Acute promyelocytic leukemia

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31 regimens on this page
48 variants on this page


Guidelines

ELN

ESMO

NCCN

Upfront induction therapy

Arsenic trioxide monotherapy

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Variant #1

Study Evidence Comparator Efficacy
Shen et al. 2004 Randomized Arsenic trioxide & ATRA Seems to have inferior DFS
ATRA Not reported

Chemotherapy

Given until complete remission

Patients in CR proceeded to consolidation, see text for details.

Variant #2

Study Evidence
Mathews et al. 2006 Non-randomized

Chemotherapy

Given until complete remission (CR) or maximum of 75 days (maximum of 60 days after 2001)

Subsequent treatment

References

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

Arsenic trioxide & ATRA

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Variant #1

Study Evidence Comparator Efficacy
Burnett et al. 2015 (AML17) Phase III ATRA & Idarubicin Seems not superior

Chemotherapy

  • Arsenic trioxide (Trisenox) 0.3 mg/kg IV once per day on days 1 to 5, then 0.25 mg/kg IV twice per week on weeks 2 to 8
  • All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days

Subsequent treatment

Variant #2

Study Evidence Comparator Efficacy
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) Phase III ATRA & Idarubicin Superior OS (*)

Patients with low- or intermediate-risk APL (white blood cell count at presentation less than or equal to 10 x 109/L) were eligible. Efficacy is based on the 2016 update.

Chemotherapy

  • 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) 45 mg/m2/day, divided into two equal doses PO BID, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days.

Supportive medications

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

One course, to remission

Subsequent treatment

Variant #3

Study Evidence Comparator Efficacy
Shen et al. 2004 Randomized Arsenic trioxide
ATRA 		Seems to have superior DFS

Chemotherapy

All patients achieving CR went on to receive chemotherapy-based consolidation and maintenance. These details are available in the original paper but are omitted here.

Variant #4

Study Evidence
Estey et al. 2006 Phase II
Ravandi et al. 2009 Phase II

The original protocol was modified between Estey et al. 2006 and Ravandi et al. 2009. Estey et al. 2006 covered part of the whole cohort. In the initial protocol, arsenic trioxide was started on day 11, and gemtuzumab ozogamicin was only used for high risk patients. After a death due to hyperleukocytosis and intracranial hemorrhage during induction, the protocol was modified as described in Ravandi et al. 2009 so arsenic trioxide was started on day 1, and gemtuzumab ozogamicin was given if WBC count went greater than 30 x 109/L for any patient in the first four weeks of therapy.

Chemotherapy

  • All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID, starting on day 1 and continuing until remission or maximum of 90 days.
  • Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 60 minutes once per day, starting on day 11 and continuing until remission (as described in Estey et al. 2006)
    • Patients in Ravandi et al. 2009 received 0.15 mg/kg IV over 60 minutes once per day, starting on day 1 and continuing until remission
  • Patients with high-risk disease (initial WBC count greater than or equal to 10 x 109/L) received: Gemtuzumab ozogamicin (Mylotarg) 9 mg/m2 IV once on day 1
    • Patients who initially were not high-risk but subsequently developed WBC count greater than or equal to 10 x 109/L during the first four weeks of therapy received: 9 mg/m2 IV once

Supportive medications

  • "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
  • Heparin or Tranexamic acid (Cyklokapron) used if clinically indicated
  • Patients in Estey et al. 2006 received: "Oral solumedrol" 20 mg PO once per day for 10 days to decrease risk of differentiation syndrome
  • Patients in Ravandi et al. 2009 recieved: Methylprednisolone 50 mg PO once per day for 5 days to decrease risk of differentiation syndrome

Subsequent treatment

References

  1. Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De Thé H, Wang ZY, Chen SJ, Chen Z. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5328-35. Epub 2004 Mar 24. link to original article contains verified protocol link to PMC article PubMed
  2. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article contains verified protocol PubMed
  3. Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009 Feb 1;27(4):504-10. Epub 2008 Dec 15. link to original article contains verified protocol link to PMC article PubMed
  4. Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WL, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3342-7. Epub 2009 Feb 18. link to original article contains verified protocol link to PMC article PubMed content property of HemOnc.org
  5. GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
    2. Update: Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. link to original article link to PMC article PubMed
  6. 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 SD article contains protocol PubMed

