Difference between revisions of "Acute promyelocytic leukemia"

From HemOnc.org - A Hematology Oncology Wiki
Jump to navigation Jump to search
m (Text replacement - "http://www.esmo.org/" to "https://www.esmo.org/")
(406 intermediate revisions by 6 users not shown)
Line 1: Line 1:
−
'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
+
<span id="BackToTop"></span>
−
 
+
<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
−
Is there a regimen missing from this list?  Would you like to share a different dosage/schedule or an additional reference for a regimen?  Have you noticed an error?  Do you have an idea that will help the site grow to better meet your needs and the needs of many others?  You are [[How_to_contribute|invited to contribute to the site]].
+
[[#top|Back to Top]]
−
 
+
</div>
 +
{{#lst:Editorial board transclusions|aml}}
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
|-
 
|-
−
|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
+
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
−
<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} 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=
 +
'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
 +
==ELN==
 +
*'''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] [https://pubmed.ncbi.nlm.nih.gov/30803991/ PubMed]
 +
 +
*'''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] [https://pubmed.ncbi.nlm.nih.gov/18812465/ PubMed]
 +
 +
==[https://www.esmo.org/ ESMO]==
 +
*'''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]
 +
==NCCN==
 +
*''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411 NCCN Guidelines - Acute Myeloid Leukemia].''
  
−
=Induction therapy=
+
=Upfront induction therapy=
−
==APL 2000 (EAPLG) induction {{#subobject:eb9e6e|Regimen=1}}==
+
==ADE & ATRA {{#subobject:e221d7|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
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">
 +
===Regimen {{#subobject:386fd2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
 +
|2002-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ATRA_.26_Idarubicin|"Spanish therapy"]]
 +
| style="background-color:#ffffbf" |Did not meet co-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.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[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>)
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 +
====Targeted therapy====
 +
*[[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
 +
'''One course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*UK MRC AML15: [[#ADE_.26_ATRA_888|ADE 8-3-5 + ATRA]] consolidation
 +
</div></div>
 +
===References===
 +
# '''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] [https://clinicaltrials.gov/study/NCT00002658 NCT00002658]
 +
## '''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]
 +
# '''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">
 +
===Regimen variant #1, 0.15 mg/kg (pediatric dosing) {{#subobject:359bzc|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates 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
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:c7080e|Variant=1}}===
+
''Note: the maximum duration was decreased from 75 to 60 days after 2001.''
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<span
+
====Targeted therapy====
−
style="background:#00CD00;
+
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 to 3 hours once per day
−
padding:3px 6px 3px 6px;
+
'''Continued until CR or up to 60 days'''
−
border-color:black;
+
</div>
−
border-width:2px;
+
<div class="toccolours" style="background-color:#cbd5e7">
−
border-style:solid;">Phase III</span>
+
====Subsequent treatment====
−
 
+
*Mathews et al. 2006, patients in CR: [[#Arsenic_trioxide_monotherapy_2|Arsenic trioxide]] consolidation
−
====Induction for young and high-risk patients====
+
</div></div><br>
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
+
<div class="toccolours" style="background-color:#eeeeee">
−
*[[Daunorubicin (Cerubidine)]] 60 mg/m2 IV on days 3 to 5
+
===Regimen variant #2, 0.16 mg/kg {{#subobject:31ae8c|Variant=1}}===
−
*[[Cytarabine (Cytosar)]] 200 mg/m2 IV on days 3 to 9
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 20%"|Study
−
'''9-day course of initial induction chemotherapy, with ongoing use of ATRA'''
+
!style="width: 20%"|Dates of enrollment
−
 
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
====Induction for older low-risk patients====
+
!style="width: 20%"|Comparator
−
''If >60 years old and WBC <10 x 10^9/L:''
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
+
|-
−
*[[Daunorubicin (Cerubidine)]] 60 mg/m2 IV on days 3 to 5
+
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC397380/ Shen et al. 2004]
−
 
+
|rowspan=2|2001-2003
−
'''9-day course of initial induction chemotherapy, with ongoing use of ATRA'''
+
| rowspan="2" style="background-color:#1a9851" |Randomized (C)
−
 
+
|1. [[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]]
−
''Treatment followed by [[#APL_2000_.28EAPLG.29_consolidation|APL 2000 (EAPLG) consolidation]] therapy.''
+
| style="background-color:#fc8d59" |Seems to have inferior DFS
 +
|-
 +
|2. [[#ATRA_monotherapy|ATRA]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 0.16 mg/kg IV once per day
 +
'''Continued until CR'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Shen et al. 2004, patients in CR: Consolidation, see text for details
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 10 mg (flat dose) {{#subobject:35af8c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates 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
 +
|-
 +
|}
 +
''Note: the maximum duration was decreased from 75 to 60 days after 2001.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 10 mg IV over 2 to 3 hours once per day
 +
'''Continued until CR or up to 60 days'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Mathews et al. 2006, patients in CR: [[#Arsenic_trioxide_monotherapy_2|Arsenic trioxide]] 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]
 +
# 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:''' 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]
 +
==Arsenic trioxide & ATRA {{#subobject:2b304d|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 0.15/45 {{#subobject:a85b5f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/107/9/3469.long Estey et al. 2005]
 +
|2002-2005
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ Ravandi et al. 2008]
 +
|2002-2007
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| 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> (secondary endpoint)<br>(HR 0.15, 95% CI 0.03-0.67)<br><br>Non-inferior EFS24 (primary endpoint)
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for GIMEMA/DSIL APL0406 is based on the 2019 update.''<br>
 +
''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.''
 +
<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.
 +
*[[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).
 +
====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 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
 +
*[[Hydroxyurea (Hydrea)]] by the following laboratory-based criteria:
 +
**WBC count more 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
 +
**WBC count more 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 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, 0.16/25 {{#subobject:9c8a05|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/PMC397380/ Shen et al. 2004]
 +
|2001-2003
 +
| style="background-color:#1a9851" |Randomized (E-esc)
 +
|1. [[#Arsenic_trioxide_monotherapy|Arsenic trioxide]]<br>2. [[#ATRA_monotherapy|ATRA]]
 +
| 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====
 +
*Shen et al. 2004, CR: [[Regimen_classes#Chemotherapy-based_regimen|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%"|Dates 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<sub>APL</sub>)]
 +
|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: While this is technically part of the larger UK NCRI AML17 trial, patients with APL were treated by a different pathway and there was a different primary endpoint; therefore we denote this as UK NCRI AML17<sub>APL</sub>. 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 once per day on days 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 42, 45, 49, 52 (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
 +
'''One course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation
 +
</div></div>
  
 
===References===
 
===References===
−
# 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; European Acute Promyelocytic Leukemia Group. 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. [http://jco.ascopubs.org/content/24/36/5703.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17116939 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]
−
# 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://bloodjournal.hematologylibrary.org/content/111/3/1078.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17975017 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]
−
==APML4 induction  {{#subobject:e30b39|Regimen=1}}==
+
# 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]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
## '''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. Epub 2016 Dec 21. [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] [https://clinicaltrials.gov/study/NCT00482833 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<sub>APL</sub>:''' 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%"|Dates 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<sub>APL</sub>)]
 +
|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
 +
|-
 +
|}
 +
''Note: While this is technically part of the larger UK NCRI AML17 trial, patients with APL were treated by a different pathway and there was a different primary endpoint; therefore we denote this as UK NCRI AML17<sub>APL</sub>.''
 +
<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 once per day on days 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 42, 45, 49, 52 (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 laboratory-based criteria:
 +
**WBC count more than 10 x 10<sup>9</sup>/L: 6 mg/m<sup>2</sup> IV once on day 1
 +
'''One course'''
 +
</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%"|Dates 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/PMC4881307/ Ravandi et al. 2008]
 +
|2002-2007
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
 +
''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 laboratory-based criteria:
 +
**WBC count more 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
 +
</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]
 +
## '''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. Epub 2016 Dec 21. [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. Epub 2016 Dec 21. [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<sub>APL</sub>:''' 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}}===
 
===Regimen {{#subobject:50c777|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
|'''Study'''
+
!style="width: 33%"|Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://bloodjournal.hematologylibrary.org/content/120/8/1570.long Iland et al. 2012 (APML4)]
+
|[https://doi.org/10.1182/blood-2012-02-410746 Iland et al. 2012 (ALLG APML4)]
−
|<span
+
|2004-2009
−
style="background:#EEEE00;
+
| style="background-color:#91cf61" |Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once per day on days 2, 4, 6, 8
+
====Targeted therapy====
−
**Patients 61 to 70 years old received: [[Idarubicin (Idamycin)]] 9 mg/m2 IV once per day on days 2, 4, 6, 8
 
−
**Patients >70 years old received: [[Idarubicin (Idamycin)]] 6 mg/m2 IV once per day on days 2, 4, 6, 8
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 36
 
 
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day on days 9 to 36
 
*[[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
−
Supportive medications:
+
====Chemotherapy====
−
*[[Prednisone (Sterapred)]] 1 mg/kg PO once per day on days 1 to 10, or until WBC falls below 1 x 10<sup>9</sup>/L (1,000/uL), or until resolution of differentiation syndrome (whichever occurs last)
+
*[[Idarubicin (Idamycin)]] by the following age-based criteria:
−
*Hemostatic support : Values checked and products transfused once or twice per day to keep platelet count > 30 x 10<sup>9</sup>/L (30,000/uL), fibrinogen >1.5 g/L (150 mg/dL), normal PT and PTT
+
**61 years old or younger: 12 mg/m<sup>2</sup> IV once per day on days 2, 4, 6, 8
−
*Electrolyte support while on [[Arsenic trioxide (Trisenox)]]: supplemental potassium and magnesium given to keep levels in the upper half of their normal ranges
+
**61 to 70 years old: 9 mg/m<sup>2</sup> IV once per day on days 2, 4, 6, 8
−
 
+
**Older than 70 years old: 6 mg/m<sup>2</sup> 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 10<sup>9</sup>/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 10<sup>9</sup>/L, fibrinogen greater than 1.5 g/L (150 mg/dL), normal PT and PTT
 +
*Electrolyte support while on arsenic trioxide: supplemental potassium and magnesium given to keep levels in the upper half of their normal ranges
 
'''36-day course'''
 
'''36-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
  
−
''Treatment followed in 3 to 4 weeks by [[#APML4_consolidation|APML4 consolidation]] therapy.''
+
====Subsequent treatment====
−
 
+
*[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation, in 3 to 4 weeks
 +
</div></div>
 
===References===
 
===References===
−
# 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. [http://bloodjournal.hematologylibrary.org/content/120/8/1570.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22715121 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
−
 
+
==ATRA monotherapy {{#subobject:45c33c|Regimen=1}}==
−
==North American Leukemia Intergroup Study C9710 induction {{#subobject:dade93|Regimen=1}}==
+
<div class="toccolours" style="background-color:#ee6b6e">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen {{#subobject:430573|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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, fewer than 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)]
 +
|1991-03-01 to 1992-12-01
 +
| 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
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:8ee9d6|Variant=1}}===
+
''Note: 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)''
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<span
+
====Targeted therapy====
−
style="background:#00CD00;
+
*[[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
−
padding:3px 6px 3px 6px;
+
'''One course'''
−
border-color:black;
+
</div>
−
border-width:2px;
+
<div class="toccolours" style="background-color:#cbd5e7">
−
border-style:solid;">Phase III</span>
+
====Subsequent treatment====
−
 
+
*EAPLG APL 91: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
+
*ECOG E2491: ATRA consolidation, then [[#Cytarabine_.26_Daunorubicin|cytarabine & daunorubicin]] consolidation
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m2 IV on days 3 to 6
+
</div></div>
−
*[[Cytarabine (Cytosar)]] 200 mg/m2/day IV continuous infusion on days 3 to 9
 
−
 
 
−
'''9-day initial induction chemotherapy, with ongoing use of ATRA'''
 
−
 
 
−
''Treatment followed by [[#North_American_Leukemia_Intergroup_Study_C9710_consolidation|North American Leukemia Intergroup Study C9710 consolidation]] therapy.''
 
