625 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209101/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25267759 Pubmed] NCT00809276
 
−
#'''FHCC 2541.00:''' Mielcarek M, Furlong T, O'Donnell PV, Storer BE, McCune JS, Storb R, Carpenter PA, Flowers ME, Appelbaum FR, Martin PJ. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016;127(11):1502-8. [http://www.bloodjournal.org/content/127/11/1502.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4797026/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26764356 Pubmed] NCT01427881
 
−
#'''GITMO-AMLR2:''' Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. [https://doi.org/10.1016/S1470-2045(15)00200-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26429297 PubMed] NCT01191957
 
−
#'''MDACC 2011-0628:''' Andersson BS, Thall PF, Ma J, Valdez BC, Bassett R Jr, Chen J, Ahmed S, Alousi A, Bashir Q, Ciurea S, Gulbis A, Cool R, Kawedia J, Hosing C, Kebriaei P, Kornblau S, Myers A, Oran B, Rezvani K, Shah N, Shpall E, Parmar S, Popat UR, Nieto Y, Champlin RE. A randomized phase III study of pretransplant conditioning for AML/MDS with fludarabine and once daily IV busulfan ± clofarabine in allogeneic stem cell transplantation. Bone Marrow Transplant. 2022 Aug;57(8):1295-1303. Epub 2022 May 24. [https://doi.org/10.1038/s41409-022-01705-7 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc9352570/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35610308/ PubMed] NCT01471444
 
−
==Cyclophosphamide & TBI {{#subobject:a9f7e8|Regimen=1}}==
 
−
Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:6ca28d|Variant=1}}===
+
===Regimen {{#subobject:71cfae|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 17%"|Study
 
!style="width: 17%"|Study
 
!style="width: 15%"|Years of enrollment
 
!style="width: 15%"|Years of enrollment
Line 296: Line 542:
 
!style="width: 17%"|Comparator
 
!style="width: 17%"|Comparator
 
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
!style="width: 17%"|[[Levels_of_Evidence#Efficacy|Non-relapse mortality]]
+
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
|-
 
|-
−
|[https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/581686 Rudolph et al. 1973]
+
|[http://www.bloodjournal.org/content/88/4/1390.long Avvisati et al. 1996 (GIMEMA AIDA)]
−
|1968-1970
+
|1993
−
| style="background-color:#91cf61" |Non-randomized
+
| style="background-color:#91cf61" |Pilot
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJM198201143060202 Fefer et al. 1982]
+
|[http://www.bloodjournal.org/content/90/3/1014.long Mandelli et al. 1997 (GIMEMA AIDA 0493)]
−
|1971-1980
+
|1993-1996
−
| style="background-color:#ffffbe" |Non-randomized, <20 pts
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/54/2/468.long Thomas et al. 1979]
+
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA96)]
−
|1976-1977
+
|1996-1999
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
Line 319: Line 565:
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJM198005083021901 Blume et al. 1980]
+
|[https://doi.org/10.1111/j.1365-2141.2011.08593.x Latagliata et al. 2011 (GIMEMA AIDA 0493 amended protocol)]
−
|1976-1979
+
|1997-2004
−
| style="background-color:#ffffbe" |Non-randomized, <20 pts
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://doi.org/10.1056/NEJM198110083051502 Johnson et al. 1981]
 
−
|1976-1980
 
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
Line 333: Line 572:
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJM198712243172602 Brochstein et al. 1987]
+
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA99)]
−
|1979-1985
+
|1999-2002
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
Line 340: Line 579:
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJM198601233140403 Goldman et al. 1986]
+
|[http://www.bloodjournal.org/content/116/17/3171.long Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
−
|1981-1984
+
|2000-2006
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
Line 347: Line 586:
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJM198708203170801 Kersey et al. 1987]
+
|[http://www.bloodjournal.org/content/115/25/5137.long Sanz et al. 2010 (PETHEMA LPA2005)]
−
|1982-1985
+
|2005-2009
−
| style="background-color:#1a9851" |Quasi-randomized
 
−
|Auto HSCT
 
−
| style="background-color:#1a9850" |Superior RFS
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://doi.org/10.1056/NEJM199804023381405 Hansen et al. 1998]
 
−
|1985-1994
 
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
Line 361: Line 593:
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.1994.12.12.2580 Sebban et al. 1994 (LALA 87)]
+
|[https://doi.org/10.1056/NEJMoa1300874 Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)]
−
|1986-1991
+
|2007-2013
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|Chemotherapy or Auto HSCT
+
|[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS
+
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
−
| style="background-color:#d3d3d3" |
+
|
−
|-
 
−
|[https://doi.org/10.1056/NEJM199501263320403 Zittoun et al. 1995]
 
−
|1986-1993
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|Intensive chemotherapy
 
−
| style="background-color:#1a9850" |Superior DFS
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2004.10.050 Thomas et al. 2004 (LALA-94)]
 
−
|1994-2002
 
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
 
|-
 
|-
−
|[https://doi.org/10.1016/S1470-2045(12)70349-2 Bornhäuser et al. 2012 (9005-2003)]
+
|[https://doi.org/10.1016/S1470-2045(15)00193-X Burnett et al. 2015 (UK NCRI AML17)]
−
|2004-2009
+
|2009-2013
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Fludarabine_.26_TBI|Fludarabine & TBI]]
+
|[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]]
 
|
 
|
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of NRM
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL
 
|-
 
|-
 
|}
 
|}
−
<section begin="6ca28d" />
+
''<sup>1</sup>Reported efficacy for GIMEMA/DSIL APL0406 is based on the 2019 update.''<br>
 +
''Note: this is the same induction used in '''multiple''' protocols. Consolidation and maintenance differ, follow the appropriate links below.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
''Details in the manuscripts are limited.''
+
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] starting day 1 and continuing until remission or maximum of 90 days, by the following criteria:
 +
**21 or older: 22.5 mg/m<sup>2</sup> PO twice per day
 +
**Less than 20 years old: 12.5 mg/m<sup>2</sup> PO twice per day
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cyclophosphamide (Cytoxan)]] 60 mg/kg IV once per day on two consecutive days
+
*[[Idarubicin (Idamycin)]] by the following criteria:
−
====Radiotherapy====
+
**Up to age 70: 12 mg/m<sup>2</sup> IV bolus once per day on days 2, 4, 6, 8
−
*[[External_beam_radiotherapy|Total body irradiation]], 10 to 12 Gy total
+
**Older than 70 years old: 12 mg/m<sup>2</sup> IV bolus once per day on days 2, 4, 6
 +
'''One course of up to 90 days'''
 
</div>
 
</div>
−
<section end="6ca28d" />
+
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
''Once CR was achieved, patients proceeded to consolidation by the following study-specific criteria:''
 +
*PETHEMA LPA96: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin|Idarubicin, then mitoxantrone, then idarubicin]] consolidation
 +
*GIMEMA AIDA & AIDA 0493: [[#Cytarabine_.26_Idarubicin.2C_then_Etoposide_.26_Mitoxantrone.2C_then_Cytarabine.2C_Idarubicin.2C_Thioguanine|Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine]] consolidation
 +
*PETHEMA LPA99: risk-adapted therapy by the following criteria:
 +
**<u>Low-risk</u> patients: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin|Idarubicin, then mitoxantrone, then idarubicin]] consolidation
 +
**<u>Intermediate- and high-risk</u> patients: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin.2C_with_ATRA|Idarubicin, then mitoxantrone, then idarubicin, with ATRA]] consolidation
 +
*PETHEMA LPA2005: risk-adapted therapy by the following criteria:
 +
**<u>High-risk</u> patients: [[#Cytarabine_.26_Idarubicin.2C_then_Mitoxantrone.2C_then_Cytarabine_.26_Idarubicin.2C_with_ATRA|Cytarabine & idarubicin, then mitoxantrone, then cytarabine & idarubicin, with ATRA]] consolidation
 +
**<u>Intermediate- and low-risk</u> patients: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin.2C_with_ATRA|Idarubicin, then mitoxantrone, then idarubicin, with ATRA]] consolidation
 +
*AIDA 2000: risk-adapted therapy by the following criteria:
 +
**<u>High-risk</u> patients: [[#Cytarabine_.26_Idarubicin.2C_then_Etoposide_.26_Mitoxantrone.2C_then_Cytarabine.2C_Idarubicin.2C_Thioguanine.2C_with_ATRA|Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine, with ATRA]] consolidation
 +
**<u>Intermediate- and low-risk</u> patients: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin.2C_with_ATRA|Idarubicin, then mitoxantrone, then idarubicin, with ATRA]] consolidation
 +
*GIMEMA AIDA 0493 amended protocol: [[#Cytarabine_.26_Idarubicin|Cytarabine & idarubicin]] consolidation
 +
*GIMEMA/DSIL APL0406 and UK NCRI AML17: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin.2C_with_ATRA|Idarubicin, then mitoxantrone, then idarubicin, with ATRA]] consolidation
 +
</div></div>
 +
===References===
 +
# '''GIMEMA AIDA:''' Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood. 1996 Aug 15;88(4):1390-8. [http://www.bloodjournal.org/content/88/4/1390.long link to full article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8695858 PubMed]
 +
# '''GIMEMA AIDA 0493:''' Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. [http://www.bloodjournal.org/content/90/3/1014.long link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/9242531 PubMed]
 +
## '''Update:''' Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA; AIEOP; EORTC. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5;117(18):4716-25. Epub 2011 Mar 8. [http://www.bloodjournal.org/content/117/18/4716.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21385856 PubMed]
 +
# '''PETHEMA LPA96:''' Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. [http://www.bloodjournal.org/content/103/4/1237.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14576047 PubMed]
 +
## '''Pooled subgroup analysis:''' Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. [http://www.bloodjournal.org/content/111/3/1078.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017 PubMed]
 +
# '''PETHEMA LPA99:''' Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. [http://www.bloodjournal.org/content/103/4/1237.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14576047 PubMed] NCT00465933
 +
## '''Pooled subgroup analysis:''' Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. [http://www.bloodjournal.org/content/111/3/1078.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017 PubMed]
 +
# '''PETHEMA LPA2005:''' Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA; HOVON. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. [http://www.bloodjournal.org/content/115/25/5137.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20393132 PubMed] NCT00408278
 +
# '''GIMEMA AIDA-2000:''' Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. [http://www.bloodjournal.org/content/116/17/3171.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20644121 PubMed] NCT001064570
 +
# '''GIMEMA AIDA 0493 amended protocol:''' Latagliata R, Breccia M, Fazi P, Vignetti M, Di Raimondo F, Sborgia M, Vincelli D, Candoni A, Salvi F, Rupoli S, Martinelli G, Kropp MG, Tonso A, Venditti A, Melillo L, Cimino G, Petti MC, Avvisati G, Lo-Coco F, Mandelli F; GIMEMA Acute Leukaemia Working Party. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia: long-term results and prognostic factors. Br J Haematol. 2011 Sep;154(5):564-8. Epub 2011 Jul 14. [https://doi.org/10.1111/j.1365-2141.2011.08593.x link to full article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21751984 PubMed]
 +
# '''GIMEMA/DSIL APL0406:''' Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. [https://doi.org/10.1056/NEJMoa1300874 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23841729 PubMed] NCT00482833
 +
## '''HRQoL analysis:''' Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. [https://doi.org/10.1200/JCO.2014.55.3453 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25245446 PubMed]
 +
## '''Update:''' Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. [https://doi.org/10.1200/JCO.2016.67.1982 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27400939 PubMed]
 +
## '''Update:''' Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. [https://doi.org/10.1038/s41375-019-0589-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31611624 PubMed]
 +
# '''UK NCRI AML17:''' Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. [https://doi.org/10.1016/S1470-2045(15)00193-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/26384238 PubMed] ISRCTN55675535
 +
## '''Update:''' Russell N, Burnett A, Hills R, Betteridge S, Dennis M, Jovanovic J, Dillon R, Grimwade D; NCRI AML Working Group. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood. 2018 Sep 27;132(13):1452-1454. Epub 2018 Aug 10. [https://doi.org/10.1182/blood-2018-05-851824 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6225356/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30097508 PubMed]
 +
=Consolidation after upfront therapy=
 +
==Arsenic trioxide monotherapy {{#subobject:f1814c|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, adult dosing {{#subobject:7befb3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1182/blood-2005-08-3532 Mathews et al. 2006]
 +
|1998-2004
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide_monotherapy|Arsenic trioxide]] induction
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 10 mg IV over 2 to 3 hours once per day
 +
'''28-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Mathews et al. 2006, patients remaining in CR: [[#Arsenic_trioxide_monotherapy_3|Arsenic trioxide]] maintenance
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, pediatric dosing {{#subobject:7bebu3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1182/blood-2005-08-3532 Mathews et al. 2006]
 +
|1998-2004
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide_monotherapy|Arsenic trioxide]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 to 3 hours once per day
 +
'''28-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Patients remaining in CR: [[#Arsenic_trioxide_monotherapy_3|Arsenic trioxide]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
#Rudolph RH, Fefer A, Thomas ED, Buckner CD, Clift RA, Storb R. Isogeneic marrow grafts for hematologic malignancy in man. Arch Intern Med. 1973 Aug;132(2):279-85. [https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/581686 link to original article] [https://pubmed.ncbi.nlm.nih.gov/4268940 PubMed]
+
# Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006 Apr 1;107(7):2627-32. Epub 2005 Dec 13. [https://doi.org/10.1182/blood-2005-08-3532 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16352810 PubMed]
−
##'''Update:''' Fefer A, Einstein AB, Thomas ED, Buckner CD, Clift RA, Glucksberg H, Neiman PE, Storb R. Bone-marrow transplantation for hematologic neoplasia in 16 patients with identical twins. N Engl J Med. 1974 Jun 20;290(25):1389-93. [https://doi.org/10.1056/NEJM197406202902501 link to original article] [https://pubmed.ncbi.nlm.nih.gov/4597885 PubMed]
+
## '''Update:''' Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, Viswabandya A, Thirugnanam R, Abraham A, Shaji RV, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010 Aug 20;28(24):3866-71. Epub 2010 Jul 19. [https://doi.org/10.1200/jco.2010.28.5031 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20644086 PubMed]
−
#Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. [http://www.bloodjournal.org/content/54/2/468.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/378292 PubMed]
+
==Arsenic trioxide, then ATRA & Daunorubicin {{#subobject:e333b6|Regimen=1}}==
−
#Blume KG, Beutler E, Bross KJ, Chillar RK, Ellington OB, Fahey JL, Farbstein MJ, Forman SJ, Schmidt GM, Scott EP, Spruce WE, Turner MA, Wolf JL. Bone-marrow ablation and allogeneic marrow transplantation in acute leukemia. N Engl J Med. 1980 May 8;302(19):1041-6. [https://doi.org/10.1056/NEJM198005083021901 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6245359 PubMed]
 
−
#Johnson FL, Thomas ED, Clark BS, Chard RL, Hartmann JR, Storb R. A comparison of marrow transplantation with chemotherapy for children with acute lymphoblastic leukemia in second or subsequent remission. N Engl J Med. 1981 Oct 8;305(15):846-51. [https://doi.org/10.1056/NEJM198110083051502 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7024804 PubMed]
 
−
#Fefer A, Cheever MA, Greenberg PD, Appelbaum FR, Boyd CN, Buckner CD, Kaplan HG, Ramberg R, Sanders JE, Storb R, Thomas ED. Treatment of chronic granulocytic leukemia with chemoradiotherapy and transplantation of marrow from identical twins. N Engl J Med. 1982 Jan 14;306(2):63-8. [https://doi.org/10.1056/NEJM198201143060202 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7031474 PubMed]
 
−
#Goldman JM, Apperley JF, Jones L, Marcus R, Goolden AW, Batchelor R, Hale G, Waldmann H, Reid CD, Hows J, Gordon-Smith E, Catovsky D, Galton DAG. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med. 1986 Jan 23;314(4):202-7. [https://pubmed.ncbi.nlm.nih.gov/3510388 PubMed]
 
−
#Kersey JH, Weisdorf D, Nesbit ME, LeBien TW, Woods WG, McGlave PB, Kim T, Vallera DA, Goldman AI, Bostrom B, Hurd D, Ramsay NKC. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987 Aug 20;317(8):461-7. [https://doi.org/10.1056/NEJM198708203170801 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3302708 PubMed]
 
−
#Brochstein JA, Kernan NA, Groshen S, Cirrincione C, Shank B, Emanuel D, Laver J, O'Reilly RJ. Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med. 1987 Dec 24;317(26):1618-24. [https://doi.org/10.1056/NEJM198712243172602 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3317056 PubMed]
 
−
#'''LALA 87:''' Sebban C, Lepage E, Vernant JP, Gluckman E, Attal M, Reiffers J, Sutton L, Racadot E, Michallet M, Maraninchi D, Dreyfus F, Fiere D; French Group of Therapy of Adult Acute Lymphoblastic Leukemia. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. J Clin Oncol. 1994 Dec;12(12):2580-7. [https://doi.org/10.1200/JCO.1994.12.12.2580 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7989932 PubMed]
 
−
##'''Update:''' Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, Lepage E, Thomas X, Fière D. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation: a follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000 Dec;14(6):1353-66. [https://doi.org/10.1016/s0889-8588(05)70190-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11147227 PubMed]
 
−
#Zittoun RA, Mandelli F, Willemze R, de Witte T, Labar B, Resegotti L, Leoni F, Damasio E, Visani G, Papa G, Caronia F, Hayat M, Stryckmans P, Rotoli B, Leoni P, Peetermans ME, Dardenne M, Vegna ML, Petti MC, Solbu G, Suciu S; [[Study_Groups#EORTC|EORTC]]; Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 1995 Jan 26;332(4):217-23. [https://doi.org/10.1056/NEJM199501263320403 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7808487 PubMed]
 
−
#Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chauncey TR, Clift RA, Petersdorf EW, Radich J, Sanders JE, Storb RF, Sullivan KM, Anasetti C. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med. 1998 Apr 2;338(14):962-8. [https://doi.org/10.1056/NEJM199804023381405 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9521984 PubMed]
 
−
#'''LALA-94:''' Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. [https://doi.org/10.1200/jco.2004.10.050 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15353542 PubMed] NCT00002700
 
−
##'''Update:''' Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; Swiss Group for Clinical Cancer Research. Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. [https://doi.org/10.1038/sj.leu.2404420 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17039234 PubMed]
 
−
#'''9005-2003:''' Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. Epub 2012 Sep 7. [https://doi.org/10.1016/S1470-2045(12)70349-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22959335 PubMed] NCT00150878
 
−
#'''Retrospective:''' Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, Aljurf M, van Besien K, Bredeson C, Cahn JY, Costa LJ, de Lima M, Gale RP, Hale GA, Halter J, Hamadani M, Inamoto Y, Kamble RT, Litzow MR, Loren AW, Marks DI, Olavarria E, Roy V, Sabloff M, Savani BN, Seftel M, Schouten HC, Ustun C, Waller EK, Weisdorf DJ, Wirk B, Horowitz MM, Arora M, Szer J, Cortes J, Kalaycio ME, Maziarz RT, Saber W. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013 Dec 5;122(24):3863-70. Epub 2013 Sep 24. [http://www.bloodjournal.org/content/122/24/3863.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854108/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24065243 PubMed]
 