Arsenic trioxide, ATRA, Idarubicin

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Regimen

Study Evidence
Iland et al. 2012 (ALLG APML4) Phase II

Chemotherapy

  • Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 2 hours once per day on days 9 to 36
  • All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 36
  • Idarubicin (Idamycin) as follows:
    • Patients up to age 61: 12 mg/m2 IV once per day on days 2, 4, 6, 8
    • Patients 61 to 70 years old: 9 mg/m2 IV once per day on days 2, 4, 6, 8
    • Patients greater than 70 years old: 6 mg/m2 IV once per day on days 2, 4, 6, 8

Supportive medications

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

36-day course

Subsequent treatment

References

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

ATRA monotherapy

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Regimen

Study Evidence Comparator Efficacy
Tallman et al. 1997 (ECOG E2491) Phase III Cytarabine & Daunorubicin Superior OS

This obsolete regimen is here for historical reference; ATRA is no longer used as monotherapy for induction.

Chemotherapy

  • All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.

Subsequent treatment

References

  1. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997 Oct 9;337(15):1021-8. Erratum in: N Engl J Med 1997 Nov 27;337(22):1639. link to original article contains verified protocol PubMed

ATRA, Cytarabine, Daunorubicin

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Variant #1

Study Evidence Comparator Efficacy
Adès et al. 2006 (EAPLG APL 2000) Phase III ATRA & Daunorubicin Superior OS

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

Chemotherapy

9-day course of initial induction chemotherapy, with ongoing use of ATRA

Subsequent treatment

Variant #2

Study Evidence
Powell et al. 2010 (C9710) Non-randomized portion of RCT

Chemotherapy

9-day initial induction chemotherapy, with ongoing use of ATRA

Subsequent treatment

References

  1. Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood. 1993 Dec 1;82(11):3241-9. link to original article PubMed
  2. 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; European Acute Promyelocytic Leukemia Group. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. link to original article contains verified protocol PubMed
    1. Update: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains verified protocol PubMed
  3. C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains verified protocol link to PMC article PubMed

ATRA & Daunorubicin

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Regimen

Study Evidence Comparator Efficacy
Adès et al. 2006 (EAPLG APL 2000) Phase III ATRA, Cytarabine, Daunorubicin Inferior OS

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

Chemotherapy

9-day course of initial induction chemotherapy, with ongoing use of ATRA

Subsequent treatment

References

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

ATRA & Idarubicin

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AIDA: ATRA, IDArubicin

Regimen

Study Evidence Comparator Efficacy
Avvisati et al. 1996 (GIMEMA AIDA) Pilot
Mandelli et al. 1997 (GIMEMA AIDA 0493) Non-randomized portion of RCT
Sanz et al. 2003 (PETHEMA LPA96/LPA99) Non-randomized
Sanz et al. 2010 (PETHEMA LPA2005) Non-randomized
Lo-Coco et al. 2010 (GIMEMA AIDA 2000) Non-randomized
Latagliata et al. 2011 (GIMEMA AIDA 0493 amended protocol) Non-randomized
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) Phase III Arsenic trioxide & ATRA Inferior OS (*)
Burnett et al. 2015 (NCRI AML17) Phase III Arsenic trioxide & ATRA Seems not superior

Note: this is the same induction used in multiple protocols. Consolidation and maintenance differ, follow the appropriate links below. Efficacy in APL0406 is based on the 2016 update.

