Acute promyelocytic leukemia

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Last updated on 2024-09-06:31 regimens on this page
48 variants on this page
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=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 EuroPMC
*2009: Sanz et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet EuroPMC
==ESMO==
*2013: Fey et al. Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
==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	Longer 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 EuroPMC 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 EuroPMC
# 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 EuroPMC 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 EuroPMC
## 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 EuroPMC
==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 shorter DFS
Shen et al. 2004	2001-2003 	Randomized (C)	2. ATRA 	Not reported
====Targeted therapy====
*Arsenic trioxide (Trisenox) 0.16 mg/kg IV once per day 
Continued until CR
====Subsequent treatment====
*Shen et al. 2004, patients in CR: Consolidation, see text for details
===Regimen variant #3, 10 mg (flat dose)===
Study 	Dates of enrollment	Evidence
Mathews et al. 2006	1998-2004 	Non-randomized
Note: the maximum duration was decreased from 75 to 60 days after 2001.
====Targeted therapy====
*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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
==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 longer 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 trioxide2. ATRA 	Seems to have longer 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 EuroPMC
## 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 EuroPMC 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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC 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 EuroPMC 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 EuroPMC
== 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC 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 EuroPMC
==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 EuroPMC 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 	Longer EFS
Tallman et al. 1997 (ECOG E2491) 	1992-1995 	Phase 3 (E-switch-ooc) 	Cytarabine & Daunorubicin	Longer 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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
==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	Longer 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 EuroPMC 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 EuroPMC
# 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 EuroPMC 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 EuroPMC 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	Shorter OS (secondary endpoint)Seems to have lower 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 EuroPMC 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 EuroPMC
==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 shorter 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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC 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 EuroPMC
# 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 EuroPMC 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 EuroPMC 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 EuroPMC
# 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 EuroPMC 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC 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 EuroPMC
=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 EuroPMC
## 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 EuroPMC
==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	Longer 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 EuroPMC 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 EuroPMC
# 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 EuroPMC 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 EuroPMC 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC 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 EuroPMC
==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	Shorter 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 EuroPMC 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	Longer 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	Longer 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 EuroPMC 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 EuroPMC
==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 EuroPMC
==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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC
==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 EuroPMC 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 EuroPMC 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	Shorter 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 EuroPMC 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 EuroPMC
==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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC 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 EuroPMC
==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 EuroPMC 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 EuroPMC
# 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 EuroPMC 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 EuroPMC 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 EuroPMC 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
=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 EuroPMC
## 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 EuroPMC
==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 shorter 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
Mandelli et al. 1997 (GIMEMA AIDA 0493)	1993-1996 	Phase 3 (E-switch-ooc)	2. 6-MP & MTX 	Did not meet primary endpoint of molecular DFS
Mandelli et al. 1997 (GIMEMA AIDA 0493)	1993-1996 	Phase 3 (E-switch-ooc)	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 	Lower 2-year relapse rate
Fenaux et al. 1999 (EAPLG APL 93) 	1993-1996 	Phase 3 (E-esc) 	2. 6-MP & MTX 3. No further treatment	Seems to have lower 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 EuroPMC 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====
*Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA consolidation
====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 longer 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
Mandelli et al. 1997 (GIMEMA AIDA 0493)	1993-1996 	Phase 3 (E-esc)	2. 6-MP & MTX 	Did not meet primary endpoint of molecular DFS
Mandelli et al. 1997 (GIMEMA AIDA 0493)	1993-1996 	Phase 3 (E-esc)	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 lower 2-year relapse rate
Fenaux et al. 1999 (EAPLG APL 93) 	1993-1996 	Phase 3 (E-esc)	2. ATRA 3. No further treatment	Higher 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 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 #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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 EuroPMC 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 EuroPMC
# 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 EuroPMC 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 EuroPMC
# 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 does not contain dosing details in manuscript; refers to Sanz et al. 2003 EuroPMC 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 EuroPMC 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 EuroPMC 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 EuroPMC 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
==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====
*Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
====Chemotherapy====
*Mercaptopurine (6-MP) 1 mg/kg PO once per day on days 1 to 7
*Methotrexate (MTX) 0.25 mg/kg IM once on day 1
7-day cycle for 104 cycles (2 years)
===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
Mandelli et al. 1997 (GIMEMA AIDA 0493)	1993-1996 	Phase 3 (C)	2. ATRA, 6-MP, MTX 	Did not meet primary endpoint of molecular DFS
Mandelli et al. 1997 (GIMEMA AIDA 0493)	1993-1996 	Phase 3 (C)	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. ATRA2. ATRA, 6-MP, MTX	Seems to have lower 2-year relapse rate
Fenaux et al. 1999 (EAPLG APL 93) 	1993-1996 	Phase 3 (C)	3. No further treatment 	Higher 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 on days 1 to 7
*Methotrexate (MTX) 15 mg/m2 IM once on day 1
7-day cycle for 104 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 EuroPMC
=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 EuroPMC
# 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 EuroPMC
# 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 EuroPMC
==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 EuroPMC NCT01908621
==Tamibarotene monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Sanford et al. 2015 (STAR-1)	2007-2011 	Phase 2, fewer than 20 pts
====Targeted therapy====
*Tamibarotene (Amnoid) 3 mg/m2 PO twice per day
Up to 56-day course
====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 EuroPMC 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 EuroPMC 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
===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 EuroPMC NCT01908621
Category:Acute promyelocytic leukemia regimens
Category:Disease-specific pages
Category:Acute leukemias
Category:Myeloid neoplasms