Difference between revisions of "Acute promyelocytic leukemia"

From HemOnc.org - A Hematology Oncology Wiki
Jump to navigation Jump to search
m (Qualified population studied in Lo-Coco study)
m
 
(424 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;"
 +
|-
 +
|<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: #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]
  
−
=Induction therapy=
+
*'''2009:''' Sanz et al. [https://doi.org/10.1182/blood-2008-04-150250 Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet] [https://pubmed.ncbi.nlm.nih.gov/18812465/ PubMed]
−
==APL 2000 (EAPLG) induction==
 
−
===Regimen===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
  
−
*[[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.
+
==[https://www.esmo.org/ ESMO]==
−
*[[Daunorubicin (Cerubidine)]] 60 mg/m2 IV on days 3 to 5
+
*'''2013:''' Fey et al. [https://doi.org/10.1093/annonc/mdt320 Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/23970018/ PubMed]
−
*[[Cytarabine (Cytosar)]] 200 mg/m2 IV on days 3 to 9
+
==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].''
  
−
'''9-day course of initial induction chemotherapy, with ongoing use of ATRA'''
+
=Upfront induction therapy=
−
 
+
==ADE & ATRA {{#subobject:e221d7|Regimen=1}}==
−
If >60 years old and WBC <10 x 10^9/L:
+
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
−
*[[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 {{#subobject:386fd2|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
To be followed by [[#APL_2000_.28EAPLG.29_consolidation|APL 2000 (EAPLG) consolidation]] therapy.
+
!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/10.1182/blood.V93.12.4131 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. [https://doi.org/10.1182/blood.V93.12.4131 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
 +
|-
 +
|}
 +
''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)]] 0.15 mg/kg 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><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 0.16 mg/kg {{#subobject:31ae8c|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="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC397380/ Shen et al. 2004]
 +
|rowspan=2|2001-2003
 +
| rowspan="2" style="background-color:#1a9851" |Randomized (C)
 +
|1. [[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]]
 +
| 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. [https://doi.org/10.1073/pnas.0400053101 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]]
 +
|-
 +
|[https://doi.org/10.1182/blood-2005-10-4006 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. [https://doi.org/10.1073/pnas.0400053101 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. [https://doi.org/10.1073/pnas.0813280106 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 [https://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. [https://doi.org/10.1182/blood-2005-10-4006 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16373661/ PubMed]
 +
# Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009 Feb 1;27(4):504-10. Epub 2008 Dec 15. [https://doi.org/10.1200/jco.2008.18.6130 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19075265/ PubMed]
 +
## '''Update:''' Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. Epub 2016 Dec 21. [https://doi.org/10.1182/blood-2016-09-736686 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]]
 +
|-
 +
|[https://doi.org/10.1182/blood-2005-10-4006 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
 +
|-
 +
|}
 +
''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. [https://doi.org/10.1182/blood-2005-10-4006 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. [https://doi.org/10.1182/blood-2016-09-736686 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. [https://doi.org/10.1182/blood-2016-09-736686 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]
  
−
==APML4 induction ==
+
==Arsenic trioxide, ATRA, Idarubicin {{#subobject:e30b39|Regimen=1}}==
−
===Regimen, Iland, et al. 2012 (APML4)===
+
<div class="toccolours" style="background-color:#eeeeee">
−
Level of Evidence:
+
===Regimen {{#subobject:50c777|Variant=1}}===
−
<span
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
style="background:#EEEE00;
+
!style="width: 33%"|Study
−
padding:3px 6px 3px 6px;
+
!style="width: 33%"|Dates of enrollment
−
border-color:black;
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-width:2px;
+
|-
−
border-style:solid;">Phase II</span>
+
|[https://doi.org/10.1182/blood-2012-02-410746 Iland et al. 2012 (ALLG APML4)]
−
 
+
|2004-2009
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once per day on days 2, 4, 6, 8
+
| style="background-color:#91cf61" |Phase 2
−
**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
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day on days 9 to 36
 
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day on days 9 to 36
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 36
 +
====Chemotherapy====
 +
*[[Idarubicin (Idamycin)]] by the following age-based criteria:
 +
**61 years old or younger: 12 mg/m<sup>2</sup> IV once per day on days 2, 4, 6, 8
 +
**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'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
  
−
'''36-day course'''; after 3 to 4 weeks, proceed to [[#APML4_consolidation|consolidation cycle 1]]
+
====Subsequent treatment====
 +
*[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation, in 3 to 4 weeks
 +
</div></div>
 +
===References===
 +
# '''ALLG APML4:''' Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. [https://doi.org/10.1182/blood-2012-02-410746 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22715121/ PubMed] ACTRN12605000070639
 +
==ATRA monotherapy {{#subobject:45c33c|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#ee6b6e">
 +
===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" |
 +
|-
 +
|[https://doi.org/10.1182/blood.V82.11.3241.3241 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
 +
|-
 +
|}
 +
''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">
 +
====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
 +
'''One course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*EAPLG APL 91: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation
 +
*ECOG E2491: ATRA consolidation, then [[#Cytarabine_.26_Daunorubicin|cytarabine & daunorubicin]] consolidation
 +
</div></div>
  
−
Supportive medications:
+
===References===
−
*[[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)
+
# 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]
−
*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
+
# '''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. [https://doi.org/10.1182/blood.V82.11.3241.3241 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8241496/ PubMed]
−
*Electrolyte support while on [[Arsenic trioxide (Trisenox)]]: supplemental potassium and magnesium given to keep levels in the upper half of their normal ranges
+
## '''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]
  
−
To be followed by [[#APML4_consolidation|APML4 consolidation]] therapy
+
==ATRA, Cytarabine, Daunorubicin {{#subobject:dade93|Regimen=1}}==
 +
<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)
 +
|-
 +
|}
 +
''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">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day, starting day 1 and continuing until remission or maximum of 90 days
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 3 (total dose: 1400 mg/m<sup>2</sup>)
 +
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 3 to 5
 +
'''Up to 90-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 45/1400/200 {{#subobject:8ee9d6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|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===
−
# 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]
+
# '''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. [https://doi.org/10.1182/blood-2007-07-099978 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed]
−
==North American Leukemia Intergroup Study C9710 induction==
+
# '''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. [https://doi.org/10.1182/blood-2010-02-269621 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]
−
===Regimen===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[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)]] 50 mg/m2 IV on days 3 to 6
 
−
*[[Cytarabine (Cytosar)]] 200 mg/m2/day IV continuous infusion on days 3 to 9
 
−
 
 
−
'''9-day initial induction chemotherapy, with ongoing use of ATRA'''
 
−
 
 
−
To be followed by [[#North_American_Leukemia_Intergroup_Study_C9710_consolidation|North American Leukemia Intergroup Study C9710 consolidation]] therapy.
 