Chemotherapy

  • All-trans retinoic acid (ATRA) as follows, starting day 1 and continuing until remission or maximum of 90 days:
    • 21 or older: 45 mg/m2/day, divided into two equal doses PO BID
    • Less than 20 years old: 25 mg/m2/day, divided into two equal doses PO BID
  • Idarubicin (Idamycin) as follows:
    • Up to age 70: 12 mg/m2 IV bolus once per day on days 2, 4, 6, 8
    • Older than 70 years old: 12 mg/m2 IV bolus once per day on days 2, 4, 6

8-day initial induction chemotherapy, with ongoing use of ATRA as described

Subsequent treatment

Once CR was achieved, patients proceeded to consolidation as follows:

References

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

Arsenic trioxide, ATRA, Gemtuzumab

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Variant #1

Study Evidence
Abaza et al. 2017 High Risk Patients from 3 trials

Chemotherapy

Subsequent treatment

Once CR was achieved, patients proceeded to consolidation as follows:

  • Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 1 to 2 hours once per day, 5 consecutive days per week, on weeks 1 to 4, 9 to 12, 17 to 20, 25 to 28
  • All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID, 7 days per week on weeks 1 to 2, 5 to 6, 9 to 10, 13 to 14, 17 to 18, 21 to 22, 25 to 26

References

  1. 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, arsenictrioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. link to full article contains verified protocol PubMed
  2. Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009 Feb 1;27(4):504-10. link to full article contains verified protocol PubMed
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Variant #2

Study Evidence Comparator Efficacy
Burnett et al. 2015 (AML17) Phase III ATRA & Idarubicin Seems not superior

Chemotherapy

Subsequent treatment

References

  1. NCRI AML17: Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. link to original article PubMed

Consolidation after upfront therapy

Arsenic trioxide monotherapy

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Regimen

Study Evidence
Mathews et al. 2006 Non-randomized

Preceding treatment

Chemotherapy

28-day course

Subsequent treatment

References

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

Arsenic trioxide, then ATRA & Daunorubicin

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Regimen

Study Evidence Comparator Efficacy
Powell et al. 2010 (C9710) Phase III ATRA & Daunorubicin Superior EFS

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

Preceding treatment

Chemotherapy, part 1

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

Chemotherapy, part 2

7-day cycle for 2 cycles

Subsequent treatment

References

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

Arsenic trioxide & ATRA

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Variant #1

Study Evidence
Estey et al. 2006 Phase II
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

  • Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 1 to 2 hours once per day, 5 consecutive days per week, on weeks 1 to 4, 9 to 12, 17 to 20, 25 to 28
  • All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID, 7 days per week on weeks 1 to 2, 5 to 6, 9 to 10, 13 to 14, 17 to 18, 21 to 22, 25 to 26

28 week course of therapy

There is no maintenance in this protocol.

Variant #2

Study Evidence
Iland et al. 2012 (ALLG APML4) Phase II

Consolidation starts 3 to 4 weeks after completion of induction.

Preceding treatment

Chemotherapy, part 1

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

Chemotherapy, part 2

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

5-week course

Subsequent treatment

References

  1. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article contains verified protocol PubMed
  2. ALLG APML4: Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. link to original article contains verified protocol PubMed
  3. GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
    2. Update: Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. link to original article link to PMC article PubMed
  4. 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 SD article PubMed

ATRA & Daunorubicin

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Regimen

Study Evidence Comparator Efficacy
Powell et al. 2010 (C9710) Phase III Arsenic trioxide, then ATRA & Daunorubicin Inferior EFS

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

Preceding treatment

Chemotherapy

7-day cycle for 2 cycles

Subsequent treatment

References

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

Cytarabine & Daunorubicin

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Regimen

Study Evidence Comparator Efficacy
Adès et al. 2006 (EAPLG APL 2000) Phase III Daunorubicin Superior OS

Preceding treatment

Chemotherapy

  • Cytarabine (Cytosar) as follows:
    • Cycle 1: 200 mg/m2/day IV continuous infusion on days 1 to 7
    • Cycle 2 as follows:
      • Younger (less than 60) low-risk (WBC count less than 10 x 109/L) or older (greater than 60) high-risk (WBC count greater than 10 x 109/L): 1000 mg/m2 IV every 12 hours on days 1 to 4 (8 total doses)
      • Younger (less than 60) high-risk (WBC count greater than 10 x 109/L): 2000 mg/m2 IV every 12 hours on days 1 to 5 (10 total doses)
  • 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

Intrathecal for high-risk (WBC count greater than 10 x 109/L) patients

Subsequent treatment

References

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

Cytarabine & Idarubicin

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Regimen

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

This consolidation protocol was intended for patients older than 60.