  
 
===References===
 
===References===
−
# 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://bloodjournal.hematologylibrary.org/content/116/19/3751.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20705755 PubMed]
+
# 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. [https://doi.org/10.1182/blood-2002-02-0632 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12393590/ PubMed]
  
−
==AIDA 0493 & AIDA 2000 induction {{#subobject:772861|Regimen=1}}==
+
==ATRA, Cytarabine, Daunorubicin {{#subobject:dade93|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 45/1400/180 {{#subobject:c7080e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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 (C)
 +
|[[#ATRA_.26_Daunorubicin|ATRA & Daunorubicin]]
 +
| style="background-color:#1a9850" |Superior OS (secondary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AIDA: '''<u>A</u>'''TRA, '''<u>IDA</u>'''rubicin
+
''Note: 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 more than 10 x 10<sup>9</sup>/L) patients received this regimen in a non-randomized fashion, along with intrathecal therapy during consolidation.''
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen, Avvisati et al. 1996; Lo-Coco et al. 2010 (AIDA 2000); Latagliata et al. 2011 (AIDA 0493); Avvisati et al. 2011 (AIDA 0493); Lo-Coco et al. 2013 {{#subobject:71cfae|Variant=1}}===
+
====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
−
<span
+
====Chemotherapy====
−
style="background:#00CD00;
+
*[[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>)
−
padding:3px 6px 3px 6px;
+
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 3 to 5
−
border-color:black;
+
'''Up to 90-day course'''
−
border-width:2px;
+
</div>
−
border-style:solid;">Phase III</span>
+
<div class="toccolours" style="background-color:#cbd5e7">
−
 
+
====Subsequent treatment====
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
+
*[[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation
−
**For patients <20 years old, [[All-trans retinoic acid (ATRA)]] dose was 25 mg/m2/day, divided into two equal doses PO BID
+
</div></div><br>
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on days 2, 4, 6, 8
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen variant #2, 45/1400/200 {{#subobject:8ee9d6|Variant=1}}===
−
'''8-day initial induction chemotherapy, with ongoing use of ATRA'''
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
 
+
!style="width: 33%"|Study
−
''Treatment followed by [[#AIDA_0493_consolidation|AIDA 0493 consolidation]] or [[#AIDA_2000_consolidation|AIDA 2000 consolidation]] therapy.''
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ Powell et al. 2010 (C9710)]
 +
|1999-2005
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
|-
 +
|}
 +
<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====
 +
*[[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)]] 50 mg/m<sup>2</sup> IV once per day on days 3 to 6
 +
'''Up to 90-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Arsenic_trioxide-ATRA_.26_Daunorubicin|Arsenic trioxide-ATRA & Ddaunorubicin]] versus [[#ATRA_.26_Daunorubicin|ATRA & Daunorubicin]] consolidation
 +
</div></div>
  
 
===References===
 
===References===
−
# 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://bloodjournal.hematologylibrary.org/content/88/4/1390.long link to full article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/8695858 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] [https://clinicaltrials.gov/study/NCT00591526 NCT00591526]
−
# 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; Italian GIMEMA Cooperative Group. 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://bloodjournal.hematologylibrary.org/content/116/17/3171.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20644121 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]
−
# 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. [http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08593.x/full link to full article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21751984 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] [https://clinicaltrials.gov/study/NCT00003934 NCT00003934]
−
# 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, and EORTC Cooperative Groups. 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://bloodjournal.hematologylibrary.org/content/117/18/4716.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21385856 PubMed]
 
−
# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1300874 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23841729 PubMed]
 
  
−
==PETHEMA LPA99, LPA2005 induction {{#subobject:abb186|Regimen=1}}==
+
==ATRA, Cytarabine, Idarubicin {{#subobject:e4a23d|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:124ac5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6269295/ Adès et al. 2018 (APL 2006)]
 +
|2006-2013
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
PETHEMA: '''<u>P</u>'''rograma '''<u>E</u>'''spañol de '''<u>T</u>'''ratamientos en '''<u>HEMA</u>'''tología
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Targeted therapy====
−
===Regimen {{#subobject:de27c8|Variant=1}}===
+
*[[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
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
+
====Chemotherapy====
−
**For patients <20 years old, [[All-trans retinoic acid (ATRA)]] dose was 25 mg/m2/day, divided into two equal doses PO BID
+
*[[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>)
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV bolus on days 2, 4, 6, 8
+
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once per day on days 3 to 5
−
**For patients >70 years old, [[Idarubicin (Idamycin)]] 12 mg/m2 IV bolus on days 2, 4, 6 (day 8 dose omitted)
+
'''One course until CR'''
−
 
+
</div>
−
'''8-day initial induction chemotherapy, with ongoing use of ATRA'''
+
<div class="toccolours" style="background-color:#cbd5e7">
−
 
+
====Subsequent treatment====
−
''Treatment followed by [[#PETHEMA_LPA99_consolidation|PETHEMA LPA99]] or [[#PETHEMA_LPA2005_consolidation|PETHEMA LPA2005]] consolidation therapy.''
+
*APL 2006, patients with baseline WBC less than 10 x 10<sup>9</sup>/L: [[#Cytarabine_.26_Idarubicin|Cytarabine & Idarubicin]] versus [[#Arsenic_trioxide_.26_Idarubicin_999|Arsenic trioxide & Idarubicin]] versus [[#ATRA_.26_Idarubicin_999|ATRA & Idarubicin]] consolidation
−
 
+
*APL 2006, patients with baseline WBC greater than 10 x 10<sup>9</sup>/L: [[#Cytarabine_.26_Idarubicin|Cytarabine & Idarubicin]] versus [[#Arsenic_trioxide.2C_Cytarabine.2C_Idarubicin_999|Arsenic trioxide, Cytarabine, Idarubicin]] consolidation
 +
</div></div>
 
===References===
 
===References===
−
# 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://bloodjournal.hematologylibrary.org/content/103/4/1237.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/14576047 PubMed]
+
# '''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] [https://clinicaltrials.gov/study/NCT00378365 NCT00378365]
−
# 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 and HOVON Groups. 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://bloodjournal.hematologylibrary.org/content/115/25/5137.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20393132 PubMed]
+
==ATRA & Daunorubicin {{#subobject:6c0f66|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
==Arsenic trioxide (Trisenox) {{#subobject:bdedf2|Regimen=1}}==
+
===Regimen {{#subobject:aa790b|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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 (secondary endpoint)<br><br>Seems to have inferior CIR24 (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:31ae8c|Variant=1}}===
+
''Note: 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.''
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<span
+
====Targeted therapy====
−
style="background:#00CD00;
+
*[[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
−
padding:3px 6px 3px 6px;
+
====Chemotherapy====
−
border-color:black;
+
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 3 to 5
−
border-width:2px;
+
'''Up to 90-day course'''
−
border-style:solid;">Phase III</span>
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e7">
−
*[[Arsenic trioxide (Trisenox)]] 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day  
+
====Subsequent treatment====
−
 
+
*[[#Daunorubicin_monotherapy|Daunorubicin]] consolidation
−
'''Given until complete remission (CR) or maximum of 75 days (maximum of 60 days after 2001)'''
+
</div></div>
−
 
 
−
''If in CR, wait 4 weeks, then:''
 
−
*[[Arsenic trioxide (Trisenox)]] 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day x 28 days
 
−
 
 
−
'''28-day course'''
 
−
 
 
−
''If in CR, wait 4 weeks, then:''
 
−
*[[Arsenic trioxide (Trisenox)]] 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day x "10 days a month"
 
−
 
 
−
'''1-month cycles x 6 months'''
 
−
 
 
 
===References===
 
===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 verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15044693 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] [https://clinicaltrials.gov/study/NCT00591526 NCT00591526]
−
# 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. [http://bloodjournal.hematologylibrary.org/content/107/7/2627.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16352810 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]
−
# 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. [http://jco.ascopubs.org/content/28/24/3866.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/20644086 PubMed]
 
  
−
==ATRA & Arsenic {{#subobject:2b304d|Regimen=1}}==
+
==ATRA & Idarubicin {{#subobject:772861|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
AIDA: '''<u>A</u>'''TRA, '''<u>IDA</u>'''rubicin
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:71cfae|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates 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]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[http://www.bloodjournal.org/content/88/4/1390.long Avvisati et al. 1996 (GIMEMA AIDA)]
−
|}
+
|1993
−
===Regimen #1 {{#subobject:a85b5f|Variant=1}}===
+
| style="background-color:#91cf61" |Pilot
−
{| border="1" style="text-align:center;" !align="left"  
+
| style="background-color:#d3d3d3" |
−
|'''Study'''
+
| style="background-color:#d3d3d3" |
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
| style="background-color:#d3d3d3" |
−
|'''Comparator'''
+
|-
 +
|[http://www.bloodjournal.org/content/90/3/1014.long Mandelli et al. 1997 (GIMEMA AIDA 0493)]
 +
|1993-1996
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA96)]
 +
|1996-1999
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1111/j.1365-2141.2011.08593.x Latagliata et al. 2011 (GIMEMA AIDA 0493 amended protocol)]
 +
|1997-2004
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1300874 Lo-Coco et al. 2013]
+
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA99)]
−
|<span
+
|1999-2002
−
style="background:#00CD00;
+
| style="background-color:#91cf61" |Non-randomized
−
padding:3px 6px 3px 6px;
+
| style="background-color:#d3d3d3" |
−
border-color:black;
+
| style="background-color:#d3d3d3" |
−
border-width:2px;
+
| style="background-color:#d3d3d3" |
−
border-style:solid;">Phase III</span>
 
−
|[[Acute_promyelocytic_leukemia#AIDA_0493_.26_AIDA_2000_induction|AIDA-2000 induction]]
 
 
|-
 
|-
−
|}
+
|[http://www.bloodjournal.org/content/116/17/3171.long Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
−
 
+
|2000-2006
−
''Patients with low or intermediate-risk APL (white blood cell count at presentation ≤10 x 10<sup>9</sup>/L) were eligible.''
+
| style="background-color:#91cf61" |Non-randomized
−
 
+
| style="background-color:#d3d3d3" |
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days.
+
| style="background-color:#d3d3d3" |
−
*[[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.
+
| style="background-color:#d3d3d3" |
−
 
 
−
Supportive medications:
 
−
*[[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 >30 x 10<sup>9</sup>/L (30,000/uL) for the first 10 days of induction and >20 x 10<sup>9</sup>/L (20,000/uL) for the remainder of induction
 
−
*Patients with WBC >10 x 10<sup>9</sup>/L (10,000/uL) and < 50 x 10<sup>9</sup>/L (50,000/uL) after the start of therapy received: [[Hydroxyurea (Hydrea)]] 500 mg PO four times per day, given until WBC is <10 x 10<sup>9</sup>/L (10,000/uL)
 
−
**Patients with WBC >50 x 10<sup>9</sup>/L (50,000/uL) after the start of therapy received: [[Hydroxyurea (Hydrea)]] 1000 mg PO four times per day, given until WBC is <10 x 10<sup>9</sup>/L (10,000/uL)
 
−
 
 
−
'''One course, to remission'''
 
−
 
 
−
''Treatment followed by [[#ATRA_.26_Arsenic_-_consolidation|ATRA & Arsenic consolidation therapy]].''
 