  
 +
==ATRA, Cytarabine, Idarubicin {{#subobject:e4a23d|Regimen=1}}==
 +
<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
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day, starting on day 1 and continuing until complete remission
 +
====Chemotherapy====
 +
*[[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/m<sup>2</sup> IV once per day on days 3 to 5
 +
'''One course until CR'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*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===
 +
# '''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. [https://doi.org/10.3324/haematol.2018.198614 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]
 +
==ATRA & Daunorubicin {{#subobject:6c0f66|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:aa790b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|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)
 +
|-
 +
|}
 +
''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">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day, starting on day 1 and continuing until remission or maximum of 90 days
 +
====Chemotherapy====
 +
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 3 to 5
 +
'''Up to 90-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Daunorubicin_monotherapy|Daunorubicin]] consolidation
 +
</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. [https://doi.org/10.1182/blood-2007-07-099978 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed]
  
−
==AIDA 0493 induction==
+
==ATRA & Idarubicin {{#subobject:772861|Regimen=1}}==
 
AIDA: '''<u>A</u>'''TRA, '''<u>IDA</u>'''rubicin
 
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]]
 +
|-
 +
|[https://doi.org/10.1182/blood.V88.4.1390.bloodjournal8841390 Avvisati et al. 1996 (GIMEMA AIDA)]
 +
|1993
 +
| style="background-color:#91cf61" |Pilot
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1182/blood.V90.3.1014 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" |
 +
|-
 +
|[https://doi.org/10.1182/blood-2003-07-2462 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" |
 +
|-
 +
|[https://doi.org/10.1182/blood-2003-07-2462 Sanz et al. 2003 (PETHEMA LPA99)]
 +
|1999-2002
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1182/blood-2010-03-276196 Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
 +
|2000-2006
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1182/blood-2010-01-266007 Sanz et al. 2010 (PETHEMA LPA2005)]
 +
|2005-2009
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| 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 (C)
 +
|[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 +
|
 +
|-
 +
|[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 (C)
 +
|[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]]
 +
|
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of QoL
 +
|-
 +
|}
 +
''<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. [https://doi.org/10.1182/blood.V88.4.1390.bloodjournal8841390 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. [https://doi.org/10.1182/blood.V90.3.1014 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. [https://doi.org/10.1182/blood-2010-08-302950 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. [https://doi.org/10.1182/blood-2003-07-2462 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. [https://doi.org/10.1182/blood-2007-07-099978 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. [https://doi.org/10.1182/blood-2003-07-2462 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. [https://doi.org/10.1182/blood-2007-07-099978 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. [https://doi.org/10.1182/blood-2010-01-266007 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. [https://doi.org/10.1182/blood-2010-03-276196 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]
  
−
===Regimen===
+
=Consolidation after upfront therapy=
−
Level of Evidence:
+
==Arsenic trioxide monotherapy {{#subobject:f1814c|Regimen=1}}==
−
<span
+
<div class="toccolours" style="background-color:#eeeeee">
−
style="background:#00CD00;
+
===Regimen {{#subobject:7befb3|Variant=1}}===
−
padding:3px 6px 3px 6px;
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
border-color:black;
+
!style="width: 33%"|Study
−
border-width:2px;
+
!style="width: 33%"|Dates of enrollment
−
border-style:solid;">Phase III</span>
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1182/blood-2005-08-3532 Mathews et al. 2006]
 +
|1998-2004
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide_monotherapy|Arsenic trioxide]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 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===
 +
# 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]
  
−
*[[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.
+
==Arsenic trioxide-ATRA & Daunorubicin {{#subobject:e333b6|Regimen=1}}==
−
:*For patients <20 years old, [[All-trans retinoic acid (ATRA)]] dose was 25 mg/m2/day, divided into two equal doses PO BID
+
<div class="toccolours" style="background-color:#eeeeee">
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on days 2, 4, 6, 8
+
===Regimen {{#subobject:24bfd3|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_.26_Daunorubicin_2|ATRA & Daunorubicin]]
 +
| style="background-color:#1a9850" |Superior EFS (primary endpoint)
 +
|-
 +
|}
 +
''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====
 +
*[[Arsenic trioxide (Trisenox)]] as follows:
 +
**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:
 +
**Cycles 2 & 3: 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 7
 +
====Chemotherapy====
 +
*[[Daunorubicin (Cerubidine)]] as follows:
 +
**Cycles 2 & 3: 50 mg/m<sup>2</sup> IV once per day on days 1 to 3
 +
'''7-week course, then 39-day cycle for 2 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA_monotherapy_2|ATRA]] maintenance versus [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</div></div>
 +
===References===
 +
# '''C9710:''' Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. [https://doi.org/10.1182/blood-2010-02-269621 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]
  
−
'''8-day initial induction chemotherapy, with ongoing use of ATRA'''
+
==Arsenic trioxide & ATRA {{#subobject:7ce78a|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:a5626f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1182/blood-2005-10-4006 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
 +
|-
 +
|}
 +
''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">
  
−
To be followed by [[#AIDA_0493_consolidation|AIDA 0493 consolidation]] therapy.
+
===Regimen variant #2 {{#subobject:575577|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
 +
|-
 +
|}
 +
''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>
  
 
===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]
+
# 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. [https://doi.org/10.1182/blood-2005-10-4006 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16373661/ 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. doi: 10.1111/j.1365-2141.2011.08593.x. 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]
+
# '''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
−
# 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]
+
# '''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]
−
# 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
+
## '''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]
−
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,
+
## '''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]
−
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,
+
## '''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]
−
Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study
+
# '''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
−
Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. doi: 10.1056/NEJMoa1300874. [http://www.nejm.org/doi/full/10.1056/NEJMoa1300874 link to original article] '''contains link to verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23841729 PubMed]
+
## '''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. [https://doi.org/10.1182/blood-2010-02-269621 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]
  