Preceding treatment

Chemotherapy

  • Cytarabine (Cytosar) 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

One course

Subsequent treatment

References

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

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

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Regimen

Study Evidence
Mandelli et al. 1997 (GIMEMA AIDA 0493) Non-randomized portion of RCT
Avvisati et al. 2002 (GIMEMA LAP 0389) Non-randomized portion of RCT

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

Preceding treatment

  • GIMEMA LAP 0389: Idarubicin induction versus cytarabine & idarubicin induction (neither with ATRA; no longer standard of care)
  • GIMEMA AIDA 0493: ATRA & idarubicin induction

Chemotherapy, part 1

  • Cytarabine (Cytosar) 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

One course

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

Chemotherapy, part 2

One course

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

Chemotherapy, part 3

One course

Subsequent treatment

References

  1. Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood. 1996 Aug 15;88(4):1390-8. link to full article contains verified protocol PubMed
  2. GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
    1. Update: Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, Latagliata R, Specchia G, Baccarani M, Di Bona E, Fioritoni G, Marmont F, Rambaldi A, Di Raimondo F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F; GIMEMA, AIEOP, and EORTC Cooperative Groups. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5;117(18):4716-25. Epub 2011 Mar 8. link to original article contains verified protocol PubMed
  3. PETHEMA LPA96/LPA99: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains verified protocol PubMed
    1. Update: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains verified protocol PubMed
  4. 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 (Gruppo Italiano Malattie Ematologische dell'Adulto) Italian Cooperative Group. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. link to original article contains verified protocol PubMed

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

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Regimen

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

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

Preceding treatment

Chemotherapy, part 1

4-day course of therapy, followed by:

Chemotherapy, part 2

5-day course of therapy, followed by:

Chemotherapy, part 3

5-day course of therapy

CNS prophylaxis

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

"Total of 3 cycles"

Subsequent treatment

References

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

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

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Regimen

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

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

Preceding treatment

Chemotherapy, consolidation #1

1-month cycle, followed by:

Chemotherapy, consolidation #2

1-month cycle, followed by:

Chemotherapy, consolidation #3

1-month cycle

Subsequent treatment

References

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

Daunorubicin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Adès et al. 2006 (EAPLG APL 2000) Phase III Cytarabine & Daunorubicin Inferior OS

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

Preceding treatment

Chemotherapy

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

Subsequent treatment

References

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

Idarubicin, then Mitoxantrone, then Idarubicin

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Regimen

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

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

Preceding treatment

Chemotherapy, part 1

1-month cycle, followed by:

Chemotherapy, part 2

1-month cycle, followed by:

Chemotherapy, part 3

1-month cycle

Subsequent treatment

References

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

Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA

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Variant #1

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

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

Preceding treatment

Chemotherapy, part 1

1-month cycle, followed by:

Chemotherapy, part 2

1-month cycle, followed by:

Chemotherapy, part 3

1-month cycle

Subsequent treatment

Variant #2

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

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

Preceding treatment

Chemotherapy, part 1

1-month cycle, followed by:

Chemotherapy, part 2

1-month cycle, followed by:

Chemotherapy, part 3

1-month cycle

Subsequent treatment

References

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

Maintenance after upfront therapy

Arsenic trioxide monotherapy

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Regimen

Study Evidence
Mathews et al. 2006 Non-randomized

Preceding treatment

Chemotherapy

10 consecutive days of each month for 6 months

References

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

ATRA monotherapy

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Variant #1

Study Evidence Comparator Efficacy
Powell et al. 2010 (C9710) Phase III ATRA, 6-MP, MTX Might have inferior DFS

