Difference between revisions of "Acute promyelocytic leukemia"
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+ | <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"> | ||
+ | [[#top|Back to Top]] | ||
+ | </div> | ||
+ | {{#lst:Editorial board transclusions|aml}} | ||
{| class="wikitable" style="float:right; margin-right: 5px;" | {| class="wikitable" style="float:right; margin-right: 5px;" | ||
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div> | <div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div> | ||
|} | |} | ||
+ | ''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Acute promyelocytic leukemia - null regimens|this page]]. If you still can't find it, please let us know so we can add it.'' | ||
{{TOC limit|limit=3}} | {{TOC limit|limit=3}} | ||
− | |||
=Guidelines= | =Guidelines= | ||
+ | '''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== | ==ELN== | ||
− | *''' | + | *'''2019:''' Sanz et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509567/ Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet] [https://pubmed.ncbi.nlm.nih.gov/30803991/ PubMed] |
− | + | *'''2009:''' Sanz et al. [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] | |
− | *''' | ||
− | ==[https://www. | + | ==[https://www.esmo.org/ ESMO]== |
− | *[https://www.nccn.org/ | + | *'''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] |
+ | ==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].'' | ||
=Upfront induction therapy= | =Upfront induction therapy= | ||
+ | ==ADE & ATRA {{#subobject:e221d7|Regimen=1}}== | ||
+ | ADE & ATRA: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide, '''<u>A</u>'''ll-'''<u>T</u>'''rans '''<u>R</u>'''etinoic '''<u>A</u>'''cid | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:386fd2|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[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://doi.org/10.1038/leu.2012.360 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [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}}== | ==Arsenic trioxide monotherapy {{#subobject:bdedf2|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <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.'' |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | !style="width: | + | ====Targeted therapy==== |
− | !style="width: | + | *[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 to 3 hours once per day |
− | !style="width: | + | '''Continued until CR or up to 60 days''' |
− | !style="width: | + | </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" |[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) | | rowspan="2" style="background-color:#1a9851" |Randomized (C) | ||
− | |[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]] | + | |1. [[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]] |
| style="background-color:#fc8d59" |Seems to have inferior DFS | | style="background-color:#fc8d59" |Seems to have inferior DFS | ||
|- | |- | ||
− | |ATRA | + | |2. [[#ATRA_monotherapy|ATRA]] |
| style="background-color:#d3d3d3" |Not reported | | 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 | *[[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> |
− | {| class="wikitable" style="width: | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | !style="width: | + | ===Regimen variant #3, 10 mg (flat dose) {{#subobject:35af8c|Variant=1}}=== |
− | !style="width: | + | {| 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 | | style="background-color:#91cf61" |Non-randomized | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''Note: the maximum duration was decreased from 75 to 60 days after 2001.'' |
− | *[[Arsenic trioxide (Trisenox)]] 10 mg | + | <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==== | ====Subsequent treatment==== | ||
− | * | + | *Mathews et al. 2006, patients in CR: [[#Arsenic_trioxide_monotherapy_2|Arsenic trioxide]] consolidation |
− | + | </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. [ | + | # 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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | # 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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | ## '''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}}== | ==Arsenic trioxide & ATRA {{#subobject:2b304d|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <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:#91cf61" |Phase | ||
| style="background-color:#d3d3d3" | | | style="background-color:#d3d3d3" | | ||
| style="background-color:#d3d3d3" | | | style="background-color:#d3d3d3" | | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ Ravandi et al. 2008] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ Ravandi et al. 2008] | ||
− | | style="background-color:#91cf61" |Phase | + | |2002-2007 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
| style="background-color:#d3d3d3" | | | 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)] |
− | | style="background-color:#1a9851" |Phase | + | |2007-2013 |
+ | | style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc) | ||
|[[#ATRA_.26_Idarubicin|ATRA & Idarubicin]] | |[[#ATRA_.26_Idarubicin|ATRA & Idarubicin]] | ||
− | | style="background-color:# | + | | 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) |
|- | |- | ||
|} | |} | ||
− | ''Note: In Estey et al. | + | ''<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. | *[[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)]] | + | *[[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==== | |
− | ====Supportive | ||
*''As described in GIMEMA/DSIL APL0406:'' | *''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 | *[[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 | **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 | *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)]] | + | *[[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==== | ====Subsequent treatment==== | ||
− | *[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA | + | *[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation |
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | ===Regimen variant #2, 0.16/25 {{#subobject:9c8a05|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !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] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC397380/ Shen et al. 2004] | ||
− | | style="background-color:#1a9851" |Randomized (E) | + | |2001-2003 |
− | |[[#Arsenic_trioxide_monotherapy|Arsenic trioxide]]<br> ATRA | + | | 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 | | 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 | *[[Arsenic trioxide (Trisenox)]] 0.16 mg/kg IV once per day, starting day 1 and continuing until remission | ||
− | *[[All-trans retinoic acid (ATRA)]] | + | *[[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> |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | !style="width: | + | ===Regimen variant #3, 0.3/45 {{#subobject:e391b9|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 17%"|Study |
− | !style="width: | + | !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:// | + | |[https://doi.org/10.1016/S1470-2045(15)00193-X Burnett et al. 2015 (UK NCRI AML17<sub>APL</sub>)] |
− | | style="background-color:#1a9851" |Phase | + | |2009-2013 |
+ | | style="background-color:#1a9851" |Phase 3 (E-switch-ooc) | ||
|[[#ATRA_.26_Idarubicin|ATRA & Idarubicin]] | |[[#ATRA_.26_Idarubicin|ATRA & Idarubicin]] | ||
− | | style="background-color:#ffffbf" | | + | | |
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of QoL | ||
|- | |- | ||
|} | |} | ||
− | ''Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.'' | + | ''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"> |
− | *[[Arsenic trioxide (Trisenox)]] 0.3 mg/kg IV once per day on days 1 to 5, then 0.25 mg/kg IV twice per week on weeks 2 to 8 | + | ====Targeted therapy==== |
− | *[[All-trans retinoic acid (ATRA)]] | + | *[[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==== | ====Subsequent treatment==== | ||
− | *[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA | + | *[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation |
+ | </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. [ | + | # 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] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC397380/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/15044693/ PubMed] |
− | ## '''Update:''' Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WL, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3342-7. Epub 2009 Feb 18. [ | + | ## '''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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | # 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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | # 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] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19075265/ PubMed] |
− | ## '''Update:''' Abaza Y, | + | ## '''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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | ## '''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. [ | + | ## '''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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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}} == | == Arsenic trioxide, ATRA, Gemtuzumab ozogamicin {{#subobject:533ccc|Regimen=1}} == | ||
− | {| class="wikitable" style=" | + | <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) | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |[https:// | ||
− | | style="background-color:#1a9851" |Phase | ||
|[[#ATRA_.26_Idarubicin|ATRA & Idarubicin]] | |[[#ATRA_.26_Idarubicin|ATRA & Idarubicin]] | ||
− | | style="background-color:#ffffbf" | | + | | |
+ | | 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>.'' |
− | *[[Arsenic trioxide (Trisenox)]] 0.3 mg/kg IV once per day on days 1 to 5, then 0.25 mg/kg IV twice per week on weeks 2 to 8 | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | *[[All-trans retinoic acid (ATRA)]] | + | ====Targeted therapy==== |
− | *[[Gemtuzumab ozogamicin (Mylotarg)]] 6 mg/m<sup>2</sup> on day 1 | + | *[[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==== | ====Subsequent treatment==== | ||
− | *[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA | + | *[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation |
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2, GO 9 mg/m<sup>2</sup> {{#subobject:7f2ac1|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !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] |
− | | style="background-color:#91cf61" |Phase | + | |2002-2005 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ Ravandi et al. 2008] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ Ravandi et al. 2008] | ||
− | | style="background-color:#91cf61" |Phase | + | |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. | + | ''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"> |
− | *[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day on days 1 to 28 or until CR | + | ====Targeted therapy==== |
− | *[[All-trans retinoic acid (ATRA)]] | + | *[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day on days 1 to 28, or until CR |
− | *[[Gemtuzumab ozogamicin | + | *[[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==== | |
− | ====Supportive | + | *[[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 | *"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)]] | + | *[[Methylprednisolone (Solumedrol)]] by the following study-specific criteria: |
− | **Estey et al. | + | **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 | **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==== | ====Subsequent treatment==== | ||
− | *[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA | + | *[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation |
− | + | </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. [ | + | # 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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/16373661/ PubMed] |
− | ## '''Update:''' Abaza Y, | + | ## '''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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | # 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] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881307/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19075265/ PubMed] |
− | ## '''Update:''' Abaza Y, | + | ## '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5413297/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28003274/ PubMed] |
− | # '''UK NCRI AML17:''' Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. [https:// | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/26384238/ PubMed] ISRCTN55675535 |
+ | ## '''Update:''' Russell N, Burnett A, Hills R, Betteridge S, Dennis M, Jovanovic J, Dillon R, Grimwade D; NCRI AML Working Group. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood. 2018 Sep 27;132(13):1452-1454. Epub 2018 Aug 10. [https://doi.org/10.1182/blood-2018-05-851824 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6225356/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30097508/ PubMed] | ||
==Arsenic trioxide, ATRA, Idarubicin {{#subobject:e30b39|Regimen=1}}== | ==Arsenic trioxide, ATRA, Idarubicin {{#subobject:e30b39|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:50c777|Variant=1}}=== | ===Regimen {{#subobject:50c777|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !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)] |