−
==PETHEMA LPA99, LPA2005 induction==
+
==Cytarabine & Daunorubicin {{#subobject:f3ec97|Regimen=1}}==
−
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:#eeeeee">
−
===Regimen===
+
===Regimen variant #1 {{#subobject:198c4e|Variant=1}}===
−
*[[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.
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
**For patients <20 years old, [[All-trans retinoic acid (ATRA)]] dose was 25 mg/m2/day, divided into two equal doses PO BID
+
!style="width: 20%"|Study
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV bolus on days 2, 4, 6, 8
+
!style="width: 20%"|Dates of enrollment
−
**For patients >70 years old, [[Idarubicin (Idamycin)]] 12 mg/m2 IV bolus on days 2, 4, 6 (day 8 dose omitted)
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
!style="width: 20%"|Comparator
−
'''8-day initial induction chemotherapy, with ongoing use of ATRA'''
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
 
+
|-
−
To be followed by [[#PETHEMA_LPA99_consolidation|PETHEMA LPA99]] or [[#PETHEMA_LPA2005_consolidation|PETHEMA LPA2005]] consolidation therapy.
+
|[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)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*Younger 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: 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:
 +
**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, prophylaxis====
 +
*[[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>
 +
===References===
 +
# '''EAPLG APL 2000:''' Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; EAPLG. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. [https://doi.org/10.1200/jco.2006.08.1596 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17116939/ PubMed] [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. [https://doi.org/10.1182/blood-2007-07-099978 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed]
  
 +
==Cytarabine & Idarubicin {{#subobject:b76471|Regimen=1}}==
 +
<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
 +
|-
 +
|}
 +
''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===
 
===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]
+
# '''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]
−
# 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]
+
==Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine {{#subobject:cb4263|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
==Arsenic monotherapy==
+
===Regimen {{#subobject:13180d|Variant=1}}===
−
===Regimen===
+
{| class="wikitable" style="width: 60%; text-align:center;"
−
Level of Evidence:
+
!style="width: 33%"|Study
−
<span
+
!style="width: 33%"|Dates of enrollment
−
style="background:#00CD00;
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
padding:3px 6px 3px 6px;
+
|-
−
border-color:black;
+
|[https://doi.org/10.1182/blood-2002-02-0352 Avvisati et al. 2002 (GIMEMA LAP 0389)]
−
border-width:2px;
+
|1989-1993
−
border-style:solid;">Phase III</span>
+
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
−
 
+
|-
−
*[[Arsenic trioxide (Trisenox)]] 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours daily
+
|[https://doi.org/10.1182/blood.V88.4.1390.bloodjournal8841390 Avvisati et al. 1996 (GIMEMA AIDA)]
−
 
+
|1993
−
'''given until complete remission (CR) or maximum of 75 days (maximum of 60 days after 2001)'''
+
| style="background-color:#91cf61" |Pilot
−
 
+
|-
−
''If in CR, wait 4 weeks, then:''
+
|[https://doi.org/10.1182/blood.V90.3.1014 Mandelli et al. 1997 (GIMEMA AIDA 0493)]
−
*[[Arsenic trioxide (Trisenox)]] 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours daily x 28 days
+
|1993-1996
−
 
+
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
−
'''28-day course'''
+
|-
−
 
+
|}
−
''If in CR, wait 4 weeks, then:''
+
''Note that the consolidation portion of the AIDA 0493 protocol is only described in Avvisati et al. 1996.''
−
*[[Arsenic trioxide (Trisenox)]] 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours daily x "10 days a month"
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
'''1-month cycles x 6 months'''
+
*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===
 
===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]
+
# '''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. [https://doi.org/10.1182/blood.V88.4.1390.bloodjournal8841390 link to full article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8695858/ 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. [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]
+
# '''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. [https://doi.org/10.1182/blood.V90.3.1014 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/9242531/ 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. doi: 10.1200/JCO.2010.28.5031. 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]
+
## '''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. [https://doi.org/10.1182/blood-2010-08-302950 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. [https://doi.org/10.1182/blood-2002-02-0352 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12384411/ PubMed]
−
==ATRA & Arsenic==
+
==Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine, with ATRA {{#subobject:632192|Regimen=1}}==
−
===Regimen #1, Lo-Coco, et al. 2013===
+
<div class="toccolours" style="background-color:#eeeeee">
−
Level of Evidence:
+
===Regimen {{#subobject:6e3780|Variant=1}}===
−
<span
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
style="background:#00CD00;
+
!style="width: 33%"|Study
−
padding:3px 6px 3px 6px;
+
!style="width: 33%"|Dates of enrollment
−
border-color:black;
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-width:2px;
+
|-
−
border-style:solid;">Phase III</span>
+
|[https://doi.org/10.1182/blood-2010-03-276196 Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
−
 
+
|2000-2006
−
''Study of this regimen specifically excluded patients with high-risk APML (white blood cell count at presentation ≥ 10 X 10<sup>9</sup>/L)''
+
| style="background-color:#91cf61" |Non-randomized
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting day 1 and continuing until hematologic complete remission or maximum of 60 days.
+
|-
−
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day, starting day 1 and continuing until hematologic complete remission or maximum of 60 days.
+
|}
−
 
+
''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.''
−
Supportive medications:
+
<div class="toccolours" style="background-color:#cbd5e8">
−
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day from days 1 until the end of induction or the onset of differentiation syndrome
+
====Preceding treatment====
−
*Hemostatic support : Transfusion to keep platelet count > 30 x 10<sup>9</sup>/L (30,000/uL) for first 10 days of induction and > 20 x 10<sup>9</sup>/L (20,000/uL) for the remainder of induction
+
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
−
 
+
</div>
−
''If WBC > 10 X 10<sup>9</sup>/L (10,000/uL)''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Hydroxyurea (Hydrea)]] 500 mg PO four times a day if WBC > 10 X 10<sup>9</sup>/L (10,000/uL) but less than 50 X 10<sup>9</sup>/L (50,000/uL); [[Hydroxyurea (Hydrea)]] 1000 mg (1 gram) PO four times a day if WBC > 50 X 10<sup>9</sup>/L (50,000/uL) to be continued until WBC count falls below 10 X 10<sup>9</sup>/L (10,000/uL)
+
====Targeted therapy, all portions====
−
 
+
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
−
To be followed by [[#ATRA_.26_arsenic_-_consolidation|ATRA & arsenic]] consolidation therapy.
+
====Chemotherapy, A portion (cycle 1)====
−
 