−
#'''SWOG S9920:''' NCT00005866
 
−
==Etoposide & TBI {{#subobject:b389e1|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, weight-based etoposide {{#subobject:45f841|Variant=1}}===
+
===Protocol {{#subobject:24bfd3|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 429: Line 720:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1016/S014067360566998X Balduzzi et al. 2005]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ Powell et al. 2010 (C9710)]
−
|1995-2000
+
|1999-2005
−
| style="background-color:#1a9851" |Quasi-randomized
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|Chemotherapy
+
|[[#ATRA_.26_Daunorubicin|ATRA & Daunorubicin]]
−
| style="background-color:#91cf60" |Seems to have superior DFS
+
| style="background-color:#1a9850" |Superior EFS
 +
|-
 +
|}
 +
''Consolidation therapy starts within 2 to 4 weeks of hematologic remission.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy, part 1====
 +
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
 +
'''7-week cycles (5 weeks of therapy, then 2 weeks off), followed by:'''
 +
====Targeted therapy, part 2====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 7
 +
====Chemotherapy, part 2====
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3
 +
'''39-day cycle for 2 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA_monotherapy_2|ATRA]] maintenance versus [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div>
 +
===References===
 +
# '''C9710:''' Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. [http://www.bloodjournal.org/content/116/19/3751.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20705755 PubMed] NCT00003934
 +
==Arsenic trioxide & ATRA {{#subobject:7ce78a|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:a5626f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/107/9/3469.long Estey et al. 2005]
 +
|2002-2005
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1300874 Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)]
 +
|2007-2013
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|}
 +
''Note: There is no maintenance in this protocol.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] as follows:
 +
**Cycles 1, 3, 5, 7: 0.15 mg/kg IV over 1 to 2 hours once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
'''28-cycle for 7 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Protocol variant #2 {{#subobject:575577|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2014.58.9747 Peters et al. 2015 (ALL-SCT-BFM 2003)]
+
|[https://doi.org/10.1182/blood-2012-02-410746 Iland et al. 2012 (ALLG APML4)]
−
|2003-2011
+
|2004-2009
−
| style="background-color:#91cf61" |Non-randomized
+
| style="background-color:#91cf61" |Phase 2
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
 
|-
 
|-
 
|}
 
|}
−
''This regimen was evaluated in the treatment of high-risk pediatric acute lymphoblastic leukemia in CR1.''
+
''Consolidation starts 3 to 4 weeks after completion of induction.''
−
<section begin="45f841" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide.2C_ATRA.2C_Idarubicin|Arsenic trioxide, ATRA, idarubicin]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy, part 1====
−
*[[Etoposide (Vepesid)]] 60 mg/kg (maximum dose of 3600 mg) IV once on day -3
+
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 28
−
====Radiotherapy====
+
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV once per day on days 1 to 28
−
*[[External_beam_radiotherapy|Total body irradiation (TBI)]] 200 cGy twice per day in 6 fractions on days -6 to -4 with lung shielding at 10 Gy (total dose: 1200 cGy)
+
'''4-week course'''; after 3 to 4 weeks, proceed to consolidation cycle 2
 +
====Targeted therapy, part 2====
 +
''Given 3 to 4 weeks after completion of consolidation cycle 1.''
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 7, 15 to 21, 29 to 35
 +
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
 +
'''5-week course'''
 
</div>
 
</div>
−
<section end="45f841" />
+
<div class="toccolours" style="background-color:#cbd5e7">
−
</div><br>
+
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance, after 3 to 4 weeks
 +
</div></div>
 +
===References===
 +
# Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. [http://www.bloodjournal.org/content/107/9/3469.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16373661 PubMed]
 +
# '''ALLG APML4:''' Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. [https://doi.org/10.1182/blood-2012-02-410746 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22715121 PubMed] ACTRN12605000070639
 +
# '''GIMEMA/DSIL APL0406:''' Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. [https://doi.org/10.1056/NEJMoa1300874 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23841729 PubMed] NCT00482833
 +
## '''HRQoL analysis:''' Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. [https://doi.org/10.1200/JCO.2014.55.3453 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25245446 PubMed]
 +
## '''Update:''' Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. [https://doi.org/10.1200/JCO.2016.67.1982 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27400939 PubMed]
 +
## '''Update:''' Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. [https://doi.org/10.1038/s41375-019-0589-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31611624 PubMed]
 +
# '''UK NCRI AML17:''' Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. [https://doi.org/10.1016/S1470-2045(15)00193-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/26384238 PubMed] ISRCTN55675535
 +
## '''Update:''' Russell N, Burnett A, Hills R, Betteridge S, Dennis M, Jovanovic J, Dillon R, Grimwade D; NCRI AML Working Group. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood. 2018 Sep 27;132(13):1452-1454. Epub 2018 Aug 10. [https://doi.org/10.1182/blood-2018-05-851824 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6225356/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30097508 PubMed]
 +
==ATRA & Daunorubicin {{#subobject:5d419b|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, BSA-based etoposide {{#subobject:45u7g1|Variant=1}}===
+
===Regimen {{#subobject:b8d811|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 461: Line 828:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078415/ Peters et al. 2020 (FORUM)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ Powell et al. 2010 (C9710)]
−
|2013-2018
+
|1999-2005
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[#Busulfan.2C_Fludarabine.2C_Thiotepa_99|Busulfan, Fludarabine, Thiotepa]]<br>2. [[#Fludarabine.2C_Thiotepa.2C_Treosulfan_77|Fludarabine, Thiotepa, Treosulfan]]
+
|[[#Arsenic_trioxide.2C_then_ATRA_.26_Daunorubicin|Arsenic trioxide, then ATRA & Daunorubicin]]
−
| style="background-color:#1a9850" |Superior OS
+
| style="background-color:#d73027" |Inferior EFS
 
|-
 
|-
 
|}
 
|}
−
''This regimen was evaluated in the treatment of high-risk pediatric acute lymphoblastic leukemia in CMR.''
+
''Consolidation therapy starts within 2 to 4 weeks of hematologic remission.''
−
<section begin="45u7g1" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 7
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Etoposide (Vepesid)]] 1800 mg/m<sup>2</sup> (maximum dose of 3600 mg) IV once on day -3
+
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3
−
====Radiotherapy====
+
'''39-day cycle for 2 cycles'''
−
*[[External_beam_radiotherapy|Total body irradiation (TBI)]]  200 cGy twice per day in 6 fractions on days -6 to -4 with lung shielding at 10 Gy (total dose: 1200 cGy)
 
 
</div>
 
</div>
−
<section end="45u7g1" />
+
<div class="toccolours" style="background-color:#cbd5e7">
−
</div><br>
+
====Subsequent treatment====
 +
*[[#ATRA_monotherapy_2|ATRA]] maintenance versus [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div>
 +
===References===
 +
# '''C9710:''' Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. [http://www.bloodjournal.org/content/116/19/3751.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20705755 PubMed] NCT00003934
 +
==Cytarabine & Daunorubicin {{#subobject:f3ec97|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #3, 13.2 Gy {{#subobject:e4216b|Variant=1}}===
+
===Regimen {{#subobject:198c4e|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 20%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
+
|[https://doi.org/10.1200/jco.2006.08.1596 Adès et al. 2006 (EAPLG APL 2000)]
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
+
|2000-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Daunorubicin_monotherapy|Daunorubicin]]
 +
| style="background-color:#1a9850" |Superior OS
 
|-
 
|-
 
|}
 
|}
−
''Note: this is the same preparative regimen used for autologous transplant for certain patients; see reference for details. This regimen was evaluated in the treatment of acute lymphoblastic leukemia in CR1.''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
<section begin="e4216b" />
+
====Preceding treatment====
 +
*[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Etoposide (Vepesid)]] 60 mg/kg IV once on day -3
+
*[[Cytarabine (Ara-C)]] as follows:
−
====Radiotherapy====
+
**Cycle 1: 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)
−
*[[External_beam_radiotherapy|Total body irradiation (TBI)]] 220 cGy twice per day in 6 fractions on days -6 to -4 (total dose: 1320 cGy)
+
**Cycle 2, younger than 60 & low-risk (WBC count less than 10 x 10<sup>9</sup>/L) or older than 60 & high-risk (WBC count greater than 10 x 10<sup>9</sup>/L): 1000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 4 (total dose: 8000 mg/m<sup>2</sup>)
−
</div>
+
**Cycle 2, younger than 60 & high-risk (WBC count greater than 10 x 10<sup>9</sup>/L): 2000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 5 (total dose: 20,000 mg/m<sup>2</sup>)
−
<section end="e4216b" />
+
*[[Daunorubicin (Cerubidine)]] as follows:
 +
**Cycle 1: 60 mg/m<sup>2</sup> IV once per day on days 1 to 3
 +
**Cycle 2: 45 mg/m<sup>2</sup> IV once per day on days 1 to 3
 +
====CNS therapy, high-risk (WBC count greater than 10 x 10<sup>9</sup>/L) patients====
 +
*5 doses of intrathecal chemotherapy with [[Methotrexate (MTX)]] 15 mg IT, [[Cytarabine (Ara-C)]] 50 mg IT, and corticosteroids given during consolidation
 +
'''2 cycles (length not specified)'''
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
#Balduzzi A, Valsecchi MG, Uderzo C, De Lorenzo P, Klingebiel T, Peters C, Stary J, Felice MS, Magyarosy E, Conter V, Reiter A, Messina C, Gadner H, Schrappe M. Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet. 2005 Aug 20-26;366(9486):635-42. [https://doi.org/10.1016/S014067360566998X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16112299 PubMed]
+
# '''EAPLG APL 2000:''' Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; EAPLG. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. [https://doi.org/10.1200/jco.2006.08.1596 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17116939 PubMed] NCT00591526
−
#'''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
+
## '''Pooled subgroup analysis:''' Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. [http://www.bloodjournal.org/content/111/3/1078.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017 PubMed]
−
##'''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
+
==Cytarabine & Idarubicin {{#subobject:b76471|Regimen=1}}==
−
##'''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
 
−
##'''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
 
−
#'''ALL-SCT-BFM-2003:''' Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, Lang P, Sykora KW, Schrum J, Kremens B, Ehlert K, Albert MH, Meisel R, Matthes-Martin S, Gungor T, Holter W, Strahm B, Gruhn B, Schulz A, Woessmann W, Poetschger U, Zimmermann M, Klingebiel T. Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors-the ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015 Apr 10;33(11):1265-74. Epub 2015 Mar 9. [https://doi.org/10.1200/jco.2014.58.9747 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25753432 PubMed] NCT01423747
 
−
#'''FORUM:''' Peters C, Dalle JH, Locatelli F, Poetschger U, Sedlacek P, Buechner J, Shaw PJ, Staciuk R, Ifversen M, Pichler H, Vettenranta K, Svec P, Aleinikova O, Stein J, Güngör T, Toporski J, Truong TH, Diaz-de-Heredia C, Bierings M, Ariffin H, Essa M, Burkhardt B, Schultz K, Meisel R, Lankester A, Ansari M, Schrappe M, von Stackelberg A, Balduzzi A, Corbacioglu S, Bader P; IBFM Study Group; IntReALL Study Group; I-BFM SCT Study Group; EBMT Paediatric Diseases Working Party. Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study. J Clin Oncol. 2021 Feb 1;39(4):295-307. Epub 2020 Dec 17. [https://doi.org/10.1200/jco.20.02529 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078415/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33332189/ PubMed] NCT01949129
 
−
==Fludarabine, Busulfan, Cyclophosphamide {{#subobject:84acb0|Regimen=1}}==
 
−
FluBuCy: '''<u>Flu</u>'''darabine, '''<u>Bu</u>'''sulfan, '''<u>Cy</u>'''clophosphamide
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:bfe434|Variant=1}}===
+
===Regimen {{#subobject:f5d960|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1016/S1470-2045(14)70161-5 Glass et al. 2014 (DSHNHL R3)]
+
|[https://doi.org/10.1111/j.1365-2141.2011.08593.x Latagliata et al. 2011 (GIMEMA AIDA 0493 amended protocol)]
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
''This is described by the authors as a lymphoma-directed myeloablative conditioning regimen''
+
''This consolidation protocol was intended for patients older than 60.''
−
<section begin="bfe434" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup>/day IV on days -8 to -4
+
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 6 hours once per day on days 1 to 4, '''given first'''
−
*[[Busulfan (Myleran)]] by one of the following:
+
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4, '''given second, 3 hours after cytarabine infusion complete'''
−
**Oral: 4 mg/kg/day PO on days -6 to -4
+
'''4-day course'''
−
**Intravenous: 3.2 mg/kg/day IV on days -6 to -4
 
−
*[[Cyclophosphamide (Cytoxan)]] 60 mg/kg/day IV on days -3 and -2
 
−
====Immunosuppressive therapy====
 
−
*[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]] 2 mg/kg IV from day -3 to -1 (''unclear if this is a total dose or a daily dose'')
 
−
**Option also to use [[Antithymocyte globulin, rabbit ATG (Grafalon)|ATG-Fresenius S]] at a higher dose of 10 mg/kg
 
−
====GVHD prophylaxis====
 
−
*[[Tacrolimus (Prograf)]] 8 to 12 mcg/L (route/frequency not specified) starting on day -1, tapered from day +100 in absence of GVHD
 
−
*[[Mycophenolate mofetil (CellCept)]] 1000 mg (route not specified) twice per day from day +1 to +28
 
−
</div>
 
−
<section end="bfe434" />
 
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA_monotherapy_2|ATRA]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
<!-- # Glass B, rabbits Kamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M Silling G, Wilhelm C, Zeis M, Görlitz A, Pfeiffer S, Hilgers R, Truemper L, Schmitz N. High-dose chemotherapy Followed by allogeneic stem cell transplantation in relapsed and refractory high-risk aggressive non-Hodgkin's lymphoma: Results of a prospective study of the German high-grade non-Hodgkin's lymphoma study group. J Clin Oncol 30, 2012 (suppl; abstr 8004) -->
+
# '''GIMEMA AIDA 0493 amended protocol:''' Latagliata R, Breccia M, Fazi P, Vignetti M, Di Raimondo F, Sborgia M, Vincelli D, Candoni A, Salvi F, Rupoli S, Martinelli G, Kropp MG, Tonso A, Venditti A, Melillo L, Cimino G, Petti MC, Avvisati G, Lo-Coco F, Mandelli F; GIMEMA Acute Leukaemia Working Party. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia: long-term results and prognostic factors. Br J Haematol. 2011 Sep;154(5):564-8. Epub 2011 Jul 14. [https://doi.org/10.1111/j.1365-2141.2011.08593.x link to full article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21751984 PubMed]
−
#'''DSHNHL R3:''' Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M, Silling G, Wilhelm C, Zeis M, Görlitz A, Pfeiffer S, Hilgers R, Truemper L, Schmitz N; German High-Grade Lymphoma Study Group. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014 Jun;15(7):757-66. Epub 2014 May 11. [https://doi.org/10.1016/S1470-2045(14)70161-5 link to original article] [http://www.dshnhl.org/app/download/9495510598/Studienprotokoll+DSHNHL+alloFBC+final+vollst.pdf link to original protocol (in German)] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24827808 PubMed] NCT00785330
+
==Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine {{#subobject:cb4263|Regimen=1}}==
−
==Fludarabine & TBI for haploidentical transplant==
 
−
Flu/TBI: <u>'''Flu'''</u>darabine and '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen===
+
===Protocol {{#subobject:13180d|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable" style="width: 60%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 33%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/100/9/3141.long Avvisati et al. 2002 (GIMEMA LAP 0389)]
 +
|1989-1993
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|[http://www.bloodjournal.org/content/88/4/1390.long Avvisati et al. 1996 (GIMEMA AIDA)]
 +
|1993
 +
| style="background-color:#91cf61" |Pilot
 +
|-
 +
|[http://www.bloodjournal.org/content/90/3/1014.long Mandelli et al. 1997 (GIMEMA AIDA 0493)]
 +
|1993-1996
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
|-
 
|-
−
|[https://doi.org/10.1016/j.bbmt.2015.03.003 Soloman et al. 2014]
 
−
| style="background-color:#91cf61" |Phase 2
 
 
|}
 
|}
 +
''Note that the consolidation portion of the AIDA 0493 protocol is only described in Avvisati et al. 1996.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*GIMEMA LAP 0389: [[#Idarubicin_monotherapy_88|Idarubicin]] induction versus [[#Cytarabine_.26_Idarubicin_88|cytarabine & idarubicin]] induction (neither with ATRA; no longer standard of care)
 +
*GIMEMA AIDA & AIDA 0493: [[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Chemotherapy, part 1====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup>/day IV on days -7 to -5 (3 consecutive days)
+
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 6 hours once per day on days 1 to 4, '''given first'''
−
====Radiotherapy====
+
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4, '''given second, 3 hours after cytarabine infusion complete'''
−
*[[External_beam_radiotherapy|Total body irradiation]], 12 Gy total
+
'''4-day course; next course to begin "at recovery from the previous one, when polymorphonuclear cells numbered 1500/uL or more and platelets numbered 100 x 10<sup>9</sup>/L or more."'''
−
====GVHD prophylaxis====
+
====Chemotherapy, part 2====
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg/kg IBW IV over 1 to 2 hours once per day on days +3 & +4, started 60 to 72 hours after marrow infusion
+
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 45 to 60 minutes once per day on days 1 to 5, '''given second, 12 hours after start of mitoxantrone'''
−
*[[Mycophenolate mofetil (CellCept)]] 15 mg/kg (maximum daily dose of 3000 mg; route not specified) every 8 hours, starting on day +5, continued until day +35 or longer at physician discretion if active GVHD was present
+
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given first'''
−
*[[Tacrolimus (Prograf)]] (route not specified) with a goal trough level of 5 to 10 ng/mL, starting on day +5, continued until day +180
+
'''5-day course; next course to begin "at recovery from the previous one, when polymorphonuclear cells numbered 1500/uL or more and platelets numbered 100 x 10<sup>9</sup>/L or more."'''
 +
====Chemotherapy, part 3====
 +
*[[Cytarabine (Ara-C)]] 150 mg/m<sup>2</sup> SC every 8 hours on days 1 to 5
 +
*[[Idarubicin (Idamycin)]] by the following study-specific criteria:
 +
**GIMEMA LAP 0389: 5 mg/m<sup>2</sup> IV once on day 1
 +
**GIMEMA AIDA & AIDA 0493: 12 mg/m<sup>2</sup> IV once on day 1
 +
*[[Thioguanine (Tabloid)]] 70 mg/m<sup>2</sup> PO every 8 hours on days 1 to 5
 +
'''5-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*GIMEMA LAP 0389: [[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]] maintenance versus [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|no further treatment]]
 +
*GIMEMA AIDA 0493: [[#ATRA_monotherapy_2|ATRA]] maintenance versus [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance versus [[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]] maintenance versus [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|no further treatment]]
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, Morris LE, Bashey A. Total Body Irradiation-Based Myeloablative Haploidentical Stem Cell Transplantation Is a Safe and Effective Alternative to Unrelated Donor Transplantation in Patients Without Matched Sibling Donors. Biol Blood Marrow Transplant. 2015 Jul;21(7):1299-307. Epub 2015 Mar 19. [https://doi.org/10.1016/j.bbmt.2015.03.003 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25797174/ PubMed]
+
# '''GIMEMA AIDA:''' Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood. 1996 Aug 15;88(4):1390-8. [http://www.bloodjournal.org/content/88/4/1390.long link to full article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8695858 PubMed]
−
==BEAM {{#subobject:bda306|Regimen=1}}==
+
# '''GIMEMA AIDA 0493:''' Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. [http://www.bloodjournal.org/content/90/3/1014.long link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/9242531 PubMed]
−
BEAM: '''<u>B</u>'''CNU (Carmustine), '''<u>E</u>'''toposide, '''<u>A</u>'''ra-C (Cytarabine), '''<u>M</u>'''elphalan
+
## '''Update:''' Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA; AIEOP; EORTC. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5;117(18):4716-25. Epub 2011 Mar 8. [http://www.bloodjournal.org/content/117/18/4716.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21385856 PubMed]
 +
# '''GIMEMA LAP 0389:''' Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F; GIMEMA. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. [http://www.bloodjournal.org/content/100/9/3141.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12384411 PubMed]
 +
==Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine, with ATRA {{#subobject:632192|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a8d4a|Variant=1}}===
+
===Protocol {{#subobject:6e3780|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1093/oxfordjournals.annonc.a010369 Przepiorka et al. 1999]
+
|[http://www.bloodjournal.org/content/116/17/3171.long Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized
−
|-
 
−
|[https://doi.org/10.3109/10428194.2013.838233 Sobol et al. 2013]
 