−
 
 
−
===Regimen #2 {{#subobject:32a130|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
 
|-
 
|-
−
|[http://bloodjournal.hematologylibrary.org/content/107/9/3469.long Estey et al. 2006]
+
|[http://www.bloodjournal.org/content/115/25/5137.long Sanz et al. 2010 (PETHEMA LPA2005)]
−
|<span
+
|2005-2009
−
style="background:#EEEE00;
+
| style="background-color:#91cf61" |Non-randomized
−
padding:3px 6px 3px 6px;
+
| style="background-color:#d3d3d3" |
−
border-color:black;
+
| style="background-color:#d3d3d3" |
−
border-width:2px;
+
| style="background-color:#d3d3d3" |
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
−
!colspan="4" align="center"|
+
|[https://doi.org/10.1056/NEJMoa1300874 Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)]
 +
|2007-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 +
|
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/27/4/504.long Ravandi et al. 2009]
+
|[https://doi.org/10.1016/S1470-2045(15)00193-X Burnett et al. 2015 (UK NCRI AML17<sub>APL</sub>)]
−
|<span
+
|2009-2013
−
style="background:#EEEE00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]]
−
border-color:black;
+
|
−
border-width:2px;
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
 +
''<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. While this is technically part of the larger UK NCRI AML17 trial, patients with APL were treated by a different pathway and there was a different primary endpoint; therefore we denote this as UK NCRI AML17<sub>APL</sub>.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] by the following age-based criteria:
 +
**21 years old or older: 22.5 mg/m<sup>2</sup> PO twice per day from day 1 until remission or maximum of 90 days
 +
**Younger than 20 years old: 12.5 mg/m<sup>2</sup> PO twice per day from day 1 until remission or maximum of 90 days
 +
====Chemotherapy====
 +
*[[Idarubicin (Idamycin)]] by the following age-based criteria:
 +
**70 years old or younger: 12 mg/m<sup>2</sup> IV bolus once per day on days 2, 4, 6, 8
 +
**Older than 70 years old: 12 mg/m<sup>2</sup> IV bolus once per day on days 2, 4, 6
 +
'''Up to 90-day course'''
 +
</div>
 +
<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 & 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
 +
*PETHEMA LPA99, low-risk patients: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin|Idarubicin, then mitoxantrone, then idarubicin]] consolidation
 +
*PETHEMA LPA99, intermediate-risk and high-risk patients: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin.2C_with_ATRA|Idarubicin, then mitoxantrone, then idarubicin, with ATRA]] consolidation
 +
*PETHEMA LPA2005, high-risk 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
 +
*PETHEMA LPA2005, intermediate-risk and low-risk patients: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin.2C_with_ATRA|Idarubicin, then mitoxantrone, then idarubicin, with ATRA]] consolidation
 +
*GIMEMA AIDA-2000, high-risk 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
 +
*GIMEMA AIDA-2000, intermediate-risk and low-risk 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<sub>APL</sub>: [[#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] [https://clinicaltrials.gov/study/NCT00465933 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] [https://clinicaltrials.gov/study/NCT00408278 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] [https://clinicaltrials.gov/study/NCT01064570 NCT01064570]
 +
# '''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] [https://clinicaltrials.gov/study/NCT00482833 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<sub>APL</sub>:''' 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]
  
−
''The original protocol was modified between Estey et al. 2006 and Ravandi et al. 2009.  Estey et al. 2006 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. 2009 so arsenic trioxide was started on day 1, and gemtuzumab ozogamicin was given if WBC count went >30 x 10<sup>9</sup>/L for any patient in the first four weeks of therapy.''
+
=Consolidation after upfront therapy=
−
 
+
==Arsenic trioxide monotherapy {{#subobject:f1814c|Regimen=1}}==
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting on day 1 and continuing until remission or maximum of 90 days.
+
<div class="toccolours" style="background-color:#eeeeee">
−
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 1 hour once per day, starting on day 11 and continuing until remission (as described in Estey et al. 2006)
+
===Regimen {{#subobject:7befb3|Variant=1}}===
−
**Patients in Ravandi et al. 2009 received [[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 1 hour once per day, starting on day 1 and continuing until remission
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
*Patients with high-risk disease (initial WBC =10 x 10<sup>9</sup>/L) received: [[Gemtuzumab ozogamicin (Mylotarg)]] 9 mg/m2 IV once on day 1
+
!style="width: 33%"|Study
−
**Patients who initially were not high-risk but subsequently developed WBC =10 x 10<sup>9</sup>/L during the first four weeks of therapy received: [[Gemtuzumab ozogamicin (Mylotarg)]] 9 mg/m2 IV once
+
!style="width: 33%"|Dates of enrollment
−
 
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
Supportive medications:
 
−
*"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
 
−
*[[Heparin]] or [[Tranexamic acid (Cyklokapron)]] used if clinically indicated
 
−
*Patients in Estey et al. 2006 received: "Oral solumedrol" 20 mg PO once per day x 10 days to decrease risk of differentiation syndrome
 
−
*Patients in Ravandi et al. 2009 recieved: [[Methylprednisolone (Solumedrol)|Methylprednisolone]] 50 mg PO once per day x 5 days to decrease risk of differentiation syndrome
 
−
 
 
−
''Treatment followed by [[#ATRA_.26_Arsenic_-_consolidation|ATRA & Arsenic consolidation therapy]].''
 
−
 
 
−
===Regimen #3 {{#subobject:9c8a05|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
 
|-
 
|-
−
|[http://www.pnas.org/content/101/15/5328.long Shen et al. 2004]
+
|[https://doi.org/10.1182/blood-2005-08-3532 Mathews et al. 2006]
−
|<span
+
|1998-2004
−
style="background:#EEEE00;
+
| style="background-color:#91cf61" |Non-randomized
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
''All patients achieving CR went on to receive chemotherapy-based consolidation and maintenance. These details are available in the original paper but are omitted here.''
+
====Preceding treatment====
−
 
+
*[[#Arsenic_trioxide_monotherapy|Arsenic trioxide]] induction
−
*[[All-trans retinoic acid (ATRA)]] 25 mg/m2/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
+
</div>
−
*[[Arsenic trioxide (Trisenox)]] 0.16 mg/kg IV once per day, starting day 1 and continuing until remission
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] by the following age-based criteria:
 +
**Adult patients: 10 mg IV over 2 to 3 hours once per day
 +
**Pediatric patients: 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====
 +
*Mathews et al. 2006, patients remaining in CR: [[#Arsenic_trioxide_monotherapy_3|Arsenic trioxide]] maintenance
 +
</div></div>
 
===References===
 
===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 verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15044693 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]
−
# 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://bloodjournal.hematologylibrary.org/content/107/9/3469.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16373661 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]
−
# 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. [http://jco.ascopubs.org/content/27/4/504.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19075265 PubMed]
 
−
# 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 verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19225113 PubMed] content property of [http://hemonc.org HemOnc.org]
 
−
# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1300874 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1300874/suppl_file/nejmoa1300874_protocol.pdf link to supplementary appendix] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1300874/suppl_file/nejmoa1300874_protocol.pdf link to protocol] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23841729 PubMed]
 
  
−
=Consolidation therapy=
+
==Arsenic trioxide-ATRA & Daunorubicin {{#subobject:e333b6|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
==APL 2000 (EAPLG) consolidation {{#subobject:f3ec97|Regimen=1}}==
+
===Regimen {{#subobject:24bfd3|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/PMC2981533/ Powell et al. 2010 (C9710)]
 +
|1999-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#ATRA_.26_Daunorubicin_2|ATRA & Daunorubicin]]
 +
| style="background-color:#1a9850" |Superior EFS (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Consolidation therapy starts within 2 to 4 weeks of hematologic remission.''
−
===Regimen {{#subobject:198c4e|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
<span
+
*[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin]] induction
−
style="background:#00CD00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
border-color:black;
+
====Targeted therapy====
−
border-width:2px;
+
*[[Arsenic trioxide (Trisenox)]] as follows:
−
border-style:solid;">Phase III</span>
+
**Cycle 1: 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
−
 
+
*[[All-trans retinoic acid (ATRA)]] as follows:
−
''Treatment preceded by [[#APL_2000_.28EAPLG.29_induction|APL 2000 (EAPLG) induction]] therapy.''
+
**Cycles 2 & 3: 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 7
−
 
+
====Chemotherapy====
−
===Consolidation regimen for patients ≤60 years old and WBC <10 x 10^9/L or age >60 and WBC >10 x 10^9/L===
+
*[[Daunorubicin (Cerubidine)]] as follows:
−
*[[Daunorubicin (Cerubidine)]] 60 mg/m2 IV once per day on days 1 to 3
+
**Cycles 2 & 3: 50 mg/m<sup>2</sup> IV once per day on days 1 to 3
−
*[[Cytarabine (Cytosar)]] 200 mg/m2/day IV continuous infusion on days 1 to 7
+
'''7-week course, then 39-day cycle for 2 cycles'''
−
 
+
</div>
−
Followed by:
+
<div class="toccolours" style="background-color:#cbd5e7">
−
*[[Daunorubicin (Cerubidine)]] 45 mg/m2 IV once per day on days 1 to 3
+
====Subsequent treatment====
−
*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV every 12 hours on days 1 to 4 (8 total doses)
+
*[[#ATRA_monotherapy_2|ATRA]] maintenance versus [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
−
 
+
</div></div>
−
'''Note: Adès et al. 2006 and Adès et al. 2008 both do not say that IT chemotherapy is used for patients with age >60 and WBC >10 x 10^9/L, but figure 1 in Adès et al. 2006 depicts IT chemotherapy in this patient group.  I did not see a reference that clearly resolved this contradiction.'''
 
−
 
 
−
===Consolidation regimen for patients ≤60 years old and WBC >10 x 10^9/L===
 
−
*[[Daunorubicin (Cerubidine)]] 60 mg/m2 IV once per day on days 1 to 3
 
−
*[[Cytarabine (Cytosar)]] 200 mg/m2/day IV continuous infusion on days 1 to 7
 
−
*3 doses of intrathecal chemotherapy with [[Methotrexate (MTX)]] 15 mg IT, [[Cytarabine (Cytosar)]] 50 mg IT, and corticosteroids
 
−
 
 
−
Followed by:
 
−
*[[Daunorubicin (Cerubidine)]] 45 mg/m2 IV on days 1 to 3
 
−
*[[Cytarabine (Cytosar)]] as follows:
 
−
**If age <50 years old: 2000 mg/m2 IV every 12 hours on days 1 to 5 (10 total doses)
 
−
**If age 50-60 years old: 1500 mg/m2 IV every 12 hours on days 1 to 5 (10 total doses)
 
−
*2 doses of intrathecal chemotherapy with [[Methotrexate (MTX)]] 15 mg IT, [[Cytarabine (Cytosar)]] 50 mg IT, and corticosteroids
 
−
 
 
−
===Consolidation regimen for patients >60 years old and WBC <10 x 10^9/L===
 
−
*[[Daunorubicin (Cerubidine)]] 60 mg/m2 IV once per day on days 1 to 3
 
−
 
 
−
Followed by:
 
−
*[[Daunorubicin (Cerubidine)]] 45 mg/m2 IV once per day on days 1 to 3
 
−
 
 
−
''Treatment followed by [[#APL_2000_.28EAPLG.29_maintenance|APL 2000 (EAPLG) maintenance]] therapy.''
 