+
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
===Regimen #2, Estey, et al. 2006 and Ravandi, et al. 2009===
+
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
Level of Evidence:
+
====Chemotherapy, B portion (cycle 2)====
−
<span
+
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
style="background:#EEEE00;
+
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
padding:3px 6px 3px 6px;
+
====Chemotherapy, C portion (cycle 3)====
−
border-color:black;
+
*[[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>)
−
border-width:2px;
+
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase II</span>
+
*[[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====
−
''There are two variations of this regimen as published. The earlier publication covers a part of the whole cohort and includes only the initial protocol where arsenic trioxide was started on day 10.  Additionally in the initial protocol gemtuzumab ozogamicin was only used for high risk patients.  After a death due to hyperleukocytosis and intracranial hemorrhage the protocol was modified so arsenic trioxide was started on day 1 as published in Ravandi, et al. 2009. 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.''
+
''It is not explicitly stated but presumably these are admixed and given together.''
−
 
+
*[[Methotrexate (MTX)]] 12 mg IT once prior to each consolidation cycle
−
*[[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.
+
*[[Methylprednisolone (Solumedrol)]] 40 mg IT once prior to each consolidation cycle
−
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 1 hour once per day, starting day 11 and continuing until remission or starting day 1 and continuing until remission
+
'''3 cycles (see note)'''
−
 
+
</div>
−
''and for High Risk Patients (Initial WBC ≥ 10 X 10<sup>9</sup>/L)''
+
<div class="toccolours" style="background-color:#cbd5e7">
−
 
+
====Subsequent treatment====
−
*[[Gemtuzumab ozogamicin (Mylotarg)]]  9 mg/m2 IV once on day 1
+
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA alternating with 6-MP, MTX]] maintenance
−
 
+
</div></div>
−
 
 
−
To be followed by [[#ATRA_.26_arsenic_-_consolidation|ATRA & arsenic]] consolidation therapy.
 
−
 
 
−
===Regimen #3, Shen, et al. 2004===
 
−
*[[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.
 
−
*[[Arsenic trioxide (Trisenox)]] 0.16 mg/kg IV daily, starting day 1 and continuing until remission
 
−
 
 
 
===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]
+
# '''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. [https://doi.org/10.1182/blood-2010-03-276196 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20644121/ PubMed] [https://clinicaltrials.gov/study/NCT01064570 NCT01064570]
−
# 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]
+
==Cytarabine & Idarubicin, then Mitoxantrone, then Cytarabine & Idarubicin, with ATRA {{#subobject:ca29a4|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. doi: 10.1200/JCO.2008.18.6130. Epub 2008 Dec 15. [http://jco.ascopubs.org/content/27/4/504.abstract?sid=391321bf-2b10-480f-85fe-416f57140273] '''contains link to verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19075265 PubMed]
+
<div class="toccolours" style="background-color:#eeeeee">
−
# 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. doi: 10.1056/NEJMoa1300874. [http://www.nejm.org/doi/full/10.1056/NEJMoa1300874 link to original article] '''contains link to verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23841729 PubMed]
+
===Regimen {{#subobject:46f412|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
 
+
!style="width: 33%"|Study
−
 
+
!style="width: 33%"|Dates of enrollment
−
=Consolidation therapy=
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
|-
−
==APL 2000 (EAPLG) consolidation==
+
|[https://doi.org/10.1182/blood-2010-01-266007 Sanz et al. 2010 (PETHEMA LPA2005)]
−
 
+
|2005-2009
−
Preceded by [[#APL_2000_.28EAPLG.29_induction|APL 2000 (EAPLG) induction]] therapy.
+
| style="background-color:#91cf61" |Non-randomized
−
 
+
|-
−
===Regimen===
+
|}
−
Level of Evidence:
+
''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.''
−
<span
+
<div class="toccolours" style="background-color:#cbd5e8">
−
style="background:#00CD00;
+
====Preceding treatment====
−
padding:3px 6px 3px 6px;
+
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
−
border-color:black;
+
</div>
−
border-width:2px;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
border-style:solid;">Phase III</span>
+
====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
−
===Consolidation regimen for patients ≤60 years old and WBC <10 x 10^9/L or age >60 and WBC >10 x 10^9/L===
+
====Chemotherapy, A portion (cycle 1)====
−
*[[Daunorubicin (Cerubidine)]] 60 mg/m2 IV on days 1 to 3
+
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
*[[Cytarabine (Cytosar)]] 200 mg/m2 IV on days 1 to 7
+
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 4
−
 
+
====Chemotherapy, B portion (cycle 2)====
−
Followed by:
+
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
*[[Daunorubicin (Cerubidine)]] 45 mg/m2 IV on days 1 to 3
+
====Chemotherapy, C portion (cycle 3)====
−
*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV every 12 hours on days 1 to 4 (8 total doses)
+
*[[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>)
−
'''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.'''
+
'''1-month cycle for 3 cycles'''
−
 
+
</div>
−
===Consolidation regimen for patients ≤60 years old and WBC >10 x 10^9/L===
+
<div class="toccolours" style="background-color:#cbd5e7">
−
*[[Daunorubicin (Cerubidine)]] 60 mg/m2 IV on days 1 to 3
+
====Subsequent treatment====
−
*[[Cytarabine (Cytosar)]] 200 mg/m2 IV on days 1 to 7
+
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
−
*3 doses of intrathecal chemotherapy with [[Methotrexate (MTX)]] 15 mg IT, [[Cytarabine (Cytosar)]] 50 mg IT, and corticosteroids
+
</div></div>
−
 
 
−
Followed by:
 
−
*[[Daunorubicin (Cerubidine)]] 45 mg/m2 IV on days 1 to 3
 
−
*If age <50 years old: [[Cytarabine (Cytosar)]] 2000 mg/m2 IV every 12 hours on days 1 to 5 (10 total doses)
 
−
*If age 50-60 years old: [[Cytarabine (Cytosar)]] 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 on days 1 to 3
 
−
 
 
−
Followed by:
 
−
*[[Daunorubicin (Cerubidine)]] 45 mg/m2 IV on days 1 to 3
 
−
 
 
−
To be 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]
+
# '''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. [https://doi.org/10.1182/blood-2010-01-266007 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20393132/ PubMed] [https://clinicaltrials.gov/study/NCT00408278 NCT00408278]
−
# 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]
+
==Daunorubicin monotherapy {{#subobject:76a47b|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
==APML4 consolidation==
+
===Regimen {{#subobject:82b9d5|Variant=1}}===
−
Preceded by [[#APML4_induction|APML4 induction]] therapy.
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 20%"|Study
−
===Regimen, Iland, et al. 2012 (APML4)===
+
!style="width: 20%"|Dates of enrollment
−
Level of Evidence:
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
<span
+
!style="width: 20%"|Comparator
−
style="background:#EEEE00;
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
padding:3px 6px 3px 6px;
+
|-
−
border-color:black;
+
|[https://doi.org/10.1200/jco.2006.08.1596 Adès et al. 2006 (EAPLG APL 2000)]
−
border-width:2px;
+
|2000-2004
−
border-style:solid;">Phase II</span>
+
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
−
 