− | | style="background-color:#91cf61" |Phase | + | |2004-2009 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day on days 9 to 36 | ||
+ | *[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 36 | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | + | *[[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 | |
− | *[[Idarubicin (Idamycin)]] | + | **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==== |
− | ** | ||
− | |||
− | ====Supportive | ||
*[[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) | *[[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 | *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 | + | *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"> | ||
− | |||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA | + | *[[#Arsenic_trioxide_.26_ATRA_2|Arsenic trioxide & ATRA]] consolidation, in 3 to 4 weeks |
− | + | </div></div> | |
===References=== | ===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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/22715121/ PubMed] ACTRN12605000070639 |
− | |||
==ATRA monotherapy {{#subobject:45c33c|Regimen=1}}== | ==ATRA monotherapy {{#subobject:45c33c|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#ee6b6e"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:430573|Variant=1}}=== | ===Regimen {{#subobject:430573|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1056/NEJM199105163242002 Warrell et al. 1991] |
− | | style="background-color:#ffffbe" |Pilot, | + | |Not reported |
+ | | style="background-color:#ffffbe" |Pilot, fewer than 20 pts | ||
| style="background-color:#d3d3d3" | | | style="background-color:#d3d3d3" | | ||
| 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)] |
− | | style="background-color:#1a9851" |Phase | + | |1991-03-01 to 1992-12-01 |
+ | | style="background-color:#1a9851" |Phase 3 (E-switch-ooc) | ||
|7+3d | |7+3d | ||
| style="background-color:#1a9850" |Superior EFS | | style="background-color:#1a9850" |Superior EFS | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1056/NEJM199710093371501 Tallman et al. 1997 (ECOG E2491)] |
− | | style="background-color:#1a9851" |Phase | + | |1992-1995 |
+ | | style="background-color:#1a9851" |Phase 3 (E-switch-ooc) | ||
|Cytarabine & Daunorubicin | |Cytarabine & Daunorubicin | ||
| style="background-color:#1a9850" |Superior OS | | style="background-color:#1a9850" |Superior OS | ||
|- | |- | ||
|} | |} | ||
− | ''These obsolete regimens are here for historical reference; ATRA is no longer used as monotherapy for induction; some patients in EAPLG APL 91 received concurrent chemotherapy (see paper for details)'' | + | ''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"> |
− | *[[All-trans retinoic acid (ATRA)]] | + | ====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==== | ====Subsequent treatment==== | ||
− | *EAPLG APL 91: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin | + | *EAPLG APL 91: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation |
− | *ECOG E2491: ATRA consolidation, then [[#Cytarabine_.26_Daunorubicin|cytarabine & daunorubicin | + | *ECOG E2491: ATRA consolidation, then [[#Cytarabine_.26_Daunorubicin|cytarabine & daunorubicin]] consolidation |
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # Warrell RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri LM, Hittelman WN, Vyas R, Andreeff M, Tafuri A, Jakubowski A, Gabrilove J, Gordon MS, Dmitrovsky E. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991 May 16;324(20):1385-93. [https:// | + | # Warrell RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri LM, Hittelman WN, Vyas R, Andreeff M, Tafuri A, Jakubowski A, Gabrilove J, Gordon MS, Dmitrovsky E. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991 May 16;324(20):1385-93. [https://doi.org/10.1056/NEJM199105163242002 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1850498/ PubMed] |
− | # '''EAPLG APL 91:''' Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D, Huebner G, Bauters F, Fegueux N, Fey M, Sanz M, Lowenberg B, Maloisel F, Auzanneau G, Sadoun A, Gardin C, Bastion Y, Ganser A, Jacky E, Dombret H, Chastang C, Degos L; European APL | + | # '''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] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/8241496/ PubMed] |
− | ## '''Update:''' Fenaux P, Chevret S, Guerci A, Fegueux N, Dombret H, Thomas X, Sanz M, Link H, Maloisel F, Gardin C, Bordessoule D, Stoppa AM, Sadoun A, Muus P, Wandt H, Mineur P, Whittaker JA, Fey M, Daniel MT, Castaigne S, Degos L; European APL | + | ## '''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. --> | <!-- 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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | ## '''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] |
==ATRA, Cytarabine, Daunorubicin {{#subobject:dade93|Regimen=1}}== | ==ATRA, Cytarabine, Daunorubicin {{#subobject:dade93|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <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) | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | | style="background-color:#1a9851" |Phase | ||
|[[#ATRA_.26_Daunorubicin|ATRA & Daunorubicin]] | |[[#ATRA_.26_Daunorubicin|ATRA & Daunorubicin]] | ||
− | | style="background-color:#1a9850" |Superior OS | + | | style="background-color:#1a9850" |Superior OS (secondary endpoint) |
|- | |- | ||
|} | |} | ||
− | ''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 | + | ''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==== | ====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 | *[[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==== | ====Subsequent treatment==== | ||
− | *[[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin | + | *[[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation |
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2, 45/1400/200 {{#subobject:8ee9d6|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !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)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ Powell et al. 2010 (C9710)] | ||
− | | style="background-color:#91cf61" |Non-randomized | + | |1999-2005 |
+ | | style="background-color:#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==== | ====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 | *[[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==== | ====Subsequent treatment==== | ||
− | *[[#Arsenic_trioxide | + | *[[#Arsenic_trioxide-ATRA_.26_Daunorubicin|Arsenic trioxide-ATRA & Ddaunorubicin]] versus [[#ATRA_.26_Daunorubicin|ATRA & Daunorubicin]] consolidation |
+ | </div></div> | ||
===References=== | ===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 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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed] |
− | # '''C9710:''' Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20705755/ PubMed] [https://clinicaltrials.gov/study/NCT00003934 NCT00003934] |
− | ==ATRA | + | ==ATRA, Cytarabine, Idarubicin {{#subobject:e4a23d|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <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] '''dosing details in manuscript have been reviewed by our editors''' [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}}=== | ===Regimen {{#subobject:aa790b|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !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)] |
− | | style="background-color:#1a9851" |Phase | + | |2000-2004 |
+ | | style="background-color:#1a9851" |Phase 3 (E-de-esc) | ||
|[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, Cytarabine, Daunorubicin]] | |[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, Cytarabine, Daunorubicin]] | ||
− | | style="background-color:#d73027" |Inferior OS | + | | style="background-color:#d73027" |Inferior OS (secondary endpoint)<br><br>Seems to have inferior CIR24 (primary endpoint) |
|- | |- | ||
|} | |} | ||
− | ''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.'' | + | ''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==== | ====Chemotherapy==== | ||
− | |||
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 3 to 5 | *[[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==== | ====Subsequent treatment==== | ||
− | *[[#Daunorubicin_monotherapy|Daunorubicin | + | *[[#Daunorubicin_monotherapy|Daunorubicin]] consolidation |
− | + | </div></div> | |
===References=== | ===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 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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed] |
==ATRA & Idarubicin {{#subobject:772861|Regimen=1}}== | ==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}}=== | ===Regimen {{#subobject:71cfae|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 17%"|Study |
− | !style="width: | + | !style="width: 15%"|Dates of enrollment |
− | !style="width: | + | !style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !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:#91cf61" |Pilot | ||
+ | | style="background-color:#d3d3d3" | | ||
| style="background-color:#d3d3d3" | | | 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)] |
− | | style="background-color:#91cf61" |Non-randomized | + | |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" | | ||
| 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:#91cf61" |Non-randomized | ||
+ | | style="background-color:#d3d3d3" | | ||
| style="background-color:#d3d3d3" | | | 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:#91cf61" |Non-randomized | ||
+ | | style="background-color:#d3d3d3" | | ||
| style="background-color:#d3d3d3" | | | 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:#91cf61" |Non-randomized | ||
+ | | style="background-color:#d3d3d3" | | ||
| style="background-color:#d3d3d3" | | | style="background-color:#d3d3d3" | | ||
| style="background-color:#d3d3d3" | | | style="background-color:#d3d3d3" | | ||
|- | |- | ||
− | |[https:// | + | |[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:#91cf61" |Non-randomized | ||
+ | | style="background-color:#d3d3d3" | | ||
| style="background-color:#d3d3d3" | | | 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)] |
− | | style="background-color:#1a9851" |Phase | + | |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]] | |[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]] | ||
− | | style="background-color:# | + | | style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup> |
+ | | | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/S1470-2045(15)00193-X Burnett et al. 2015 (UK NCRI AML17<sub>APL</sub>)] |
− | | style="background-color:#1a9851" |Phase | + | |2009-2013 |
+ | | style="background-color:#1a9851" |Phase 3 (C) | ||
|[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]] | |[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]] | ||
− | | style="background-color:#ffffbf" | | + | | |
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of QoL | ||
|- | |- | ||
|} | |} | ||
− | ''Note: this is the same induction used in '''multiple''' protocols. Consolidation and maintenance differ, follow the appropriate links below. | + | ''<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==== | ====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 | |
− | |||
− | *[[Idarubicin (Idamycin)]] | ||
− | ** | ||
**Older than 70 years old: 12 mg/m<sup>2</sup> IV bolus once per day on days 2, 4, 6 | **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==== | ====Subsequent treatment==== | ||
− | ''Once CR was achieved, patients proceeded to consolidation | + | ''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 | + | *PETHEMA LPA96: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin|Idarubicin, then mitoxantrone, then idarubicin]] consolidation |
− | *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 | + | *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 | + | *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 | + | *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 |
− | *AIDA 2000 | + | *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> |
− | *GIMEMA AIDA 0493 amended protocol: [[#Cytarabine_.26_Idarubicin|Cytarabine & idarubicin | ||
− | *GIMEMA/DSIL APL0406 and UK NCRI AML17: [[#Idarubicin.2C_then_Mitoxantrone.2C_then_Idarubicin.2C_with_ATRA|Idarubicin, then mitoxantrone, then idarubicin, with ATRA | ||
− | |||
===References=== | ===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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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 | + | # '''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 | + | ## '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/21385856/ PubMed] |
− | # '''PETHEMA LPA96 | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed] |
− | # '''PETHEMA | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/20393132/ PubMed] [https://clinicaltrials.gov/study/NCT00408278 NCT00408278] |
− | # '''GIMEMA | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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] | ||
=Consolidation after upfront therapy= | =Consolidation after upfront therapy= | ||
− | |||
