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31 regimens on this page 48 variants on this page

Induction therapy

Arsenic trioxide (Trisenox)

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Regimen #1

Study	Evidence	Comparator
Shen et al. 2004	Randomized	Arsenic trioxide & ATRA ATRA

Chemotherapy

Arsenic trioxide (Trisenox) 0.16 mg/kg IV once per day

Given until complete remission

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

Regimen #2

Study	Evidence
Mathews et al. 2006	Non-randomized

Chemotherapy

Arsenic trioxide (Trisenox) 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day

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

Patients in CR proceed after 4 weeks to 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 contains verified protocol PubMed
Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006 Apr 1;107(7):2627-32. Epub 2005 Dec 13. link to original article 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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Regimen #1

Study	Evidence	Comparator
Burnett et al. 2015 (AML17)	Phase III	ATRA & Idarubicin

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

Treatment followed by arsenic trioxide & ATRA consolidation.

Regimen #2

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

Patients with low- or intermediate-risk APL (white blood cell count at presentation ≤10 x 10⁹/L) were eligible.

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 >30 x 10⁹/L (30,000/uL) for the first 10 days of induction and >20 x 10⁹/L (20,000/uL) for the remainder of induction
Patients with WBC >10 x 10⁹/L (10,000/uL) and < 50 x 10⁹/L (50,000/uL) after the start of therapy received: Hydroxyurea (Hydrea) 500 mg PO four times per day, given until WBC is <10 x 10⁹/L (10,000/uL)
- Patients with WBC >50 x 10⁹/L (50,000/uL) after the start of therapy received: Hydroxyurea (Hydrea) 1000 mg PO four times per day, given until WBC is <10 x 10⁹/L (10,000/uL)

One course, to remission

Treatment followed by arsenic trioxide & ATRA consolidation.

Regimen #3

Study	Evidence	Comparator
Shen et al. 2004	Randomized	Arsenic trioxide ATRA

Chemotherapy

All-trans retinoic acid (ATRA) 25 mg/m²/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
Arsenic trioxide (Trisenox) 0.16 mg/kg IV once per day, starting day 1 and continuing until remission

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.

Regimen #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 >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 1 hour 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 Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 1 hour once per day, starting on day 1 and continuing until remission
Patients with high-risk disease (initial WBC =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 =10 x 10⁹/L during the first four weeks of therapy received: Gemtuzumab ozogamicin (Mylotarg) 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

Treatment followed by 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 contains verified protocol PubMed
Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article contains verified protocol PubMed
Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009 Feb 1;27(4):504-10. Epub 2008 Dec 15. link to original article contains verified protocol PubMed
Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WL, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3342-7. Epub 2009 Feb 18. link to original article contains verified protocol PubMed content property of HemOnc.org
Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article link to supplementary appendix link to protocol contains verified protocol PubMed
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 (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 >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 falls below 1 x 10⁹/L (1,000/uL), 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 > 30 x 10⁹/L (30,000/uL), fibrinogen >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

Treatment followed in 3 to 4 weeks by arsenic trioxide & ATRA consolidation.

References

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

ATRA, Cytarabine, Daunorubicin

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Regimen #1

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

This induction arm was a randomization for young (<60), low-risk (WBC <10k) patients. High-risk (WBC >10k) patients received this regimen in a non-randomized fashion, along with intrathecal therapy during consolidation.

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.
Cytarabine (Cytosar) 200 mg/m² IV continuous infusion on days 3 to 9
Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 3 to 5

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

Treatment followed by cytarabine & daunorubicin consolidation.

Regimen #2

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

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.
Cytarabine (Cytosar) 200 mg/m²/day IV continuous infusion on days 3 to 9
Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 3 to 6

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

Treatment followed by randomization to arsenic trioxide -> ATRA & daunorubicin consolidation versus ATRA & daunorubicin consolidation.

References

Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; European Acute Promyelocytic Leukemia Group. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. link to original article contains verified protocol PubMed
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 PubMed

ATRA & Daunorubicin

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Regimen

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

This induction arm was a randomization for young (<60), low-risk (WBC <10k) patients. Low-risk (WBC <10k) older (>60) patients received this regimen in a non-randomized fashion.

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.
Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 3 to 5

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

Treatment followed by daunorubicin consolidation.