+
|[[#Cytarabine_.26_Daunorubicin|Cytarabine & Daunorubicin]]
−
====Consolidation cycle 1====
+
| style="background-color:#d73027" |Inferior OS (secondary endpoint)
−
''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
+
''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.''
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
'''4-week course'''; after 3 to 4 weeks, proceed to consolidation cycle 2
+
====Preceding treatment====
−
 
+
*[[#ATRA_.26_Daunorubicin|ATRA & daunorubicin]] induction
−
====Consolidation cycle 2====
+
</div>
−
''Given 3 to 4 weeks after completion of consolidation cycle 1.''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[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
+
====Chemotherapy====
−
*[[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
+
*[[Daunorubicin (Cerubidine)]] as follows:
−
 
+
**Cycle 1: 60 mg/m<sup>2</sup> IV once per day on days 1 to 3
−
'''5-week course'''; after 3 to 4 weeks, proceed to [[#APML4_maintenance|APML4 maintenance]]
+
**Cycle 2: 45 mg/m<sup>2</sup> IV once per day on days 1 to 3
−
 
+
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance
 +
</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]
+
# '''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. [https://doi.org/10.1182/blood-2007-07-099978 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed]
−
==North American Leukemia Intergroup Study C9710 consolidation==
+
==Idarubicin, then Mitoxantrone, then Idarubicin {{#subobject:6af14e|Regimen=1}}==
−
Preceded by [[#North_American_Leukemia_Intergroup_Study_C9710_induction|North American Leukemia Intergroup Study C9710 induction]] therapy.
+
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen===
+
===Regimen {{#subobject:11923f|Variant=1}}===
−
Level of Evidence:
+
{| class="wikitable sortable" 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;
+
|[https://doi.org/10.1182/blood-2003-07-2462 Sanz et al. 2003 (PETHEMA LPA96)]
−
border-style:solid;">Phase III</span>
+
|1996-1999
−
 
+
| style="background-color:#91cf61" |Non-randomized
−
Consolidation therapy starts within 2 to 4 weeks of hematologic remission:
+
|-
−
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV once daily on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+
|[https://doi.org/10.1182/blood-2003-07-2462 Sanz et al. 2003 (PETHEMA LPA99)]
−
 
+
|1999-2002
−
'''7-week cycles (5 weeks of therapy, then 2 weeks off), THEN'''
+
| style="background-color:#91cf61" |Non-randomized
−
 
+
|-
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting days 1 to 7
+
|}
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m2 IV once daily on days 1 to 3
+
''This was the <u>low-risk</u> treatment arm of '''PETHEMA LPA99'''; <u>all patients</u> on '''PETHEMA LPA96''' underwent this consolidation protocol.''
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
'''7-day cycles x 2 cycles'''
+
====Preceding treatment====
−
 
+
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
−
To be followed by [[#North_American_Leukemia_Intergroup_Study_C9710_maintenance|North American Leukemia Intergroup Study C9710 maintenance]] therapy.
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[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
 +
*[[Mitoxantrone (Novantrone)]] as follows:
 +
**Cycle 2: 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
 +
'''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===
−
# 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]
+
# '''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. [https://doi.org/10.1182/blood-2003-07-2462 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. [https://doi.org/10.1182/blood-2007-07-099978 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed]
−
==AIDA 0493 consolidation==
+
# '''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. [https://doi.org/10.1182/blood-2003-07-2462 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14576047/ PubMed] [https://clinicaltrials.gov/study/NCT00465933 NCT00465933]
−
AIDA: '''<u>A</u>'''TRA, '''<u>IDA</u>'''rubicin <br>
+
## '''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. [https://doi.org/10.1182/blood-2007-07-099978 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed]
−
Preceded by [[#AIDA_0493_induction|AIDA 0493 induction]] therapy.
+
==Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA {{#subobject:49fc49|Regimen=1}}==
−
===Regimen===
+
<div class="toccolours" style="background-color:#eeeeee">
−
Level of Evidence:
+
===Regimen variant #1 {{#subobject:8d3f07|Variant=1}}===
−
<span
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
style="background:#00CD00;
+
!style="width: 33%"|Study
−
padding:3px 6px 3px 6px;
+
!style="width: 33%"|Dates of enrollment
−
border-color:black;
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-width:2px;
+
|-
−
border-style:solid;">Phase III</span>
+
|[https://doi.org/10.1182/blood-2010-03-276196 Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
−
 
+
|2000-2006
−
As detailed in Avvisati, et al., 2002:
+
| style="background-color:#91cf61" |Non-randomized
−
*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once daily on days 1 to 4 (administered second, 3 hours after cytarabine infusion complete)
+
|-
−
*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV over 6 hours on days 1 to 4 (administered first)
+
|[https://doi.org/10.1182/blood-2010-01-266007 Sanz et al. 2010 (PETHEMA LPA2005)]
−
 
+
|2005-2009
−
'''4-day course of therapy, THEN'''
+
| style="background-color:#91cf61" |Non-randomized
−
 
+
|-
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once daily on days 1 to 5 (administered first)
+
|[https://doi.org/10.1056/NEJMoa1300874 Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)]
−
*[[Etoposide (Vepesid)]] 100 mg/m2 IV over 45 to 60 minutes (administered second, 12 hours after start of mitoxantrone) days 1 to 5
+
|2007-2013
−
 
+
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
−
'''5-day course of therapy, THEN'''
+
|-
−
 
+
|}
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV day 1
+
''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.''
−
*[[Cytarabine (Cytosar)]] 150 mg/m2 SC every 8 hours (450 mg/m2/day total dosage) days 1 to 5
+
<div class="toccolours" style="background-color:#cbd5e8">
−
*[[Thioguanine (Tabloid)]] 70 mg/m2 PO every 8 hours (210 mg/m2/day total dosage) days 1 to 5
+
====Preceding treatment====
−
 