==Arsenic trioxide monotherapy {{#subobject:f1814c|Regimen=1}}== | ==Arsenic trioxide monotherapy {{#subobject:f1814c|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:7befb3|Variant=1}}=== | ===Regimen {{#subobject:7befb3|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !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 | | style="background-color:#91cf61" |Non-randomized | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#Arsenic_trioxide_monotherapy|Arsenic trioxide | + | *[[#Arsenic_trioxide_monotherapy|Arsenic trioxide]] induction |
− | ==== | + | </div> |
− | *[[Arsenic trioxide (Trisenox)]] 10 mg | + | <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''' | '''28-day course''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | * | + | *Mathews et al. 2006, patients remaining in CR: [[#Arsenic_trioxide_monotherapy_3|Arsenic trioxide]] maintenance |
− | + | </div></div> | |
===References=== | ===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. [ | + | # 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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | ## '''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 | + | ==Arsenic trioxide-ATRA & Daunorubicin {{#subobject:e333b6|Regimen=1}}== |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:24bfd3|Variant=1}}=== | ===Regimen {{#subobject:24bfd3|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !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)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ Powell et al. 2010 (C9710)] | ||
− | | style="background-color:#1a9851" |Phase | + | |1999-2005 |
− | |[[#ATRA_. | + | | style="background-color:#1a9851" |Phase 3 (E-esc) |
− | | style="background-color:#1a9850" |Superior EFS | + | |[[#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.'' | ''Consolidation therapy starts within 2 to 4 weeks of hematologic remission.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin | + | *[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin]] induction |
− | ==== | + | </div> |
− | *[[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 | + | <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: | |
− | *[[All-trans retinoic acid (ATRA)]] | + | **Cycles 2 & 3: 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 7 |
− | *[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3 | + | ====Chemotherapy==== |
− | + | *[[Daunorubicin (Cerubidine)]] as follows: | |
− | '''7-day cycle for 2 cycles''' | + | **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==== | ====Subsequent treatment==== | ||
− | *[[#ATRA_monotherapy_2|ATRA | + | *[[#ATRA_monotherapy_2|ATRA]] maintenance versus [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance |
− | + | </div></div> | |
===References=== | ===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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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] |
==Arsenic trioxide & ATRA {{#subobject:7ce78a|Regimen=1}}== | ==Arsenic trioxide & ATRA {{#subobject:7ce78a|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <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 | |
− | |||
− | | style="background-color:#91cf61" |Non-randomized | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: There is no maintenance in this protocol.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA | + | *[[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA]] induction |
− | ==== | + | </div> |
− | *[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 1 to 2 hours once per day | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | *[[All-trans retinoic acid (ATRA)]] | + | ====Targeted therapy==== |
− | + | *[[Arsenic trioxide (Trisenox)]] as follows: | |
− | '''28 | + | **Cycles 1, 3, 5, 7: 0.15 mg/kg IV over 1 to 2 hours once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26 |
+ | *[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 14 | ||
+ | '''28-day cycle for 7 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
− | + | ===Regimen variant #2 {{#subobject:575577|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | === | + | !style="width: 33%"|Study |
− | {| class="wikitable" style="width: | + | !style="width: 33%"|Dates of enrollment |
− | !style="width: | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2012-02-410746 Iland et al. 2012 (ALLG APML4)] |
− | | style="background-color:#91cf61" |Phase | + | |2004-2009 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|} | |} | ||
''Consolidation starts 3 to 4 weeks after completion of induction.'' | ''Consolidation starts 3 to 4 weeks after completion of induction.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#Arsenic_trioxide.2C_ATRA.2C_Idarubicin|Arsenic trioxide, ATRA, idarubicin | + | *[[#Arsenic_trioxide.2C_ATRA.2C_Idarubicin|Arsenic trioxide, ATRA, idarubicin]] induction |
− | ==== | + | </div> |
− | *[[All-trans retinoic acid (ATRA)]] | + | <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 | |
− | *[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 | + | '''7- to 8-week course, then 5-week course''' |
− | + | </div> | |
− | '''5-week course''' | + | <div class="toccolours" style="background-color:#cbd5e7"> |
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX | + | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance, after 3 to 4 weeks |
+ | </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. [ | + | # 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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/16373661/ PubMed] |
− | # '''ALLG APML4:''' Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/22715121/ PubMed] ACTRN12605000070639 |
− | # '''GIMEMA/DSIL APL0406:''' Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | ## '''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. [ | + | ## '''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] |
− | # '''UK NCRI AML17:''' Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. [https:// | + | ## '''Update:''' Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. [https://doi.org/10.1038/s41375-019-0589-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31611624/ PubMed] |
− | + | # '''UK NCRI AML17<sub>APL</sub>:''' Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. [https://doi.org/10.1016/S1470-2045(15)00193-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/26384238/ PubMed] ISRCTN55675535 | |
+ | ## '''Update:''' Russell N, Burnett A, Hills R, Betteridge S, Dennis M, Jovanovic J, Dillon R, Grimwade D; NCRI AML Working Group. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood. 2018 Sep 27;132(13):1452-1454. Epub 2018 Aug 10. [https://doi.org/10.1182/blood-2018-05-851824 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6225356/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30097508/ PubMed] | ||
==ATRA & Daunorubicin {{#subobject:5d419b|Regimen=1}}== | ==ATRA & Daunorubicin {{#subobject:5d419b|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:b8d811|Variant=1}}=== | ===Regimen {{#subobject:b8d811|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !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)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ Powell et al. 2010 (C9710)] | ||
− | | style="background-color:#1a9851" |Phase | + | |1999-2005 |
− | |[[#Arsenic_trioxide | + | | style="background-color:#1a9851" |Phase 3 (C) |
+ | |[[#Arsenic_trioxide-ATRA_.26_Daunorubicin|Arsenic trioxide-ATRA & Daunorubicin]] | ||
| style="background-color:#d73027" |Inferior EFS | | style="background-color:#d73027" |Inferior EFS | ||
|- | |- | ||
|} | |} | ||
''Consolidation therapy starts within 2 to 4 weeks of hematologic remission.'' | ''Consolidation therapy starts within 2 to 4 weeks of hematologic remission.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin induction]] | + | *[[#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==== | ====Chemotherapy==== | ||
− | |||
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3 | *[[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==== | ====Subsequent treatment==== | ||
− | *[[#ATRA_monotherapy_2|ATRA | + | *[[#ATRA_monotherapy_2|ATRA]] versus [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance |
− | + | </div></div> | |
===References=== | ===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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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] |
==Cytarabine & Daunorubicin {{#subobject:f3ec97|Regimen=1}}== | ==Cytarabine & Daunorubicin {{#subobject:f3ec97|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen variant #1 {{#subobject:198c4e|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1200/jco.2006.08.1596 Adès et al. 2006 (EAPLG APL 2000)] | ||
+ | |2000-2004 | ||
+ | | style="background-color:#1a9851" |Phase 3 (C) | ||
+ | |[[#Daunorubicin_monotherapy|Daunorubicin]] | ||
+ | | style="background-color:#1a9850" |Superior OS (secondary endpoint) | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#fdcdac"> | |
− | ===Regimen {{#subobject: | + | ====Eligibility criteria==== |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | *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) |
− | !style="width: | + | </div> |
− | !style="width: | + | <div class="toccolours" style="background-color:#cbd5e8"> |
− | !style="width: | + | ====Preceding treatment==== |
− | !style="width: | + | *[[#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)] |
− | | style="background-color:#1a9851" |Phase | + | |2000-2004 |
+ | | style="background-color:#1a9851" |Phase 3 (C) | ||
|[[#Daunorubicin_monotherapy|Daunorubicin]] | |[[#Daunorubicin_monotherapy|Daunorubicin]] | ||
− | | style="background-color:#1a9850" |Superior OS | + | | 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==== | ====Preceding treatment==== | ||
− | *[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin | + | *[[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin]] induction |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cytarabine ( | + | *[[Cytarabine (Ara-C)]] as follows: |
− | **Cycle 1: 200 mg/m<sup>2</sup>/day IV continuous infusion on | + | **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: | *[[Daunorubicin (Cerubidine)]] as follows: | ||
**Cycle 1: 60 mg/m<sup>2</sup> IV once per day on days 1 to 3 | **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 | **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==== | ====Subsequent treatment==== | ||
− | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX | + | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance |
− | + | </div></div> | |
===References=== | ===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 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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed] |
==Cytarabine & Idarubicin {{#subobject:b76471|Regimen=1}}== | ==Cytarabine & Idarubicin {{#subobject:b76471|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:f5d960|Variant=1}}=== | ===Regimen {{#subobject:f5d960|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable" style="width: 40%; text-align:center;" |
− | !style="width: | + | !style="width: 25%"|Study |
− | !style="width: | + | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] |
|- | |- | ||
− | |[https:// | + | |[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 | | style="background-color:#91cf61" |Non-randomized | ||
|- | |- | ||
|} | |} | ||
''This consolidation protocol was intended for patients older than 60.'' | ''This consolidation protocol was intended for patients older than 60.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin | + | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cytarabine ( | + | *[[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''' | *[[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==== | ====Subsequent treatment==== | ||
− | *[[#ATRA_monotherapy_2|ATRA | + | *[[#ATRA_monotherapy_2|ATRA]] maintenance |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''GIMEMA AIDA 0493 amended protocol:''' Latagliata R, Breccia M, Fazi P, Vignetti M, Di Raimondo F, Sborgia M, Vincelli D, Candoni A, Salvi F, Rupoli S, Martinelli G, Kropp MG, Tonso A, Venditti A, Melillo L, Cimino G, Petti MC, Avvisati G, Lo-Coco F, Mandelli F; GIMEMA Acute Leukaemia Working Party. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia: long-term results and prognostic factors. Br J Haematol. 2011 Sep;154(5):564-8. Epub 2011 Jul 14. [https:// | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/21751984/ PubMed] |
− | |||
==Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine {{#subobject:cb4263|Regimen=1}}== | ==Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine {{#subobject:cb4263|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:13180d|Variant=1}}=== | ||
+ | {| class="wikitable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2002-02-0352 Avvisati et al. 2002 (GIMEMA LAP 0389)] |
− | | | + | |1989-1993 |
− | + | | style="background-color:#91cf61" |Non-randomized part of phase 3 RCT | |
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood.V88.4.1390.bloodjournal8841390 Avvisati et al. 1996 (GIMEMA AIDA)] |
− | | style="background-color:#91cf61" | | + | |1993 |
+ | | style="background-color:#91cf61" |Pilot | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood.V90.3.1014 Mandelli et al. 1997 (GIMEMA AIDA 0493)] |
− | | style="background-color:#91cf61" |Non-randomized | + | |1993-1996 |
+ | | style="background-color:#91cf61" |Non-randomized part of phase 3 RCT | ||
|- | |- | ||
|} | |} | ||