−
| style="background-color:#91cf61" |Phase 2
 
 
|-
 
|-
 
|}
 
|}
−
<section begin="a8d4a" />
+
''This is risk-adapted therapy for <u>high-risk</u> patients in '''AIDA-2000'''. The authors were unclear about how many days were between each part of consolidation therapy.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy, part 1====
−
*[[Carmustine (BCNU)]] 300 mg/m<sup>2</sup> IV once on day -6
+
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
−
*[[Etoposide (Vepesid)]] 200 mg/m<sup>2</sup> IV twice per day on days -5 to -2
+
====Chemotherapy, part 1====
−
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup> IV twice per day on days -5 to -2
+
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day -1
+
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
====GVHD prophylaxis====
+
'''4-day course (see note), followed by:'''
−
*[[Tacrolimus (Prograf)]]
+
====Targeted therapy, part 2====
−
*[[Methotrexate (MTX)]]
+
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
−
====Supportive therapy====
+
====Chemotherapy, part 2====
−
*"Prophylactic antibiotics"
+
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day +7 and continued until engraftment
+
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
</div>
+
'''5-day course (see note), followed by:'''
−
<section end="a8d4a" />
+
====Targeted therapy, part 3====
 +
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
 +
====Chemotherapy, part 3====
 +
*[[Cytarabine (Ara-C)]] 150 mg/m<sup>2</sup> SC every 8 hours on days 1 to 5 (total dose: 2250 mg/m<sup>2</sup>)
 +
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1
 +
*[[Thioguanine (Tabloid)]] 70 mg/m<sup>2</sup> PO every 8 hours on days 1 to 5 (total dose: 1050 mg/m<sup>2</sup>)
 +
'''5-day course (see note)'''
 +
====CNS therapy, prophylaxis====
 +
''It is not explicitly stated but presumably these are admixed and given together.''
 +
*[[Methotrexate (MTX)]] 12 mg IT once prior to each consolidation cycle
 +
*[[Methylprednisolone (Solumedrol)]] 40 mg IT once prior to each consolidation cycle
 +
'''"Total of 3 cycles"'''
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA alternating with 6-MP, MTX]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
#Przepiorka D, van Besien K, Khouri I, Hagemeister F, Samuels B, Folloder J, Ueno NT, Molldrem J, Mehra R, Körbling M, Giralt S, Gajewski J, Donato M, Cleary K, Claxton D, Braunschweig I, Andersson B, Anderlini P, Champlin R. Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma. Ann Oncol. 1999 May;10(5):527-32. [https://doi.org/10.1093/oxfordjournals.annonc.a010369 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10416001 PubMed]
+
# '''GIMEMA AIDA-2000:''' Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. [http://www.bloodjournal.org/content/116/17/3171.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20644121 PubMed] NCT001064570
−
#Sobol U, Rodriguez T, Smith S, Go A, Vimr R, Parthasarathy M, Guo R, Stiff P. Seven-year follow-up of allogeneic transplant using BCNU, etoposide, cytarabine and melphalan chemotherapy in patients with Hodgkin lymphoma after autograft failure: importance of minimal residual disease. Leuk Lymphoma. 2014 Jun;55(6):1281-7. Epub 2013 Oct 3. [https://doi.org/10.3109/10428194.2013.838233 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23987822 PubMed]
+
==Cytarabine & Idarubicin, then Mitoxantrone, then Cytarabine & Idarubicin, with ATRA {{#subobject:ca29a4|Regimen=1}}==
−
==BFR {{#subobject:c2659b|Regimen=1}}==
 
−
BFR: '''<u>B</u>'''endamustine, '''<u>F</u>'''ludarabine, '''<u>R</u>'''ituximab
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:41fd04|Variant=1}}===
+
===Protocol {{#subobject:46f412|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260365/ Khouri et al. 2014 (MDACC 2008-0246)]
+
|[http://www.bloodjournal.org/content/115/25/5137.long Sanz et al. 2010 (PETHEMA LPA2005)]
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
<section begin="41fd04" />
+
''This is risk-adapted therapy for <u>high-risk younger than 60</u> patients in '''PETHEMA LPA2005'''. Note that it is unclear from the paper which route the cytarabine is given in the third consolidation; this dose can be given by IV or SC routes.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy, consolidation #1====
−
*[[Bendamustine]] 130 mg/m<sup>2</sup> IV once per day on days -5 to -3
+
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days -5 to -3
+
====Chemotherapy, consolidation #1====
−
====Targeted therapy====
+
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days -13, -6, +1, +8
+
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
====GVHD prophylaxis====
+
'''1-month course, followed by:'''
−
*See article for GVHD prophylaxis information
+
====Targeted therapy, consolidation #2====
−
</div>
+
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
−
<section end="41fd04" />
+
====Chemotherapy, consolidation #2====
 +
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
 +
'''1-month course, followed by:'''
 +
====Targeted therapy, consolidation #3====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
 +
====Chemotherapy, consolidation #3====
 +
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cytarabine (Ara-C)]] 150 mg/m<sup>2</sup> IV or SC every 8 hours on days 1 to 4 (total dose: 1800 mg/m<sup>2</sup>)
 +
'''1-month course'''
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
#'''MDACC 2008-0246:''' Khouri IF, Wei W, Korbling M, Turturro F, Ahmed S, Alousi A, Anderlini P, Ciurea S, Jabbour E, Oran B, Popat UR, Rondon G, Bassett RL Jr, Gulbis A. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood. 2014 Oct 2;124(14):2306-12. Epub 2014 Aug 21. [http://www.bloodjournal.org/content/124/14/2306.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260365/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25145344 PubMed] NCT00880815
+
# '''PETHEMA LPA2005:''' Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA; HOVON. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. [http://www.bloodjournal.org/content/115/25/5137.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20393132 PubMed] NCT00408278
−
=Reduced-intensity conditioning (RIC), all lines of therapy=
+
==Daunorubicin monotherapy {{#subobject:76a47b|Regimen=1}}==
−
==Busulfan & Fludarabine {{#subobject:3fe0f0|Regimen=1}}==
 
−
BuFlu: '''<u>Bu</u>'''sulfan & '''<u>Flu</u>'''darabine
 
−
<br>Flu/Bu: '''<u>Flu</u>'''darabine & '''<u>Bu</u>'''sulfan
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a7e574|Variant=1}}===
+
===Regimen {{#subobject:82b9d5|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 17%"|Study
+
!style="width: 20%"|Study
−
!style="width: 15%"|Years of enrollment
+
!style="width: 20%"|Years of enrollment
−
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 17%"|Comparator
+
!style="width: 20%"|Comparator
−
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
!style="width: 17%"|[[Levels_of_Evidence#Comparative_toxicity|Non-relapse mortality]]
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ Devine et al. 2015 (CALGB 100103)]
+
|[https://doi.org/10.1200/jco.2006.08.1596 Adès et al. 2006 (EAPLG APL 2000)]
−
|2004-2011
+
|2000-2004
−
| style="background-color:#ffffbe" |Phase 2, <20 pts in subgroup
+
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
−
| style="background-color:#d3d3d3" |
+
|[[#Cytarabine_.26_Daunorubicin|Cytarabine & Daunorubicin]]
−
| style="background-color:#d3d3d3" |
+
| style="background-color:#d73027" |Inferior OS
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://doi.org/10.1016/S2352-3026(19)30157-7 Beelen et al. 2019 (MC-FludT.14/L)]
 
−
|2013-2016
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Fludarabine_.26_Treosulfan_77|Fludarabine & Treosulfan]]
 
−
| style="background-color:#eeee01" |Non-inferior EFS24
 
−
| style="background-color:#d3d3d3" |
 
 
|-
 
|-
 
|}
 
|}
−
''This regimen is meant for related donors; only 8 patients received this regimen before the addition of ATG (rabbit) after 2006.''
+
''This consolidation arm was a randomization for younger (less than 60), low-risk (WBC count less than 10 x 10<sup>9</sup>/L) patients. Low-risk (WBC count less than 10 x 10<sup>9</sup>/L) older (greater than 60) patients received this regimen in a non-randomized fashion.''
−
<section begin="a7e574" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#ATRA_.26_Daunorubicin|ATRA & daunorubicin]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days -7 to -3
+
*[[Daunorubicin (Cerubidine)]] as follows:
−
**MC-FludT.14/L gave the doses on days -6 to -2
+
**Cycle 1: 60 mg/m<sup>2</sup> IV once per day on days 1 to 3
−
*[[Busulfan (Myleran)]] 0.8 mg/kg IV over 2 hours every 6 hours on days -4 & -3 (total dose: 6.4 mg/kg)
+
**Cycle 2: 45 mg/m<sup>2</sup> IV once per day on days 1 to 3
−
====GVHD prophylaxis====
 
−
*[[Tacrolimus (Prograf)]] with doses adjusted to maintain levels of 5 to 10 ng/mL, tapered on day +90 to off by day +180 (if no GVHD)
 
−
*[[Methotrexate (MTX)]] 5 mg/m<sup>2</sup> IV once per day on days +1, +3, +6, +11
 
−
</div>
 
−
<section end="a7e574" />
 
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
<!-- Presented in part as an oral presentation at the 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8-11, 2012. -->
+
# '''EAPLG APL 2000:''' Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; EAPLG. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. [https://doi.org/10.1200/jco.2006.08.1596 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17116939 PubMed] NCT00591526
−
#'''CALGB 100103:''' Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. Epub 2015 Nov 2. [https://doi.org/10.1200/jco.2015.62.7273 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26527780 PubMed] NCT00070135
+
## '''Pooled subgroup analysis:''' Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. [http://www.bloodjournal.org/content/111/3/1078.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017 PubMed]
−
#'''MC-FludT.14/L:''' Beelen DW, Trenschel R, Stelljes M, Groth C, Masszi T, Reményi P, Wagner-Drouet EM, Hauptrock B, Dreger P, Luft T, Bethge W, Vogel W, Ciceri F, Peccatori J, Stölzel F, Schetelig J, Junghanß C, Grosse-Thie C, Michallet M, Labussiere-Wallet H, Schaefer-Eckart K, Dressler S, Grigoleit GU, Mielke S, Scheid C, Holtick U, Patriarca F, Medeot M, Rambaldi A, Micò MC, Niederwieser D, Franke GN, Hilgendorf I, Winkelmann NR, Russo D, Socié G, Peffault de Latour R, Holler E, Wolff D, Glass B, Casper J, Wulf G, Menzel H, Basara N, Bieniaszewska M, Stuhler G, Verbeek M, Grass S, Iori AP, Finke J, Benedetti F, Pichlmeier U, Hemmelmann C, Tribanek M, Klein A, Mylius HA, Baumgart J, Dzierzak-Mietla M, Markiewicz M. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet Haematol. 2020 Jan;7(1):e28-e39. Epub 2019 Oct 9. [https://doi.org/10.1016/S2352-3026(19)30157-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31606445 PubMed] NCT00822393
+
==Idarubicin, then Mitoxantrone, then Idarubicin {{#subobject:6af14e|Regimen=1}}==
−
==Clofarabine & Melphalan {{#subobject:08947a|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a408ed|Variant=1}}===
+
===Protocol {{#subobject:11923f|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA96)]
 +
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
−
|[https://doi.org/10.1038/leu.2015.226 Middeke et al. 2015 (BRIDGE)]
+
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA99)]
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
''Limited details are available in the abstract. Treatment is meant to be given during aplasia.''
+
''This was the <u>low-risk</u> treatment arm of '''PETHEMA LPA99'''; <u>all patients</u> on '''PETHEMA LPA96''' underwent this consolidation protocol.''
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[Acute_myeloid_leukemia#Clofarabine_.26_Cytarabine|Clofarabine & Cytarabine]] salvage
+
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 
</div>
 
</div>
−
<section begin="a408ed" />
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Chemotherapy, part 1====
−
*[[Clofarabine (Clolar)]] 4 x 30 mg/m<sup>2</sup> IV
+
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV
+
'''1-month cycle, followed by:'''
−
</div>
+
====Chemotherapy, part 2====
−
<section end="a408ed" />
+
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
 +
'''1-month cycle, followed by:'''
 +
====Chemotherapy, part 3====
 +
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1
 +
'''1-month cycle'''
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
#'''BRIDGE:''' Middeke JM, Herbst R, Parmentier S, Bug G, Hänel M, Stuhler G, Schäfer-Eckart K, Rösler W, Klein S, Bethge W, Bitz U, Büttner B, Knoth H, Alakel N, Schaich M, Morgner A, Kramer M, Sockel K, von Bonin M, Stölzel F, Platzbecker U, Röllig C, Thiede C, Ehninger G, Bornhäuser M, Schetelig J. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial. Leukemia. 2016 Feb;30(2):261-7. Epub 2015 Aug 18. [https://doi.org/10.1038/leu.2015.226 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26283567 PubMed]
+
# '''PETHEMA LPA96:''' Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. [http://www.bloodjournal.org/content/103/4/1237.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14576047 PubMed]
−
 
+
## '''Pooled subgroup analysis:''' Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. [http://www.bloodjournal.org/content/111/3/1078.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017 PubMed]
−
==Cyclophosphamide, Fludarabine, Thiotepa {{#subobject:ee93e3|Regimen=1}}==
+
# '''PETHEMA LPA99:''' Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. [http://www.bloodjournal.org/content/103/4/1237.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14576047 PubMed] NCT00465933
 +
## '''Pooled subgroup analysis:''' Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. [http://www.bloodjournal.org/content/111/3/1078.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017 PubMed]
 +
==Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA {{#subobject:49fc49|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:81245f|Variant=1}}===
+
===Protocol variant #1 {{#subobject:8d3f07|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/99/1/75.long Corradini et al. 2002]
+
|[http://www.bloodjournal.org/content/116/17/3171.long Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
−
|}
+
|[http://www.bloodjournal.org/content/115/25/5137.long Sanz et al. 2010 (PETHEMA LPA2005)]
−
Details to be completed.
+
| style="background-color:#91cf61" |Non-randomized
−
<section begin="81245f" />
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]]
 
−
*[[Fludarabine (Fludara)]]
 
−
*[[Thiotepa (Thioplex)]]
 
−
</div>
 
−
<section end="81245f" />
 
−
</div>
 
−
===References===
 
−
#Corradini P, Tarella C, Olivieri A, Gianni AM, Voena C, Zallio F, Ladetto M, Falda M, Lucesole M, Dodero A, Ciceri F, Benedetti F, Rambaldi A, Sajeva MR, Tresoldi M, Pileri A, Bordignon C, Bregni M. Reduced-intensity conditioning followed by allografting of hematopoietic cells can produce clinical and molecular remissions in patients with poor-risk hematologic malignancies. Blood. 2002 Jan 1;99(1):75-82. [http://www.bloodjournal.org/content/99/1/75.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/11756155 PubMed]
 
−
==FC {{#subobject:1a1ed9|Regimen=1}}==
 
−
FC: '''<u>F</u>'''ludarabine & '''<u>C</u>'''yclophosphamide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, BSA-based Cy {{#subobject:886e40|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
! style="width: 25%" |Study
 
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/116/14/2438 Dreger et al. 2010 (GCLLSG CLL3X)]
+
|[https://doi.org/10.1056/NEJMoa1300874 Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)]
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
|-
 
|-
 
|}
 
|}
−
''This regimen is intended for related donors.''
+
''This is risk-adapted therapy for <u>intermediate- and low-risk</u> patients in '''AIDA-2000''' and for <u>low-risk</u> patients in '''PETHEMA LPA2005'''; all patients assigned to the chemotherapy arm of '''GIMEMA/DSIL APL0406''' received this treatment. Note that the number of mitoxantrone doses differs between the protocols.''
−
<section begin="886e40" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy, part 1====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -6 to -2
+
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days -6 to -2
+
====Chemotherapy, part 1====
 +
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
 +
'''1-month course, followed by:'''
 +
====Targeted therapy, part 2====
 +
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
 +
====Chemotherapy, part 2====
 +
*[[Mitoxantrone (Novantrone)]] by the following study-specific criteria:
 +
**AIDA-2000 & GIMEMA/DSIL APL0406: 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
 +
**PETHEMA LPA2005: 10 mg/m<sup>2</sup> IV once per day on days 1 to 3
 +
'''1-month course, followed by:'''
 +
====Targeted therapy, part 3====
 +
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
 +
====Chemotherapy, part 3====
 +
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1
 +
'''1-month course'''
 
</div>
 
</div>
−
<section end="886e40" />
+
<div class="toccolours" style="background-color:#cbd5e7">
−
</div><br>
+
====Subsequent treatment====
 +
*AIDA-2000 and GIMEMA/DSIL APL0406: [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA alternating with 6-MP, MTX]] maintenance
 +
*PETHEMA LPA2005: [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, weight-based Cy {{#subobject:9ce8f1|Variant=1}}===
+
===Protocol variant #2 {{#subobject:6744ce|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA99)]
 +
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJM200009143431101 Childs et al. 2000]
+
|[http://www.bloodjournal.org/content/115/25/5137.long Sanz et al. 2010 (PETHEMA LPA2005)]
−
| style="background-color:#ffffbe" |Non-randomized, <20 pts
+
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
<section begin="9ce8f1" />
+
''This is risk-adapted therapy for <u>intermediate-</u> and <u>high-risk</u> patients in PETHEMA LPA99 and for <u>intermediate-risk</u> and <u>high-risk older than 60</u> patients in PETHEMA LPA2005. Note that the number of mitoxantrone doses differs between the two protocols.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy, part 1====
−
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV once per day on days -5 to -1
+
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
−
*[[Cyclophosphamide (Cytoxan)]] 60 mg/kg IV once per day on days -7 & -6
+
====Chemotherapy, part 1====
−
</div>
+
*[[Idarubicin (Idamycin)]] 7 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
<section end="9ce8f1" />
+
'''1-month course, followed by:'''
 +
====Targeted therapy, part 2====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
 +
====Chemotherapy, part 2====
 +
*[[Mitoxantrone (Novantrone)]] by the following study-specific criteria:
 +
**PETHEMA LPA99: 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
 +
**PETHEMA LPA2005: 10 mg/m<sup>2</sup> IV once per day on days 1 to 3
 +
'''1-month course, followed by:'''
 +
====Targeted therapy, part 3====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
 +
====Chemotherapy, part 3====
 +
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once per day on days 1 & 2
 +
'''1-month course'''
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
#Childs R, Chernoff A, Contentin N, Bahceci E, Schrump D, Leitman S, Read EJ, Tisdale J, Dunbar C, Linehan WM, Young NS, Clave E, Epperson D, Mayo V, Barrett AJ. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med. 2000 Sep 14;343(11):750-8. [https://doi.org/10.1056/NEJM200009143431101 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10984562 PubMed]
+
# '''PETHEMA LPA99:''' Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. [http://www.bloodjournal.org/content/103/4/1237.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14576047 PubMed] NCT00465933
−
<!-- Presented in part in abstract form at the 50th annual meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2008. -->
+
## '''Pooled subgroup analysis:''' Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. [http://www.bloodjournal.org/content/111/3/1078.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017 PubMed]
−
#'''GCLLSG CLL3X:''' Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. [http://www.bloodjournal.org/content/116/14/2438 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20595516 PubMed] NCT00281983
+
# '''PETHEMA LPA2005:''' Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA; HOVON. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. [http://www.bloodjournal.org/content/115/25/5137.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20393132 PubMed] NCT00408278
−
##'''Update:''' Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Döhner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. Epub 2013 Feb 22. [http://www.bloodjournal.org/content/121/16/3284.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23435461 PubMed]
+
# '''GIMEMA AIDA-2000:''' Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. [http://www.bloodjournal.org/content/116/17/3171.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20644121 PubMed] NCT001064570
−
##'''Update:''' Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Döhner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. Epub 2017 Jul 17. [http://www.bloodjournal.org/content/130/12/1477.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28716861 PubMed]
+
# '''GIMEMA/DSIL APL0406:''' Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. [https://doi.org/10.1056/NEJMoa1300874 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23841729 PubMed] NCT00482833
−
==FBM {{#subobject:1hg71a|Regimen=1}}==
+
## '''HRQoL analysis:''' Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. [https://doi.org/10.1200/JCO.2014.55.3453 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25245446 PubMed]
−
FBM: '''<u>F</u>'''ludarabine, '''<u>B</u>'''CNU (Carmustine), '''<u>M</u>'''elphalan
+
## '''Update:''' Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. [https://doi.org/10.1200/JCO.2016.67.1982 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27400939 PubMed]
 +
## '''Update:''' Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. [https://doi.org/10.1038/s41375-019-0589-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31611624 PubMed]
 +
=Maintenance after upfront therapy=
 +
==Arsenic trioxide monotherapy {{#subobject:e1f355|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1 {{#subobject:4f0684|Variant=1}}===
+
===Regimen variant #1, 0.15 mg/kg (pediatric dosing) {{#subobject:9f326b|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 772: Line 1,244:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1182/blood-2007-08-104745 Marks et al. 2008]
+
|[https://doi.org/10.1182/blood-2005-08-3532 Mathews et al. 2006]
−
|1998-2003
+
|1998-2004
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
''Note: this variant is intended for patients younger than 55 years of age.''
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide_monotherapy_2|Arsenic trioxide]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -9 to -5
+
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 to 3 hours once per day on days 1 to 10
−
*[[Carmustine (BCNU)]] 200 mg/m<sup>2</sup> IV once per day on days -7 & -6
+
'''Monthly cycle for 6 cycles'''
−
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day -4
 
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2 {{#subobject:4f0684|Variant=1}}===
+
===Regimen variant #2, 10 mg (flat dose) {{#subobject:9f486b|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 791: Line 1,265:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1182/blood-2007-08-104745 Marks et al. 2008]
+
|[https://doi.org/10.1182/blood-2005-08-3532 Mathews et al. 2006]
−
|1998-2003
+
|1998-2004
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
''Note: this variant is intended for patients 55 years of age and older.''
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide_monotherapy_2|Arsenic trioxide]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -9 to -5
+
*[[Arsenic trioxide (Trisenox)]] 10 mg IV over 2 to 3 hours once per day on days 1 to 10
−
*[[Carmustine (BCNU)]] 150 mg/m<sup>2</sup> IV once per day on days -7 & -6
+
'''Monthly cycle for 6 cycles'''
−
*[[Melphalan (Alkeran)]] 110 mg/m<sup>2</sup> IV once on day -4
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#Marks R, Potthoff K, Hahn J, Ihorst G, Bertz H, Spyridonidis A, Holler E, Finke JM. Reduced-toxicity conditioning with fludarabine, BCNU, and melphalan in allogeneic hematopoietic cell transplantation: particular activity against advanced hematologic malignancies. Blood. 2008 Jul 15;112(2):415-25. Epub 2008 May 1. [https://doi.org/10.1182/blood-2007-08-104745 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18451310/ PubMed]
+
# Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006 Apr 1;107(7):2627-32. Epub 2005 Dec 13. [https://doi.org/10.1182/blood-2005-08-3532 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16352810 PubMed]
−
==FCR {{#subobject:18605a|Regimen=1}}==
+
## '''Update:''' Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, Viswabandya A, Thirugnanam R, Abraham A, Shaji RV, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010 Aug 20;28(24):3866-71. Epub 2010 Jul 19. [https://doi.org/10.1200/jco.2010.28.5031 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20644086 PubMed]
−
FCR: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''ituximab
+
==ATRA monotherapy {{#subobject:8c70f0|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:4f0684|Variant=1}}===
+
===Regimen variant #1 {{#subobject:f68d7e|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 20%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/98/13/3595.long Khouri et al. 2001 (MDACC ID01-233)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ Powell et al. 2010 (C9710)]
−
| style="background-color:#91cf61" |Phase 2
+
|1999-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]]
 +
| style="background-color:#fee08b" |Might have inferior DFS
 
|-
 
|-
 
|}
 
|}
−
<section begin="4f0684" />
+
''Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide.2C_then_ATRA_.26_Daunorubicin|Arsenic trioxide, then ATRA & daunorubicin]] consolidation versus [[#ATRA_.26_Daunorubicin|ATRA & daunorubicin]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
''Details are best described in the 2008 update.''
 