−
 
 
 
===References===
 
===References===
−
# 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; European Acute Promyelocytic Leukemia Group. 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. [http://jco.ascopubs.org/content/24/36/5703.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17116939 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] [https://clinicaltrials.gov/study/NCT00003934 NCT00003934]
−
# 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://bloodjournal.hematologylibrary.org/content/111/3/1078.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17975017 PubMed]
 
  
−
==APML4 consolidation {{#subobject:7ce78a|Regimen=1}}==
+
==Arsenic trioxide & ATRA {{#subobject:7ce78a|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<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%"|Dates 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 part of phase 3 RCT
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
 +
''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-day cycle for 7 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
===Regimen {{#subobject:575577|Variant=1}}===
+
===Regimen variant #2 {{#subobject:575577|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
|'''Study'''
+
!style="width: 33%"|Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://bloodjournal.hematologylibrary.org/content/120/8/1570.long Iland et al. 2012 (APML4)]
+
|[https://doi.org/10.1182/blood-2012-02-410746 Iland et al. 2012 (ALLG APML4)]
−
|<span
+
|2004-2009
−
style="background:#EEEE00;
+
| style="background-color:#91cf61" |Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
 +
''Consolidation starts 3 to 4 weeks after completion of induction.''
 +
<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">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] as follows:
 +
**Cycle 1: 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 28
 +
**Cycle 2: 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)]] as follows:
 +
**Cycle 1: 0.15 mg/kg IV once per day on days 1 to 28
 +
**Cycle 2: 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- to 8-week course, then 5-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance, after 3 to 4 weeks
 +
</div></div>
  
−
''Treatment preceded by [[#APML4_induction|APML4 induction]] therapy.''
 
−
 
−
====Consolidation cycle 1====
 
−
''Given 3 to 4 weeks after completion of induction.''
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 28
 
−
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV once per day on days 1 to 28
 
−
 
−
'''4-week course'''; after 3 to 4 weeks, proceed to consolidation cycle 2
 
−
 
−
====Consolidation cycle 2====
 
−
''Given 3 to 4 weeks after completion of consolidation cycle 1.''
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID 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'''; after 3 to 4 weeks, proceed to [[#APML4_maintenance|APML4 maintenance]]
 
−
 
 
===References===
 
===References===
−
# 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. [http://bloodjournal.hematologylibrary.org/content/120/8/1570.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22715121 PubMed]
+
# 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] [https://clinicaltrials.gov/study/NCT00482833 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<sub>APL</sub>:''' 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">
 +
===Regimen {{#subobject:b8d811|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/PMC2981533/ Powell et al. 2010 (C9710)]
 +
|1999-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Arsenic_trioxide-ATRA_.26_Daunorubicin|Arsenic trioxide-ATRA & Daunorubicin]]
 +
| style="background-color:#d73027" |Inferior 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====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 7
 +
====Chemotherapy====
 +
*[[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]] 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] [https://clinicaltrials.gov/study/NCT00003934 NCT00003934]
  
−
==North American Leukemia Intergroup Study C9710 consolidation {{#subobject:e333b6|Regimen=1}}==
+
==Cytarabine & Daunorubicin {{#subobject:f3ec97|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:198c4e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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 (C)
 +
|[[#Daunorubicin_monotherapy|Daunorubicin]]
 +
| style="background-color:#1a9850" |Superior OS (secondary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*Younger than 60 years old AND low-risk (WBC count less than 10 x 10<sup>9</sup>/L) OR Older than 60 years old AND high-risk (WBC count more than 10 x 10<sup>9</sup>/L)
 +
</div>
 +
<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">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] as follows:
 +
**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>)
 +
**Cycle 2: 1000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 4 (total dose: 8000 mg/m<sup>2</sup>)
 +
*[[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
 +
'''2 cycles (length not specified)'''
 +
====CNS therapy, high-risk (WBC count more than 10 x 10<sup>9</sup>/L) patients====
 +
*[[Methotrexate (MTX)]] 15 mg IT
 +
*[[Cytarabine (Ara-C)]] 50 mg IT
 +
*[[:Category:Steroids|Corticosteroids]] IT (type not specified)
 +
'''5 doses throughout consolidation'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:19hy3e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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 (C)
 +
|[[#Daunorubicin_monotherapy|Daunorubicin]]
 +
| style="background-color:#1a9850" |Superior OS (secondary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:24bfd3|Variant=1}}===
+
<div class="toccolours" style="background-color:#fdcdac">
−
 
+
====Eligibility criteria====
−
<span
+
*Younger than 60 years old AND high-risk (WBC count more than 10 x 10<sup>9</sup>/L)
−
style="background:#00CD00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#cbd5e8">
−
border-color:black;
+
====Preceding treatment====
−
border-width:2px;
+
*[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin]] induction
−
border-style:solid;">Phase III</span>
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''Treatment preceded by [[#North_American_Leukemia_Intergroup_Study_C9710_induction|North American Leukemia Intergroup Study C9710 induction]] therapy.''
+
====Chemotherapy====
−
 
+
*[[Cytarabine (Ara-C)]] as follows:
−
Consolidation therapy starts within 2 to 4 weeks of hematologic remission:
+
**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>)
−
*[[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
+
**Cycle 2: 2000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 5 (total dose: 20,000 mg/m<sup>2</sup>)
−
 
+
*[[Daunorubicin (Cerubidine)]] as follows:
−
'''7-week cycles (5 weeks of therapy, then 2 weeks off), THEN'''
+
**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
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting days 1 to 7
+
'''2 cycles (length not specified)'''
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m2 IV once per day on days 1 to 3
+
====CNS therapy, prophylaxis====
−
 
+
*[[Methotrexate (MTX)]] 15 mg IT
−
'''7-day cycles x 2 cycles'''
+
*[[Cytarabine (Ara-C)]] 50 mg IT
−
 
+
*[[:Category:Steroids|Corticosteroids]] IT (type not specified)
−
''Treatment followed by [[#North_American_Leukemia_Intergroup_Study_C9710_maintenance|North American Leukemia Intergroup Study C9710 maintenance]] therapy.''
+
'''5 doses throughout consolidation'''
−
 
+
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
# 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://bloodjournal.hematologylibrary.org/content/116/19/3751.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20705755 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] [https://clinicaltrials.gov/study/NCT00591526 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]
  
−
==AIDA 0493 consolidation {{#subobject:cb4263|Regimen=1}}==
+
==Cytarabine & Idarubicin {{#subobject:b76471|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:f5d960|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"  
 +
!style="width: 25%"|Study
 +
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1111/j.1365-2141.2011.08593.x Latagliata et al. 2011 (GIMEMA AIDA 0493 amended protocol)]
 +
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AIDA: '''<u>A</u>'''TRA, '''<u>IDA</u>'''rubicin <br>
+
''This consolidation protocol was intended for patients older than 60.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 6 hours once per day on days 1 to 4, '''given first'''
 +
*[[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'''
 +
'''4-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA_monotherapy_2|ATRA]] maintenance
 +
</div></div>
 +
===References===
 +
# '''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]
 +
==Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine {{#subobject:cb4263|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:13180d|Variant=1}}===
 
===Regimen {{#subobject:13180d|Variant=1}}===
−
 
+
{| class="wikitable" style="width: 60%; text-align:center;"
−
<span
+
!style="width: 33%"|Study
−
style="background:#00CD00;
+
!style="width: 33%"|Dates of enrollment
−
padding:3px 6px 3px 6px;
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-color:black;
+
|-
−
border-width:2px;
+
|[http://www.bloodjournal.org/content/100/9/3141.long Avvisati et al. 2002 (GIMEMA LAP 0389)]
−
border-style:solid;">Phase III</span>
+
|1989-1993
−
 
+
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
−
''Treatment preceded by [[#AIDA_0493_.26_AIDA_2000_induction|AIDA 0493 induction]] therapy.''
+
|-
−
 
+
|[http://www.bloodjournal.org/content/88/4/1390.long Avvisati et al. 1996 (GIMEMA AIDA)]
−
As detailed in Avvisati, et al., 2002:
+
|1993
−
*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once per day on days 1 to 4 (administered second, 3 hours after cytarabine infusion complete)
+
| style="background-color:#91cf61" |Pilot
−
*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV over 6 hours on days 1 to 4 (administered first)
+
|-
−
 
+
|[http://www.bloodjournal.org/content/90/3/1014.long Mandelli et al. 1997 (GIMEMA AIDA 0493)]
−
'''4-day course of therapy, THEN'''
+
|1993-1996
−
 
+
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 5 (administered first)
 
−
*[[Etoposide (Vepesid)]] 100 mg/m2 IV over 45 to 60 minutes (administered second, 12 hours after start of mitoxantrone) days 1 to 5
 
−
 
 
−
'''5-day course of therapy, THEN'''
 
−
 
 
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV day 1
 
−
*[[Cytarabine (Cytosar)]] 150 mg/m2 SC every 8 hours (450 mg/m2/day total dosage) days 1 to 5
 
−
*[[Thioguanine (Tabloid)]] 70 mg/m2 PO every 8 hours (210 mg/m2/day total dosage) days 1 to 5
 
−
 
 
−
'''5-day course of therapy'''
 
−
 
 
−
''Treatment followed by [[#AIDA_0493_maintenance|AIDA 0493 maintenance]] therapy.''
 
−
 
 
−
===References===
 
−
# 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 (Gruppo Italiano Malattie Ematologische dell'Adulto) Italian Cooperative Group. 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://bloodjournal.hematologylibrary.org/content/100/9/3141.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12384411 PubMed]
 
−
# 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. [http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08593.x/full link to full article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21751984 PubMed]
 
−
# 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, and EORTC Cooperative Groups. 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://bloodjournal.hematologylibrary.org/content/117/18/4716.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21385856 PubMed]
 
−
 
 
−
==AIDA 2000 consolidation {{#subobject:632192|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AIDA: '''<u>A</u>'''TRA, '''<u>IDA</u>'''rubicin <br>
+
''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_888|Idarubicin]] versus [[#Cytarabine_.26_Idarubicin_888|cytarabine & idarubicin]] induction (neither with ATRA; no longer standard of care)
 +
*GIMEMA AIDA & GIMEMA AIDA 0493: [[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, A portion (Course 1)====
 +
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 6 hours once per day on days 1 to 4, '''given first'''
 +
*[[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'''
 +
====Chemotherapy, B portion (Course 2)====
 +
*[[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'''
 +
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given first'''
 +
====Chemotherapy, C portion (Course 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 & GIMEMA 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
 +
'''3 courses; next course to begin "at recovery from the previous one, when polymorphonuclear cells numbered 1500/μL or more and platelets numbered 100 x 10<sup>9</sup>/L or more."'''
 +
</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>
 +
===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]
 +
# '''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">
 
===Regimen {{#subobject:6e3780|Variant=1}}===
 
===Regimen {{#subobject:6e3780|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
|'''Study'''
+
!style="width: 33%"|Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://bloodjournal.hematologylibrary.org/content/116/17/3171.long Lo-Coco et al. 2010 (AIDA-2000)]
+
|[http://www.bloodjournal.org/content/116/17/3171.long Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
−
|<span
+
|2000-2006
−
style="background:#EEEE00;
+
| style="background-color:#91cf61" |Non-randomized
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Non-randomized</span>
 
 
|-
 
|-
 
|}
 
|}
−
''Treatment preceded by [[#AIDA_0493_.26_AIDA_2000_induction|AIDA 0493 & AIDA 2000 induction]] therapy.''
+
''This is risk-adapted therapy for <u>high-risk</u> patients in GIMEMA AIDA-2000. The authors were unclear about how many days were between each part of consolidation therapy.''
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
====Low or intermediate risk====
+
====Preceding treatment====
−
''Patients with initial WBC <10 x 10<sup>9</sup>/L were considered to be low or intermediate risk.  Lo-Coco et al. 2010 was unclear about how many days--if any--were between each part of consolidation therapy.''
+
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
−
*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once per day on days 1 to 4
+
</div>
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Targeted therapy, all portions====
−
'''4-day course of therapy, THEN'''
+
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
−
 
+
====Chemotherapy, A portion (cycle 1)====
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 5
+
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
 
+
====Chemotherapy, B portion (cycle 2)====
−
'''5-day course of therapy, THEN'''
+
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
 
+
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on day 1
+
====Chemotherapy, C portion (cycle 3)====
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+
*[[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
−
To be followed by [[#AIDA_2000_maintenance|AIDA 2000 maintenance]] therapy.
+
*[[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>)
−
 
+
====CNS prophylaxis, all portions====
−
====High risk====
+
''It is not explicitly stated but presumably these are admixed and given together.''
−
''Patients with initial WBC >10 x 10<sup>9</sup>/L were considered to be high risk.''
 