− | ''Note that the consolidation portion of the | + | ''Note that the consolidation portion of the AIDA 0493 protocol is only described in Avvisati et al. 1996.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *GIMEMA LAP 0389: Idarubicin | + | *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 0493: [[#ATRA_.26_Idarubicin|ATRA & idarubicin | + | *GIMEMA AIDA & GIMEMA AIDA 0493: [[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction |
− | ====Chemotherapy, | + | </div> |
− | *[[Cytarabine ( | + | <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''' | *[[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''' | |
− | |||
− | |||
− | ====Chemotherapy, | ||
− | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 45 to 60 minutes | ||
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given first''' | *[[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: | |
− | |||
− | ====Chemotherapy, | ||
− | *[[Cytarabine ( | ||
− | *[[Idarubicin (Idamycin)]] | ||
**GIMEMA LAP 0389: 5 mg/m<sup>2</sup> IV once on day 1 | **GIMEMA LAP 0389: 5 mg/m<sup>2</sup> IV once on day 1 | ||
− | **GIMEMA AIDA 0493: 12 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 | *[[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==== | ====Subsequent treatment==== | ||
− | *GIMEMA LAP 0389: [[#Mercaptopurine_.26_Methotrexate|6-MP & MTX | + | *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 | + | *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=== | ||
− | # 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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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 | + | # '''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 | + | ## '''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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/12384411/ 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 | ||
− | |||
==Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine, with ATRA {{#subobject:632192|Regimen=1}}== | ==Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine, with ATRA {{#subobject:632192|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:6e3780|Variant=1}}=== | ===Regimen {{#subobject:6e3780|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[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:#91cf61" |Non-randomized | ||
|- | |- | ||
|} | |} | ||
− | ''This is risk-adapted therapy for <u>high-risk</u> patients in | + | ''This is risk-adapted therapy for <u>high-risk</u> patients in GIMEMA AIDA-2000. The authors were unclear about how many days were between each part of consolidation therapy.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin | + | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction |
− | ==== | + | </div> |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Targeted therapy, all portions==== | ||
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days | *[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days | ||
− | *[[Cytarabine ( | + | ====Chemotherapy, A portion (cycle 1)==== |
+ | *[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 4 | ||
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4 | *[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4 | ||
− | + | ====Chemotherapy, B portion (cycle 2)==== | |
− | |||
− | |||
− | ====Chemotherapy, | ||
− | |||
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
− | + | ====Chemotherapy, C portion (cycle 3)==== | |
− | + | *[[Cytarabine (Ara-C)]] 150 mg/m<sup>2</sup> SC every 8 hours on days 1 to 5 (total dose: 2250 mg/m<sup>2</sup>) | |
− | |||
− | ====Chemotherapy, | ||
− | |||
− | *[[Cytarabine ( | ||
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1 | *[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1 | ||
− | *[[Thioguanine (Tabloid)]] 70 mg/m<sup>2</sup> PO every 8 hours ( | + | *[[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==== | |
− | |||
− | |||
− | ====CNS prophylaxis==== | ||
''It is not explicitly stated but presumably these are admixed and given together.'' | ''It is not explicitly stated but presumably these are admixed and given together.'' | ||
*[[Methotrexate (MTX)]] 12 mg IT once prior to each consolidation cycle | *[[Methotrexate (MTX)]] 12 mg IT once prior to each consolidation cycle | ||
*[[Methylprednisolone (Solumedrol)]] 40 mg IT once prior to each consolidation cycle | *[[Methylprednisolone (Solumedrol)]] 40 mg IT once prior to each consolidation cycle | ||
− | + | '''3 cycles (see note)''' | |
− | ''' | + | </div> |
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA alternating with 6-MP, MTX | + | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA alternating with 6-MP, MTX]] maintenance |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''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 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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/20644121/ PubMed] [https://clinicaltrials.gov/study/NCT01064570 NCT01064570] |
− | |||
==Cytarabine & Idarubicin, then Mitoxantrone, then Cytarabine & Idarubicin, with ATRA {{#subobject:ca29a4|Regimen=1}}== | ==Cytarabine & Idarubicin, then Mitoxantrone, then Cytarabine & Idarubicin, with ATRA {{#subobject:ca29a4|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:46f412|Variant=1}}=== | ===Regimen {{#subobject:46f412|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[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:#91cf61" |Non-randomized | ||
|- | |- | ||
|} | |} | ||
''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.'' | ''This is risk-adapted therapy for <u>high-risk younger than 60</u> patients in '''PETHEMA LPA2005'''. Note that it is unclear from the paper which route the cytarabine is given in the third consolidation; this dose can be given by IV or SC routes.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin | + | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction |
− | ==== | + | </div> |
− | *[[All-trans retinoic acid (ATRA)]] | + | <div class="toccolours" style="background-color:#b3e2cd"> |
+ | ====Targeted therapy, all portions==== | ||
+ | *[[All-trans retinoic acid (ATRA)]] 22.5 mg/m<sup>2</sup> PO twice per day on days 1 to 15 | ||
+ | ====Chemotherapy, A portion (cycle 1)==== | ||
*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4 | *[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4 | ||
− | *[[Cytarabine ( | + | *[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 4 |
− | + | ====Chemotherapy, B portion (cycle 2)==== | |
− | |||
− | |||
− | ====Chemotherapy, | ||
− | |||
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
− | + | ====Chemotherapy, C portion (cycle 3)==== | |
− | |||
− | |||
− | ====Chemotherapy, | ||
− | |||
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1 | *[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1 | ||
− | *[[Cytarabine ( | + | *[[Cytarabine (Ara-C)]] 150 mg/m<sup>2</sup> IV or SC every 8 hours on days 1 to 4 (total dose: 1800 mg/m<sup>2</sup>) |
− | + | '''1-month cycle for 3 cycles''' | |
− | '''1-month cycle''' | + | </div> |
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX | + | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''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 | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/20393132/ PubMed] [https://clinicaltrials.gov/study/NCT00408278 NCT00408278] |
− | |||
==Daunorubicin monotherapy {{#subobject:76a47b|Regimen=1}}== | ==Daunorubicin monotherapy {{#subobject:76a47b|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:82b9d5|Variant=1}}=== | ===Regimen {{#subobject:82b9d5|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !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)] |
− | | style="background-color:#1a9851" |Phase | + | |2000-2004 |
+ | | style="background-color:#1a9851" |Phase 3 (E-de-esc) | ||
|[[#Cytarabine_.26_Daunorubicin|Cytarabine & Daunorubicin]] | |[[#Cytarabine_.26_Daunorubicin|Cytarabine & Daunorubicin]] | ||
− | | style="background-color:#d73027" |Inferior OS | + | | style="background-color:#d73027" |Inferior OS (secondary endpoint) |
|- | |- | ||
|} | |} | ||
''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.'' | ''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"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#ATRA_.26_Daunorubicin|ATRA & daunorubicin | + | *[[#ATRA_.26_Daunorubicin|ATRA & daunorubicin]] induction |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Daunorubicin (Cerubidine)]] as follows: | *[[Daunorubicin (Cerubidine)]] as follows: | ||
**Cycle 1: 60 mg/m<sup>2</sup> IV once per day on days 1 to 3 | **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 | **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==== | ====Subsequent treatment==== | ||
− | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX | + | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance |
− | + | </div></div> | |
===References=== | ===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 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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed] |
− | |||
==Idarubicin, then Mitoxantrone, then Idarubicin {{#subobject:6af14e|Regimen=1}}== | ==Idarubicin, then Mitoxantrone, then Idarubicin {{#subobject:6af14e|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:11923f|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2003-07-2462 Sanz et al. 2003 (PETHEMA LPA96)] |
− | | | + | |1996-1999 |
− | + | | style="background-color:#91cf61" |Non-randomized | |
− | |||
− | |||
− | |||
|- | |- | ||
− | |[ | + | |[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:#91cf61" |Non-randomized | ||
|- | |- | ||
|} | |} | ||
''This was the <u>low-risk</u> treatment arm of '''PETHEMA LPA99'''; <u>all patients</u> on '''PETHEMA LPA96''' underwent this consolidation protocol.'' | ''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"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin | + | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction |
− | ====Chemotherapy | + | </div> |
− | *[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4 | + | <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 | |
− | *[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5 | + | **Cycle 3: 12 mg/m<sup>2</sup> IV once on day 1 |
− | + | *[[Mitoxantrone (Novantrone)]] as follows: | |
− | '''1-month cycle | + | **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==== | ====Subsequent treatment==== | ||
− | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX | + | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''PETHEMA LPA96 | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed] | ||
==Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA {{#subobject:49fc49|Regimen=1}}== | ==Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA {{#subobject:49fc49|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #1 {{#subobject:8d3f07|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | === | + | !style="width: 33%"|Dates of enrollment |
− | {| class="wikitable" style="width: | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | ||
− | !style="width: | ||
|- | |- | ||
− | |[ | + | |[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:#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 | | style="background-color:#91cf61" |Non-randomized | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1056/NEJMoa1300874 Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)] |
− | | style="background-color:#91cf61" |Non-randomized | + | |2007-2013 |
+ | | style="background-color:#91cf61" |Non-randomized part of phase 3 RCT | ||
|- | |- | ||
|} | |} | ||
− | ''This is risk-adapted therapy for <u>intermediate- and low-risk</u> patients in | + | ''This is risk-adapted therapy for <u>intermediate- and low-risk</u> patients in GIMEMA AIDA-2000 and for <u>low-risk</u> patients in PETHEMA LPA2005; all patients assigned to the chemotherapy arm of GIMEMA/DSIL APL0406 received this treatment. Note that the number of mitoxantrone doses differs between the protocols.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin | + | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction |
− | ==== | + | </div> |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Targeted therapy, all portions (cycles 1 to 3)==== | ||
*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days | *[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days | ||
− | *[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4 | + | ====Chemotherapy, 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, | + | ====Chemotherapy, mitoxantrone portion (cycle 2)==== |
− | + | *[[Mitoxantrone (Novantrone)]] by the following study-specific criteria: | |
− | *[[Mitoxantrone (Novantrone)]] | + | **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> | |
− | '''1-month cycle | + | <div class="toccolours" style="background-color:#cbd5e7"> |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *AIDA-2000 and GIMEMA/DSIL APL0406: [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA alternating with 6-MP, MTX | + | *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 | + | *PETHEMA LPA2005: [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance |
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2 {{#subobject:6744ce|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !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 | | 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 | | style="background-color:#91cf61" |Non-randomized | ||
|- | |- | ||
|} | |} | ||