−
====Chemotherapy====
 
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -5 to -3
 
−
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once per day on days -5 to -3
 
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day -13, then 1000 mg/m<sup>2</sup> IV once per day on days -6, +1, +8
+
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 7
−
====GVHD prophylaxis====
+
'''14-day cycle for 26 cycles (1 year)'''
−
*[[Antithymocyte globulin, horse ATG (Atgam)]] by the following criteria:
+
</div></div><br>
−
**Matched unrelated donor: 15 mg/kg IV once per day on days -5 to -3
 
−
*[[Tacrolimus (Prograf)]] adjusted to level of 5 to 10 ng/mL for 6 months in patients in remission
 
−
*[[Methotrexate (MTX)]] by the following criteria:
 
−
**Related donors: 5 mg/m<sup>2</sup> IV once per day on days +1, +3, +6
 
−
**Unrelated donors: 5 mg/m<sup>2</sup> IV once per day on days +1, +3, +6, +11
 
−
</div>
 
−
<section end="4f0684" />
 
−
</div>
 
−
===References===
 
−
#'''MDACC ID01-233:''' Khouri IF, Saliba RM, Giralt SA, Lee MS, Okoroji GJ, Hagemeister FB, Korbling M, Younes A, Ippoliti C, Gajewski JL, McLaughlin P, Anderlini P, Donato ML, Cabanillas FF, Champlin RE. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood. 2001 Dec 15;98(13):3595-9. [http://www.bloodjournal.org/content/98/13/3595.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/11739162 PubMed] NCT00048737
 
−
##'''Update:''' Khouri IF, McLaughlin P, Saliba RM, Hosing C, Korbling M, Lee MS, Medeiros LJ, Fayad L, Samaniego F, Alousi A, Anderlini P, Couriel D, de Lima M, Giralt S, Neelapu SS, Ueno NT, Samuels BI, Hagemeister F, Kwak LW, Champlin RE. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood. 2008 Jun 15;111(12):5530-6. Epub 2008 Apr 14. Erratum in: Blood. 2009 Feb 12;113(7):1613. [http://www.bloodjournal.org/content/111/12/5530.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624452/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18411419 PubMed]
 
−
##'''Update:''' Khouri IF, Saliba RM, Erwin WD, Samuels BI, Korbling M, Medeiros LJ, Valverde R, Alousi AM, Anderlini P, Bashir Q, Ciurea S, Gulbis AM, de Lima M, Hosing C, Kebriaei P, Popat UR, Fowler N, Neelapu SS, Samaniego F, Champlin RE, Macapinlac HA. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood. 2012 Jun 28;119(26):6373-8. Epub 2012 May 14. [http://www.bloodjournal.org/content/119/26/6373.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347306/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22586182 PubMed]
 
−
==Fludarabine & TBI {{#subobject:53c6af|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:be3609|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 17%"|Study
 
−
!style="width: 15%"|Years of enrollment
 
−
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 17%"|Comparator
 
−
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
!style="width: 17%"|[[Levels_of_Evidence#Efficacy|Non-relapse mortality]]
 
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(12)70349-2 Bornhäuser et al. 2012 (9005-2003)]
 
−
|2004-2009
 
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 
−
|[[#Cyclophosphamide_.26_TBI|Cyclophosphamide & TBI]]
 
−
|
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of NRM
 
−
|-
 
−
|}
 
−
<section begin="be3609" />
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -6 to -3
 
−
====Radiotherapy====
 
−
*[[External_beam_radiotherapy|Total body irradiation (TBI)]] 200 cGy fractions x 4 doses on days -3 & -2 (8 Gy total)
 
−
</div>
 
−
<section end="be3609" />
 
−
</div><br>
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, low-dose TBI{{#subobject:7fa6ce|Variant=1}}===
+
===Regimen variant #2 {{#subobject:dc527a|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 876: Line 1,318:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2005.04.569 Sorror et al. 2005]
+
| rowspan="3" |[http://www.bloodjournal.org/content/90/3/1014.long Mandelli et al. 1997 (GIMEMA AIDA 0493)]
−
|1997-2003
+
|rowspan=3|1993-1996
−
| style="background-color:#91cf61" |Phase 2
+
| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
−
| style="background-color:#d3d3d3" |
+
|1. [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]]
−
| style="background-color:#d3d3d3" |
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ Gyukocza et al. 2010]
+
|2. [[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]]
−
|1998-2008
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS
−
| style="background-color:#91cf61" |Non-randomized
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/102/6/2021.full Maris et al. 2003]
+
|3. [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|No further treatment]]
−
|2000-2001
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS
−
| style="background-color:#91cf61" |Phase 2
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2010.32.7312 Björkstrand et al. 2011 (EBMT-NMAM2000)]
+
| rowspan="2" |[http://www.bloodjournal.org/content/94/4/1192.long Fenaux et al. 1999 (EAPLG APL 93)]
−
|2001-2005
+
|rowspan=2|1993-1996
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
+
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
−
| style="background-color:#d3d3d3" |
+
|1. [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]]
−
| style="background-color:#d3d3d3" |
+
| style="background-color:#d73027" |Inferior 2-year relapse rate
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755028/ Kornblit et al. 2013 (FHCRC 1813.00)]
+
|2. [[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]]<br> 3. [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|No further treatment]]
−
|2003-2011
+
| style="background-color:#91cf60" |Seems to have superior 2-year relapse rate
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[#Low-dose_TBI|Low-dose TBI]]
 
−
| style="background-color:#d9ef8b" |Might have superior OS
 
 
|-
 
|-
 
|}
 
|}
−
''Details are best described in Maris et al. 2003.''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
<section begin="7fa6ce" />
+
====Preceding treatment====
 +
*GIMEMA AIDA 0493: [[#Cytarabine_.26_Idarubicin.2C_then_Etoposide_.26_Mitoxantrone.2C_then_Cytarabine.2C_Idarubicin.2C_Thioguanine|Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine]] consolidation
 +
*EAPLG APL 93: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -4 to -2
+
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO on days 1 to 15
−
====Radiotherapy====
+
'''3-month cycle for 8 cycles (2 years)'''
−
*[[External_beam_radiotherapy|Total body irradiation (TBI)]]  2 Gy at a rate of 0.07 Gy/min on day 0
+
</div></div>
−
====GVHD prophylaxis====
 
−
*[[Cyclosporine]] 6.25 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 100 over 80 days (if no GVHD)
 
−
*[[Mycophenolate mofetil (CellCept)]] 15 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 40 over 56 days (if no GVHD)
 
−
</div>
 
−
<section end="7fa6ce" />
 
−
</div>
 
 
===References===
 
===References===
−
#Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D, Petersdorf E, McSweeney P, Pulsipher M, Woolfrey A, Chauncey T, Agura E, Heimfeld S, Slattery J, Hegenbart U, Anasetti C, Blume K, Storb R. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood. 2003 Sep 15;102(6):2021-30. Epub 2003 Jun 5. [http://www.bloodjournal.org/content/102/6/2021.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12791654 PubMed]
+
# '''GIMEMA AIDA 0493:''' Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. [http://www.bloodjournal.org/content/90/3/1014.long link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/9242531 PubMed]
−
<!-- Presented in part at the Tandem Bone Marrow Transplantation meeting, February 13-17, 2004, Orlando, FL (for part of the patient population). -->
+
## '''Update:''' Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA; AIEOP; EORTC. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5;117(18):4716-25. Epub 2011 Mar 8. [http://www.bloodjournal.org/content/117/18/4716.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21385856 PubMed]
−
#Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 1;23(16):3819-29. Epub 2005 Apr 4. [https://doi.org/10.1200/jco.2005.04.569 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15809448 PubMed]
+
# '''EAPLG APL 93:''' Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia; European APL Group. Blood. 1999 Aug 15;94(4):1192-200. [http://www.bloodjournal.org/content/94/4/1192.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/10438706 PubMed]
−
##'''Update:''' Sorror ML, Storer BE, Sandmaier BM, Maris M, Shizuru J, Maziarz R, Agura E, Chauncey TR, Pulsipher MA, McSweeney PA, Wade JC, Bruno B, Langston A, Radich J, Niederwieser D, Blume KG, Storb R, Maloney DG. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008 Oct 20;26(30):4912-20. Epub 2008 Sep 15. [https://doi.org/10.1200/jco.2007.15.4757 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18794548 PubMed]
+
## '''Update:''' Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, Recher C, Thomas X, Rayon C, Castaigne S, Tournilhac O, de Botton S, Ifrah N, Cahn JY, Solary E, Gardin C, Fegeux N, Bordessoule D, Ferrant A, Meyer-Monard S, Vey N, Dombret H, Degos L, Chevret S, Fenaux P; European APL Group. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010 Mar 4;115(9):1690-6. Epub 2009 Dec 17. [http://www.bloodjournal.org/content/115/9/1690.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20018913 PubMed]
−
<!-- no pre-pub disclosed -->
+
# '''C9710:''' Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. [http://www.bloodjournal.org/content/116/19/3751.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20705755 PubMed] NCT00003934
−
#Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010 Jun 10;28(17):2859-67. Epub 2010 May 3. [https://doi.org/10.1200/jco.2009.27.1460 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20439626 PubMed]
+
==ATRA, Mercaptopurine, Methotrexate {{#subobject:b44ab6|Regimen=1}}==
−
#'''EBMT-NMAM2000:''' Björkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Musto P, Beksac M, Bosi A, Milone G, Corradini P, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Gahrton G. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol. 2011 Aug 1;29(22):3016-22. Epub 2011 Jul 5. Erratum in: J Clin Oncol. 2011 Sep 20;29(27):3721. [https://doi.org/10.1200/jco.2010.32.7312 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21730266 PubMed]
 
−
##'''Update:''' Gahrton G, Iacobelli S, Björkstrand B, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Carella AM, Beksac M, Bosi A, Milone G, Corradini P, Schönland S, Friberg K, van Biezen A, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Garderet L, Kröger N; EBMT Chronic Malignancies Working Party Plasma Cell Disorders Subcommittee. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood. 2013 Jun 20;121(25):5055-63. Epub 2013 Mar 12. [http://www.bloodjournal.org/content/121/25/5055.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23482933 PubMed]
 
−
#'''9005-2003:''' Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. Epub 2012 Sep 7. [https://doi.org/10.1016/S1470-2045(12)70349-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22959335 PubMed] NCT00150878
 
−
#'''FHCRC 1813.00:''' Kornblit B, Maloney DG, Storb R, Storek J, Hari P, Vucinic V, Maziarz RT, Chauncey TR, Pulsipher MA, Bruno B, Petersen FB, Bethge WA, Hübel K, Bouvier ME, Fukuda T, Storer BE, Sandmaier BM. Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. Biol Blood Marrow Transplant. 2013 Sep;19(9):1340-7. Epub 2013 Jun 11. [https://www.bbmt.org/article/S1083-8791(13)00243-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755028/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23769990 PubMed] NCT00075478
 
−
==Fludarabine, Busulfan, ATG {{#subobject:ed545b|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1 {{#subobject:dd1486|Variant=1}}===
+
===Regimen variant #1, 45/50/15 {{#subobject:80d40a|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ Devine et al. 2015 (CALGB 100103)]
+
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA99)]
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|[http://www.bloodjournal.org/content/115/25/5137.long Sanz et al. 2010 (PETHEMA LPA2005)]
 +
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
''This regimen is meant for all types of donors.''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
<section begin="dd1486" />
+
====Preceding treatment====
 +
*PETHEMA LPA99, low-risk: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin|Idarubicin, then Mitoxantrone, then Idarubicin]] consolidation
 +
*PETHEMA LPA99, intermediate- and high-risk and PETHEMA LPA2005, low- and intermediate-risk: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin.2C_with_ATRA|Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA]] consolidation
 +
*PETHEMA LPA2005, high-risk: [[#Cytarabine_.26_Idarubicin.2C_then_Mitoxantrone.2C_then_Cytarabine_.26_Idarubicin.2C_with_ATRA|Cytarabine & Idarubicin, then Mitoxantrone, then Cytarabine & Idarubicin, with ATRA]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days -7 to -3
+
*[[Mercaptopurine (6-MP)]] 50 mg/m<sup>2</sup> PO once per day  
−
*[[Busulfan (Myleran)]] 0.8 mg/kg IV over 2 hours every 6 hours on days -4 & -3 (total dose: 6.4 mg/kg)
+
*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IM once per week
−
====Immunosuppressive therapy====
+
====Dose modifications====
−
*[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)|ATG (Rabbit)]] 2.5 mg/kg IV over 6 hours once per day on days -4 to -2
+
*[[Methotrexate (MTX)]] and [[Mercaptopurine (6-MP)]] decreased by 50% if WBC count less than 3.5 × 10<sup>9</sup>/L
−
====GVHD prophylaxis====
+
*[[Methotrexate (MTX)]] and [[Mercaptopurine (6-MP)]] stopped if WBC count less than 2.5 × 10<sup>9</sup>/L
−
*[[Tacrolimus (Prograf)]] with doses adjusted to maintain levels of 5 to 10 ng/mL, tapered on day +90 to off by day +180 (if no GVHD)
+
'''90-day cycle for 8 cycles (2 years)'''
−
*[[Methotrexate (MTX)]] 5 mg/m<sup>2</sup> IV once per day on days +1, +3, +6, +11
+
</div></div><br>
−
</div>
 
−
<section end="dd1486" />
 
−
</div><br>
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2 {{#subobject:335733|Variant=1}}===
+
===Protocol variant #2, 45/50/15, ATRA alternating with 6-MP, MTX {{#subobject:80d40a|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 33%"|Study
+
!style="width: 25%"|Study
−
!style="width: 33%"|Years of enrollment
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
 
|-
 
|-
−
|[https://doi.org/10.1002/cncr.29087 Mohty et al. 2014 (ITT 08-01)]
+
|[https://doi.org/10.1056/NEJMoa1300874 Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)]
−
|2009-2011
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
| style="background-color:#91cf61" |Phase 2
 
 
|-
 
|-
 
|}
 
|}
−
<section begin="335733" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin.2C_with_ATRA|Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Chemotherapy, part 1====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup>/day (route not specified) on days -6 to -2
+
*[[Mercaptopurine (6-MP)]] 50 mg/m<sup>2</sup> PO once per day  
−
*[[Busulfan (Myleran)]] 130 mg/m<sup>2</sup> IV over 3 hours once per day on days -5 to -3
+
*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IM or PO once per week
−
====Immunosuppressive therapy====
+
'''3-month cycle for 4 cycles, alternating with part 2'''
−
*[[:Category:Antithymocyte globulin|Antithymocyte globulin (ATG)]] (subtype not specified) 2.5 mg/kg/day IV on days -2 & -1
+
====Targeted therapy, part 2====
−
*As per [https://pubmed.ncbi.nlm.nih.gov/12931226 Mohty et al. 2003]
+
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO on days 1 to 15
−
</div>
+
'''3-month cycle for 4 cycles, alternating with part 1'''
−
<section end="335733" />
+
</div></div><br>
−
</div><br>
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #3 {{#subobject:e2d51e|Variant=1}}===
+
===Regimen variant #3, 45/60/20 {{#subobject:5c36f3|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 20%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/107/9/3474 Garban et al. 2006 (IFM99-03)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ Powell et al. 2010 (C9710)]
−
| style="background-color:#91cf61" |Non-randomized
+
|1999-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#ATRA_monotherapy_2|ATRA]]
 +
| style="background-color:#d9ef8b" |Might have superior DFS
 
|-
 
|-
 
|}
 
|}
−
''This regimen was meant for patients who had an HLA-identical sibling donor, and was evaluated in multiple myeloma patients.''
+
''Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.''
−
<section begin="e2d51e" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide.2C_then_ATRA_.26_Daunorubicin|Arsenic trioxide, then ATRA & daunorubicin]] consolidation versus [[#ATRA_.26_Daunorubicin_2|ATRA & daunorubicin]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 7
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup>/day (route not specified) for 5 days (days not specified)
+
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day  
−
*[[Busulfan (Myleran)]] 2 mg/kg<sup>2</sup> PO once per day for 2 days (days not specified)
+
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 1 & 8
−
====Immunosuppressive therapy====
+
'''14-day cycle for 26 cycles (1 year)'''
−
*[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)|ATG, rabbit (Imtix)]] 2.5 mg/kg IV over 12 hours once per day on days -5 to -1
+
</div></div><br>
−
====GVHD prophylaxis====
 
−
*[[Cyclosporine]] with starting dose on day -1 of 3 mg/kg/day, doses adjusted to "serum levels", tapered on day +60 to off by day +100 (if no GVHD)
 
−
*[[Methotrexate (MTX)]] 10 mg/m<sup>2</sup> (route not specified) once per day on days +1, +3, +6
 
−
</div>
 
−
<section end="e2d51e" />
 
−
</div><br>
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #4 {{#subobject:e2c4bf|Variant=1}}===
+
===Protocol variant #4, 45/90/15, ATRA alternating with 6-MP, MTX {{#subobject:1d7cb5|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 20%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="3" |[http://www.bloodjournal.org/content/90/3/1014.long Mandelli et al. 1997 (GIMEMA AIDA 0493)]
 +
|rowspan=3|1993-1996
 +
| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#ATRA_monotherapy_2|ATRA]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS
 +
|-
 +
|2. [[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS
 +
|-
 +
|3. [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|No further treatment]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/91/3/756.full Slavin et al. 1998]
+
| rowspan="2" |[http://www.bloodjournal.org/content/94/4/1192.long Fenaux et al. 1999 (EAPLG APL 93)]
−
| style="background-color:#91cf61" |Phase 2
+
|rowspan=2|1993-1996
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]]
 +
| style="background-color:#91cf60" |Seems to have superior 2-year relapse rate
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2003.12.011 Schetelig et al. 2003]
+
|2. [[#ATRA_monotherapy_2|ATRA]]<br> 3. [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|No further treatment]]
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#1a9850" |Superior 2-year relapse rate
 
|-
 
|-
 
|}
 
|}
−
<section begin="e2c4bf" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*GIMEMA AIDA 0493: [[#Cytarabine_.26_Idarubicin.2C_then_Etoposide_.26_Mitoxantrone.2C_then_Cytarabine.2C_Idarubicin.2C_Thioguanine|Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine]] consolidation
 +
*EAPLG APL 93: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Chemotherapy, part 1====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -10 to -5 (6 consecutive days)
+
*[[Mercaptopurine (6-MP)]] 90 mg/m<sup>2</sup> PO once per day  
−
*[[Busulfan (Myleran)]] 4 mg/kg/day PO on days -6 to -5 (2 consecutive days)
+
*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IM once per week
−
====Immunosuppressive therapy====
+
'''3-month cycle for 4 cycles, alternating with part 2'''
−
*[[Antithymocyte globulin, rabbit ATG (Grafalon)|ATG-Fresenius]] 10 mg/kg IV once per day on days -4 to -1 (4 consecutive days)
+
====Targeted therapy, part 2====
−
</div>
+
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO on days 1 to 15
−
<section end="e2c4bf" />
+
'''3-month cycle for 4 cycles, alternating with part 1'''
−
</div>
+
</div></div><br>
−
===References===
 