−
 
 
−
"Before the initiation of each consolidation cycle," high-risk patients received intracranial prophylaxis:
 
 
*[[Methotrexate (MTX)]] 12 mg IT once prior to each consolidation cycle
 
*[[Methotrexate (MTX)]] 12 mg IT once prior to each consolidation cycle
−
*[[Mercaptopurine (Purinethol)]] 40 mg IT once prior to each consolidation cycle
+
*[[Methylprednisolone (Solumedrol)]] 40 mg IT once prior to each consolidation cycle
−
 
+
'''3 cycles (see note)'''
−
'''"total of 3 courses"'''
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e7">
−
*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once per day on days 1 to 4
+
====Subsequent treatment====
−
*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV once per day on days 1 to 4
+
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA alternating with 6-MP, MTX]] maintenance
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+
</div></div>
−
 
+
===References===
−
'''4-day course of therapy, THEN'''
+
# '''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] [https://clinicaltrials.gov/study/NCT01064570 NCT01064570]
−
 
+
==Cytarabine & Idarubicin, then Mitoxantrone, then Cytarabine & Idarubicin, with ATRA {{#subobject:ca29a4|Regimen=1}}==
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 5
+
<div class="toccolours" style="background-color:#eeeeee">
−
*[[Etoposide (Vepesid)]] 100 mg/m2 IV once per day on days 1 to 5
+
===Regimen {{#subobject:46f412|Variant=1}}===
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
 
+
!style="width: 33%"|Study
−
'''5-day course of therapy, THEN'''
+
!style="width: 33%"|Dates of enrollment
−
 
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on day 1
+
|-
−
*[[Cytarabine (Cytosar)]] 150 mg/m2 SC every 8 hours (450 mg/m2/day total dosage) on days 1 to 5
+
|[http://www.bloodjournal.org/content/115/25/5137.long Sanz et al. 2010 (PETHEMA LPA2005)]
−
*[[Thioguanine (Tabloid)]] 70 mg/m2 PO every 8 hours (210 mg/m2/day total dosage) on days 1 to 5
+
|2005-2009
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+
| style="background-color:#91cf61" |Non-randomized
−
 
+
|-
−
'''5-day course of therapy'''
+
|}
−
 
+
''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.''
−
''Treatment followed by [[#AIDA_2000_maintenance|AIDA 2000 maintenance]] therapy.''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
 +
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy, all portions====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
 +
====Chemotherapy, A portion (cycle 1)====
 +
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
 +
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 4
 +
====Chemotherapy, B portion (cycle 2)====
 +
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
 +
====Chemotherapy, C portion (cycle 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 cycle for 3 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
# 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; Italian GIMEMA Cooperative Group. 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://bloodjournal.hematologylibrary.org/content/116/17/3171.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20644121 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] [https://clinicaltrials.gov/study/NCT00408278 NCT00408278]
−
 
+
==Daunorubicin monotherapy {{#subobject:76a47b|Regimen=1}}==
−
==PETHEMA LPA99 consolidation {{#subobject:49fc49|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen {{#subobject:82b9d5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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)
 +
|[[#Cytarabine_.26_Daunorubicin|Cytarabine & Daunorubicin]]
 +
| style="background-color:#d73027" |Inferior OS (secondary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
PETHEMA: '''<u>P</u>'''rograma '''<u>E</u>'''spañol de '''<u>T</u>'''ratamientos en '''<u>HEMA</u>'''tología
+
''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.''
−
===Regimen {{#subobject:6744ce|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
''Treatment preceded by [[#PETHEMA_LPA99.2C_LPA2005_induction|PETHEMA LPA99, LPA2005 induction]] therapy.''
+
====Preceding treatment====
−
 
+
*[[#ATRA_.26_Daunorubicin|ATRA & daunorubicin]] induction
−
====High risk patients====
+
</div>
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Idarubicin (Idamycin)]] 7 mg/m2 IV once per day on days 1 to 4
+
====Chemotherapy====
−
 
+
*[[Daunorubicin (Cerubidine)]] as follows:
−
'''1-month cycle, THEN'''
+
**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
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+
</div>
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 5
+
<div class="toccolours" style="background-color:#cbd5e7">
−
 
+
====Subsequent treatment====
−
'''1-month cycle, THEN'''
+
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
−
 
+
</div></div>
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
 
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on days 1 & 2
 
−
 
 
−
'''1-month cycle'''
 
−
 
 
−
====Intermediate risk patients====
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
 
−
*[[Idarubicin (Idamycin)]] 7 mg/m2 IV once per day on days 1 to 4
 
−
 
 
−
'''1-month cycle, THEN'''
 
−
 
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
 
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 5
 
−
 
 
−
'''1-month cycle, THEN'''
 
−
 
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
 
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on days 1 & 2
 
−
 
 
−
'''1-month cycle'''
 
−
 
 
−
====Low risk patients====
 
−
*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once per day on days 1 to 4
 
−
 
 
−
'''1-month cycle, THEN'''
 
−
 
 
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 5
 
−
 
 
−
'''1-month cycle, THEN'''
 
−
 
 
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV day 1
 
−
 
 
−
'''1-month cycle'''
 
−
 
 
−
''Treatment followed by [[#PETHEMA_LPA99.2C_LPA2005_maintenance|PETHEMA LPA99, LPA2005 maintenance]] therapy.''
 
−
 
 
 
===References===
 
===References===
−
# 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://bloodjournal.hematologylibrary.org/content/103/4/1237.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/14576047 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] [https://clinicaltrials.gov/study/NCT00591526 NCT00591526]
−
# 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 and HOVON Groups. 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://bloodjournal.hematologylibrary.org/content/115/25/5137.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20393132 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]
−
 
+
==Idarubicin, then Mitoxantrone, then Idarubicin {{#subobject:6af14e|Regimen=1}}==
−
==PETHEMA LPA2005 consolidation {{#subobject:ca29a4|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen {{#subobject:11923f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA96)]
 +
|1996-1999
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA99)]
 +
|1999-2002
 +
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
PETHEMA: '''<u>P</u>'''rograma '''<u>E</u>'''spañol de '''<u>T</u>'''ratamientos en '''<u>HEMA</u>'''tología
+
''This was the <u>low-risk</u> treatment arm of '''PETHEMA LPA99'''; <u>all patients</u> on '''PETHEMA LPA96''' underwent this consolidation protocol.''
−
===Regimen {{#subobject:46f412|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
''Treatment preceded by [[#PETHEMA_LPA99.2C_LPA2005_induction|PETHEMA LPA99, LPA2005 induction]] therapy.''
+
====Preceding treatment====
−
 
+
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
−
====High risk patients====
+
</div>
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once per day on days 1 to 4
+
====Chemotherapy====
−
*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV once per day on days 1 to 4
+
*[[Idarubicin (Idamycin)]] as follows:
−
 
+
**Cycle 1: 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
'''1-month cycle, THEN'''
+
**Cycle 3: 12 mg/m<sup>2</sup> IV once on day 1
−
 
+
*[[Mitoxantrone (Novantrone)]] as follows:
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+
**Cycle 2: 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 5
+
'''1-month cycle for 3 cycles'''
−
 
+
</div>
−
'''1-month cycle, THEN'''
+
<div class="toccolours" style="background-color:#cbd5e7">
−
 
+
====Subsequent treatment====
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV day 1
+
</div></div>
−
*[[Cytarabine (Cytosar)]] 150 mg/m2, IV every 8 hours (total dose of 450 mg/m2/day), days 1 to 4 (12 total doses)
 
−
 
 
−
'''1-month cycle'''
 
−
 
 
−
====Intermediate risk patients====
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
 
−
*[[Idarubicin (Idamycin)]] 7 mg/m2 IV once per day on days 1 to 4
 
−
 
 
−
'''1-month cycle, THEN'''
 
−
 
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
 
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 3
 
−
 
 
−
'''1-month cycle, THEN'''
 
−
 
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
 
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on days 1 & 2
 
−
 
 
−
'''1-month cycle'''
 
−
 
 
−
====Low risk patients====
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
 
−
*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once per day on days 1 to 4
 
−
 
 
−
'''1-month cycle, THEN'''
 
−
 
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
 
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 3
 
−
 
 
−
'''1-month cycle, THEN'''
 
−
 
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
 
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on day 1
 
−
 
 
−
'''1-month cycle'''
 
−
 
 
−
''Treatment followed by [[#PETHEMA_LPA99.2C_LPA2005_maintenance|PETHEMA LPA99, LPA2005 maintenance]] therapy.''
 
−
 
 
 
===References===
 
===References===
−
# 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://bloodjournal.hematologylibrary.org/content/103/4/1237.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/14576047 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]
−
# 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 and HOVON Groups. 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://bloodjournal.hematologylibrary.org/content/115/25/5137.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20393132 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] [https://clinicaltrials.gov/study/NCT00465933 NCT00465933]
−
==ATRA & Arsenic - consolidation {{#subobject:6adb9e|Regimen=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. [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]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
==Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA {{#subobject:49fc49|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:8d3f07|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/116/17/3171.long Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
 +
|2000-2006
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|[http://www.bloodjournal.org/content/115/25/5137.long Sanz et al. 2010 (PETHEMA LPA2005)]
 +
|2005-2009
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1300874 Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)]
 +
|2007-2013
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
|-
 +
|}
 +
''This is risk-adapted therapy for <u>intermediate- and low-risk</u> patients in GIMEMA 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.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy, all portions (cycles 1 to 3)====
 +
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
 +
====Chemotherapy, idarubicin portion====
 +
*[[Idarubicin (Idamycin)]] as follows:
 +
**Cycle 1: 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
 +
**Cycle 3: 12 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, mitoxantrone portion (cycle 2)====
 +
*[[Mitoxantrone (Novantrone)]] by the following study-specific criteria:
 +
**GIMEMA 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 cycle for 3 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*GIMEMA 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">
 +
===Regimen variant #2 {{#subobject:6744ce|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA99)]
 +
|1999-2002
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|[http://www.bloodjournal.org/content/115/25/5137.long Sanz et al. 2010 (PETHEMA LPA2005)]
 +
|2005-2009
 +
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''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.''
−
===Regimen, Estey et al. 2006 & Lo-Coco et al. 2013 {{#subobject:a5626f|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
<span
+
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
−
style="background:#EEEE00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
border-color:black;
+
====Targeted therapy, all portions (cycles 1 to 3)====
−
border-width:2px;
+
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
−
border-style:solid;">Phase II</span>
+
====Chemotherapy, idarubicin portion====
−
 
+
*[[Idarubicin (Idamycin)]] as follows:
−
''Treatment preceded by [[#ATRA_.26_Arsenic|ATRA & Arsenic]] induction therapy.''
+
**Cycle 1: 7 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
 
+
**Cycle 3: 12 mg/m<sup>2</sup> IV once per day on days 1 & 2
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, 7 days per week on weeks 1 to 2, 5 to 6, 9 to 10, 13 to 14, 17 to 18, 21 to 22, 25 to 26
+
====Chemotherapy, mitoxantrone portion (cycle 2)====
−
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 1 to 2 hours once per day, 5 consecutive days per week, on weeks 1 to 4, 9 to 12, 17 to 20, 25 to 28
+
*[[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
−
'''28 week course of therapy'''
+
**PETHEMA LPA2005: 10 mg/m<sup>2</sup> IV once per day on days 1 to 3
−
 