− | ''This is risk-adapted therapy for <u>intermediate-</u> and <u>high-risk</u> patients in | + | ''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==== | ====Preceding treatment==== | ||
− | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin | + | *[[#ATRA_.26_Idarubicin|ATRA & idarubicin]] induction |
− | ==== | + | </div> |
− | *[[All-trans retinoic acid (ATRA)]] | + | <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==== | |
− | ====Chemotherapy, | + | *[[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 | |
− | ====Chemotherapy, | + | '''1-month cycle for 3 cycles''' |
− | *[[ | + | </div> |
− | * | + | <div class="toccolours" style="background-color:#cbd5e7"> |
− | |||
− | '''1-month cycle''' | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX | + | *[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] maintenance |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # '''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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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 | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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 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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/20644121/ PubMed] [https://clinicaltrials.gov/study/NCT01064570 NCT01064570] |
− | # '''GIMEMA/DSIL APL0406:''' Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | ## '''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. [ | + | ## '''Update:''' Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. [https://doi.org/10.1200/JCO.2016.67.1982 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27400939/ PubMed] |
− | + | ## '''Update:''' Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. [https://doi.org/10.1038/s41375-019-0589-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31611624/ PubMed] | |
=Maintenance after upfront therapy= | =Maintenance after upfront therapy= | ||
− | |||
==Arsenic trioxide monotherapy {{#subobject:e1f355|Regimen=1}}== | ==Arsenic trioxide monotherapy {{#subobject:e1f355|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:9f326b|Variant=1}}=== | ===Regimen {{#subobject:9f326b|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !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 | | style="background-color:#91cf61" |Non-randomized | ||
|- | |- | ||
|} | |} | ||
− | ====Preceding treatment==== | + | <div class="toccolours" style="background-color:#cbd5e8"> |
− | *[[#Arsenic_trioxide_monotherapy_2|Arsenic trioxide | + | ====Preceding treatment==== |
− | ==== | + | *[[#Arsenic_trioxide_monotherapy_2|Arsenic trioxide]] consolidation |
− | *[[Arsenic trioxide (Trisenox)]] | + | </div> |
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
− | ''' | + | ====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''' | ||
+ | </div></div> | ||
===References=== | ===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. [ | + | # 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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | ## '''Update:''' Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, Viswabandya A, Thirugnanam R, Abraham A, Shaji RV, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010 Aug 20;28(24):3866-71. Epub 2010 Jul 19. [https://doi.org/10.1200/jco.2010.28.5031 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20644086/ PubMed] |
==ATRA monotherapy {{#subobject:8c70f0|Regimen=1}}== | ==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 |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 20%"|Comparator |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | !style="width: | ||
− | !style="width: | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ Powell et al. 2010 (C9710)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ Powell et al. 2010 (C9710)] | ||
− | | style="background-color:#1a9851" |Phase | + | |1999-2005 |
+ | | style="background-color:#1a9851" |Phase 3 (E-de-esc) | ||
|[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] | |[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] | ||
− | | style="background-color:#fee08b" |Might have inferior DFS | + | | style="background-color:#fee08b" |Might have inferior DFS (secondary endpoint) |
|- | |- | ||
|} | |} | ||
''Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.'' | ''Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#Arsenic_trioxide | + | *[[#Arsenic_trioxide-ATRA_.26_Daunorubicin|Arsenic trioxide-ATRA & Daunorubicin]] versus [[#ATRA_.26_Daunorubicin|ATRA & Daunorubicin]] consolidation |
− | ==== | + | </div> |
− | *[[All-trans retinoic acid (ATRA)]] | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | + | ====Targeted therapy==== | |
− | '''1 year | + | *[[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> |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | !style="width: | + | ===Regimen variant #2 {{#subobject:dc527a|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !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" |[ | + | | rowspan="3" |[https://doi.org/10.1182/blood.V90.3.1014 Mandelli et al. 1997 (GIMEMA AIDA 0493)] |
− | | rowspan="3" style="background-color:#1a9851" |Phase | + | |rowspan=3|1993-1996 |
− | |[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] | + | | rowspan="3" style="background-color:#1a9851" |Phase 3 (E-switch-ooc) |
− | | style="background-color:#ffffbf" | | + | |1. [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] |
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS | ||
|- | |- | ||
− | |[[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]] | + | |2. [[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]] |
− | | style="background-color:#ffffbf" | | + | | 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" | | + | | style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS |
|- | |- | ||
− | | rowspan="2" |[ | + | | rowspan="2" |[https://doi.org/10.1182/blood.V94.4.1192 Fenaux et al. 1999 (EAPLG APL 93)] |
− | | rowspan="2" style="background-color:#1a9851" |Phase | + | |rowspan=2|1993-1996 |
− | |[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] | + | | 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 | | style="background-color:#d73027" |Inferior 2-year relapse rate | ||
|- | |- | ||
− | |[[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]]<br> [[# | + | |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 | | style="background-color:#91cf60" |Seems to have superior 2-year relapse rate | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====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 | + | *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 | + | *EAPLG APL 93: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation |
− | ==== | + | </div> |
− | *[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | + | ====Targeted therapy==== | |
− | '''2 | + | *[[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=== | ||
− | # '''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 | + | # '''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 | + | ## '''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] '''dosing details in manuscript have been reviewed by our editors''' [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; | + | # '''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. [ | + | ## '''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] |
− | # '''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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20705755/ PubMed] [https://clinicaltrials.gov/study/NCT00003934 NCT00003934] |
− | |||
==ATRA, Mercaptopurine, Methotrexate {{#subobject:b44ab6|Regimen=1}}== | ==ATRA, Mercaptopurine, Methotrexate {{#subobject:b44ab6|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen variant #1, 45/50/15 {{#subobject:80d40a|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2003-07-2462 Sanz et al. 2003 (PETHEMA LPA99)] |
− | | | + | |1999-2002 |
− | + | | style="background-color:#91cf61" |Non-randomized | |
− | |||
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
− | |[https:// | + | |[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:# | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#cbd5e8"> | |
====Preceding treatment==== | ====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==== | ====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 |
− | *[[Methotrexate (MTX)]] | + | '''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 |
− | {| class="wikitable" style="width: | + | *[[Methotrexate (MTX)]] and [[Mercaptopurine (6-MP)]] stopped if WBC count less than 2.5 x 10<sup>9</sup>/L |
− | !style="width: | + | </div></div><br> |
− | !style="width: | + | <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)] |
− | | style="background-color:#91cf61" |Non-randomized | + | |2007-2013 |
+ | | style="background-color:#91cf61" |Non-randomized part of phase 3 RCT | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====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==== | ====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 |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | '''3-month cycle for 4 cycles''' |
− | !style="width: | + | </div></div><br> |
− | !style="width: | + | <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)] |
− | | style="background-color:# | + | |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 starts | + | ''Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====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==== | ====Chemotherapy==== | ||
− | + | *[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day | |
− | *[[Mercaptopurine ( | + | *[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 1 & 8 |
− | *[[Methotrexate (MTX)]] | + | '''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]] |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | !style="width: 20%"|Comparator |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | !style="width: | + | |- |
+ | | 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)] |
− | | style="background-color:# | + | |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:# | + | | style="background-color:#1a9850" |Superior 2-year relapse rate |
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====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==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Mercaptopurine (6-MP)]] as follows: |
− | * | + | **Cycles 1 & 3: 90 mg/m<sup>2</sup> PO once per day |
− | *[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IM once per week | + | *[[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" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
− | !style="width: | + | !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 | |
− | | style="background-color:# | ||
|- | |- | ||
− | | | + | |} |
− | + | <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==== | |
− | | style=" | + | *[[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)] |
− | | style="background-color:# | + | |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==== | ====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==== | ====Chemotherapy==== | ||
− | *[[Mercaptopurine ( | + | *[[Mercaptopurine (6-MP)]] 50 to 90 mg/m<sup>2</sup> PO once per day on days 15 to 90 |
− | *[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> | + | *[[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=== | ||
− | # '''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 | + | # '''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 | + | ## '''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] '''dosing details in manuscript have been reviewed by our editors''' [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; | + | # '''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. [ | + | ## '''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] |
− | # '''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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/17975017/ PubMed] |
− | # '''EAPLG APL 2000:''' Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; | + | # '''EAPLG 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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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 | + | # '''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] |
− | # '''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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20705755/ PubMed] [https://clinicaltrials.gov/study/NCT00003934 NCT00003934] |
− | # '''ALLG APML4:''' Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/22715121/ PubMed] ACTRN12605000070639 |
− | # '''GIMEMA/DSIL APL0406:''' Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [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. [ | + | ## '''Update:''' Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. [https://doi.org/10.1200/JCO.2016.67.1982 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27400939/ PubMed] |
+ | ## '''Update:''' Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, Lo-Coco F. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020 Mar;34(3):914-918. Epub 2019 Oct 14. [https://doi.org/10.1038/s41375-019-0589-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31611624/ PubMed] | ||
==Mercaptopurine & Methotrexate {{#subobject:a29183|Regimen=1}}== | ==Mercaptopurine & Methotrexate {{#subobject:a29183|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <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 | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | | style="background-color:#1a9851" |Phase | ||