−
#Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998 Feb 1;91(3):756-63. [http://www.bloodjournal.org/content/91/3/756.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9446633 PubMed]
 
−
#Schetelig J, Thiede C, Bornhauser M, Schwerdtfeger R, Kiehl M, Beyer J, Sayer HG, Kroger N, Hensel M, Scheffold C, Held TK, Hoffken K, Ho AD, Kienast J, Neubauer A, Zander AR, Fauser AA, Ehninger G, Siegert W; Cooperative German Transplant Study Group. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. 2003 Jul 15;21(14):2747-53. [https://doi.org/10.1200/jco.2003.12.011 link to original article] '''contains reference to protocol''' [https://pubmed.ncbi.nlm.nih.gov/12860954 PubMed]
 
−
#'''IFM99-03:''' Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, Dib M, Caillot D, Deprijck B, Ketterer N, Harousseau JL, Sotto JJ, Moreau P. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006 May 1;107(9):3474-80. Epub 2006 Jan 5. [http://www.bloodjournal.org/content/107/9/3474 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16397129 PubMed]
 
−
##'''Pooled update:''' Moreau P, Garban F, Attal M, Michallet M, Marit G, Hulin C, Benboubker L, Doyen C, Mohty M, Yakoub-Agha I, Leyvraz S, Casassus P, Avet-Loiseau H, Garderet L, Mathiot C, Harousseau JL; IFM. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008 Nov 1;112(9):3914-5. [http://www.bloodjournal.org/content/112/9/3914.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18948589 PubMed]
 
−
#'''ITT 08-01:''' Mohty M, Malard F, Blaise D, Milpied N, Furst S, Tabrizi R, Guillaume T, Vigouroux S, El-Cheikh J, Delaunay J, Le Gouill S, Moreau P, Labopin M, Chevallier P. Reduced-toxicity conditioning with fludarabine, once-daily intravenous busulfan, and antithymocyte globulins prior to allogeneic stem cell transplantation: results of a multicenter prospective phase 2 trial. Cancer. 2015 Feb 15;121(4):562-9. Epub 2014 Oct 3. Erratum in: Cancer. 2015 Mar 1;121(5):800. [https://doi.org/10.1002/cncr.29087 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25283774 PubMed] NCT00841724
 
−
<!-- Presented in part as an oral presentation at the 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8-11, 2012. -->
 
−
#'''CALGB 100103:''' Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. Epub 2015 Nov 2. [https://doi.org/10.1200/jco.2015.62.7273 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658453/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26527780 PubMed] NCT00070135
 
−
==Fludarabine, Busulfan, ATG, Ibritumomab tiuxetan {{#subobject:68bee2|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:822e5a|Variant=1}}===
+
===Regimen variant #5, with range of 6-MP {{#subobject:85ef36|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1093/annonc/mdu503 Bouabdallah et al. 2015 (ZEVALLO)]
+
|[https://doi.org/10.1200/jco.2006.08.1596 Adès et al. 2006 (EAPLG APL 2000)]
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
|-
 
|-
 
|}
 
|}
−
<section begin="822e5a" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation versus [[#Daunorubicin_monotherapy|daunorubicin]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -6 to -2
+
*[[Mercaptopurine (6-MP)]] 50 to 90 mg/m<sup>2</sup> PO once per day  
−
*[[Busulfan (Myleran)]] 3.2 mg/kg/day (route not specified) on days -5 & -4
+
*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> PO once per week
−
====Targeted therapy====
+
'''90-day cycle for 8 cycles (2 years)'''
−
*[[Rituximab (Rituxan)]] 250 mg/m<sup>2</sup> IV once per day on days -21 & -14
+
</div></div><br>
−
====Radioconjugate therapy====
 
−
*[[Ibritumomab tiuxetan (Zevalin)]] 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14
 
−
====GVHD prophylaxis====
 
−
*[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]] 2.5 mg/kg IV once on day -1
 
−
*[[Cyclosporine]] (dose not specified) until day +90 and tapered off by day +180 based on chimerism and GVHD
 
−
*[[Methotrexate (MTX)]] by the following criteria:
 
−
**For unrelated donors with HLA mismatch: 15 mg/m<sup>2</sup> (route not specified) once on day +1, then 10 mg/m<sup>2</sup> (route not specified) once per day on days +3 & +6
 
−
</div>
 
−
<section end="822e5a" />
 
−
</div>
 
−
===References===
 
−
#'''ZEVALLO:''' Bouabdallah K, Furst S, Asselineau J, Chevalier P, Tournilhac O, Ceballos P, Vigouroux S, Tabrizi R, Doussau A, Bouabdallah R, Mohty M, Le Gouill S, Blaise D, Milpied N. 90Y-ibritumomab tiuxetan, fludarabine, busulfan and antithymocyte globulin reduced-intensity allogeneic transplant conditioning for patients with advanced and high-risk B-cell lymphomas. Ann Oncol. 2015 Jan;26(1):193-8. Epub 2014 Oct 30. [https://doi.org/10.1093/annonc/mdu503 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25361987 PubMed] NCT00607854
 
−
==Fludarabine, Cyclophosphamide, ATG {{#subobject:f2ce14|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:3e71d0|Variant=1}}===
+
===Regimen variant #6, with range of 6-MP & MTX {{#subobject:ac797|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 33%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/116/14/2438 Dreger et al. 2010 (GCLLSG CLL3X)]
+
|[https://doi.org/10.1182/blood-2012-02-410746 Iland et al. 2012 (ALLG APML4)]
 +
|2004-2009
 
| style="background-color:#91cf61" |Phase 2
 
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
−
''This regimen is intended for unrelated donors.''
+
''Maintenance starts 3 to 4 weeks after completion of consolidation cycle 2.''
−
<section begin="3e71d0" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -6 to -2 (5 consecutive days)
+
*[[Mercaptopurine (6-MP)]] 50 to 90 mg/m<sup>2</sup> PO once per day on days 15 to 90
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days -6 to -2 (5 consecutive days)
+
*[[Methotrexate (MTX)]] 5 to 15 mg/m<sup>2</sup>/week PO on days 15 to 90
−
====Immunosuppressive therapy====
+
====Dose modifications====
−
*[[Antithymocyte globulin, rabbit ATG (Grafalon)|ATG-Fresenius]] 10 mg/kg/day IV on days -4 to -1 (4 consecutive days)
+
*[[Methotrexate (MTX)]] and [[Mercaptopurine (6-MP)]] doses titrated to ANC 1000 to 2000/uL and minimizing hepatotoxicity
−
</div>
+
'''90-day cycle for 8 cycles (2 years)'''
−
<section end="3e71d0" />
+
</div></div>
−
</div>
 
 
===References===
 
===References===
−
<!-- Presented in part in abstract form at the 50th annual meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2008. -->
+
# '''GIMEMA AIDA 0493:''' Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. [http://www.bloodjournal.org/content/90/3/1014.long link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/9242531 PubMed]
−
#'''GCLLSG CLL3X:''' Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. [http://www.bloodjournal.org/content/116/14/2438 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20595516 PubMed] NCT00281983
+
## '''Update:''' Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA; AIEOP; EORTC. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5;117(18):4716-25. Epub 2011 Mar 8. [http://www.bloodjournal.org/content/117/18/4716.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21385856 PubMed]
−
##'''Update:''' Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Döhner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. Epub 2013 Feb 22. [http://www.bloodjournal.org/content/121/16/3284.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23435461 PubMed]
+
# '''EAPLG APL 93:''' Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia; European APL Group. Blood. 1999 Aug 15;94(4):1192-200. [http://www.bloodjournal.org/content/94/4/1192.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/10438706 PubMed]
−
##'''Update:''' Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Döhner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. Epub 2017 Jul 17. [http://www.bloodjournal.org/content/130/12/1477.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28716861 PubMed]
+
## '''Update:''' Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, Recher C, Thomas X, Rayon C, Castaigne S, Tournilhac O, de Botton S, Ifrah N, Cahn JY, Solary E, Gardin C, Fegeux N, Bordessoule D, Ferrant A, Meyer-Monard S, Vey N, Dombret H, Degos L, Chevret S, Fenaux P; European APL Group. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010 Mar 4;115(9):1690-6. Epub 2009 Dec 17. [http://www.bloodjournal.org/content/115/9/1690.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20018913 PubMed]
−
==Fludarabine, Cyclophosphamide, TBI for dUCB or haploidentical transplant {{#subobject:3a1faf|Regimen=1}}==
+
# '''PETHEMA LPA99:''' Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. [http://www.bloodjournal.org/content/103/4/1237.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14576047 PubMed] NCT00465933
−
dUCB: '''<u>d</u>'''ouble '''<u>U</u>'''mbilical '''<u>C</u>'''ord '''<u>B</u>'''lood
+
## '''Pooled subgroup analysis:''' Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. [http://www.bloodjournal.org/content/111/3/1078.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017 PubMed]
 +
# '''EAPLG APL 2000:''' Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; EAPLG. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. [https://doi.org/10.1200/jco.2006.08.1596 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17116939 PubMed] NCT00591526
 +
## '''Pooled subgroup analysis:''' Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. [http://www.bloodjournal.org/content/111/3/1078.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017 PubMed]
 +
# '''PETHEMA LPA2005:''' Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA; HOVON. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. [http://www.bloodjournal.org/content/115/25/5137.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20393132 PubMed] NCT00408278
 +
# '''C9710:''' Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. [http://www.bloodjournal.org/content/116/19/3751.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20705755 PubMed] NCT00003934
 +
# '''ALLG APML4:''' Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. [https://doi.org/10.1182/blood-2012-02-410746 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22715121 PubMed] ACTRN12605000070639
 +
# '''GIMEMA/DSIL APL0406:''' Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. [https://doi.org/10.1056/NEJMoa1300874 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23841729 PubMed] NCT00482833
 +
## '''HRQoL analysis:''' Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. [https://doi.org/10.1200/JCO.2014.55.3453 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25245446 PubMed]
 +
## '''Update:''' Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. [https://doi.org/10.1200/JCO.2016.67.1982 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27400939 PubMed]
 +
## '''Update:''' Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. [https://doi.org/10.1038/s41375-019-0589-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31611624 PubMed]
 +
==Mercaptopurine & Methotrexate {{#subobject:a29183|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, dUCB transplantation {{#subobject:f5d1b1|Variant=1}}===
+
===Regimen variant #1 {{#subobject:ce7c69|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 20%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138683/ Brunstein et al. 2011]
+
|[http://www.bloodjournal.org/content/100/9/3141.long Avvisati et al. 2002 (GIMEMA LAP 0389)]
−
| style="background-color:#91cf61" |Phase 2
+
|1989-1993
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Acute_promyelocytic_leukemia_-_null_regimens#Observation|No further treatment]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 
|-
 
|-
 
|}
 
|}
−
<section begin="f5d1b1" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Cytarabine_.26_Idarubicin.2C_then_Etoposide_.26_Mitoxantrone.2C_then_Cytarabine.2C_Idarubicin.2C_Thioguanine|Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 40 mg/m<sup>2</sup> IV once per day on days -6 to -2 (5 consecutive days)
+
*[[Mercaptopurine (6-MP)]] 1 mg/kg PO once per day  
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg/kg IV once on day -6
+
*[[Methotrexate (MTX)]] 0.25 mg/kg IM once per week
−
====Radiotherapy====
+
'''2-year course'''
−
*[[External_beam_radiotherapy|Total body irradiation (TBI)]] 2 Gy once on day -1
+
</div></div><br>
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] (dose/route/schedule not specified) and "vigorous IV hydration for uroprotection."
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day +1, continued until ANC greater than or equal to 2000/uL for 3 consecutive days
 
−
====GVHD prophylaxis====
 
−
*[[Mycophenolate mofetil (CellCept)]] 1000 mg (route not specified) every 8 hours for patients greater than 50 kg, starting on day -3 "and continuing until day +30 or 7 days after engraftment, whichever was later"
 
−
**Patients less than 50 kg received 15 mg/kg (route not specified) every 8 hours, starting on day -3 "and continuing until day +30 or 7 days after engraftment, whichever was later"
 
−
*[[Cyclosporine]] (route not specified) with a goal trough of 200 to 400 ng/mL (starting date not specified) until day +100. Patients without GVHD had their dose tapered by 10% each week starting on day +101, with discontinuation of cyclosporine A around day +180 to +200.
 
−
*[[Tacrolimus (Prograf)]] (route not specified) with a goal trough level of 5 to 10 ng/mL could be substituted for cyclosporine.
 
−
</div>
 
−
<section end="f5d1b1" />
 
−
</div><br>
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, Haploidentical {{#subobject:61264d|Variant=1}}===
+
===Regimen variant #2 {{#subobject:bab868|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 20%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="3" |[http://www.bloodjournal.org/content/90/3/1014.long Mandelli et al. 1997 (GIMEMA AIDA 0493)]
 +
|rowspan=3|1993-1996
 +
| rowspan="3" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#ATRA_monotherapy_2|ATRA]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS
 +
|-
 +
|2. [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS
 +
|-
 +
|3. [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|No further treatment]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS
 +
|-
 +
| rowspan="2" |[http://www.bloodjournal.org/content/94/4/1192.long Fenaux et al. 1999 (EAPLG APL 93)]
 +
|rowspan=2|1993-1996
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#ATRA_monotherapy_2|ATRA]]<br>2. [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]]
 +
| style="background-color:#fc8d59" |Seems to have inferior 2-year relapse rate
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138683/ Brunstein et al. 2011]
+
|3. [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|No further treatment]]
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#1a9850" |Superior 2-year relapse rate
 
|-
 
|-
 
|}
 
|}
−
<section begin="61264d" />
+
''Note that this arm was dropped from AIDA 0493 from February 1997.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*GIMEMA AIDA 0493: [[#Cytarabine_.26_Idarubicin.2C_then_Etoposide_.26_Mitoxantrone.2C_then_Cytarabine.2C_Idarubicin.2C_Thioguanine|Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine]] consolidation
 +
*EAPLG APL 93: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -6 to -2 (5 consecutive days)
+
*[[Mercaptopurine (6-MP)]] 90 mg/m<sup>2</sup> PO once per day  
−
*[[Cyclophosphamide (Cytoxan)]] 14.5 mg/kg IV once per day on days -6 and -5 (2 consecutive days)
+
*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IM once per week
−
====Radiotherapy====
+
'''2-year course'''
−
*[[External_beam_radiotherapy|Total body irradiation (TBI)]]  2 Gy once on day -1
+
</div></div>
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] (dose/route/schedule not specified) and "vigorous IV hydration for uroprotection."
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day +5, continued until ANC greater than or equal to 1000/uL for 3 consecutive days
 
−
====GVHD prophylaxis====
 
−
*[[Cyclophosphamide (Cytoxan)]] 50 mg/kg IBW IV over 1 to 2 hours once per day on days +3 & +4, started 60 to 72 hours after marrow infusion
 
−
*[[Mycophenolate mofetil (CellCept)]] 15 mg/kg (maximum daily dose of 3000 mg; route not specified) every 8 hours, starting on day +5, continued until day +35 or longer at physician discretion if active GVHD was present
 
−
*[[Tacrolimus (Prograf)]] (route not specified) with a goal trough level of 5 to 10 ng/mL, starting on day +5, continued until day +180
 
−
</div>
 
−
<section end="61264d" />
 
−
</div>
 
 
===References===
 
===References===
−
#Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, Devine SM, Wingard JR, Aljitawi OS, Cutler CS, Jagasia MH, Ballen KK, Eapen M, O'Donnell PV; BMT CTN. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011 Jul 14;118(2):282-8. [http://www.bloodjournal.org/content/118/2/282.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138683/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21527516 PubMed]
+
# '''GIMEMA AIDA 0493:''' Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. [http://www.bloodjournal.org/content/90/3/1014.long link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/9242531 PubMed]
−
==Fludarabine & Melphalan {{#subobject:1e26e2|Regimen=1}}==
+
## '''Update:''' Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA; AIEOP; EORTC. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5;117(18):4716-25. Epub 2011 Mar 8. [http://www.bloodjournal.org/content/117/18/4716.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21385856 PubMed]
−
Flu-Mel: '''<u>Flu</u>'''darabine & '''<u>Mel</u>'''phalan
+
# '''EAPLG APL 93:''' Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia; European APL Group. Blood. 1999 Aug 15;94(4):1192-200. [http://www.bloodjournal.org/content/94/4/1192.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/10438706 PubMed]
 +
## '''Update:''' Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, Recher C, Thomas X, Rayon C, Castaigne S, Tournilhac O, de Botton S, Ifrah N, Cahn JY, Solary E, Gardin C, Fegeux N, Bordessoule D, Ferrant A, Meyer-Monard S, Vey N, Dombret H, Degos L, Chevret S, Fenaux P; European APL Group. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010 Mar 4;115(9):1690-6. Epub 2009 Dec 17. [http://www.bloodjournal.org/content/115/9/1690.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20018913 PubMed]
 +
# '''GIMEMA LAP 0389:''' Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F; GIMEMA. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. [http://www.bloodjournal.org/content/100/9/3141.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12384411 PubMed]
 +
=Relapsed or refractory, salvage induction therapy=
 +
==Arsenic trioxide monotherapy {{#subobject:734f95|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 132/140 {{#subobject:efd75c|Variant=1}}===
+
===Regimen variant #1, 0.15 mg/kg/day {{#subobject:ffaa29|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable" style="width: 60%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 33%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM199811053391901 Soignet et al. 1998]
 +
|NR
 +
| style="background-color:#ffffbe" |Non-randomized, <20 pts
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4238917/ Anderlini et al. 2008]
+
|[https://doi.org/10.1200/JCO.2001.19.18.3852 Soignet et al. 2001 (PLRXAS01)]
−
| style="background-color:#91cf61" |Phase 2
+
|1998-1999
 +
| style="background-color:#91cf61" |Phase 2 (RT)
 
|-
 
|-
 
|}
 
|}
−
<section begin="efd75c" />
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy====
−
*[[Fludarabine (Fludara)]] 33 mg/m<sup>2</sup> IV once per day on days -5 to -2
+
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day  
−
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -3 & -2
+
'''Continued until CR or up to 60 days'''
−
====Immunosuppressive therapy====
 
−
*Recipients of stem cells from matched unrelated donors also received:
 
−
**[[:Category:Antithymocyte globulin|ATG]] (type not specified) 2 mg/kg IV once per day on days -4 to -2
 
−
====GVHD prophylaxis====
 
−
*[[Tacrolimus (Prograf)]] IV starting on day -2, dosed to achieve serum levels 4 to 12 ng/mL and switched to PO as soon as possible. Continued for at least 6 months and then "tapered off" (instructions not given).
 
−
*[[Methotrexate (MTX)]] 5 mg/m<sup>2</sup> IV once per day on days +1, +3, +6 (extra dose on day +11 for MUD recipients)
 
 
</div>
 
</div>
−
<section end="efd75c" />
+
<div class="toccolours" style="background-color:#cbd5e7">
−
</div><br>
+
====Subsequent treatment====
 +
*Confirmed CR: Arsenic trioxide consolidation and optional maintenance
 +
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, 150/140 {{#subobject:3239ec|Variant=1}}===
+
===Regimen variant #2, 10 mg/day {{#subobject:e2687c|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bbmt.org/article/S1083-8791(05)00673-7 Alvarez et al. 2006]
+
|[http://www.bloodjournal.org/content/89/9/3354.long Shen et al. 1997]
−
| style="background-color:#91cf61" |Prospective
+
| style="background-color:#ffffbe" |Non-randomized, <20 pts
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269494/ Sureda et al. 2011 (HDR-ALLO)]
 
−
| style="background-color:#91cf61" |Phase 2
 
 
|-
 
|-
 
|}
 
|}
−
<section begin="3239ec" />
 
−
''Note: Alvarez et al. 2006 began CsA on day -1 and did not give day +11 MTX.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -8 to -4
+
*[[Arsenic trioxide (Trisenox)]] 10 mg IV over 2 to 3 hours once per day  
−
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -3 & -2
+
'''Continued until CR'''
−
====Immunosuppressive therapy====
 
−
*Recipients of stem cells from matched unrelated donors also received:
 
−
**Alvarez et al. 2006: [[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]] 2.5 mg/kg IV once per day on days -4 to -2
 
−
**HDR-ALLO: [[:Category:Antithymocyte globulin|ATG]] (type not specified) 45 mg/kg IV once per day on days -4 to -2
 
−
====GVHD prophylaxis====
 
−
*[[Cyclosporine]] starting on day -2 at 1.5 mg/kg IV twice per day
 
−
**''If no acute GVHD of grade 2 or more, cyclosporine A is tapered down by 10% per week starting on day +90 with planned discontinuation by day +150 (Alvarez et al. 2006) or +180 (HDR-ALLO).''
 