+
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
−
'''5-day course of therapy'''
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
To be followed by [[#AIDA_0493_maintenance|AIDA 0493 maintenance]] therapy.
+
====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]]
 +
|-
 +
|[https://doi.org/10.1182/blood-2003-07-2462 Sanz et al. 2003 (PETHEMA LPA99)]
 +
|1999-2002
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|[https://doi.org/10.1182/blood-2010-01-266007 Sanz et al. 2010 (PETHEMA LPA2005)]
 +
|2005-2009
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
''This is risk-adapted therapy for <u>intermediate-</u> and <u>high-risk</u> patients in PETHEMA LPA99 and for <u>intermediate-risk</u> and <u>high-risk older than 60</u> patients in PETHEMA LPA2005. Note that the number of mitoxantrone doses differs between the two protocols.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy, all portions (cycles 1 to 3)====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15
 +
====Chemotherapy, idarubicin portion====
 +
*[[Idarubicin (Idamycin)]] as follows:
 +
**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
 +
====Chemotherapy, mitoxantrone portion (cycle 2)====
 +
*[[Mitoxantrone (Novantrone)]] by the following study-specific criteria:
 +
**PETHEMA LPA99: 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
 +
**PETHEMA LPA2005: 10 mg/m<sup>2</sup> IV once per day on days 1 to 3
 +
'''1-month 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===
−
# 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]
+
# '''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. [https://doi.org/10.1182/blood-2003-07-2462 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14576047/ PubMed] [https://clinicaltrials.gov/study/NCT00465933 NCT00465933]
−
# 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. doi: 10.1111/j.1365-2141.2011.08593.x. 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]
+
## '''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. [https://doi.org/10.1182/blood-2007-07-099978 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ 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]
+
# '''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. [https://doi.org/10.1182/blood-2010-01-266007 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. [https://doi.org/10.1182/blood-2010-03-276196 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20644121/ PubMed] [https://clinicaltrials.gov/study/NCT01064570 NCT01064570]
−
==PETHEMA LPA99 consolidation==
+
# '''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]
−
PETHEMA: '''<u>P</u>'''rograma '''<u>E</u>'''spañol de '''<u>T</u>'''ratamientos en '''<u>HEMA</u>'''tología
+
## '''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]
−
<br>Preceded by [[#PETHEMA_LPA99.2C_LPA2005_induction|PETHEMA LPA99, LPA2005 induction]] therapy.
+
## '''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]
−
===Regimen===
+
## '''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]
−
High risk:
+
=Maintenance after upfront therapy=
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+
==Arsenic trioxide monotherapy {{#subobject:e1f355|Regimen=1}}==
−
*[[Idarubicin (Idamycin)]] 7 mg/m2 IV once daily on days 1 to 4
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen {{#subobject:9f326b|Variant=1}}===
−
'''1-month cycle, THEN'''
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
 
+
!style="width: 33%"|Study
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+
!style="width: 33%"|Dates of enrollment
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once daily on days 1 to 5
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
|-
−
'''1-month cycle, THEN'''
+
|[https://doi.org/10.1182/blood-2005-08-3532 Mathews et al. 2006]
−
 
+
|1998-2004
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+
| style="background-color:#91cf61" |Non-randomized
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on days 1 & 2
+
|-
−
 
+
|}
−
'''1-month cycle'''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
Intermediate risk:
+
*[[#Arsenic_trioxide_monotherapy_2|Arsenic trioxide]] consolidation
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+
</div>
−
*[[Idarubicin (Idamycin)]] 7 mg/m2 IV once daily on days 1 to 4
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Targeted therapy====
−
'''1-month cycle, THEN'''
+
*[[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
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+
**Adult patients: 10 mg IV over 2 to 3 hours once per day on days 1 to 10
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once daily on days 1 to 5
+
'''Monthly cycle for 6 cycles'''
−
 
+
</div></div>
−
'''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:
 
−
*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once daily on days 1 to 4
 
−
 
 
−
'''1-month cycle, THEN'''
 
−
 
 
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once daily on days 1 to 5
 
−
 
 
−
'''1-month cycle, THEN'''
 
−
 
 
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV day 1
 
−
 
 
−
'''1-month cycle'''
 
−
 
 
−
To be 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]
+
# 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]
−
# 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]
+
## '''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]
−
 
 
−
==PETHEMA LPA2005 consolidation==
 
−
PETHEMA: '''<u>P</u>'''rograma '''<u>E</u>'''spañol de '''<u>T</u>'''ratamientos en '''<u>HEMA</u>'''tología
 
−
<br>Preceded by [[#PETHEMA_LPA99.2C_LPA2005_induction|PETHEMA LPA99, LPA2005 induction]] therapy.
 
−
===Regimen===
 
−
High risk:
 
−
*[[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 daily on days 1 to 4
 
−
*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV once daily 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 daily 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 day 1
 
−
*[[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:
 
−
*[[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 daily 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 daily 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:
 
−
*[[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 daily 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 daily 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'''
 
−
 
 
−
To be followed by [[#PETHEMA_LPA99.2C_LPA2005_maintenance|PETHEMA LPA99, LPA2005 maintenance]] therapy.
 
  
 +
==ATRA monotherapy {{#subobject:8c70f0|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===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)
 +
|-
 +
|}
 +
''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|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
 +
'''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" |[https://doi.org/10.1182/blood.V90.3.1014 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" |[https://doi.org/10.1182/blood.V94.4.1192 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
 +
|-
 +
|2. [[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]]<br> 3. [[Acute_promyelocytic_leukemia_-_null_regimens#Observation|No further treatment]]
 +
| style="background-color:#91cf60" |Seems to have 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">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO on days 1 to 15
 +
'''3-month cycle for 8 cycles (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]
+
# '''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. [https://doi.org/10.1182/blood.V90.3.1014 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/9242531/ 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]
+
## '''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. [https://doi.org/10.1182/blood-2010-08-302950 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. [https://doi.org/10.1182/blood.V94.4.1192 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10438706/ PubMed]
−
==ATRA & arsenic - consolidation==
+
## '''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. [https://doi.org/10.1182/blood-2009-07-233387 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20018913/ PubMed]
−
Preceded by [[#ATRA_.26_arsenic|ATRA & arsenic]] induction therapy.
+
# '''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. [https://doi.org/10.1182/blood-2010-02-269621 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]
−
===Regimen===
+
==ATRA, Mercaptopurine, Methotrexate {{#subobject:b44ab6|Regimen=1}}==
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#eeeeee">
−
<span
+
===Regimen variant #1, 45/50/15 {{#subobject:80d40a|Variant=1}}===
−
style="background:#EEEE00;
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
padding:3px 6px 3px 6px;
+
!style="width: 33%"|Study
−
border-color:black;
+
!style="width: 33%"|Dates of enrollment
−
border-width:2px;
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-style:solid;">Phase II</span>
+
|-
−
 