− | |[[# | ||
− | | style="background-color:#ffffbf" | | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====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 | + | *[[#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==== | ====Chemotherapy==== | ||
− | *[[Mercaptopurine ( | + | *[[Mercaptopurine (6-MP)]] 1 mg/kg PO once per day |
*[[Methotrexate (MTX)]] 0.25 mg/kg IM once per week | *[[Methotrexate (MTX)]] 0.25 mg/kg IM once per week | ||
− | + | '''2-year course''' | |
− | '''2-year course | + | </div></div><br> |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | === | + | ===Regimen variant #2 {{#subobject:bab868|Variant=1}}=== |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !style="width: | + | !style="width: 20%"|Study |
− | !style="width: | + | !style="width: 20%"|Dates of enrollment |
− | !style="width: | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | | rowspan="3" |[ | + | | rowspan="3" |[https://doi.org/10.1182/blood.V90.3.1014 Mandelli et al. 1997 (GIMEMA AIDA 0493)] |
− | | rowspan="3" style="background-color:#1a9851" |Phase | + | |rowspan=3|1993-1996 |
− | |[[#ATRA_monotherapy_2|ATRA]] | + | | rowspan="3" style="background-color:#1a9851" |Phase 3 (C) |
− | | style="background-color:#ffffbf" | | + | |1. [[#ATRA_monotherapy_2|ATRA]] |
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS | ||
|- | |- | ||
− | |[[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] | + | |2. [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] |
− | | style="background-color:#ffffbf" | | + | | 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" | | + | | style="background-color:#ffffbf" |Did not meet primary endpoint of molecular DFS |
|- | |- | ||
− | | rowspan="2" |[ | + | | rowspan="2" |[https://doi.org/10.1182/blood.V94.4.1192 Fenaux et al. 1999 (EAPLG APL 93)] |
− | | rowspan="2" style="background-color:#1a9851" |Phase | + | |rowspan=2|1993-1996 |
− | |[[#ATRA_monotherapy_2|ATRA]]<br> [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX]] | + | | 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 | | 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 | | style="background-color:#1a9850" |Superior 2-year relapse rate | ||
|- | |- | ||
|} | |} | ||
− | ''Note that this arm was dropped from | + | ''Note that this arm was dropped from AIDA 0493 from February 1997.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====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 | + | *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 | + | *EAPLG APL 93: [[#Cytarabine_.26_Daunorubicin|Cytarabine & daunorubicin]] consolidation |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Mercaptopurine ( | + | *[[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 | *[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IM once per week | ||
− | + | '''2-year course''' | |
− | '''2-year course | + | </div></div> |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
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− | |||
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− | |||
− | |||
− | |||
− | |||
===References=== | ===References=== | ||
− | # '''GIMEMA AIDA 0493:''' Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto | + | # '''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 | + | ## '''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] '''dosing details in manuscript have been reviewed by our editors''' [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; | + | # '''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. [ | + | ## '''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] |
− | # '''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 | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/12384411/ PubMed] |
− | |||
=Relapsed or refractory, salvage induction therapy= | =Relapsed or refractory, salvage induction therapy= | ||
− | |||
==Arsenic trioxide monotherapy {{#subobject:734f95|Regimen=1}}== | ==Arsenic trioxide monotherapy {{#subobject:734f95|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #1, 0.15 mg/kg/day {{#subobject:ffaa29|Variant=1}}=== | |
− | + | {| class="wikitable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | === | + | !style="width: 33%"|Dates of enrollment |
− | {| class="wikitable" style="width: | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | !style="width: | ||
− | !style="width: | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1056/NEJM199811053391901 Soignet et al. 1998] |
− | | style="background-color:#ffffbe" |Non-randomized, | + | |Not reported |
+ | | style="background-color:#ffffbe" |Non-randomized, fewer than 20 pts | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/JCO.2001.19.18.3852 Soignet et al. 2001 (PLRXAS01)] |
− | | style="background-color:#91cf61" |Phase | + | |1998-1999 |
+ | | style="background-color:#91cf61" |Phase 2 (RT) | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#b3e2cd"> |
+ | ====Targeted therapy==== | ||
*[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 2 hours once per day | *[[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==== | ====Subsequent treatment==== | ||
− | * | + | *PLRXAS01, CR: [[#Arsenic_trioxide_monotherapy_5|Arsenic trioxide]] consolidation, then optional maintenance |
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2, 10 mg/day {{#subobject:e2687c|Variant=1}}=== |
− | !style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !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] |
− | | style="background-color:#ffffbe" |Non-randomized, | + | |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 | *[[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=== | ||
− | # 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. [ | + | # 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. [ | + | # 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] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/9801394/ PubMed] |
− | # 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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/11559723/ PubMed] |
− | |||
==Arsenic trioxide & Idarubicin {{#subobject:90ec9f|Regimen=1}}== | ==Arsenic trioxide & Idarubicin {{#subobject:90ec9f|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:4d76db|Variant=1}}=== | ===Regimen {{#subobject:4d76db|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2012-11-466862 Yanada et al. 2013 (JALSG APL205R)] |
− | | style="background-color:#91cf61" |Phase | + | |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==== | ====Chemotherapy==== | ||
− | + | *[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 | |
− | *[[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==== | ====Subsequent treatment==== | ||
− | *[[#Arsenic_trioxide_monotherapy_5|Arsenic trioxide | + | *[[#Arsenic_trioxide_monotherapy_5|Arsenic trioxide]] consolidation |
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/23412094/ PubMed] [https://clinicaltrials.gov/study/NCT01908621 NCT01908621] |
==Tamibarotene monotherapy {{#subobject:fbdb9f|Regimen=1}}== | ==Tamibarotene monotherapy {{#subobject:fbdb9f|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:5d009e|Variant=1}}=== | ===Regimen {{#subobject:5d009e|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !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] | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770883/ Sanford et al. 2015 (STAR-1)] |
− | | style="background-color:#ffffbe" |Phase | + | |2007-2011 |
+ | | style="background-color:#ffffbe" |Phase 2, fewer than 20 pts | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | *[[Tamibarotene (Amnoid)]] | + | ====Targeted therapy==== |
− | + | *[[Tamibarotene (Amnoid)]] 3 mg/m<sup>2</sup> PO twice per day | |
'''Up to 56-day course''' | '''Up to 56-day course''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | * | + | *STAR-1, patients achieving CR: [[#Tamibarotene_monotherapy_888|Tamibarotene]] consolidation, if not proceeding to transplant |
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # 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:// | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/26205361/ PubMed] [https://clinicaltrials.gov/study/NCT00520208 NCT00520208] |
− | |||
=Consolidation after salvage therapy= | =Consolidation after salvage therapy= | ||
==Arsenic trioxide monotherapy {{#subobject:5de745|Regimen=1}}== | ==Arsenic trioxide monotherapy {{#subobject:5de745|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:36556f|Variant=1}}=== | ===Regimen {{#subobject:36556f|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2012-11-466862 Yanada et al. 2013 (JALSG APL205R)] |
− | | style="background-color:#91cf61" |Phase | + | |2005-2009 |
+ | | 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==== | ====Preceding treatment==== | ||
− | *[[#Arsenic_trioxide_.26_Idarubicin|Arsenic trioxide & Idarubicin re-induction | + | *[[#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 | *[[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''' | '''2 cycles''' | ||
− | ==== | + | </div> |
− | *[[Stem_cell_mobilization#Cytarabine_.26_G-CSF|HiDAC & G-CSF stem cell mobilization | + | <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=== | ||
− | # 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. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/23412094/ PubMed] [https://clinicaltrials.gov/study/NCT01908621 NCT01908621] |
− | |||
==Busulfan & Melphalan, then auto HSCT {{#subobject:ceba5e|Regimen=1}}== | ==Busulfan & Melphalan, then auto HSCT {{#subobject:ceba5e|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:8c92e5|Variant=1}}=== | ===Regimen {{#subobject:8c92e5|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !style="width: | + | !style="width: 33%"|Study |
− | !style="width: | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2012-11-466862 Yanada et al. 2013 (JALSG APL205R)] |
− | | style="background-color:#91cf61" |Phase | + | |2005-2009 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[Stem_cell_mobilization#Cytarabine_.26_G-CSF|HiDAC & G-CSF stem cell mobilization | + | *[[Stem_cell_mobilization#Cytarabine_.26_G-CSF|HiDAC & G-CSF]] stem cell mobilization |
+ | </div> | ||
{{#lst:Autologous HSCT|c5fc8f}} | {{#lst:Autologous HSCT|c5fc8f}} | ||
+ | </div> | ||
===References=== | ===References=== | ||
− | # Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. [ | + | # '''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/23412094/ PubMed] [https://clinicaltrials.gov/study/NCT01908621 NCT01908621] |
− | |||
[[Category:Acute promyelocytic leukemia regimens]] | [[Category:Acute promyelocytic leukemia regimens]] | ||
[[Category:Disease-specific pages]] | [[Category:Disease-specific pages]] | ||
[[Category:Acute leukemias]] | [[Category:Acute leukemias]] | ||
+ | [[Category:Myeloid neoplasms]] |
Latest revision as of 23:37, 15 July 2024
Section editor | |
---|---|
Ashwin Kishtagari, MD Vanderbilt University Nashville, TN, USA |
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
- 2019: Sanz et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet PubMed
- 2009: Sanz et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet PubMed
ESMO
- 2013: Fey et al. Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
NCCN
- NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Acute Myeloid Leukemia.
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
- Cytarabine (Ara-C) 100 mg/m2 IV once every 12 hours on days 1 to 10 (total dose: 2000 mg/m2)
- Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1, 3, 5
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
Targeted therapy
- All-trans retinoic acid (ATRA) 45 mg/m2/day PO, starting on day 1 and continuing until remission or maximum of 60 days
One course
Subsequent treatment
- UK MRC AML15: ADE 8-3-5 + ATRA consolidation
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. link to original article PubMed 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. link to original article 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. link to original article 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. link to original article dosing details in manuscript have been reviewed by our editors 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. 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
- Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 2 to 3 hours once per day
Continued until CR or up to 60 days
Subsequent treatment
- Mathews et al. 2006, patients in CR: Arsenic trioxide consolidation
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 |
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
- Arsenic trioxide (Trisenox) 10 mg IV over 2 to 3 hours once per day
Continued until CR or up to 60 days
Subsequent treatment
- Mathews et al. 2006, patients in CR: Arsenic trioxide consolidation
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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article 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. link to original article dosing details in manuscript have been reviewed by our editors 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. 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
- Arsenic trioxide & ATRA consolidation
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
- 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/m2 PO twice per day, starting day 1 and continuing until remission or maximum of 90 days.