−
*[[Methotrexate (MTX)]] 10 mg/m<sup>2</sup> IV once per day on days +1, +3, +6, +11
 
−
</div>
 
−
<section end="3239ec" />
 
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Patients in CR: proceed after 30 days to another 28-day course of arsenic trioxide
 +
</div></div>
 
===References===
 
===References===
−
#Alvarez I, Sureda A, Caballero MD, Urbano-Ispizua A, Ribera JM, Canales M, García-Conde J, Sanz G, Arranz R, Bernal MT, de la Serna J, Díez JL, Moraleda JM, Rubió-Félix D, Xicoy B, Martínez C, Mateos MV, Sierra J. Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed Hodgkin lymphoma: results of a Spanish prospective cooperative protocol. Biol Blood Marrow Transplant. 2006 Feb;12(2):172-83. [http://www.bbmt.org/article/S1083-8791(05)00673-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16443515 PubMed]
+
# Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma J, Zhang P, Zhang TD, Chen SJ, Chen Z, Wang ZY. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997 May 1;89(9):3354-60. [http://www.bloodjournal.org/content/89/9/3354.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/9129042 PubMed]
−
#Anderlini P, Saliba R, Acholonu S, Giralt SA, Andersson B, Ueno NT, Hosing C, Khouri IF, Couriel D, de Lima M, Qazilbash MH, Pro B, Romaguera J, Fayad L, Hagemeister F, Younes A, Munsell MF, Champlin RE. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: the updated MD Anderson Cancer Center experience. Haematologica. 2008 Feb;93(2):257-64. Epub 2008 Jan 26. [http://www.haematologica.org/content/93/2/257.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4238917/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18223284 PubMed]
+
# Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, Corso D, DeBlasio A, Gabrilove J, Scheinberg DA, Pandolfi PP, Warrell RP Jr. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998 Nov 5;339(19):1341-8. [https://doi.org/10.1056/NEJM199811053391901 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/9801394 PubMed]
−
#'''HDR-ALLO:''' Sureda A, Canals C, Arranz R, Caballero D, Ribera JM, Brune M, Passweg J, Martino R, Valcárcel D, Besalduch J, Duarte R, León A, Pascual MJ, García-Noblejas A, López Corral L, Xicoy B, Sierra J, Schmitz N; GEL/TAMO. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma: results of the HDR-ALLO study - a prospective clinical trial by the Grupo Español de Linfomas/Trasplante de Médula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2012 Feb;97(2):310-7. Epub 2011 Oct 11. [http://www.haematologica.org/content/97/2/310.long link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269494/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21993674 PubMed]
+
# '''PLRXAS01:''' Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers EL, Coutré S, Dahlberg S, Ellison R, Warrell RP Jr. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001 Sep 15;19(18):3852-60. [https://doi.org/10.1200/JCO.2001.19.18.3852 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11559723 PubMed]
−
==Fludarabine, Melphalan, Alemtuzumab {{#subobject:99386e|Regimen=1}}==
+
==Arsenic trioxide & Idarubicin {{#subobject:90ec9f|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:149798|Variant=1}}===
+
===Regimen {{#subobject:4d76db|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1016/S0140673605666597 Peggs et al. 2005]
+
|[http://www.bloodjournal.org/content/121/16/3095.long Yanada et al. 2013 (JALSG APL205R)]
−
| style="background-color:#91cf61" |Non-randomized
+
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
−
<section begin="149798" />
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -7 to -3
+
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 (Idarubicin was added under special conditions; see text for details)
−
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day -2
+
====CNS therapy====
−
====Immunosuppressive therapy====
+
*''Given once after platelet recovery, consisting of:''
−
*[[Alemtuzumab (Campath)]]
+
**[[Cytarabine (Ara-C)]] 40 mg IT, admixed with MTX & steroids
−
</div>
+
**[[Methotrexate (MTX)]] 15 mg IT, admixed with Ara-C & steroids
−
<section end="149798" />
+
**ONE of the following corticosteroids:
 +
***[[Prednisolone (Millipred)]] 10 mg IT, admixed with Ara-C & MTX
 +
***[[Dexamethasone (Decadron)]] 4 mg IT, admixed with Ara-C & MTX
 +
'''One course of up to 60 days'''
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Arsenic_trioxide_monotherapy_5|Arsenic trioxide]] consolidation
 +
</div></div>
 
===References===
 
===References===
−
#Peggs KS, Hunter A, Chopra R, Parker A, Mahendra P, Milligan D, Craddock C, Pettengell R, Dogan A, Thomson KJ, Morris EC, Hale G, Waldmann H, Goldstone AH, Linch DC, Mackinnon S. Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet. 2005 Jun 4-10;365(9475):1934-41. [https://doi.org/10.1016/S0140673605666597 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15936420 PubMed]
+
# '''JALSG APL205R:''' Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. [http://www.bloodjournal.org/content/121/16/3095.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23412094 PubMed] UMIN C000000302
−
==Low-dose TBI {{#subobject:529ee7|Regimen=1}}==
+
==Tamibarotene monotherapy {{#subobject:fbdb9f|Regimen=1}}==
−
TBI: '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:174a8e|Variant=1}}===
+
===Regimen {{#subobject:5d009e|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ Gyukocza et al. 2010]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770883/ Sanford et al. 2015 (STAR-1)]
−
| style="background-color:#91cf61" |Non-randomized
+
| style="background-color:#ffffbe" |Phase 2, <20 pts
 
|-
 
|-
 
|}
 
|}
−
<section begin="174a8e" />
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Radiotherapy====
+
====Targeted therapy====
−
*[[External_beam_radiotherapy|Total body irradiation (TBI)]] 2 Gy at a rate of 0.07 to 0.20 Gy/min on day 0
+
*[[Tamibarotene (Amnoid)]] 3 mg/m<sup>2</sup> PO twice per day
−
====GVHD prophylaxis====
+
'''Up to 56-day course'''
−
*One of the following (further details not specified):
 
−
**[[Cyclosporine]]
 
−
**[[Tacrolimus (Prograf)]]
 
−
*[[Mycophenolate mofetil (CellCept)]]
 
−
</div>
 
−
<section end="174a8e" />
 
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Patients achieving CR: [[#Tamibarotene_monotherapy_77|Tamibarotene]] consolidation, if not proceeding to transplant
 +
</div></div>
 
===References===
 
===References===
−
<!-- no pre-pub disclosed -->
+
# '''STAR-1:''' Sanford D, Lo-Coco F, Sanz MA, Di Bona E, Coutre S, Altman JK, Wetzler M, Allen SL, Ravandi F, Kantarjian H, Cortes JE. Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all-trans retinoic acid and arsenic trioxide. Br J Haematol. 2015 Nov;171(4):471-7. Epub 2015 Jul 24. [https://doi.org/10.1111/bjh.13607 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770883/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26205361 PubMed] NCT00520208
−
#Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010 Jun 10;28(17):2859-67. Epub 2010 May 3. [https://doi.org/10.1200/jco.2009.27.1460 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903320/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20439626 PubMed]
+
=Consolidation after salvage therapy=
−
==TLI & ATG {{#subobject:49eb63|Regimen=1}}==
+
==Arsenic trioxide monotherapy {{#subobject:5de745|Regimen=1}}==
−
TLI & ATG: '''<u>T</u>'''otal '''<u>L</u>'''ymphocyte '''<u>I</u>'''rradiation & '''<u>A</u>'''nti-'''<u>T</u>'''hymocyte '''<u>G</u>'''lobulin
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:dad2af|Variant=1}}===
+
===Regimen {{#subobject:36556f|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJMoa050642 Lowsky et al. 2005]
+
|[http://www.bloodjournal.org/content/121/16/3095.long Yanada et al. 2013 (JALSG APL205R)]
−
| style="background-color:#91cf61" |Non-randomized
+
| style="background-color:#91cf61" |Phase 2
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721787/ Kohrt et al. 2009]
 
−
| style="background-color:#91cf61" |Non-randomized
 
 
|-
 
|-
 
|}
 
|}
−
''Note: the schedule for TLI in Kohrt et al. 2009 is slightly different, although the manuscript states that the protocol from Lowsky et al. 2006 was followed. See paper for details.''
+
''Note: intrathecal therapy is given at the conclusion of each cycle (3 doses total, including re-induction)''
−
<section begin="dad2af" />
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide_.26_Idarubicin|Arsenic trioxide & Idarubicin re-induction]]
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Radiotherapy====
+
====Targeted therapy====
−
*[[External_beam_radiotherapy|TLI]] 800 cGy once per day on days -11 to -1 (10 fractions)
+
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV once per day on days 1 to 25
−
====Immunosuppressive therapy====
+
====CNS therapy====
−
*[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]] 1.5 mg/kg IV once per day on days -11 to -7
+
*[[Cytarabine (Ara-C)]] 40 mg IT once at the conclusion of each cycle, admixed with MTX & steroids
−
</div>
+
*[[Methotrexate (MTX)]] 15 mg IT once at the conclusion of each cycle, admixed with Ara-C & steroids
−
<section end="dad2af" />
+
*ONE of the following corticosteroids:
 +
**[[Prednisolone (Millipred)]] 10 mg IT once at the conclusion of each cycle, admixed with Ara-C & MTX
 +
**[[Dexamethasone (Decadron)]] 4 mg IT once at the conclusion of each cycle, admixed with Ara-C & MTX
 +
'''2 cycles'''
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Stem_cell_mobilization#Cytarabine_.26_G-CSF|HiDAC & G-CSF stem cell mobilization]], then [[#Busulfan_.26_Melphalan.2C_then_auto_HSCT|Bu/Mel with auto HSCT]]
 +
</div></div>
 
===References===
 
===References===
−
#Lowsky R, Takahashi T, Liu YP, Dejbakhsh-Jones S, Grumet FC, Shizuru JA, Laport GG, Stockerl-Goldstein KE, Johnston LJ, Hoppe RT, Bloch DA, Blume KG, Negrin RS, Strober S. Protective conditioning for acute graft-versus-host disease. N Engl J Med. 2005 Sep 29;353(13):1321-31. Erratum in: N Engl J Med. 2006 Feb 23;354(8):884. [https://doi.org/10.1056/NEJMoa050642 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16192477 PubMed]
+
# '''JALSG APL205R:''' Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. [http://www.bloodjournal.org/content/121/16/3095.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23412094 PubMed] UMIN C000000302
−
#Kohrt HE, Turnbull BB, Heydari K, Shizuru JA, Laport GG, Miklos DB, Johnston LJ, Arai S, Weng WK, Hoppe RT, Lavori PW, Blume KG, Negrin RS, Strober S, Lowsky R. TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors. Blood. 2009 Jul 30;114(5):1099-109. [http://www.bloodjournal.org/content/114/5/1099.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721787/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19423725 PubMed]
+
==Busulfan & Melphalan, then auto HSCT {{#subobject:ceba5e|Regimen=1}}==
−
==(90)YFC {{#subobject:ed22a7|Regimen=1}}==
 
−
(90)YFC: Ibritumomab tiuxetan, '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:efc342|Variant=1}}===
+
===Regimen {{#subobject:8c92e5|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 25%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/98/13/3595.long Khouri et al. 2012 (MDACC ID01-233)]
+
|[http://www.bloodjournal.org/content/121/16/3095.long Yanada et al. 2013 (JALSG APL205R)]
−
| style="background-color:#91cf61" |Non-randomized
+
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
−
''Note: this regimen is specifically addressed in the 2012 update.''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
<section begin="efc342" />
+
====Preceding treatment====
 +
*[[Stem_cell_mobilization#Cytarabine_.26_G-CSF|HiDAC & G-CSF stem cell mobilization]]
 +
{{#lst:Autologous HSCT|c5fc8f}}
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
 
−
*[[Rituximab (Rituxan)]] 250 mg/m<sup>2</sup> IV once per day on days -14 & -7
 
−
====Radioconjugate therapy====
 
−
*[[Ibritumomab tiuxetan (Zevalin)|Ibritumomab tiuxetan & Indium-111 5 mCi]] IV once on day -14 for dosimetry
 
−
*[[Ibritumomab tiuxetan (Zevalin)|Ibritumomab tiuxetan & Yttrium-90 (Zevalin)]] 0.4 mCi/kg (15 MBq/kg) (maximum dose of 32 mCi/1.2 GBq) IV once on day -7
 
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days -5 to -3
 
−
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once per day on days -5 to -3
 
−
====Immunosuppressive therapy====
 
−
*[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]] by the following criteria:
 
−
**Matched unrelated or mismatched donors: 1 mg/kg IV once per day on days -2 & -1
 
−
====GVHD prophylaxis====
 
−
*[[Tacrolimus (Prograf)]]
 
−
*[[Methotrexate (MTX)]]
 
−
</div>
 
−
<section end="efc342" />
 
−
</div>
 
−
===References===
 
−
#'''MDACC ID01-233:''' Khouri IF, Saliba RM, Giralt SA, Lee MS, Okoroji GJ, Hagemeister FB, Korbling M, Younes A, Ippoliti C, Gajewski JL, McLaughlin P, Anderlini P, Donato ML, Cabanillas FF, Champlin RE. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood. 2001 Dec 15;98(13):3595-9. [http://www.bloodjournal.org/content/98/13/3595.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/11739162 PubMed] NCT00048737
 
−
##'''Update:''' Khouri IF, McLaughlin P, Saliba RM, Hosing C, Korbling M, Lee MS, Medeiros LJ, Fayad L, Samaniego F, Alousi A, Anderlini P, Couriel D, de Lima M, Giralt S, Neelapu SS, Ueno NT, Samuels BI, Hagemeister F, Kwak LW, Champlin RE. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood. 2008 Jun 15;111(12):5530-6. Epub 2008 Apr 14. Erratum in: Blood. 2009 Feb 12;113(7):1613. [http://www.bloodjournal.org/content/111/12/5530.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624452/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18411419 PubMed]
 
−
##'''Update:''' Khouri IF, Saliba RM, Erwin WD, Samuels BI, Korbling M, Medeiros LJ, Valverde R, Alousi AM, Anderlini P, Bashir Q, Ciurea S, Gulbis AM, de Lima M, Hosing C, Kebriaei P, Popat UR, Fowler N, Neelapu SS, Samaniego F, Champlin RE, Macapinlac HA. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood. 2012 Jun 28;119(26):6373-8. Epub 2012 May 14. [http://www.bloodjournal.org/content/119/26/6373.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347306/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22586182 PubMed]
 
−
=Hepatic veno-occlusive disease (VOD), all lines of therapy=
 
−
''Also known as sinusoidal obstructive syndrome (SOS)''
 
−
==Defibrotide monotherapy {{#subobject:pyr1|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, treatment {{#subobject:pyv1|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817309/ Richardson et al. 2016 (DFCI 2005-01)]
 
−
|2006-2008
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|"32 historical controls"
 
−
| style="background-color:#91cf60" |Seems to have superior survival at day +100
 
−
|-
 
−
|}
 
−
''Note: If after 21 days signs and symptoms of VOD have not resolved, give until VOD is resolved, up to a maximum of 60 days.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Supportive therapy====
 
−
*[[Defibrotide (Defitelio)]] 6.25 mg/kg IV over 2 hours every 6 hours
 
−
'''21- to 60-day course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, prophylaxis {{#subobject:0e9fee|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1016/s0140-6736(11)61938-7 Corbacioglu et al. 2012 (VOD-DF)]
 
−
|2006-2009
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[#Observation_88|Observation]]
 
−
| style="background-color:#91cf60" |Seems to have lower incidence of VOD
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Supportive therapy====
 
−
*[[Defibrotide (Defitelio)]] 6.25 mg/kg IV over 2 hours every 6 hours
 
−
'''Begins on first day of preparative regimen, continues for at least 14 days or until day +30'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''VOD-DF:''' Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, Boelens JJ, Hewitt A, Schrum J, Schulz AS, Müller I, Stein J, Wynn R, Greil J, Sykora KW, Matthes-Martin S, Führer M, O'Meara A, Toporski J, Sedlacek P, Schlegel PG, Ehlert K, Fasth A, Winiarski J, Arvidson J, Mauz-Körholz C, Ozsahin H, Schrauder A, Bader P, Massaro J, D'Agostino R, Hoyle M, Iacobelli M, Debatin KM, Peters C, Dini G. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012 Apr 7;379(9823):1301-9. Epub 2012 Feb 23. [https://doi.org/10.1016/s0140-6736(11)61938-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22364685 PubMed] NCT00272948
+
# '''JALSG APL205R:''' Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. [http://www.bloodjournal.org/content/121/16/3095.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23412094 PubMed] UMIN C000000302
−
#'''DFCI 2005-01:''' Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, Arai S, Grupp SA, Guinan EC, Martin PL, Steinbach G, Krishnan A, Nemecek ER, Giralt S, Rodriguez T, Duerst R, Doyle J, Antin JH, Smith A, Lehmann L, Champlin R, Gillio A, Bajwa R, D'Agostino RB Sr, Massaro J, Warren D, Miloslavsky M, Hume RL, Iacobelli M, Nejadnik B, Hannah AL, Soiffer RJ. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016 Jan 29. [https://doi.org/10.1182/blood-2015-10-676924 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817309/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26825712 PubMed] NCT00358501
+
[[Category:Acute promyelocytic leukemia regimens]]
−
[[Category:Allogeneic HSCT regimens]]
+
[[Category:Disease-specific pages]]
−
[[Category:Site-agnostic regimens]]
+
[[Category:Acute leukemias]]

Revision as of 12:44, 23 October 2022

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Section editor transclusions

0 regimens on this page
0 variants on this page

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Guidelines

ELN

Older

ESMO

NCCN

Upfront induction therapy

ADE & ATRA

ADE & ATRA: Ara-C (Cytarabine), Daunorubicin, Etoposide, All-Trans Retinoic Acid

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 1999 (UK MRC AML12) 1993-1997 Phase 3 (E-esc) ADE & ATRA, shorter duration Superior OS
Burnett et al. 2010 (UK MRC AML15) 2002-2006 Phase 3 (C) "Spanish therapy" Did not meet primary endpoints of RR/OS

Note: this is included for historic purposes. Efficacy for UK MRC AML15 is based on the 2012 update, which was specifically pertinent to APL.

Chemotherapy

Targeted therapy

One course

Subsequent treatment

References

  1. UK MRC AML12: Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the randomized MRC trial. Blood. 1999 Jun 15;93(12):4131-43. link to original article PubMed NCT00002658
    1. Update: Burnett AK, Hills RK, Milligan DW, Goldstone AH, Prentice AG, McMullin MF, Duncombe A, Gibson B, Wheatley K. Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol. 2010 Feb 1;28(4):586-95. Epub 2009 Dec 28. link to original article PubMed
  2. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed ISRCTN17161961
    1. Update: Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. link to original article contains dosing details in manuscript PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed

Arsenic trioxide monotherapy

Regimen variant #1, 0.15 mg/kg (pediatric dosing)

Study Years of enrollment Evidence
Mathews et al. 2006 1998-2004 Non-randomized

Note: the maximum duration was decreased from 75 to 60 days after 2001.

Targeted therapy

Continued until CR or up to 60 days

Subsequent treatment


Regimen variant #2, 0.16 mg/kg

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shen et al. 2004 2001-2003 Randomized (C) 1. Arsenic trioxide & ATRA Seems to have inferior DFS
2. ATRA Not reported

Targeted therapy

Continued until CR

Subsequent treatment

  • Patients in CR: Consolidation, see text for details


Regimen variant #3, 10 mg (flat dose)

Study Years of enrollment Evidence
Mathews et al. 2006 1998-2004 Non-randomized

Note: the maximum duration was decreased from 75 to 60 days after 2001.

Targeted therapy

Continued until CR or up to 60 days

Subsequent treatment

References

  1. Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De Thé H, Wang ZY, Chen SJ, Chen Z. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5328-35. Epub 2004 Mar 24. link to original article contains dosing details in manuscript link to PMC article PubMed
  2. Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006 Apr 1;107(7):2627-32. Epub 2005 Dec 13. link to original article contains dosing details in manuscript PubMed
    1. Update: Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, Viswabandya A, Thirugnanam R, Abraham A, Shaji RV, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010 Aug 20;28(24):3866-71. Epub 2010 Jul 19. link to original article PubMed

Arsenic trioxide & ATRA

Regimen variant #1, 0.15/45

Study Years of enrollment Evidence Comparator Comparative Efficacy
Estey et al. 2005 2002-2005 Phase 2
Ravandi et al. 2008 2002-2007 Phase 2
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) 2007-2013 Phase 3 (E-RT-switch-ooc) ATRA & Idarubicin Seems to have superior OS1
(HR 0.15, 95% CI 0.03-0.67)

1Reported efficacy for GIMEMA/DSIL APL0406 is based on the 2019 update.
Note: In Estey et al. 2005, arsenic trioxide was started on day 11, but was later modified to start on day 1 after a death due to hyperleukocytosis and intracranial hemorrhage during induction. GIMEMA/DSIL APL0406: Patients with low- or intermediate-risk APL (white blood cell count at presentation less than or equal to 10 x 109/L) were eligible.