+
|[https://doi.org/10.1182/blood-2003-07-2462 Sanz et al. 2003 (PETHEMA LPA99)]
−
*[[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
+
|1999-2002
−
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 1 hour daily, 5 consecutive days per week on weeks 1 to 4, 9 to 12, 17 to 20, 25 to 28
+
| style="background-color:#91cf61" |Non-randomized
−
 
+
|-
−
'''28 weeks of therapy'''
+
|[https://doi.org/10.1182/blood-2010-01-266007 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" |[https://doi.org/10.1182/blood.V90.3.1014 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" |[https://doi.org/10.1182/blood.V94.4.1192 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
 +
|-
 +
|}
 +
''Maintenance starts 3 to 4 weeks after completion of consolidation cycle 2.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
====Chemotherapy====
 +
*[[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===
−
# 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]
+
# '''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. [https://doi.org/10.1182/blood.V90.3.1014 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. [https://doi.org/10.1182/blood-2010-08-302950 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21385856/ PubMed]
−
=Maintenance therapy=
+
# '''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. [https://doi.org/10.1182/blood.V94.4.1192 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. [https://doi.org/10.1182/blood-2009-07-233387 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20018913/ PubMed]
−
==APL 2000 (EAPLG) maintenance==
+
# '''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. [https://doi.org/10.1182/blood-2003-07-2462 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14576047/ PubMed] [https://clinicaltrials.gov/study/NCT00465933 NCT00465933]
−
Preceded by [[#APL_2000_.28EAPLG.29_consolidation|APL 2000 (EAPLG) consolidation]] therapy.
+
## '''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. [https://doi.org/10.1182/blood-2007-07-099978 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed]
−
===Regimen===
+
# '''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]
−
Level of Evidence:
+
## '''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. [https://doi.org/10.1182/blood-2007-07-099978 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed]
−
<span
+
# '''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. [https://doi.org/10.1182/blood-2010-01-266007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20393132/ PubMed] [https://clinicaltrials.gov/study/NCT00408278 NCT00408278]
−
style="background:#00CD00;
+
# '''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. [https://doi.org/10.1182/blood-2010-02-269621 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]
−
padding:3px 6px 3px 6px;
+
# '''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
−
border-color:black;
+
# '''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]
−
border-width:2px;
+
## '''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]
−
border-style:solid;">Phase III</span>
+
## '''Update:''' Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. [https://doi.org/10.1200/JCO.2016.67.1982 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27400939/ PubMed]
−
 
+
## '''Update:''' Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. [https://doi.org/10.1038/s41375-019-0589-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31611624/ PubMed]
−
*[[Mercaptopurine (Purinethol)]] 50-90 mg/m2 PO daily
 
−
*[[Methotrexate (MTX)]] 15 mg/m2 PO weekly
 
−
*[[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'''
 
  
 +
==Mercaptopurine & Methotrexate {{#subobject:a29183|Regimen=1}}==
 +
<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]]
 +
|-
 +
|[https://doi.org/10.1182/blood-2002-02-0352 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
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Cytarabine_.26_Idarubicin.2C_then_Etoposide_.26_Mitoxantrone.2C_then_Cytarabine.2C_Idarubicin.2C_Thioguanine|Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine]] consolidation
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Mercaptopurine (6-MP)]] 1 mg/kg PO once per day
 +
*[[Methotrexate (MTX)]] 0.25 mg/kg IM once per week
 +
'''2-year course'''
 +
</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" |[https://doi.org/10.1182/blood.V90.3.1014 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" |[https://doi.org/10.1182/blood.V94.4.1192 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===
 
===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]
+
# '''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. [https://doi.org/10.1182/blood.V90.3.1014 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/9242531/ 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:''' 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. [https://doi.org/10.1182/blood-2010-08-302950 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. [https://doi.org/10.1182/blood.V94.4.1192 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. [https://doi.org/10.1182/blood-2009-07-233387 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20018913/ PubMed]
−
==APML4 maintenance==
+
# '''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. [https://doi.org/10.1182/blood-2002-02-0352 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12384411/ PubMed]
−
Preceded by [[#APML4_consolidation|APML4 consolidation]] therapy.
+
=Relapsed or refractory, salvage induction therapy=
−
 
+
==Arsenic trioxide monotherapy {{#subobject:734f95|Regimen=1}}==
−
===Regimen, Iland, et al. 2012 (APML4)===
+
<div class="toccolours" style="background-color:#eeeeee">
−
Level of Evidence:
+
===Regimen variant #1, 0.15 mg/kg/day {{#subobject:ffaa29|Variant=1}}===
−
<span
+
{| class="wikitable" style="width: 60%; text-align:center;"
−
style="background:#EEEE00;
+
!style="width: 33%"|Study
−
padding:3px 6px 3px 6px;
+
!style="width: 33%"|Dates of enrollment
−
border-color:black;
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-width:2px;
+
|-
−
border-style:solid;">Phase II</span>
+
|[https://doi.org/10.1056/NEJM199811053391901 Soignet et al. 1998]
−
 
+
|NR
−
''Given 3 to 4 weeks after completion of consolidation cycle 2.''
+
| style="background-color:#ffffbe" |Non-randomized, fewer than 20 pts
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 14
+
|-
−
*[[Methotrexate (MTX)]] 5 to 15 mg/m2/week PO on days 15 to 90
+
|[https://doi.org/10.1200/JCO.2001.19.18.3852 Soignet et al. 2001 (PLRXAS01)]
−
*[[Mercaptopurine (Purinethol)]] 50 to 90 mg/m2 PO once per day on days 15 to 90
+
|1998-1999
−
*[[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
+
| style="background-color:#91cf61" |Phase 2 (RT)
−
 
+
|-
−
'''90-day cycles x 8 cycles'''
+
|}
 +
<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]]
 +
|-
 +
|[https://doi.org/10.1182/blood.V89.9.3354 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===
−
# 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]
+
# 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. [https://doi.org/10.1182/blood.V89.9.3354 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9129042/ 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]
−
==North American Leukemia Intergroup Study C9710 maintenance==
+
# '''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]
−
Preceded by [[#North_American_Leukemia_Intergroup_Study_C9710_consolidation|North American Leukemia Intergroup Study C9710 consolidation]] therapy.
+
==Arsenic trioxide & Idarubicin {{#subobject:90ec9f|Regimen=1}}==
−
===Regimen===
+
<div class="toccolours" style="background-color:#eeeeee">
−
Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy:
+
===Regimen {{#subobject:4d76db|Variant=1}}===
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID x 7 days every other week
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
With or without:
+
!style="width: 33%"|Study
−
*[[Mercaptopurine (Purinethol)]] 60 mg/m2 PO daily
+
!style="width: 33%"|Dates of enrollment
−
*[[Methotrexate (MTX)]] 20 mg/m2 PO weekly
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
|-
−
'''1 year of therapy'''
+
|[https://doi.org/10.1182/blood-2012-11-466862 Yanada et al. 2013 (JALSG APL205R)]
−
 