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
- Arsenic trioxide & ATRA consolidation
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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article 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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed content property of 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. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article 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. link to full article dosing details in manuscript have been reviewed by our editors link to PMC article 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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00482833
- HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article 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. link to original article 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. link to original article 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. link to original article dosing details in manuscript have been reviewed by our editors PubMed ChiCTR-TRC-12002151
- 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 dosing details in manuscript have been reviewed by our editors 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. 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
- Gemtuzumab ozogamicin (Mylotarg) by the following laboratory-based criteria:
- WBC count more than 10 x 109/L: 6 mg/m2 IV once on day 1
One course
Subsequent treatment
- Arsenic trioxide & ATRA consolidation
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
- 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/m2 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 109/L: 9 mg/m2 IV once on day 1
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
- Arsenic trioxide & ATRA consolidation
References
- Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article dosing details in manuscript have been reviewed by our editors 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. link to full article dosing details in manuscript have been reviewed by our editors link to PMC article 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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article 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. link to full article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
- 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 dosing details in manuscript have been reviewed by our editors 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. 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
- 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/m2 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/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
- Arsenic trioxide & ATRA consolidation, in 3 to 4 weeks
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. link to original article dosing details in manuscript have been reviewed by our editors PubMed ACTRN12605000070639
ATRA monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Warrell et al. 1991 | Not reported | 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
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day, starting day 1 and continuing until remission or maximum of 90 days
One course
Subsequent treatment
- EAPLG APL 91: Cytarabine & daunorubicin consolidation
- ECOG E2491: ATRA consolidation, then cytarabine & daunorubicin consolidation
References
- Warrell RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri LM, Hittelman WN, Vyas R, Andreeff M, Tafuri A, Jakubowski A, Gabrilove J, Gordon MS, Dmitrovsky E. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991 May 16;324(20):1385-93. link to original article PubMed
- EAPLG APL 91: Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D, Huebner G, Bauters F, Fegueux N, Fey M, Sanz M, Lowenberg B, Maloisel F, Auzanneau G, Sadoun A, Gardin C, Bastion Y, Ganser A, Jacky E, Dombret H, Chastang C, Degos L; European APL Group. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. Blood. 1993 Dec 1;82(11):3241-9. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Update: Fenaux P, Chevret S, Guerci A, Fegueux N, Dombret H, Thomas X, Sanz M, Link H, Maloisel F, Gardin C, Bordessoule D, Stoppa AM, Sadoun A, Muus P, Wandt H, Mineur P, Whittaker JA, Fey M, Daniel MT, Castaigne S, Degos L; European APL Group. Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. Leukemia. 2000 Aug;14(8):1371-7. link to original article PubMed
- 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 dosing details in manuscript have been reviewed by our editors 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. 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
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day, starting day 1 and continuing until remission or maximum of 90 days
Chemotherapy
- Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 3 (total dose: 1400 mg/m2)
- Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 3 to 5
Up to 90-day course
Subsequent treatment
- Cytarabine & daunorubicin consolidation
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
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day, starting day 1 and continuing until remission or maximum of 90 days
Chemotherapy
- Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 3 (total dose: 1400 mg/m2)
- Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 3 to 6
Up to 90-day course
Subsequent treatment
- Arsenic trioxide-ATRA & Ddaunorubicin versus ATRA & Daunorubicin consolidation
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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00591526
- Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article dosing details in manuscript have been reviewed by our editors 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
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day, starting on day 1 and continuing until complete remission
Chemotherapy
- Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 3 (total dose: 1400 mg/m2)
- Idarubicin (Idamycin) 12 mg/m2 IV once per day on days 3 to 5
One course until CR
Subsequent treatment
- APL 2006, patients with baseline WBC less than 10 x 109/L: Cytarabine & Idarubicin versus Arsenic trioxide & Idarubicin versus ATRA & Idarubicin consolidation
- APL 2006, patients with baseline WBC greater than 10 x 109/L: Cytarabine & Idarubicin versus Arsenic trioxide, Cytarabine, Idarubicin consolidation
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. link to original article dosing details in manuscript have been reviewed by our editors 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
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day, starting on day 1 and continuing until remission or maximum of 90 days
Chemotherapy
- Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 3 to 5
Up to 90-day course
Subsequent treatment
- Daunorubicin consolidation
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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00591526
- Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article dosing details in manuscript have been reviewed by our editors 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:
- PETHEMA LPA96: Idarubicin, then mitoxantrone, then idarubicin consolidation
- GIMEMA AIDA & GIMEMA AIDA 0493: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
- PETHEMA LPA99, low-risk patients: Idarubicin, then mitoxantrone, then idarubicin consolidation
- PETHEMA LPA99, intermediate-risk and high-risk patients: Idarubicin, then mitoxantrone, then idarubicin, with ATRA consolidation
- PETHEMA LPA2005, high-risk patients: Cytarabine & idarubicin, then mitoxantrone, then cytarabine & idarubicin, with ATRA consolidation
- PETHEMA LPA2005, intermediate-risk and low-risk patients: Idarubicin, then mitoxantrone, then idarubicin, with ATRA consolidation
- GIMEMA AIDA-2000, high-risk patients: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine, with ATRA consolidation
- GIMEMA AIDA-2000, intermediate-risk and low-risk patients: Idarubicin, then mitoxantrone, then idarubicin, with ATRA consolidation
- GIMEMA AIDA 0493 amended protocol: Cytarabine & idarubicin consolidation
- GIMEMA/DSIL APL0406 and UK NCRI AML17APL: Idarubicin, then mitoxantrone, then idarubicin, with ATRA consolidation
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. link to full article dosing details in manuscript have been reviewed by our editors 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. link to original article contains partial protocol 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. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00465933
- Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00408278
- GIMEMA AIDA-2000: Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed 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. link to full article dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00482833
- HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article 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. link to original article 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. link to original article PubMed
- 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
- 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
- Arsenic trioxide induction
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
- Mathews et al. 2006, patients remaining in CR: Arsenic trioxide maintenance
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. link to original article dosing details in manuscript have been reviewed by our editors 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. 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
- ATRA, cytarabine, daunorubicin induction
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/m2 PO twice per day on days 1 to 7
Chemotherapy
- Daunorubicin (Cerubidine) as follows:
- Cycles 2 & 3: 50 mg/m2 IV once per day on days 1 to 3
7-week course, then 39-day cycle for 2 cycles
Subsequent treatment
- ATRA maintenance versus ATRA, 6-MP, MTX maintenance
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. link to original article dosing details in manuscript have been reviewed by our editors 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
- Arsenic trioxide & ATRA induction
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/m2 PO twice per day on days 1 to 14
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
- Arsenic trioxide, ATRA, idarubicin induction
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
- ATRA, 6-MP, MTX maintenance, after 3 to 4 weeks
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. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors PubMed ACTRN12605000070639
- GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00482833
- HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article 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. link to original article 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. link to original article PubMed
- 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
- 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
- ATRA, cytarabine, daunorubicin induction
Targeted therapy
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day on days 1 to 7
Chemotherapy
- Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3
39-day cycle for 2 cycles
Subsequent treatment
- ATRA versus ATRA, 6-MP, MTX maintenance
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. link to original article dosing details in manuscript have been reviewed by our editors 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
- ATRA, cytarabine, daunorubicin induction
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
- Methotrexate (MTX) 15 mg IT
- Cytarabine (Ara-C) 50 mg IT
- Corticosteroids IT (type not specified)
5 doses throughout consolidation
Subsequent treatment
- ATRA, 6-MP, MTX maintenance
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
- ATRA, cytarabine, daunorubicin induction
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
- Methotrexate (MTX) 15 mg IT
- Cytarabine (Ara-C) 50 mg IT
- Corticosteroids IT (type not specified)
5 doses throughout consolidation
Subsequent treatment
- ATRA, 6-MP, MTX maintenance
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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00591526
- Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article dosing details in manuscript have been reviewed by our editors 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
- ATRA & idarubicin induction
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
- ATRA maintenance
References
- GIMEMA AIDA 0493 amended protocol: Latagliata R, Breccia M, Fazi P, Vignetti M, Di Raimondo F, Sborgia M, Vincelli D, Candoni A, Salvi F, Rupoli S, Martinelli G, Kropp MG, Tonso A, Venditti A, Melillo L, Cimino G, Petti MC, Avvisati G, Lo-Coco F, Mandelli F; GIMEMA Acute Leukaemia Working Party. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia: long-term results and prognostic factors. Br J Haematol. 2011 Sep;154(5):564-8. Epub 2011 Jul 14. link to full article dosing details in manuscript have been reviewed by our editors 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
- GIMEMA LAP 0389: Idarubicin versus cytarabine & idarubicin induction (neither with ATRA; no longer standard of care)
- GIMEMA AIDA & GIMEMA AIDA 0493: ATRA & idarubicin induction
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)
- Etoposide (Vepesid) 100 mg/m2 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/m2 IV once per day on days 1 to 5, given first
Chemotherapy, C portion (Course 3)
- Cytarabine (Ara-C) 150 mg/m2 SC every 8 hours on days 1 to 5
- Idarubicin (Idamycin) by the following study-specific criteria:
- GIMEMA LAP 0389: 5 mg/m2 IV once on day 1
- GIMEMA AIDA & GIMEMA AIDA 0493: 12 mg/m2 IV once on day 1
- Thioguanine (Tabloid) 70 mg/m2 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 109/L or more."