Targeted therapy

  • Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 2 hours once per day, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days.
  • All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days (GIMEMA/DSIL APL0406) or 90 days (Estey et al. 2005 & Ravandi et al. 2008).

Supportive therapy

  • As described in GIMEMA/DSIL APL0406:
  • Prednisone (Sterapred) 0.5 mg/kg PO once per day from days 1 until the end of induction or the onset of differentiation syndrome
    • Patients who develop differentiation syndrome then received: Dexamethasone (Decadron) 10 mg IV every 12 hours until signs and symptoms resolve, and for a minimum of 3 days
  • Hemostatic support: Transfusions to keep platelet count greater than 30 x 109/L for the first 10 days of induction and greater than 20 x 109/L for the remainder of induction
  • Hydroxyurea (Hydrea) by the following criteria:
    • Patients with WBC count greater than 10 x 109/L and less than 50 x 109/L after the start of therapy: 500 mg PO four times per day, given until WBC count is less than 10 x 109/L
    • Patients with WBC count greater than 50 x 109/L after the start of therapy: 1000 mg PO four times per day, given until WBC count is less than 10 x 109/L

Up to 60- to 90-day course

Subsequent treatment


Regimen variant #2, 0.16/25

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shen et al. 2004 2001-2003 Randomized (E-esc) 1. Arsenic trioxide
2. ATRA 		Seems to have superior DFS
Zhu et al. 2013 2007-2011 Phase 3 (C) Realgar-Indigo naturalis formula Non-inferior DFS

Targeted therapy

Up to 90-day course

Subsequent treatment

  • Patients achieving CR: chemotherapy-based consolidation and maintenance. These details are available in the original paper but are omitted here.


Regimen variant #3, 0.3/45

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Burnett et al. 2015 (UK NCRI AML17) 2009-2013 Phase 3 (E-switch-ooc) ATRA & Idarubicin Did not meet primary endpoint of QoL

Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Targeted therapy

Subsequent treatment

References

  1. Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De Thé H, Wang ZY, Chen SJ, Chen Z. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5328-35. Epub 2004 Mar 24. link to original article contains dosing details in manuscript link to PMC article PubMed
    1. Update: Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WL, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3342-7. Epub 2009 Feb 18. link to original article contains dosing details in manuscript link to PMC article PubMed content property of HemOnc.org
  2. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article contains dosing details in manuscript PubMed
  3. Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009 Feb 1;27(4):504-10. Epub 2008 Dec 15. link to original article contains dosing details in manuscript link to PMC article PubMed
    1. Update: Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. link to full article contains dosing details in manuscript link to PMC article PubMed
  4. GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains dosing details in manuscript PubMed NCT00482833
    1. HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
    2. Update: Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. link to original article PubMed
    3. Update: Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. link to original article PubMed
  5. Zhu HH, Wu DP, Jin J, Li JY, Ma J, Wang JX, Jiang H, Chen SJ, Huang XJ. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial. J Clin Oncol. 2013 Nov 20;31(33):4215-21. Epub 2013 Oct 14. link to original article contains dosing details in manuscript PubMed ChiCTR-TRC-12002151
  6. UK NCRI AML17: Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. link to original article contains dosing details in abstract PubMed ISRCTN55675535
    1. Update: Russell N, Burnett A, Hills R, Betteridge S, Dennis M, Jovanovic J, Dillon R, Grimwade D; NCRI AML Working Group. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood. 2018 Sep 27;132(13):1452-1454. Epub 2018 Aug 10. link to original article link to PMC article PubMed

Arsenic trioxide, ATRA, Gemtuzumab ozogamicin

Regimen variant #1, GO 6 mg/m2

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Burnett et al. 2015 (UK NCRI AML17) 2009-2013 Phase 3 (E-esc) ATRA & Idarubicin Did not meet primary endpoint of QoL

Targeted therapy

Antibody-drug conjugate therapy

Subsequent treatment


Regimen variant #2, GO 9 mg/m2

Study Years of enrollment Evidence
Estey et al. 2005 2002-2005 Phase 2
Ravandi et al. 2008 2002-2007 Phase 2

Note: in some protocols, if GO was unavailable, Idarubicin 12mg/m2 given instead. The original protocol was modified between Estey et al. 2005 and Ravandi et al. 2008. Estey et al. 2005 covered part of the whole cohort. In the initial protocol, arsenic trioxide was started on day 11, and gemtuzumab ozogamicin was only used for high risk patients. After a death due to hyperleukocytosis and intracranial hemorrhage during induction, the protocol was modified as described in Ravandi et al. 2008 so arsenic trioxide was started on day 1, and gemtuzumab ozogamicin was given if WBC count went greater than 30 x 109/L for any patient in the first four weeks of therapy.

Targeted therapy

Antibody-drug conjugate therapy

Supportive therapy

  • "Prophylactic and therapeutic antibiotics and transfusion of blood products to maintain platelet counts more than 30 x 109/L, fibrinogen more than 150 mg/dL, and the international normalized ratio for prothrombin time less than 1.5" per institutional guidelines
  • Unfractionated heparin (UFH) or Tranexamic acid (Cyklokapron) used if clinically indicated
  • Methylprednisolone (Solumedrol) by the following study-specific criteria:
    • Estey et al. 2005: 20 mg PO once per day for 10 days to decrease risk of differentiation syndrome
    • Ravandi et al. 2008: 50 mg PO once per day for 5 days to decrease risk of differentiation syndrome

28-day course

Subsequent treatment

References

  1. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article contains dosing details in manuscript PubMed
    1. Update: Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. link to full article contains dosing details in manuscript link to PMC article PubMed
  2. Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009 Feb 1;27(4):504-10. Epub 2008 Dec 15. link to original article contains dosing details in manuscript link to PMC article PubMed
    1. Update: Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. link to full article contains dosing details in manuscript link to PMC article PubMed
  3. UK NCRI AML17: Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. link to original article PubMed ISRCTN55675535
    1. Update: Russell N, Burnett A, Hills R, Betteridge S, Dennis M, Jovanovic J, Dillon R, Grimwade D; NCRI AML Working Group. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood. 2018 Sep 27;132(13):1452-1454. Epub 2018 Aug 10. link to original article link to PMC article PubMed

Arsenic trioxide, ATRA, Idarubicin

Regimen

Study Years of enrollment Evidence
Iland et al. 2012 (ALLG APML4) 2004-2009 Phase 2

Targeted therapy

Chemotherapy

  • Idarubicin (Idamycin) by the following criteria:
    • Patients up to age 61: 12 mg/m2 IV once per day on days 2, 4, 6, 8
    • Patients 61 to 70 years old: 9 mg/m2 IV once per day on days 2, 4, 6, 8
    • Patients older than 70: 6 mg/m2 IV once per day on days 2, 4, 6, 8

Supportive therapy

  • Prednisone (Sterapred) 1 mg/kg PO once per day on days 1 to 10, or until WBC count falls below 1 x 109/L, or until resolution of differentiation syndrome (whichever occurs last)
  • Hemostatic support : Values checked and products transfused once or twice per day to keep platelet count greater than 30 x 109/L, fibrinogen greater than 1.5 g/L (150 mg/dL), normal PT and PTT
  • Electrolyte support while on Arsenic trioxide (Trisenox): supplemental potassium and magnesium given to keep levels in the upper half of their normal ranges

36-day course

Subsequent treatment

References

  1. ALLG APML4: Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. link to original article contains dosing details in manuscript PubMed ACTRN12605000070639

ATRA monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Warrell et al. 1991 NR Pilot, <20 pts
Fenaux et al. 1993 (EAPLG APL 91) 1991-1992 Phase 3 (E-switch-ooc) 7+3d Superior EFS
Tallman et al. 1997 (ECOG E2491) 1992-1995 Phase 3 (E-switch-ooc) Cytarabine & Daunorubicin Superior OS

These obsolete regimens are here for historical reference; ATRA is no longer used as monotherapy for induction; some patients in EAPLG APL 91 received concurrent chemotherapy (see paper for details)

Targeted therapy

Subsequent treatment

References

  1. Warrell RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri LM, Hittelman WN, Vyas R, Andreeff M, Tafuri A, Jakubowski A, Gabrilove J, Gordon MS, Dmitrovsky E. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991 May 16;324(20):1385-93. link to original article PubMed
  2. EAPLG APL 91: Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D, Huebner G, Bauters F, Fegueux N, Fey M, Sanz M, Lowenberg B, Maloisel F, Auzanneau G, Sadoun A, Gardin C, Bastion Y, Ganser A, Jacky E, Dombret H, Chastang C, Degos L; European APL Group. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. Blood. 1993 Dec 1;82(11):3241-9. link to original article contains dosing details in abstract PubMed
    1. Update: Fenaux P, Chevret S, Guerci A, Fegueux N, Dombret H, Thomas X, Sanz M, Link H, Maloisel F, Gardin C, Bordessoule D, Stoppa AM, Sadoun A, Muus P, Wandt H, Mineur P, Whittaker JA, Fey M, Daniel MT, Castaigne S, Degos L; European APL Group. Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. Leukemia. 2000 Aug;14(8):1371-7. link to original article PubMed
  3. ECOG E2491: Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997 Oct 9;337(15):1021-8. Erratum in: N Engl J Med 1997 Nov 27;337(22):1639. link to original article contains dosing details in manuscript PubMed
    1. Update: Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, Ogden A, Weinstein H, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002 Dec 15;100(13):4298-302. Epub 2002 Aug 15. link to original article PubMed

ATRA, Cytarabine, Daunorubicin

Regimen variant #1, 45/1400/180

Study Years of enrollment Evidence Comparator Comparative Efficacy
Adès et al. 2006 (EAPLG APL 2000) 2000-2004 Phase 3 (C) ATRA & Daunorubicin Superior OS

This induction arm was a randomization for young (less than 60), low-risk (WBC count less than 10 x 109/L) patients. High-risk (WBC count greater than 10 x 109/L) patients received this regimen in a non-randomized fashion, along with intrathecal therapy during consolidation.

Targeted therapy

Chemotherapy

One course of up to 90 days

Subsequent treatment


Regimen variant #2, 45/1400/200

Study Years of enrollment Evidence
Powell et al. 2010 (C9710) 1999-2004 Non-randomized portion of phase 3 RCT

Targeted therapy

Chemotherapy

One course of up to 90 days

Subsequent treatment

References

  1. EAPLG APL 2000: Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; EAPLG. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. link to original article contains dosing details in manuscript PubMed NCT00591526
    1. Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains dosing details in manuscript PubMed
  2. C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003934

ATRA, Cytarabine, Idarubicin

Regimen

Study Years of enrollment Evidence
Adès et al. 2018 (APL 2006) 2006-2013 Non-randomized portion of phase 3 RCT

Targeted therapy

Chemotherapy

One course until CR

Subsequent treatment

  • Patients with baseline WBC less than 10 x 109/L: Cytarabine & Idarubicin versus Arsenic trioxide & Idarubicin versus ATRA & Idarubicin consolidation
  • Patients with baseline WBC greater than 10 x 109/L: Cytarabine & Idarubicin versus Arsenic trioxide, Cytarabine, Idarubicin consolidation

References

  1. APL 2006: Adès L, Thomas X, Guerci Bresler A, Raffoux E, Spertini O, Vey N, Marchand T, Récher C, Pigneux A, Girault S, Deconinck E, Gardin C, Tournilhac O, Lambert JF, Chevallier P, de Botton S, Lejeune J, Dombret H, Chevret S, Fenaux P; French Belgian Swiss APL group. Arsenic trioxide is required in the treatment of newly diagnosed acute promyelocytic leukemia: analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL group. Haematologica. 2018 Dec;103(12):2033-9. Epub 2018 Jul 19. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00378365

ATRA & Daunorubicin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Adès et al. 2006 (EAPLG APL 2000) 2000-2004 Phase 3 (E-de-esc) ATRA, Cytarabine, Daunorubicin Inferior OS

This induction arm was a randomization for young (less than 60), low-risk (WBC count less than 10 x 109/L) patients. Low-risk (WBC count less than 10 x 109/L) older (greater than 60) patients received this regimen in a non-randomized fashion.

Targeted therapy

Chemotherapy

One course of up to 90 days

Subsequent treatment

References

  1. EAPLG APL 2000: Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; EAPLG. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. link to original article contains dosing details in manuscript PubMed NCT00591526
    1. Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains dosing details in manuscript PubMed

ATRA & Idarubicin

AIDA: ATRA, IDArubicin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Avvisati et al. 1996 (GIMEMA AIDA) 1993 Pilot
Mandelli et al. 1997 (GIMEMA AIDA 0493) 1993-1996 Non-randomized portion of RCT
Sanz et al. 2003 (PETHEMA LPA96) 1996-1999 Non-randomized
Latagliata et al. 2011 (GIMEMA AIDA 0493 amended protocol) 1997-2004 Non-randomized
Sanz et al. 2003 (PETHEMA LPA99) 1999-2002 Non-randomized
Lo-Coco et al. 2010 (GIMEMA AIDA-2000) 2000-2006 Non-randomized
Sanz et al. 2010 (PETHEMA LPA2005) 2005-2009 Non-randomized
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) 2007-2013 Phase 3 (C) Arsenic trioxide & ATRA Seems to have inferior OS1
Burnett et al. 2015 (UK NCRI AML17) 2009-2013 Phase 3 (C) Arsenic trioxide & ATRA Did not meet primary endpoint of QoL

1Reported efficacy for GIMEMA/DSIL APL0406 is based on the 2019 update.
Note: this is the same induction used in multiple protocols. Consolidation and maintenance differ, follow the appropriate links below.

Targeted therapy

  • All-trans retinoic acid (ATRA) starting day 1 and continuing until remission or maximum of 90 days, by the following criteria:
    • 21 or older: 22.5 mg/m2 PO twice per day
    • Less than 20 years old: 12.5 mg/m2 PO twice per day

Chemotherapy

  • Idarubicin (Idamycin) by the following criteria:
    • Up to age 70: 12 mg/m2 IV bolus once per day on days 2, 4, 6, 8
    • Older than 70 years old: 12 mg/m2 IV bolus once per day on days 2, 4, 6

One course of up to 90 days

Subsequent treatment

Once CR was achieved, patients proceeded to consolidation by the following study-specific criteria:

References

  1. GIMEMA AIDA: Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood. 1996 Aug 15;88(4):1390-8. link to full article contains dosing details in manuscript PubMed
  2. GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
    1. Update: Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA; AIEOP; EORTC. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5;117(18):4716-25. Epub 2011 Mar 8. link to original article contains dosing details in manuscript PubMed
  3. PETHEMA LPA96: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains dosing details in manuscript PubMed
    1. Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains dosing details in manuscript PubMed
  4. PETHEMA LPA99: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains dosing details in manuscript PubMed NCT00465933
    1. Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains dosing details in manuscript PubMed
  5. PETHEMA LPA2005: Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA; HOVON. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. link to original article contains dosing details in manuscript PubMed NCT00408278
  6. GIMEMA AIDA-2000: Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. link to original article contains dosing details in manuscript PubMed NCT001064570
  7. GIMEMA AIDA 0493 amended protocol: Latagliata R, Breccia M, Fazi P, Vignetti M, Di Raimondo F, Sborgia M, Vincelli D, Candoni A, Salvi F, Rupoli S, Martinelli G, Kropp MG, Tonso A, Venditti A, Melillo L, Cimino G, Petti MC, Avvisati G, Lo-Coco F, Mandelli F; GIMEMA Acute Leukaemia Working Party. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia: long-term results and prognostic factors. Br J Haematol. 2011 Sep;154(5):564-8. Epub 2011 Jul 14. link to full article contains dosing details in manuscript PubMed
  8. GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains dosing details in manuscript PubMed NCT00482833
    1. HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
    2. Update: Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. link to original article PubMed
    3. Update: Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. link to original article PubMed
  9. UK NCRI AML17: Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. link to original article PubMed ISRCTN55675535
    1. Update: Russell N, Burnett A, Hills R, Betteridge S, Dennis M, Jovanovic J, Dillon R, Grimwade D; NCRI AML Working Group. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood. 2018 Sep 27;132(13):1452-1454. Epub 2018 Aug 10. link to original article link to PMC article PubMed

Consolidation after upfront therapy

Arsenic trioxide monotherapy

Regimen variant #1, adult dosing

Study Years of enrollment Evidence
Mathews et al. 2006 1998-2004 Non-randomized

Preceding treatment

Targeted therapy

28-day course

Subsequent treatment


Regimen variant #2, pediatric dosing

Study Years of enrollment Evidence
Mathews et al. 2006 1998-2004 Non-randomized

Preceding treatment

Targeted therapy

28-day course

Subsequent treatment

References

  1. Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006 Apr 1;107(7):2627-32. Epub 2005 Dec 13. link to original article contains dosing details in manuscript PubMed
    1. Update: Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, Viswabandya A, Thirugnanam R, Abraham A, Shaji RV, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010 Aug 20;28(24):3866-71. Epub 2010 Jul 19. link to original article PubMed

Arsenic trioxide, then ATRA & Daunorubicin

Protocol

Study Years of enrollment Evidence Comparator Comparative Efficacy
Powell et al. 2010 (C9710) 1999-2005 Phase 3 (E-esc) ATRA & Daunorubicin Superior EFS

Consolidation therapy starts within 2 to 4 weeks of hematologic remission.

Preceding treatment

Targeted therapy, part 1

7-week cycles (5 weeks of therapy, then 2 weeks off), followed by:

Targeted therapy, part 2

Chemotherapy, part 2

39-day cycle for 2 cycles

Subsequent treatment

References

  1. C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003934

Arsenic trioxide & ATRA

Regimen variant #1

Study Years of enrollment Evidence
Estey et al. 2005 2002-2005 Phase 2
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) 2007-2013 Non-randomized portion of RCT

Note: There is no maintenance in this protocol.

Preceding treatment

Targeted therapy

28-cycle for 7 cycles


Protocol variant #2

Study Years of enrollment Evidence
Iland et al. 2012 (ALLG APML4) 2004-2009 Phase 2

Consolidation starts 3 to 4 weeks after completion of induction.

Preceding treatment

Targeted therapy, part 1

4-week course; after 3 to 4 weeks, proceed to consolidation cycle 2

Targeted therapy, part 2

Given 3 to 4 weeks after completion of consolidation cycle 1.

5-week course

Subsequent treatment

References

  1. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article contains dosing details in manuscript PubMed
  2. ALLG APML4: Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. link to original article contains dosing details in manuscript PubMed ACTRN12605000070639
  3. GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains dosing details in manuscript PubMed NCT00482833
    1. HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
    2. Update: Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. link to original article PubMed
    3. Update: Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. link to original article PubMed
  4. UK NCRI AML17: Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. link to original article PubMed ISRCTN55675535
    1. Update: Russell N, Burnett A, Hills R, Betteridge S, Dennis M, Jovanovic J, Dillon R, Grimwade D; NCRI AML Working Group. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood. 2018 Sep 27;132(13):1452-1454. Epub 2018 Aug 10. link to original article link to PMC article PubMed

ATRA & Daunorubicin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Powell et al. 2010 (C9710) 1999-2005 Phase 3 (C) Arsenic trioxide, then ATRA & Daunorubicin Inferior EFS

Consolidation therapy starts within 2 to 4 weeks of hematologic remission.

Preceding treatment

Targeted therapy

Chemotherapy

39-day cycle for 2 cycles

Subsequent treatment

References

  1. C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003934

Cytarabine & Daunorubicin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Adès et al. 2006 (EAPLG APL 2000) 2000-2004 Phase 3 (C) Daunorubicin Superior OS

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) as follows:
    • Cycle 1: 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
    • Cycle 2, younger than 60 & low-risk (WBC count less than 10 x 109/L) or older than 60 & high-risk (WBC count greater than 10 x 109/L): 1000 mg/m2 IV every 12 hours on days 1 to 4 (total dose: 8000 mg/m2)
    • Cycle 2, younger than 60 & high-risk (WBC count greater than 10 x 109/L): 2000 mg/m2 IV every 12 hours on days 1 to 5 (total dose: 20,000 mg/m2)
  • Daunorubicin (Cerubidine) as follows:
    • Cycle 1: 60 mg/m2 IV once per day on days 1 to 3
    • Cycle 2: 45 mg/m2 IV once per day on days 1 to 3

CNS therapy, high-risk (WBC count greater than 10 x 109/L) patients

2 cycles (length not specified)

Subsequent treatment

References

  1. EAPLG APL 2000: Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; EAPLG. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. link to original article contains dosing details in manuscript PubMed NCT00591526
    1. Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains dosing details in manuscript PubMed

Cytarabine & Idarubicin

Regimen

Study Evidence
Latagliata et al. 2011 (GIMEMA AIDA 0493 amended protocol) Non-randomized

This consolidation protocol was intended for patients older than 60.