+
'''1-month cycle for 3 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div>
 
===References===
 
===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://bloodjournal.hematologylibrary.org/content/107/9/3469.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16373661 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] [https://clinicaltrials.gov/study/NCT00465933 NCT00465933]
−
# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1300874 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1300874/suppl_file/nejmoa1300874_protocol.pdf link to supplementary appendix] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1300874/suppl_file/nejmoa1300874_protocol.pdf link to protocol] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23841729 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 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] [https://clinicaltrials.gov/study/NCT00408278 NCT00408278]
−
=Maintenance therapy=
+
# '''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] [https://clinicaltrials.gov/study/NCT01064570 NCT01064570]
−
 
+
# '''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] [https://clinicaltrials.gov/study/NCT00482833 NCT00482833]
−
==APL 2000 (EAPLG) maintenance {{#subobject:851018|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]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
## '''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">
 +
===Regimen {{#subobject:9f326b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates 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
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:85ef36|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
<span
+
*[[#Arsenic_trioxide_monotherapy_2|Arsenic trioxide]] consolidation
−
style="background:#00CD00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
border-color:black;
+
====Targeted therapy====
−
border-width:2px;
+
*[[Arsenic trioxide (Trisenox)]] by the following age-based criteria:
−
border-style:solid;">Phase III</span>
+
**Pediatric patients: 0.15 mg/kg IV over 2 to 3 hours once per day on days 1 to 10
−
 
+
**Adult patients: 10 mg IV over 2 to 3 hours once per day on days 1 to 10
−
''Treatment preceded by [[#APL_2000_.28EAPLG.29_consolidation|APL 2000 (EAPLG) consolidation]] therapy.''
+
'''Monthly cycle for 6 cycles'''
−
 
+
</div></div>
−
*[[Mercaptopurine (Purinethol)]] 50 to 90 mg/m2 PO once per day  
 
−
*[[Methotrexate (MTX)]] 15 mg/m2 PO once per week
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 15
 
−
 
 
−
'''90-day cycles x 2 years'''
 
−
 
 
 
===References===
 
===References===
−
# 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; European Acute Promyelocytic Leukemia Group. 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. [http://jco.ascopubs.org/content/24/36/5703.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17116939 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]
−
# 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://bloodjournal.hematologylibrary.org/content/111/3/1078.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17975017 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]
  
−
 
+
==ATRA monotherapy {{#subobject:8c70f0|Regimen=1}}==
−
==APML4 maintenance {{#subobject:d0aa2c|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen variant #1 {{#subobject:f68d7e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/PMC2981533/ Powell et al. 2010 (C9710)]
 +
|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 (secondary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.''
−
===Regimen {{#subobject:ac797|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
{| border="1" style="text-align:center;" !align="left"  
+
====Preceding treatment====
−
|'''Study'''
+
*[[#Arsenic_trioxide-ATRA_.26_Daunorubicin|Arsenic trioxide-ATRA & Daunorubicin]] versus [[#ATRA_.26_Daunorubicin|ATRA & Daunorubicin]] consolidation
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
</div>
 +
<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
 +
'''14-day cycle for 26 cycles (1 year)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:dc527a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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-switch-ooc)
 +
|1. [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]]
 +
| 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
 +
|-
 +
| 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 (E-esc)
 +
|1. [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]]
 +
| style="background-color:#d73027" |Inferior 2-year relapse rate
 
|-
 
|-
−
|[http://bloodjournal.hematologylibrary.org/content/120/8/1570.long Iland et al. 2012 (APML4)]
+
|2. [[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]]<br> 3. [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|No further treatment]]
−
|<span
+
| style="background-color:#91cf60" |Seems to have superior 2-year relapse rate
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
''Treatment preceded by [[#APML4_consolidation|APML4 consolidation]] therapy. Maintenance starts 3 to 4 weeks after completion of consolidation cycle 2.''
+
====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
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 14
+
*EAPLG APL 93: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation
−
*[[Methotrexate (MTX)]] 5 to 15 mg/m2/week PO on days 15 to 90
+
</div>
−
*[[Mercaptopurine (Purinethol)]] 50 to 90 mg/m2 PO once per day on days 15 to 90
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Methotrexate (MTX)]] and [[Mercaptopurine (Purinethol)]] doses titrated to ANC 1 to 2 x 10<sup>9</sup>/L (1,000 to 2,000/uL) and minimizing hepatotoxicity
+
====Targeted therapy====
−
 
+
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO on days 1 to 15
−
'''90-day cycle x 8 cycles'''
+
'''3-month cycle for 8 cycles (2 years)'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# 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. [http://bloodjournal.hematologylibrary.org/content/120/8/1570.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22715121 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]
−
==North American Leukemia Intergroup Study C9710 maintenance {{#subobject:8c70f0|Regimen=1}}==
+
# '''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]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
## '''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]
 +
# '''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] [https://clinicaltrials.gov/study/NCT00003934 NCT00003934]
 +
==ATRA, Mercaptopurine, Methotrexate {{#subobject:b44ab6|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 45/50/15 {{#subobject:80d40a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/103/4/1237.full Sanz et al. 2003 (PETHEMA LPA99)]
 +
|1999-2002
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|[http://www.bloodjournal.org/content/115/25/5137.long Sanz et al. 2010 (PETHEMA LPA2005)]
 +
|2005-2009
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====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">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
 +
====Chemotherapy====
 +
*[[Mercaptopurine (6-MP)]] 50 mg/m<sup>2</sup> PO once per day
 +
*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IM once per week
 +
'''90-day cycle for 8 cycles (2 years)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#fff2ae">
 +
====Dose and schedule modifications====
 +
*[[Methotrexate (MTX)]] and [[Mercaptopurine (6-MP)]] decreased by 50% if WBC count less than 3.5 x 10<sup>9</sup>/L
 +
*[[Methotrexate (MTX)]] and [[Mercaptopurine (6-MP)]] stopped if WBC count less than 2.5 x 10<sup>9</sup>/L
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 45/50/15, ATRA alternating with 6-MP, MTX {{#subobject:80d40a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1300874 Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)]
 +
|2007-2013
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
|-
 +
|}
 +
<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">
 +
====Chemotherapy====
 +
*[[Mercaptopurine (6-MP)]] as follows:
 +
**Cycles 1 & 3: 50 mg/m<sup>2</sup> PO once per day
 +
*[[Methotrexate (MTX)]] as follows:
 +
**Cycles 1 & 3: 15 mg/m<sup>2</sup> IM or PO once per week
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] as follows:
 +
**Cycles 2 & 4: 45 mg/m<sup>2</sup>/day PO on days 1 to 15
 +
'''3-month cycle for 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 45/60/20 {{#subobject:5c36f3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/PMC2981533/ Powell et al. 2010 (C9710)]
 +
|1999-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#ATRA_monotherapy_2|ATRA]]
 +
| style="background-color:#d9ef8b" |Might have superior DFS (secondary endpoint)
 +
|-
 +
|}
 +
''Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide-ATRA_.26_Daunorubicin|Arsenic trioxide-ATRA & Daunorubicin]] versus [[#ATRA_.26_Daunorubicin_2|ATRA & daunorubicin]] consolidation
 +
</div>
 +
<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====
 +
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day
 +
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 1 & 8
 +
'''14-day cycle for 26 cycles (1 year)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 45/90/15, ATRA alternating with 6-MP, MTX {{#subobject:1d7cb5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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
 +
|-
 +
| 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 (E-esc)
 +
|1. [[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]]
 +
| style="background-color:#91cf60" |Seems to have superior 2-year relapse rate
 +
|-
 +
|2. [[#ATRA_monotherapy_2|ATRA]]<br> 3. [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|No further treatment]]
 +
| style="background-color:#1a9850" |Superior 2-year relapse rate
 +
|-
 +
|}
 +
<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">
 +
====Chemotherapy====
 +
*[[Mercaptopurine (6-MP)]] as follows:
 +
**Cycles 1 & 3: 90 mg/m<sup>2</sup> PO once per day
 +
*[[Methotrexate (MTX)]] as follows:
 +
**Cycles 1 & 3: 15 mg/m<sup>2</sup> IM once per week
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] as follows:
 +
**Cycles 2 & 4: 45 mg/m<sup>2</sup>/day PO on days 1 to 15
 +
'''3-month cycle for 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, with range of 6-MP {{#subobject:85ef36|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2006.08.1596 Adès et al. 2006 (EAPLG APL 2000)]
 +
|2000-2004
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
|-
 +
|}
 +
<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">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
 +
====Chemotherapy====
 +
*[[Mercaptopurine (6-MP)]] 50 to 90 mg/m<sup>2</sup> PO once per day
 +
*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> PO once per week
 +
'''90-day cycle for 8 cycles (2 years)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #6, with range of 6-MP & MTX {{#subobject:ac797|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates 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
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:f68d7e|Variant=1}}===
+
''Maintenance starts 3 to 4 weeks after completion of consolidation cycle 2.''
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
''Treatment preceded by [[#North_American_Leukemia_Intergroup_Study_C9710_consolidation|North American Leukemia Intergroup Study C9710 consolidation]] therapy. Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.''
+
====Preceding treatment====
−
 
+
*[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID x 7 days every other week
+
</div>
−
With or without:
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Mercaptopurine (Purinethol)]] 60 mg/m2 PO once per day  
+
====Targeted therapy====
−
*[[Methotrexate (MTX)]] 20 mg/m2 PO once per week
+
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
 
+
====Chemotherapy====
−
'''1 year of therapy'''
+
*[[Mercaptopurine (6-MP)]] 50 to 90 mg/m<sup>2</sup> PO once per day on days 15 to 90
−
 
+
*[[Methotrexate (MTX)]] 5 to 15 mg/m<sup>2</sup>/week PO on days 15 to 90
 +
'''90-day cycle for 8 cycles (2 years)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#fff2ae">
 +
====Dose and schedule modifications====
 +
*[[Methotrexate (MTX)]] and [[Mercaptopurine (6-MP)]] doses titrated to ANC 1000 to 2000/μL and minimizing hepatotoxicity
 +
</div></div>
 
===References===
 
===References===
−
# 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://bloodjournal.hematologylibrary.org/content/116/19/3751.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20705755 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]
 +
# '''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]
 +
# '''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] [https://clinicaltrials.gov/study/NCT00465933 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]
 +
# '''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] [https://clinicaltrials.gov/study/NCT00591526 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] [https://clinicaltrials.gov/study/NCT00408278 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] [https://clinicaltrials.gov/study/NCT00003934 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] [https://clinicaltrials.gov/study/NCT00482833 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]
  
−
==AIDA 0493 maintenance {{#subobject:a29183|Regimen=1}}==
+
==Mercaptopurine & Methotrexate {{#subobject:a29183|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:ce7c69|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/100/9/3141.long Avvisati et al. 2002 (GIMEMA LAP 0389)]
 +
|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
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
===Regimen {{#subobject:8d4297|Variant=1}}===
+
====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
−
<span
+
</div>
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
padding:3px 6px 3px 6px;
+
====Chemotherapy====
−
border-color:black;
+
*[[Mercaptopurine (6-MP)]] 1 mg/kg PO once per day  
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
''Treatment preceded by [[#AIDA_0493_consolidation|AIDA 0493 consolidation]] therapy. See Avvisati et al. 2011 for details about outcomes with or without maintenance therapy.  Treatment options investigated included only using Part A, only using Part B, or alternating between the two, in all cases for a total of 2 years.''
 