Subsequent treatment
- GIMEMA LAP 0389: 6-MP & MTX maintenance versus no further treatment
- GIMEMA AIDA 0493: ATRA maintenance versus ATRA, 6-MP, MTX maintenance versus 6-MP & MTX maintenance versus no further treatment
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. link to full article dosing details in manuscript have been reviewed by our editors 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. link to original article contains partial protocol 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. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors 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
- ATRA & idarubicin induction
Targeted therapy, all portions
- All-trans retinoic acid (ATRA) 45 mg/m2/day PO for a total of 15 days
Chemotherapy, A portion (cycle 1)
- Cytarabine (Ara-C) 1000 mg/m2 IV once per day on days 1 to 4
- Idarubicin (Idamycin) 5 mg/m2 IV once per day on days 1 to 4
Chemotherapy, B portion (cycle 2)
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
- Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 to 5
Chemotherapy, C portion (cycle 3)
- Cytarabine (Ara-C) 150 mg/m2 SC every 8 hours on days 1 to 5 (total dose: 2250 mg/m2)
- Idarubicin (Idamycin) 12 mg/m2 IV once on day 1
- Thioguanine (Tabloid) 70 mg/m2 PO every 8 hours on days 1 to 5 (total dose: 1050 mg/m2)
CNS prophylaxis, all portions
It is not explicitly stated but presumably these are admixed and given together.
- Methotrexate (MTX) 12 mg IT once prior to each consolidation cycle
- Methylprednisolone (Solumedrol) 40 mg IT once prior to each consolidation cycle
3 cycles (see note)
Subsequent treatment
- ATRA alternating with 6-MP, MTX maintenance
References
- 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 dosing details in manuscript have been reviewed by our editors 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
- ATRA & idarubicin induction
Targeted therapy, all portions
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day on days 1 to 15
Chemotherapy, A portion (cycle 1)
- Idarubicin (Idamycin) 5 mg/m2 IV once per day on days 1 to 4
- Cytarabine (Ara-C) 1000 mg/m2 IV once per day on days 1 to 4
Chemotherapy, B portion (cycle 2)
- Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 to 5
Chemotherapy, C portion (cycle 3)
- Idarubicin (Idamycin) 12 mg/m2 IV once on day 1
- Cytarabine (Ara-C) 150 mg/m2 IV or SC every 8 hours on days 1 to 4 (total dose: 1800 mg/m2)
1-month cycle for 3 cycles
Subsequent treatment
- ATRA, 6-MP, MTX maintenance
References
- 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 dosing details in manuscript have been reviewed by our editors 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
- ATRA & daunorubicin induction
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
- ATRA, 6-MP, MTX maintenance
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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00591526
- Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article dosing details in manuscript have been reviewed by our editors 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
- ATRA & idarubicin induction
Chemotherapy
- 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
- Mitoxantrone (Novantrone) as follows:
- Cycle 2: 10 mg/m2 IV once per day on days 1 to 5
1-month cycle for 3 cycles
Subsequent treatment
- ATRA, 6-MP, MTX maintenance
References
- 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 dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00465933
- Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article dosing details in manuscript have been reviewed by our editors 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
- ATRA & idarubicin induction
Targeted therapy, all portions (cycles 1 to 3)
- All-trans retinoic acid (ATRA) 45 mg/m2/day PO for a total of 15 days
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
- GIMEMA AIDA-2000 and GIMEMA/DSIL APL0406: ATRA alternating with 6-MP, MTX maintenance
- PETHEMA LPA2005: ATRA, 6-MP, MTX maintenance
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
- ATRA & idarubicin induction
Targeted therapy, all portions (cycles 1 to 3)
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day on days 1 to 15
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
- ATRA, 6-MP, MTX maintenance
References
- 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00465933
- Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00408278
- GIMEMA AIDA-2000: Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01064570
- GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00482833
- HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article 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. link to original article 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. 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
- Arsenic trioxide consolidation
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
- 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 dosing details in manuscript have been reviewed by our editors 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. 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
- Arsenic trioxide-ATRA & Daunorubicin versus ATRA & Daunorubicin consolidation
Targeted therapy
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day on days 1 to 7
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
- GIMEMA AIDA 0493: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
- EAPLG APL 93: Cytarabine & daunorubicin consolidation
Targeted therapy
- All-trans retinoic acid (ATRA) 45 mg/m2/day PO on days 1 to 15
3-month cycle for 8 cycles (2 years)
References
- GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol 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. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article 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. link to original article PubMed
- C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article dosing details in manuscript have been reviewed by our editors 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
- PETHEMA LPA99, low-risk: Idarubicin, then Mitoxantrone, then Idarubicin consolidation
- PETHEMA LPA99, intermediate- and high-risk and PETHEMA LPA2005, low- and intermediate-risk: Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA consolidation
- PETHEMA LPA2005, high-risk: Cytarabine & Idarubicin, then Mitoxantrone, then Cytarabine & Idarubicin, with ATRA consolidation
Targeted therapy
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day on days 1 to 15
Chemotherapy
- Mercaptopurine (6-MP) 50 mg/m2 PO once per day
- Methotrexate (MTX) 15 mg/m2 IM once per week
90-day cycle for 8 cycles (2 years)
Dose and schedule modifications
- Methotrexate (MTX) and Mercaptopurine (6-MP) decreased by 50% if WBC count less than 3.5 x 109/L
- Methotrexate (MTX) and Mercaptopurine (6-MP) stopped if WBC count less than 2.5 x 109/L
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
- Mercaptopurine (6-MP) as follows:
- Cycles 1 & 3: 50 mg/m2 PO once per day
- Methotrexate (MTX) as follows:
- Cycles 1 & 3: 15 mg/m2 IM or PO once per week
Targeted therapy
- All-trans retinoic acid (ATRA) as follows:
- Cycles 2 & 4: 45 mg/m2/day PO on days 1 to 15
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
- Arsenic trioxide-ATRA & Daunorubicin versus ATRA & daunorubicin consolidation
Targeted therapy
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day on days 1 to 7
Chemotherapy
- Mercaptopurine (6-MP) 60 mg/m2 PO once per day
- Methotrexate (MTX) 20 mg/m2 PO once per day on days 1 & 8
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
- GIMEMA AIDA 0493: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
- EAPLG APL 93: Cytarabine & daunorubicin consolidation
Chemotherapy
- Mercaptopurine (6-MP) as follows:
- Cycles 1 & 3: 90 mg/m2 PO once per day
- Methotrexate (MTX) as follows:
- Cycles 1 & 3: 15 mg/m2 IM once per week
Targeted therapy
- All-trans retinoic acid (ATRA) as follows:
- Cycles 2 & 4: 45 mg/m2/day PO on days 1 to 15
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
- Cytarabine & daunorubicin consolidation versus daunorubicin consolidation
Targeted therapy
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day on days 1 to 15
Chemotherapy
- Mercaptopurine (6-MP) 50 to 90 mg/m2 PO once per day
- Methotrexate (MTX) 15 mg/m2 PO once per week
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
- Arsenic trioxide & ATRA consolidation
Targeted therapy
- All-trans retinoic acid (ATRA) 22.5 mg/m2 PO twice per day on days 1 to 14
Chemotherapy
- Mercaptopurine (6-MP) 50 to 90 mg/m2 PO once per day on days 15 to 90
- Methotrexate (MTX) 5 to 15 mg/m2/week PO on days 15 to 90
90-day cycle for 8 cycles (2 years)
Dose and schedule modifications
- Methotrexate (MTX) and Mercaptopurine (6-MP) doses titrated to ANC 1000 to 2000/μL and minimizing hepatotoxicity
References
- GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol 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. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article 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. link to original article 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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00465933
- Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00591526
- Pooled subgroup analysis: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article PubMed NCT00408278
- C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00003934
- ALLG APML4: Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed ACTRN12605000070639
- GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00482833
- HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article 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. link to original article 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. 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
- Mercaptopurine (6-MP) 1 mg/kg PO once per day
- Methotrexate (MTX) 0.25 mg/kg IM once per week
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
- GIMEMA AIDA 0493: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
- EAPLG APL 93: Cytarabine & daunorubicin consolidation
Chemotherapy
- Mercaptopurine (6-MP) 90 mg/m2 PO once per day
- Methotrexate (MTX) 15 mg/m2 IM once per week
2-year course
References
- GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto; Associazione Italiana di Ematologia ed Oncologia Pediatrica. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol 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. link to original article dosing details in manuscript have been reviewed by our editors 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. link to original article 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. link to original article 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. link to original article dosing details in manuscript have been reviewed by our editors 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 | Not reported | Non-randomized, fewer than 20 pts |
Soignet et al. 2001 (PLRXAS01) | 1998-1999 | Phase 2 (RT) |
Targeted therapy
- Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 2 hours once per day
Continued until CR or up to 60 days
Subsequent treatment
- PLRXAS01, CR: Arsenic trioxide consolidation, then optional maintenance
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
- Arsenic trioxide (Trisenox) 10 mg IV over 2 to 3 hours once per day
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
- 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
- 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 dosing details in abstract have been reviewed by our editors PubMed
- PLRXAS01: Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers EL, Coutré S, Dahlberg S, Ellison R, Warrell RP Jr. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001 Sep 15;19(18):3852-60. link to original article dosing details in manuscript have been reviewed by our editors 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
- Idarubicin (Idamycin) 12 mg/m2 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
Subsequent treatment
- Arsenic trioxide consolidation
References
- JALSG APL205R: Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01908621
Tamibarotene monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Sanford et al. 2015 (STAR-1) | 2007-2011 | Phase 2, fewer than 20 pts |
Subsequent treatment
- STAR-1, patients achieving CR: Tamibarotene consolidation, if not proceeding to transplant
References
- 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 dosing details in manuscript have been reviewed by our editors 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
- Arsenic trioxide & Idarubicin re-induction
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
Subsequent treatment
- HiDAC & G-CSF stem cell mobilization, then Bu/Mel with auto HSCT consolidation
References
- JALSG APL205R: Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. link to original article dosing details in manuscript have been reviewed by our editors 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
- HiDAC & G-CSF stem cell mobilization
Chemotherapy
- Busulfan (Myleran) 1 mg/kg PO every 6 hours on days -6 to -4 (total dose of 12 mg/kg)
- Melphalan (Alkeran) 70 mg/m2 IV bolus once per day on days -3 & -2
Supportive therapy
- Autologous stem cells re-infused on day 0
One course
References
- JALSG APL205R: Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01908621