+
|2005-2009
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
''Note: Idarubicin was added under special conditions; see text for details.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days
 +
====Chemotherapy====
 +
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2
 +
'''Up to 60-day course'''
 +
====CNS therapy====
 +
*[[Cytarabine (Ara-C)]] 40 mg IT, admixed with MTX & steroids
 +
*[[Methotrexate (MTX)]] 15 mg IT, admixed with Ara-C & steroids
 +
*Select ONE of these corticosteroids:
 +
**[[Prednisolone (Millipred)]] 10 mg IT, admixed with Ara-C & MTX
 +
**[[Dexamethasone (Decadron)]] 4 mg IT, admixed with Ara-C & MTX
 +
'''Given once after platelet recovery'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Arsenic_trioxide_monotherapy_5|Arsenic trioxide]] consolidation
 +
</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]
+
# '''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. [https://doi.org/10.1182/blood-2012-11-466862 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23412094/ PubMed] [https://clinicaltrials.gov/study/NCT01908621 NCT01908621]
−
 
 
−
==AIDA 0493 maintenance==
 
−
Preceded by [[#AIDA_0493_consolidation|AIDA 0493 consolidation]] therapy.
 
−
===Regimen===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
''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.''
 
−
<br>Part A:
 
−
*[[Mercaptopurine (Purinethol)]] 90 mg/m2 PO daily
 
−
*[[Methotrexate (MTX)]] 15 mg/m2 IM weekly
 
−
 
 
−
'''90-day course of therapy, THEN'''
 
−
 
 
−
Part B:
 
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 15
 
−
 
 
−
'''15-day course of therapy'''
 
  
−
===Alternate regimen (Avvisati, et al. 2002)===
+
==Tamibarotene monotherapy {{#subobject:fbdb9f|Regimen=1}}==
−
*[[Mercaptopurine (Purinethol)]] 1 mg/kg PO daily
+
<div class="toccolours" style="background-color:#eeeeee">
−
*[[Methotrexate (MTX)]] 0.25 mg/kg IM weekly
+
===Regimen {{#subobject:5d009e|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
'''2-year course of therapy'''
+
!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
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Tamibarotene (Amnoid)]] 3 mg/m<sup>2</sup> PO twice per day
 +
'''Up to 56-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*STAR-1, patients achieving CR: [[#Tamibarotene_monotherapy_888|Tamibarotene]] consolidation, if not proceeding to transplant
 +
</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]
+
# '''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]
−
# 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]
+
=Consolidation after salvage therapy=
−
# 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. doi: 10.1111/j.1365-2141.2011.08593.x. 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]
+
==Arsenic trioxide monotherapy {{#subobject:5de745|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
==PETHEMA LPA99, LPA2005 maintenance==
+
===Regimen {{#subobject:36556f|Variant=1}}===
−
PETHEMA: '''<u>P</u>'''rograma '''<u>E</u>'''spañol de '''<u>T</u>'''ratamientos en '''<u>HEMA</u>'''tología
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
<br>Preceded by [[#PETHEMA_LPA99_consolidation|PETHEMA LPA99]] or [[#PETHEMA_LPA2005_consolidation|PETHEMA LPA2005]] consolidation therapy.
+
!style="width: 33%"|Study
−
===Regimen===
+
!style="width: 33%"|Dates of enrollment
−
*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 15
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Mercaptopurine (Purinethol)]] 50 mg/m2 PO daily
+
|-
−
*[[Methotrexate (MTX)]] 15 mg/m2 IM weekly
+
|[https://doi.org/10.1182/blood-2012-11-466862 Yanada et al. 2013 (JALSG APL205R)]
−
 
+
|2005-2009
−
'''90-day cycles x 2 years'''
+
| style="background-color:#91cf61" |Phase 2
−
 
+
|-
 +
|}
 +
''Note: intrathecal therapy is given at the conclusion of each cycle (3 doses total, including re-induction)''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Arsenic_trioxide_.26_Idarubicin|Arsenic trioxide & Idarubicin]] re-induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====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===
 
===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]
+
# '''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. [https://doi.org/10.1182/blood-2012-11-466862 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23412094/ PubMed] [https://clinicaltrials.gov/study/NCT01908621 NCT01908621]
−
# 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]
+
==Busulfan & Melphalan, then auto HSCT {{#subobject:ceba5e|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
=Relapsed/refractory=
+
===Regimen {{#subobject:8c92e5|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
==Arsenic-based re-induction followed by consolidation and autologous stem cell transplant==
+
!style="width: 33%"|Study
−
 
+
!style="width: 33%"|Dates of enrollment
−
===Regimen===
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
Level of Evidence:
+
|-
−
<span
+
|[https://doi.org/10.1182/blood-2012-11-466862 Yanada et al. 2013 (JALSG APL205R)]
−
style="background:#EEEE00;
+
|2005-2009
−
padding:3px 6px 3px 6px;
+
| style="background-color:#91cf61" |Phase 2
−
border-color:black;
+
|-
−
border-width:2px;
+
|}
−
border-style:solid;">Phase II</span>
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
'''Induction'''
+
*[[Stem_cell_mobilization#Cytarabine_.26_G-CSF|HiDAC & G-CSF]] stem cell mobilization
−
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once daily days 1 to [*]
+
</div>
−
*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once over 30 minutes on days 1 & 2 [**]
+
{{#lst:Autologous HSCT|c5fc8f}}
−
*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
+
</div>
−
 
 
−
Special notes:
 
−
[*] Arsenic was continued until complete remission or maximum of 60 days
 
−
[**] Idarubicin was added under special conditions, see text for details
 
−
 
 
−
'''Consolidation #1 and #2'''
 
−
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once daily days 1 to [*]
 
−
*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 daily 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/melphalan autologous stem cell transplant, see [[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. doi: 10.1182/blood-2012-11-466862. 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. [https://doi.org/10.1182/blood-2012-11-466862 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:Disease-specific pages]]
 +
[[Category:Acute leukemias]]
 +
[[Category:Myeloid neoplasms]]

Latest revision as of 21:09, 24 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=86630"