−
 
 
−
====Part A====
 
−
*[[Mercaptopurine (Purinethol)]] 90 mg/m2 PO once per day
 
−
*[[Methotrexate (MTX)]] 15 mg/m2 IM once per week
 
−
 
 
−
'''90-day course of therapy, alternating with part B, given for a total of 2 years'''
 
−
 
 
−
====Part B====
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 15
 
−
 
 
−
'''90-day course of therapy, alternating with part A, given for a total of 2 years'''
 
−
 
 
−
===Alternate regimen (Avvisati et al. 2002) {{#subobject:7d4396|Variant=1}}===
 
−
*[[Mercaptopurine (Purinethol)]] 1 mg/kg PO once per day  
 
 
*[[Methotrexate (MTX)]] 0.25 mg/kg IM once per week  
 
*[[Methotrexate (MTX)]] 0.25 mg/kg IM once per week  
−
 
+
'''2-year course'''
−
'''2-year course of therapy'''
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:bab868|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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
 +
|-
 +
|3. [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|No further treatment]]
 +
| style="background-color:#1a9850" |Superior 2-year relapse rate
 +
|-
 +
|}
 +
''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">
 +
====Chemotherapy====
 +
*[[Mercaptopurine (6-MP)]] 90 mg/m<sup>2</sup> PO once per day
 +
*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IM once per week
 +
'''2-year course'''
 +
</div></div>
 +
===References===
 +
# '''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]
 +
# '''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">
 +
===Regimen variant #1, 0.15 mg/kg/day {{#subobject:ffaa29|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates 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, fewer than 20 pts
 +
|-
 +
|[https://doi.org/10.1200/JCO.2001.19.18.3852 Soignet et al. 2001 (PLRXAS01)]
 +
|1998-1999
 +
| style="background-color:#91cf61" |Phase 2 (RT)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day
 +
'''Continued until CR or up to 60 days'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*PLRXAS01, CR: [[#Arsenic_trioxide_monotherapy_5|Arsenic trioxide]] consolidation, then optional maintenance
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 10 mg/day {{#subobject:e2687c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/89/9/3354.long Shen et al. 1997]
 +
|1994-1996
 +
| style="background-color:#ffffbe" |Non-randomized, fewer than 20 pts
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 10 mg IV over 2 to 3 hours once per day
 +
'''Continued until CR'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Shen et al. 1997, patients in CR: proceed after 30 days to another 28-day course of [[#Arsenic_trioxide_monotherapy_5|arsenic trioxide]] consolidation
 +
</div></div>
  
 
===References===
 
===References===
−
# 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 (Gruppo Italiano Malattie Ematologische dell'Adulto) Italian Cooperative Group. 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://bloodjournal.hematologylibrary.org/content/100/9/3141.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12384411 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]
−
# 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, and EORTC Cooperative Groups. 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://bloodjournal.hematologylibrary.org/content/117/18/4716.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21385856 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]
−
# 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. [http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08593.x/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21751984 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]
−
 
+
==Arsenic trioxide & Idarubicin {{#subobject:90ec9f|Regimen=1}}==
−
==AIDA 2000 maintenance {{#subobject:914532|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen {{#subobject:4d76db|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/121/16/3095.long Yanada et al. 2013 (JALSG APL205R)]
 +
|2005-2009
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Note: Idarubicin was added under special conditions; see text for details.''
−
===Regimen, Lo-Coco et al. 2010 (AIDA 2000) {{#subobject:89b02e|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Targeted therapy====
−
<span
+
*[[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
−
style="background:#EEEE00;
+
====Chemotherapy====
−
padding:3px 6px 3px 6px;
+
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2
−
border-color:black;
+
'''Up to 60-day course'''
−
border-width:2px;
+
====CNS therapy====
−
border-style:solid;">Phase II</span>
+
*[[Cytarabine (Ara-C)]] 40 mg IT, admixed with MTX & steroids
−
 
+
*[[Methotrexate (MTX)]] 15 mg IT, admixed with Ara-C & steroids
−
''Treatment preceded by [[#AIDA_2000_consolidation|AIDA 2000 consolidation]] therapy. Patients RT-PCR negative for PML/RARA after consolidation received maintenance therapy. Patients who were RT-PCR positive for PML/RARA after consolidation were considered to have resistant disease and were given salvage therapy.''
+
*Select ONE of these corticosteroids:
−
 
+
**[[Prednisolone (Millipred)]] 10 mg IT, admixed with Ara-C & MTX
−
====Part A====
+
**[[Dexamethasone (Decadron)]] 4 mg IT, admixed with Ara-C & MTX
−
*[[Mercaptopurine (Purinethol)]] 50 mg/m2 PO once per day
+
'''Given once after platelet recovery'''
−
*[[Methotrexate (MTX)]] 15 mg/m2 IM once per week
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e7">
−
'''90-day course of therapy, alternating with part B, given for a total of 2 years'''
+
====Subsequent treatment====
−
 
+
*[[#Arsenic_trioxide_monotherapy_5|Arsenic trioxide]] consolidation
−
====Part B====
+
</div></div>
−
''Lo-Coco et al. 2010 did not list details about ATRA; this is how it was given in Avvisati et al. 2011 (AIDA 0493).''
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 15
 
−
 
 
−
'''90-day course of therapy, alternating with part A, given for a total of 2 years'''
 
−
 
 
 
===References===
 
===References===
−
# 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; Italian GIMEMA Cooperative Group. 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://bloodjournal.hematologylibrary.org/content/116/17/3171.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20644121 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] [https://clinicaltrials.gov/study/NCT01908621 NCT01908621]
  
−
==PETHEMA LPA99, LPA2005 maintenance {{#subobject:1b1235|Regimen=1}}==
+
==Tamibarotene monotherapy {{#subobject:fbdb9f|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:5d009e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770883/ Sanford et al. 2015 (STAR-1)]
 +
|2007-2011
 +
| style="background-color:#ffffbe" |Phase 2, fewer than 20 pts
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
PETHEMA: '''<u>P</u>'''rograma '''<u>E</u>'''spañol de '''<u>T</u>'''ratamientos en '''<u>HEMA</u>'''tología
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:80d40a|Variant=1}}===
+
====Targeted therapy====
−
''Treatment preceded by [[#PETHEMA_LPA99_consolidation|PETHEMA LPA99]] or [[#PETHEMA_LPA2005_consolidation|PETHEMA LPA2005]] consolidation therapy.''
+
*[[Tamibarotene (Amnoid)]] 3 mg/m<sup>2</sup> PO twice per day
−
 
+
'''Up to 56-day course'''
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 15
+
</div>
−
*[[Mercaptopurine (Purinethol)]] 50 mg/m2 PO once per day
+
<div class="toccolours" style="background-color:#cbd5e7">
−
*[[Methotrexate (MTX)]] 15 mg/m2 IM once per week
+
====Subsequent treatment====
−
 
+
*STAR-1, patients achieving CR: [[#Tamibarotene_monotherapy_888|Tamibarotene]] consolidation, if not proceeding to transplant
−
'''90-day cycles x 2 years'''
+
</div></div>
  
 
===References===
 
===References===
−
# 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://bloodjournal.hematologylibrary.org/content/103/4/1237.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/14576047 PubMed]
+
# '''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] [https://clinicaltrials.gov/study/NCT00520208 NCT00520208]
−
# 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 and HOVON Groups. 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://bloodjournal.hematologylibrary.org/content/115/25/5137.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/20393132 PubMed]
+
=Consolidation after salvage therapy=
−
 
+
==Arsenic trioxide monotherapy {{#subobject:5de745|Regimen=1}}==
−
=Relapsed/refractory=
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen {{#subobject:36556f|Variant=1}}===
−
==Arsenic-based re-induction followed by consolidation and autologous stem cell transplant {{#subobject:90ec9f|Regimen=1}}==
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/121/16/3095.long Yanada et al. 2013 (JALSG APL205R)]
 +
|2005-2009
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Note: intrathecal therapy is given at the conclusion of each cycle (3 doses total, including re-induction)''
−
===Regimen {{#subobject:4d76db|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
{| border="1" style="text-align:center;" !align="left"  
+
====Preceding treatment====
−
|'''Study'''
+
*[[#Arsenic_trioxide_.26_Idarubicin|Arsenic trioxide & Idarubicin]] re-induction
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV once per day on days 1 to 25
 +
====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
 +
*Select ONE of these 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 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]] consolidation
 +
</div></div>
 +
===References===
 +
# '''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] [https://clinicaltrials.gov/study/NCT01908621 NCT01908621]
 +
==Busulfan & Melphalan, then auto HSCT {{#subobject:ceba5e|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:8c92e5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://bloodjournal.hematologylibrary.org/content/121/16/3095.long Yanada et al. 2013]
+
|[http://www.bloodjournal.org/content/121/16/3095.long Yanada et al. 2013 (JALSG APL205R)]
−
|<span
+
|2005-2009
−
style="background:#EEEE00;
+
| style="background-color:#91cf61" |Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
====Induction====
+
<div class="toccolours" style="background-color:#cbd5e8">
−
*[[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
+
====Preceding treatment====
−
*[[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)
+
*[[Stem_cell_mobilization#Cytarabine_.26_G-CSF|HiDAC & G-CSF]] stem cell mobilization
−
*Intrathecal therapy given once after platelet recovery, consisting of:
+
</div>
−
**[[Methotrexate (MTX)]] 15 mg IT,
+
{{#lst:Autologous HSCT|c5fc8f}}
−
**[[Cytarabine (Cytosar)]] 40 mg IT, and
+
</div>
−
**Corticosteroids: ([[Prednisolone (Millipred)]] 10 mg IT or [[Dexamethasone (Decadron)]] 4 mg IT
 
−
 
 
−
====Consolidation #1 and #2====
 
−
*[[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
 
−
*Intrathecal therapy given once after platelet recovery, consisting of:
 
−
**[[Methotrexate (MTX)]] 15 mg IT,
 
−
**[[Cytarabine (Cytosar)]] 40 mg IT, and
 
−
**Corticosteroids: ([[Prednisolone (Millipred)]] 10 mg IT or [[Dexamethasone (Decadron)]] 4 mg IT
 
−
 
 
−
====Consolidation #3====
 
−
*[[Cytarabine (Cytosar)]] 2 g/m2 IV over 3 hours twice per day on days 1 to 4 (8 doses total)
 
−
*[[Filgrastim (Neupogen)]] starting on day 6 (dose, frequency not specified)
 
−
 
 
−
'''Peripheral blood stem cells collected upon WBC recovery, followed by:'''
 
−
 
 
−
*[[Busulfan (Myleran)]] & [[Melphalan (Alkeran)]] autologous stem cell transplant; see [[Transplant_conditioning_regimens#Busulfan_.26_Melphalan|transplant conditioning regimens]]
 
−
 
 
 
===References===
 
===References===
−
# 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://bloodjournal.hematologylibrary.org/content/121/16/3095.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23412094 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] [https://clinicaltrials.gov/study/NCT01908621 NCT01908621]
−
 
+
[[Category:Acute promyelocytic leukemia regimens]]
−
[[Category:Malignant hematology regimens]]
+
[[Category:Disease-specific pages]]
−
[[Category:Chemotherapy regimens]]
+
[[Category:Acute leukemias]]
 +
[[Category:Myeloid neoplasms]]

Revision as of 17:53, 23 June 2024

Back to Top

Section editor
AK.JPG
 Ashwin Kishtagari, MD
Vanderbilt University
Nashville, TN, USA
LinkedIn
31 regimens on this page
48 variants on this page

Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it.