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 1000 mg/m2 IV over 6 hours once per day on days 1 to 4, given first
  • Idarubicin (Idamycin) 5 mg/m2 IV once per day on days 1 to 4, given second, 3 hours after cytarabine infusion complete

4-day course

Subsequent treatment

References

  1. GIMEMA AIDA 0493 amended protocol: Latagliata R, Breccia M, Fazi P, Vignetti M, Di Raimondo F, Sborgia M, Vincelli D, Candoni A, Salvi F, Rupoli S, Martinelli G, Kropp MG, Tonso A, Venditti A, Melillo L, Cimino G, Petti MC, Avvisati G, Lo-Coco F, Mandelli F; GIMEMA Acute Leukaemia Working Party. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia: long-term results and prognostic factors. Br J Haematol. 2011 Sep;154(5):564-8. Epub 2011 Jul 14. link to full article contains dosing details in manuscript PubMed

Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine

Protocol

Study Years of enrollment Evidence
Avvisati et al. 2002 (GIMEMA LAP 0389) 1989-1993 Non-randomized portion of RCT
Avvisati et al. 1996 (GIMEMA AIDA) 1993 Pilot
Mandelli et al. 1997 (GIMEMA AIDA 0493) 1993-1996 Non-randomized portion of RCT

Note that the consolidation portion of the AIDA 0493 protocol is only described in Avvisati et al. 1996.

Preceding treatment

Chemotherapy, part 1

  • Cytarabine (Ara-C) 1000 mg/m2 IV over 6 hours once per day on days 1 to 4, given first
  • Idarubicin (Idamycin) 5 mg/m2 IV once per day on days 1 to 4, given second, 3 hours after cytarabine infusion complete

4-day course; next course to begin "at recovery from the previous one, when polymorphonuclear cells numbered 1500/uL or more and platelets numbered 100 x 109/L or more."

Chemotherapy, part 2

5-day course; next course to begin "at recovery from the previous one, when polymorphonuclear cells numbered 1500/uL or more and platelets numbered 100 x 109/L or more."

Chemotherapy, part 3

5-day course

Subsequent treatment

References

  1. GIMEMA AIDA: Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood. 1996 Aug 15;88(4):1390-8. link to full article contains dosing details in manuscript PubMed
  2. GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
    1. Update: Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA; AIEOP; EORTC. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5;117(18):4716-25. Epub 2011 Mar 8. link to original article contains dosing details in manuscript PubMed
  3. GIMEMA LAP 0389: Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F; GIMEMA. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. link to original article contains dosing details in manuscript PubMed

Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine, with ATRA

Protocol

Study Evidence
Lo-Coco et al. 2010 (GIMEMA AIDA-2000) Non-randomized

This is risk-adapted therapy for high-risk patients in AIDA-2000. The authors were unclear about how many days were between each part of consolidation therapy.

Preceding treatment

Targeted therapy, part 1

Chemotherapy, part 1

4-day course (see note), followed by:

Targeted therapy, part 2

Chemotherapy, part 2

5-day course (see note), followed by:

Targeted therapy, part 3

Chemotherapy, part 3

5-day course (see note)

CNS therapy, prophylaxis

It is not explicitly stated but presumably these are admixed and given together.

"Total of 3 cycles"

Subsequent treatment

References

  1. GIMEMA AIDA-2000: Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. link to original article contains dosing details in manuscript PubMed NCT001064570

Cytarabine & Idarubicin, then Mitoxantrone, then Cytarabine & Idarubicin, with ATRA

Protocol

Study Evidence
Sanz et al. 2010 (PETHEMA LPA2005) Non-randomized

This is risk-adapted therapy for high-risk younger than 60 patients in PETHEMA LPA2005. Note that it is unclear from the paper which route the cytarabine is given in the third consolidation; this dose can be given by IV or SC routes.

Preceding treatment

Targeted therapy, consolidation #1

Chemotherapy, consolidation #1

1-month course, followed by:

Targeted therapy, consolidation #2

Chemotherapy, consolidation #2

1-month course, followed by:

Targeted therapy, consolidation #3

Chemotherapy, consolidation #3

1-month course

Subsequent treatment

References

  1. PETHEMA LPA2005: Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA; HOVON. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. link to original article contains dosing details in manuscript PubMed NCT00408278

Daunorubicin monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Adès et al. 2006 (EAPLG APL 2000) 2000-2004 Phase 3 (E-de-esc) Cytarabine & Daunorubicin Inferior OS

This consolidation arm was a randomization for younger (less than 60), low-risk (WBC count less than 10 x 109/L) patients. Low-risk (WBC count less than 10 x 109/L) older (greater than 60) patients received this regimen in a non-randomized fashion.

Preceding treatment

Chemotherapy

  • Daunorubicin (Cerubidine) as follows:
    • Cycle 1: 60 mg/m2 IV once per day on days 1 to 3
    • Cycle 2: 45 mg/m2 IV once per day on days 1 to 3

Subsequent treatment

References

  1. EAPLG APL 2000: Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; EAPLG. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. link to original article contains dosing details in manuscript PubMed NCT00591526
    1. Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains dosing details in manuscript PubMed

Idarubicin, then Mitoxantrone, then Idarubicin

Protocol

Study Evidence
Sanz et al. 2003 (PETHEMA LPA96) Non-randomized
Sanz et al. 2003 (PETHEMA LPA99) Non-randomized

This was the low-risk treatment arm of PETHEMA LPA99; all patients on PETHEMA LPA96 underwent this consolidation protocol.

Preceding treatment

Chemotherapy, part 1

1-month cycle, followed by:

Chemotherapy, part 2

1-month cycle, followed by:

Chemotherapy, part 3

1-month cycle

Subsequent treatment

References

  1. PETHEMA LPA96: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains dosing details in manuscript PubMed
    1. Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains dosing details in manuscript PubMed
  2. PETHEMA LPA99: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains dosing details in manuscript PubMed NCT00465933
    1. Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains dosing details in manuscript PubMed

Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA

Protocol variant #1

Study Evidence
Lo-Coco et al. 2010 (GIMEMA AIDA-2000) Non-randomized
Sanz et al. 2010 (PETHEMA LPA2005) Non-randomized
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) Non-randomized portion of RCT

This is risk-adapted therapy for intermediate- and low-risk patients in AIDA-2000 and for low-risk patients in PETHEMA LPA2005; all patients assigned to the chemotherapy arm of GIMEMA/DSIL APL0406 received this treatment. Note that the number of mitoxantrone doses differs between the protocols.

Preceding treatment

Targeted therapy, part 1

Chemotherapy, part 1

1-month course, followed by:

Targeted therapy, part 2

Chemotherapy, part 2

  • Mitoxantrone (Novantrone) by the following study-specific criteria:
    • AIDA-2000 & GIMEMA/DSIL APL0406: 10 mg/m2 IV once per day on days 1 to 5
    • PETHEMA LPA2005: 10 mg/m2 IV once per day on days 1 to 3

1-month course, followed by:

Targeted therapy, part 3

Chemotherapy, part 3

1-month course

Subsequent treatment


Protocol variant #2

Study Evidence
Sanz et al. 2003 (PETHEMA LPA99) Non-randomized
Sanz et al. 2010 (PETHEMA LPA2005) Non-randomized

This is risk-adapted therapy for intermediate- and high-risk patients in PETHEMA LPA99 and for intermediate-risk and high-risk older than 60 patients in PETHEMA LPA2005. Note that the number of mitoxantrone doses differs between the two protocols.

Preceding treatment

Targeted therapy, part 1

Chemotherapy, part 1

1-month course, followed by:

Targeted therapy, part 2

Chemotherapy, part 2

  • Mitoxantrone (Novantrone) by the following study-specific criteria:
    • PETHEMA LPA99: 10 mg/m2 IV once per day on days 1 to 5
    • PETHEMA LPA2005: 10 mg/m2 IV once per day on days 1 to 3

1-month course, followed by:

Targeted therapy, part 3

Chemotherapy, part 3

1-month course

Subsequent treatment

References

  1. PETHEMA LPA99: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains dosing details in manuscript PubMed NCT00465933
    1. Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains dosing details in manuscript PubMed
  2. PETHEMA LPA2005: Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA; HOVON. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. link to original article contains dosing details in manuscript PubMed NCT00408278
  3. GIMEMA AIDA-2000: Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. link to original article contains dosing details in manuscript PubMed NCT001064570
  4. GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains dosing details in manuscript PubMed NCT00482833
    1. HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
    2. Update: Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. link to original article PubMed
    3. Update: Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. link to original article PubMed

Maintenance after upfront therapy

Arsenic trioxide monotherapy

Regimen variant #1, 0.15 mg/kg (pediatric dosing)

Study Years of enrollment Evidence
Mathews et al. 2006 1998-2004 Non-randomized

Preceding treatment

Targeted therapy

Monthly cycle for 6 cycles


Regimen variant #2, 10 mg (flat dose)

Study Years of enrollment Evidence
Mathews et al. 2006 1998-2004 Non-randomized

Preceding treatment

Targeted therapy

Monthly cycle for 6 cycles

References

  1. Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006 Apr 1;107(7):2627-32. Epub 2005 Dec 13. link to original article contains dosing details in manuscript PubMed
    1. Update: Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, Viswabandya A, Thirugnanam R, Abraham A, Shaji RV, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010 Aug 20;28(24):3866-71. Epub 2010 Jul 19. link to original article PubMed

ATRA monotherapy

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Powell et al. 2010 (C9710) 1999-2005 Phase 3 (E-de-esc) ATRA, 6-MP, MTX Might have inferior DFS

Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.

Preceding treatment

Targeted therapy

14-day cycle for 26 cycles (1 year)


Regimen variant #2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Mandelli et al. 1997 (GIMEMA AIDA 0493) 1993-1996 Phase 3 (E-switch-ooc) 1. ATRA, 6-MP, MTX Did not meet primary endpoint of molecular DFS
2. 6-MP & MTX Did not meet primary endpoint of molecular DFS
3. No further treatment Did not meet primary endpoint of molecular DFS
Fenaux et al. 1999 (EAPLG APL 93) 1993-1996 Phase 3 (E-esc) 1. ATRA, 6-MP, MTX Inferior 2-year relapse rate
2. 6-MP & MTX
3. No further treatment 		Seems to have superior 2-year relapse rate

Preceding treatment

Targeted therapy

3-month cycle for 8 cycles (2 years)

References

  1. GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
    1. Update: Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA; AIEOP; EORTC. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5;117(18):4716-25. Epub 2011 Mar 8. link to original article contains dosing details in manuscript PubMed
  2. EAPLG APL 93: Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia; European APL Group. Blood. 1999 Aug 15;94(4):1192-200. link to original article PubMed
    1. Update: Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, Recher C, Thomas X, Rayon C, Castaigne S, Tournilhac O, de Botton S, Ifrah N, Cahn JY, Solary E, Gardin C, Fegeux N, Bordessoule D, Ferrant A, Meyer-Monard S, Vey N, Dombret H, Degos L, Chevret S, Fenaux P; European APL Group. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010 Mar 4;115(9):1690-6. Epub 2009 Dec 17. link to original article PubMed
  3. C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003934

ATRA, Mercaptopurine, Methotrexate

Regimen variant #1, 45/50/15

Study Evidence
Sanz et al. 2003 (PETHEMA LPA99) Non-randomized
Sanz et al. 2010 (PETHEMA LPA2005) Non-randomized

Preceding treatment

Targeted therapy

Chemotherapy

Dose modifications

90-day cycle for 8 cycles (2 years)


Protocol variant #2, 45/50/15, ATRA alternating with 6-MP, MTX

Study Evidence
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) Non-randomized portion of RCT

Preceding treatment

Chemotherapy, part 1

3-month cycle for 4 cycles, alternating with part 2

Targeted therapy, part 2

3-month cycle for 4 cycles, alternating with part 1


Regimen variant #3, 45/60/20

Study Years of enrollment Evidence Comparator Comparative Efficacy
Powell et al. 2010 (C9710) 1999-2005 Phase 3 (E-esc) ATRA Might have superior DFS

Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.

Preceding treatment

Targeted therapy

Chemotherapy

14-day cycle for 26 cycles (1 year)


Protocol variant #4, 45/90/15, ATRA alternating with 6-MP, MTX

Study Years of enrollment Evidence Comparator Comparative Efficacy
Mandelli et al. 1997 (GIMEMA AIDA 0493) 1993-1996 Phase 3 (E-esc) 1. ATRA Did not meet primary endpoint of molecular DFS
2. 6-MP & MTX Did not meet primary endpoint of molecular DFS
3. No further treatment Did not meet primary endpoint of molecular DFS
Fenaux et al. 1999 (EAPLG APL 93) 1993-1996 Phase 3 (E-esc) 1. 6-MP & MTX Seems to have superior 2-year relapse rate
2. ATRA
3. No further treatment 		Superior 2-year relapse rate

Preceding treatment

Chemotherapy, part 1

3-month cycle for 4 cycles, alternating with part 2

Targeted therapy, part 2

3-month cycle for 4 cycles, alternating with part 1


Regimen variant #5, with range of 6-MP

Study Evidence
Adès et al. 2006 (EAPLG APL 2000) Non-randomized portion of RCT

Preceding treatment

Targeted therapy

Chemotherapy

90-day cycle for 8 cycles (2 years)


Regimen variant #6, with range of 6-MP & MTX

Study Years of enrollment Evidence
Iland et al. 2012 (ALLG APML4) 2004-2009 Phase 2

Maintenance starts 3 to 4 weeks after completion of consolidation cycle 2.

Preceding treatment

Targeted therapy

Chemotherapy

Dose modifications

90-day cycle for 8 cycles (2 years)

References

  1. GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
    1. Update: Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA; AIEOP; EORTC. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5;117(18):4716-25. Epub 2011 Mar 8. link to original article contains dosing details in manuscript PubMed
  2. EAPLG APL 93: Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia; European APL Group. Blood. 1999 Aug 15;94(4):1192-200. link to original article PubMed
    1. Update: Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, Recher C, Thomas X, Rayon C, Castaigne S, Tournilhac O, de Botton S, Ifrah N, Cahn JY, Solary E, Gardin C, Fegeux N, Bordessoule D, Ferrant A, Meyer-Monard S, Vey N, Dombret H, Degos L, Chevret S, Fenaux P; European APL Group. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010 Mar 4;115(9):1690-6. Epub 2009 Dec 17. link to original article PubMed
  3. PETHEMA LPA99: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains dosing details in manuscript PubMed NCT00465933
    1. Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains dosing details in manuscript PubMed
  4. EAPLG APL 2000: Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; EAPLG. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. link to original article contains dosing details in manuscript PubMed NCT00591526
    1. Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains dosing details in manuscript PubMed
  5. PETHEMA LPA2005: Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA; HOVON. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. link to original article PubMed NCT00408278
  6. C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003934
  7. ALLG APML4: Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. link to original article contains dosing details in manuscript PubMed ACTRN12605000070639
  8. GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains dosing details in manuscript PubMed NCT00482833
    1. HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
    2. Update: Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. link to original article PubMed
    3. Update: Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. link to original article PubMed

Mercaptopurine & Methotrexate

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Avvisati et al. 2002 (GIMEMA LAP 0389) 1989-1993 Phase 3 (C) No further treatment Did not meet primary endpoint of EFS

Preceding treatment

Chemotherapy

2-year course


Regimen variant #2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Mandelli et al. 1997 (GIMEMA AIDA 0493) 1993-1996 Phase 3 (C) 1. ATRA Did not meet primary endpoint of molecular DFS
2. ATRA, 6-MP, MTX Did not meet primary endpoint of molecular DFS
3. No further treatment Did not meet primary endpoint of molecular DFS
Fenaux et al. 1999 (EAPLG APL 93) 1993-1996 Phase 3 (C) 1. ATRA
2. ATRA, 6-MP, MTX 		Seems to have inferior 2-year relapse rate
3. No further treatment Superior 2-year relapse rate

Note that this arm was dropped from AIDA 0493 from February 1997.

Preceding treatment

Chemotherapy

2-year course

References

  1. GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
    1. Update: Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA; AIEOP; EORTC. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5;117(18):4716-25. Epub 2011 Mar 8. link to original article contains dosing details in manuscript PubMed
  2. EAPLG APL 93: Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia; European APL Group. Blood. 1999 Aug 15;94(4):1192-200. link to original article PubMed
    1. Update: Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, Recher C, Thomas X, Rayon C, Castaigne S, Tournilhac O, de Botton S, Ifrah N, Cahn JY, Solary E, Gardin C, Fegeux N, Bordessoule D, Ferrant A, Meyer-Monard S, Vey N, Dombret H, Degos L, Chevret S, Fenaux P; European APL Group. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010 Mar 4;115(9):1690-6. Epub 2009 Dec 17. link to original article PubMed
  3. GIMEMA LAP 0389: Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F; GIMEMA. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. link to original article contains dosing details in manuscript PubMed

Relapsed or refractory, salvage induction therapy

Arsenic trioxide monotherapy

Regimen variant #1, 0.15 mg/kg/day

Study Years of enrollment Evidence
Soignet et al. 1998 NR Non-randomized, <20 pts
Soignet et al. 2001 (PLRXAS01) 1998-1999 Phase 2 (RT)

Targeted therapy

Continued until CR or up to 60 days

Subsequent treatment

  • Confirmed CR: Arsenic trioxide consolidation and optional maintenance


Regimen variant #2, 10 mg/day

Study Evidence
Shen et al. 1997 Non-randomized, <20 pts

Targeted therapy

Continued until CR

Subsequent treatment

  • Patients in CR: proceed after 30 days to another 28-day course of arsenic trioxide

References

  1. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma J, Zhang P, Zhang TD, Chen SJ, Chen Z, Wang ZY. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997 May 1;89(9):3354-60. link to original article PubMed
  2. Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, Corso D, DeBlasio A, Gabrilove J, Scheinberg DA, Pandolfi PP, Warrell RP Jr. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998 Nov 5;339(19):1341-8. link to original article contains dosing details in abstract PubMed
  3. PLRXAS01: Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers EL, Coutré S, Dahlberg S, Ellison R, Warrell RP Jr. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001 Sep 15;19(18):3852-60. link to original article contains dosing details in manuscript PubMed

Arsenic trioxide & Idarubicin

Regimen

Study Evidence
Yanada et al. 2013 (JALSG APL205R) Phase 2

Targeted therapy

  • Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 2 hours once per day, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days

Chemotherapy

  • Idarubicin (Idamycin) 12 mg/m2 IV over 30 minutes once per day on days 1 & 2 (Idarubicin was added under special conditions; see text for details)

CNS therapy

One course of up to 60 days

Subsequent treatment

References

  1. JALSG APL205R: Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. link to original article contains dosing details in manuscript PubMed UMIN C000000302

Tamibarotene monotherapy

Regimen

Study Evidence
Sanford et al. 2015 (STAR-1) Phase 2, <20 pts

Targeted therapy

Up to 56-day course

Subsequent treatment

  • Patients achieving CR: Tamibarotene consolidation, if not proceeding to transplant

References

  1. STAR-1: Sanford D, Lo-Coco F, Sanz MA, Di Bona E, Coutre S, Altman JK, Wetzler M, Allen SL, Ravandi F, Kantarjian H, Cortes JE. Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all-trans retinoic acid and arsenic trioxide. Br J Haematol. 2015 Nov;171(4):471-7. Epub 2015 Jul 24. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00520208

Consolidation after salvage therapy

Arsenic trioxide monotherapy

Regimen

Study Evidence
Yanada et al. 2013 (JALSG APL205R) Phase 2

Note: intrathecal therapy is given at the conclusion of each cycle (3 doses total, including re-induction)

Preceding treatment

Targeted therapy

CNS therapy

  • Cytarabine (Ara-C) 40 mg IT once at the conclusion of each cycle, admixed with MTX & steroids
  • Methotrexate (MTX) 15 mg IT once at the conclusion of each cycle, admixed with Ara-C & steroids
  • ONE of the following corticosteroids:

2 cycles

Subsequent treatment

References

  1. JALSG APL205R: Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. link to original article contains dosing details in manuscript PubMed UMIN C000000302

Busulfan & Melphalan, then auto HSCT

Regimen

Study Evidence
Yanada et al. 2013 (JALSG APL205R) Phase 2

Preceding treatment

Chemotherapy

Supportive therapy

One course

Chemotherapy

References

  1. JALSG APL205R: Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. link to original article contains dosing details in manuscript PubMed UMIN C000000302
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