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

Preceding treatment

Chemotherapy

1 year of therapy

Variant #2

Study Evidence Comparator Efficacy
Mandelli et al. 1997 (GIMEMA AIDA 0493) Phase III ATRA, 6-MP, MTX Seems not superior
6-MP & MTX Seems not superior
No further treatment Seems not superior
Fenaux et al. 1999 (EAPLG APL 93) Phase III ATRA, 6-MP, MTX Inferior 2-year relapse rate
6-MP & MTX
No further treatment 		Seems to have superior 2-year relapse rate

Preceding treatment

Chemotherapy

2 year course of therapy

References

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

ATRA, Mercaptopurine, Methotrexate

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Variant #1

Study Evidence Comparator Efficacy
Powell et al. 2010 (C9710) Phase III ATRA Might have superior DFS

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

Preceding treatment

Chemotherapy

1 year of therapy

Variant #2

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

Preceding treatment

Chemotherapy

90-day cycle for 2 years

Variant #3

Study Evidence
Iland et al. 2012 (ALLG APML4) Phase II

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

Preceding treatment

Chemotherapy

Dose adjustments

90-day cycle for 8 cycles

Variant #4

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

Preceding treatment

Chemotherapy

Dose adjustments:

90-day cycle for 2 years

Variant #5, ATRA alternating with 6-MP, MTX

Study Evidence Comparator Efficacy
Mandelli et al. 1997 (GIMEMA AIDA 0493) Phase III ATRA Seems not superior
6-MP & MTX Seems not superior
No further treatment Seems not superior
Fenaux et al. 1999 (EAPLG APL 93) Phase III 6-MP & MTX Seems to have superior 2-year relapse rate
ATRA
No further treatment 		Superior 2-year relapse rate

Preceding treatment

Chemotherapy

3-month cycle, alternating with

2 year course of therapy

References

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

Mercaptopurine & Methotrexate

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Variant #1

Study Evidence Comparator Efficacy
Avvisati et al. 2002 (GIMEMA LAP 0389) Phase III No further treatment Seems not superior

Preceding treatment

Chemotherapy

2-year course of therapy

Variant #2

Study Evidence Comparator Efficacy
Mandelli et al. 1997 (GIMEMA AIDA 0493) Phase III ATRA Seems not superior
ATRA, 6-MP, MTX Seems not superior
No further treatment Seems not superior
Fenaux et al. 1999 (EAPLG APL 93) Phase III ATRA
ATRA, 6-MP, MTX 		Seems to have inferior 2-year relapse rate
No further treatment Superior 2-year relapse rate

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

Preceding treatment

Chemotherapy

2-year course of therapy

References

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

No further treatment

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Regimen

Study Evidence Comparator Efficacy
Mandelli et al. 1997 (GIMEMA AIDA 0493) Phase III ATRA Seems not superior
ATRA, 6-MP, MTX Seems not superior
6-MP & MTX Seems not superior
Fenaux et al. 1999 (EAPLG APL 93) Phase III ATRA Seems to have inferior 2-year relapse rate
ATRA, 6-MP, MTX
6-MP & MTX 		Inferior 2-year relapse rate
Avvisati et al. 2002 (GIMEMA LAP 0389) Phase III 6-MP & MTX Seems not superior

No further treatment given after consolidation. Note that this arm was dropped from AIDA 0493 from February 1997.

Preceding treatment

References

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

Relapsed or refractory, salvage therapy

Arsenic trioxide monotherapy

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Regimen

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

Chemotherapy

Given until complete remission (CR)

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

References

  1. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma J, Zhang P, Zhang TD, Chen SJ, Chen Z, Wang ZY. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997 May 1;89(9):3354-60. link to original article PubMed
  2. Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, Corso D, DeBlasio A, Gabrilove J, Scheinberg DA, Pandolfi PP, Warrell RP Jr. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998 Nov 5;339(19):1341-8. link to original article PubMed
  3. 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 PubMed

Arsenic-based re-induction followed by consolidation and autologous stem cell transplant

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Regimen

Study Evidence
Yanada et al. 2013 Phase II

Induction

Consolidation #1 and #2

Consolidation #3

Peripheral blood stem cells collected upon WBC count recovery, followed by:

Subsequent treatment

References

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

Investigational agents

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