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ELN

ESMO

NCCN

Upfront induction therapy

ADE & ATRA

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

Regimen

Study Dates 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 co-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 Dates 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 Dates 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

  • Shen et al. 2004, patients in CR: Consolidation, see text for details


Regimen variant #3, 10 mg (flat dose)

Study Dates 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 Dates 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 (secondary endpoint)
(HR 0.15, 95% CI 0.03-0.67)

Non-inferior EFS24 (primary endpoint)

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 laboratory-based criteria:
    • WBC count more 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
    • WBC count more 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 Dates 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

  • Shen et al. 2004, 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 Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Burnett et al. 2015 (UK NCRI AML17APL) 2009-2013 Phase 3 (E-switch-ooc) ATRA & Idarubicin Did not meet primary endpoint of QoL

Note: While this is technically part of the larger UK NCRI AML17 trial, patients with APL were treated by a different pathway and there was a different primary endpoint; therefore we denote this as UK NCRI AML17APL. 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

  • Arsenic trioxide (Trisenox) 0.3 mg/kg IV once per day on days 1 to 5, then 0.25 mg/kg IV once per day on days 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 42, 45, 49, 52 (twice per week on weeks 2 to 8)
  • 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

One course

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. Epub 2016 Dec 21. 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 AML17APL: 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 Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Burnett et al. 2015 (UK NCRI AML17APL) 2009-2013 Phase 3 (E-esc) ATRA & Idarubicin Did not meet primary endpoint of QoL

Note: While this is technically part of the larger UK NCRI AML17 trial, patients with APL were treated by a different pathway and there was a different primary endpoint; therefore we denote this as UK NCRI AML17APL.

Targeted therapy

  • Arsenic trioxide (Trisenox) 0.3 mg/kg IV once per day on days 1 to 5, then 0.25 mg/kg IV once per day on days 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 42, 45, 49, 52 (twice per week on weeks 2 to 8)
  • 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

Antibody-drug conjugate therapy

One course

Subsequent treatment


Regimen variant #2, GO 9 mg/m2

Study Dates 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. Epub 2016 Dec 21. 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. Epub 2016 Dec 21. link to full article contains dosing details in manuscript link to PMC article PubMed
  3. UK NCRI AML17APL: 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 Dates of enrollment Evidence
Iland et al. 2012 (ALLG APML4) 2004-2009 Phase 2

Targeted therapy

Chemotherapy

  • Idarubicin (Idamycin) by the following age-based criteria:
    • 61 years old or younger: 12 mg/m2 IV once per day on days 2, 4, 6, 8
    • 61 to 70 years old: 9 mg/m2 IV once per day on days 2, 4, 6, 8
    • Older than 70 years old: 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: 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 Dates of enrollment Evidence Comparator Comparative Efficacy
Warrell et al. 1991 NR Pilot, fewer than 20 pts
Fenaux et al. 1993 (EAPLG APL 91) 1991-03-01 to 1992-12-01 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

Note: 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

One course

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

Note: 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 more than 10 x 109/L) patients received this regimen in a non-randomized fashion, along with intrathecal therapy during consolidation.

Targeted therapy

Chemotherapy

Up to 90-day course

Subsequent treatment


Regimen variant #2, 45/1400/200

Study Dates of enrollment Evidence
Powell et al. 2010 (C9710) 1999-2005 Non-randomized part of phase 3 RCT

Targeted therapy

Chemotherapy

Up to 90-day course

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 Dates of enrollment Evidence
Adès et al. 2018 (APL 2006) 2006-2013 Non-randomized part of phase 3 RCT

Targeted therapy

Chemotherapy

One course until CR

Subsequent treatment

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 Dates 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 (secondary endpoint)

Seems to have inferior CIR24 (primary endpoint)

Note: 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

Up to 90-day course

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 Dates 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 part of phase 3 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 AML17APL) 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. While this is technically part of the larger UK NCRI AML17 trial, patients with APL were treated by a different pathway and there was a different primary endpoint; therefore we denote this as UK NCRI AML17APL.

Targeted therapy

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

Chemotherapy

  • Idarubicin (Idamycin) by the following age-based criteria:
    • 70 years old or younger: 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

Up to 90-day course

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 NCT01064570
  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 AML17APL: 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

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

Preceding treatment

Targeted therapy

  • Arsenic trioxide (Trisenox) by the following age-based criteria:
    • Adult patients: 10 mg IV over 2 to 3 hours once per day
    • Pediatric patients: 0.15 mg/kg IV over 2 to 3 hours once per day

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-ATRA & Daunorubicin

Regimen

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

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

Preceding treatment

Targeted therapy

Chemotherapy

7-week course, then 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 Dates of enrollment Evidence
Estey et al. 2005 2002-2005 Phase 2
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) 2007-2013 Non-randomized part of phase 3 RCT

Note: There is no maintenance in this protocol.

Preceding treatment

Targeted therapy

28-day cycle for 7 cycles


Regimen variant #2

Study Dates 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

  • All-trans retinoic acid (ATRA) as follows:
    • Cycle 1: 22.5 mg/m2 PO twice per day on days 1 to 28
    • Cycle 2: 22.5 mg/m2 PO twice per day on days 1 to 7, 15 to 21, 29 to 35
  • Arsenic trioxide (Trisenox) as follows:
    • Cycle 1: 0.15 mg/kg IV once per day on days 1 to 28
    • Cycle 2: 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- to 8-week course, then 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 AML17APL: 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 Dates of enrollment Evidence Comparator Comparative Efficacy
Powell et al. 2010 (C9710) 1999-2005 Phase 3 (C) Arsenic trioxide-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 variant #1

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

Eligibility criteria

  • Younger than 60 years old AND low-risk (WBC count less than 10 x 109/L) OR Older than 60 years old AND high-risk (WBC count more than 10 x 109/L)

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: 1000 mg/m2 IV every 12 hours on days 1 to 4 (total dose: 8000 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

2 cycles (length not specified)

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

5 doses throughout consolidation

Subsequent treatment


Regimen variant #2

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

Eligibility criteria

  • Younger than 60 years old AND high-risk (WBC count more than 10 x 109/L)

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: 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

2 cycles (length not specified)

CNS therapy, prophylaxis

5 doses throughout consolidation

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

Regimen

Study Dates of enrollment Evidence
Avvisati et al. 2002 (GIMEMA LAP 0389) 1989-1993 Non-randomized part of phase 3 RCT
Avvisati et al. 1996 (GIMEMA AIDA) 1993 Pilot
Mandelli et al. 1997 (GIMEMA AIDA 0493) 1993-1996 Non-randomized part of phase 3 RCT

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

Preceding treatment

Chemotherapy, A portion (Course 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

Chemotherapy, B portion (Course 2)

Chemotherapy, C portion (Course 3)

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

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

Regimen

Study Dates of enrollment Evidence
Lo-Coco et al. 2010 (GIMEMA AIDA-2000) 2000-2006 Non-randomized

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

Preceding treatment

Targeted therapy, all portions

Chemotherapy, A portion (cycle 1)

Chemotherapy, B portion (cycle 2)

Chemotherapy, C portion (cycle 3)

CNS prophylaxis, all portions

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

3 cycles (see note)

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 NCT01064570

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

Regimen

Study Dates of enrollment Evidence
Sanz et al. 2010 (PETHEMA LPA2005) 2005-2009 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, all portions

Chemotherapy, A portion (cycle 1)

Chemotherapy, B portion (cycle 2)

Chemotherapy, C portion (cycle 3)

1-month cycle for 3 cycles

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

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

Regimen

Study Dates of enrollment Evidence
Sanz et al. 2003 (PETHEMA LPA96) 1996-1999 Non-randomized
Sanz et al. 2003 (PETHEMA LPA99) 1999-2002 Non-randomized

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

Preceding treatment

Chemotherapy

1-month cycle for 3 cycles

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

Regimen variant #1

Study Dates of enrollment Evidence
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 Non-randomized part of phase 3 RCT

This is risk-adapted therapy for intermediate- and low-risk patients in GIMEMA 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, all portions (cycles 1 to 3)

Chemotherapy, idarubicin portion

  • Idarubicin (Idamycin) as follows:
    • Cycle 1: 5 mg/m2 IV once per day on days 1 to 4
    • Cycle 3: 12 mg/m2 IV once on day 1

Chemotherapy, mitoxantrone portion (cycle 2)

  • Mitoxantrone (Novantrone) by the following study-specific criteria:
    • GIMEMA 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 cycle for 3 cycles

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence
Sanz et al. 2003 (PETHEMA LPA99) 1999-2002 Non-randomized
Sanz et al. 2010 (PETHEMA LPA2005) 2005-2009 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, all portions (cycles 1 to 3)

Chemotherapy, idarubicin portion

  • Idarubicin (Idamycin) as follows:
    • Cycle 1: 7 mg/m2 IV once per day on days 1 to 4
    • Cycle 3: 12 mg/m2 IV once per day on days 1 & 2

Chemotherapy, mitoxantrone portion (cycle 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 cycle for 3 cycles

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 NCT01064570
  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

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

Preceding treatment

Targeted therapy

  • Arsenic trioxide (Trisenox) by the following age-based criteria:
    • Pediatric patients: 0.15 mg/kg IV over 2 to 3 hours once per day on days 1 to 10
    • Adult patients: 10 mg IV over 2 to 3 hours once per day on days 1 to 10

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 Dates 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 (secondary endpoint)

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 Dates 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 Dates of enrollment Evidence
Sanz et al. 2003 (PETHEMA LPA99) 1999-2002 Non-randomized
Sanz et al. 2010 (PETHEMA LPA2005) 2005-2009 Non-randomized

Preceding treatment

Targeted therapy

Chemotherapy

90-day cycle for 8 cycles (2 years)

Dose and schedule modifications


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

Study Dates of enrollment Evidence
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) 2007-2013 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

Targeted therapy

3-month cycle for 4 cycles


Regimen variant #3, 45/60/20

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

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)


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

Study Dates 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

Targeted therapy

3-month cycle for 4 cycles


Regimen variant #5, with range of 6-MP

Study Dates of enrollment Evidence
Adès et al. 2006 (EAPLG APL 2000) 2000-2004 Non-randomized part of phase 3 RCT

Preceding treatment

Targeted therapy

Chemotherapy

90-day cycle for 8 cycles (2 years)


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

Study Dates 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

90-day cycle for 8 cycles (2 years)

Dose and schedule modifications

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 Dates 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 Dates 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 Dates of enrollment Evidence
Soignet et al. 1998 NR Non-randomized, fewer than 20 pts
Soignet et al. 2001 (PLRXAS01) 1998-1999 Phase 2 (RT)

Targeted therapy

Continued until CR or up to 60 days

Subsequent treatment


Regimen variant #2, 10 mg/day

Study Dates of enrollment Evidence
Shen et al. 1997 1994-1996 Non-randomized, fewer than 20 pts

Targeted therapy

Continued until CR

Subsequent treatment

  • Shen et al. 1997, patients in CR: proceed after 30 days to another 28-day course of arsenic trioxide consolidation

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 Dates of enrollment Evidence
Yanada et al. 2013 (JALSG APL205R) 2005-2009 Phase 2

Note: Idarubicin was added under special conditions; see text for details.

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

Up to 60-day course

CNS therapy

Given once after platelet recovery

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 NCT01908621

Tamibarotene monotherapy

Regimen

Study Dates of enrollment Evidence
Sanford et al. 2015 (STAR-1) 2007-2011 Phase 2, fewer than 20 pts

Targeted therapy

Up to 56-day course

Subsequent treatment

  • STAR-1, 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 Dates of enrollment Evidence
Yanada et al. 2013 (JALSG APL205R) 2005-2009 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

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 NCT01908621

Busulfan & Melphalan, then auto HSCT

Regimen

Study Dates of enrollment Evidence
Yanada et al. 2013 (JALSG APL205R) 2005-2009 Phase 2

Preceding treatment

Chemotherapy

Supportive therapy

One course

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 NCT01908621
Retrieved from "https://hemonc.org/w/index.php?title=Acute_promyelocytic_leukemia&oldid=86513"