References

Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; European Acute Promyelocytic Leukemia Group. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. link to original article contains verified protocol PubMed

ATRA & Idarubicin

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AIDA: ATRA, IDArubicin
PETHEMA: Programa Español de Tratamientos en HEMAtología

Regimen

Study	Evidence	Comparator
Avvisati et al. 1996	Pilot
Mandelli et al. 1997 (AIDA 0493)	Non-randomized
Sanz et al. 2004 (PETHEMA LPA96/LPA99)	Non-randomized
Sanz et al. 2010 (PETHEMA LPA2005)	Non-randomized
Lo-Coco et al. 2010 (AIDA 2000)	Non-randomized
Latagliata et al. 2011 (AIDA 0493 amended protocol)	Non-randomized
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)	Phase III	Arsenic trioxide & ATRA
Burnett et al. 2015 (NCRI AML17)	Phase III	Arsenic trioxide & ATRA

Note: this is the same induction used in multiple protocols. Consolidation and maintenance differ, follow the appropriate links below.

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
- <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
- >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

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

Patients in PETHEMA LPA96 proceeded to receive idarubicin -> mitoxantrone -> idarubicin consolidation.
Patients in AIDA 0493 proceeded to receive cytarabine & idarubicin -> etoposide & mitoxantrone -> cytarabine, idarubicin, thioguanine consolidation.
Patients in PETHEMA LPA99 proceeded to receive risk-adapted therapy:
- Low-risk patients received idarubicin -> mitoxantrone -> idarubicin consolidation.
- Intermediate- and high-risk patients received idarubicin -> mitoxantrone -> idarubicin, with ATRA consolidation.
Patients in PETHEMA LPA2005 proceeded to receive risk-adapted therapy:
- High-risk patients received cytarabine & idarubicin -> mitoxantrone -> cytarabine & idarubicin, with ATRA consolidation.
- Intermediate- and low-risk patients received idarubicin -> mitoxantrone -> idarubicin, with ATRA consolidation.
Patients in AIDA 2000 proceeded to receive risk-adapted therapy:
- High-risk patients received cytarabine & idarubicin -> etoposide & mitoxantrone -> cytarabine, idarubicin, thioguanine, with ATRA consolidation.
- Intermediate- and low-risk patients received idarubicin -> mitoxantrone -> idarubicin, with ATRA consolidation.
Patients in the AIDA 0493 amended protocol proceeded to receive cytarabine & idarubicin consolidation.
Patients in GIMEMA/DSIL APL0406 and NCRI AML17 proceeded to receive idarubicin -> mitoxantrone -> idarubicin, with ATRA consolidation.

References

Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood. 1996 Aug 15;88(4):1390-8. link to full article contains verified protocol PubMed
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. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. 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
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
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
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
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
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
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 therapy

Arsenic trioxide (Trisenox)

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Regimen

Study	Evidence
Mathews et al. 2006	Non-randomized

Treatment preceded by arsenic trioxide induction.

Chemotherapy

Arsenic trioxide (Trisenox) 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day

28-day course

Patients remaining in CR proceed to 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 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 & Daunorubicin

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Regimen

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

Treatment preceded by ATRA, cytarabine, daunorubicin induction. Consolidation therapy starts within 2 to 4 weeks of hematologic remission.

Chemotherapy

Arsenic trioxide (Trisenox) 0.15 mg/kg IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33

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

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID, starting days 1 to 7
Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1 to 3

7-day cycle for 2 cycles

Treatment followed by ATRA maintenance versus ATRA, 6-MP, MTX maintenance.

References

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

Arsenic trioxide & ATRA

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Regimen #1

Study	Evidence	Comparator
Estey et al. 2006	Phase II
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)	Phase III	Idarubicin -> Mitoxantrone -> Idarubicin, with ATRA

Treatment preceded by Arsenic trioxide & ATRA induction.

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.

Regimen #2

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

Treatment preceded by arsenic trioxide, ATRA, idarubicin induction therapy.

Consolidation cycle 1

Given 3 to 4 weeks after completion of induction.

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID on days 1 to 28
Arsenic trioxide (Trisenox) 0.15 mg/kg IV once per day on days 1 to 28

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

Consolidation cycle 2

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

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID on days 1 to 7, 15 to 21, 29 to 35
Arsenic trioxide (Trisenox) 0.15 mg/kg IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33

5-week course

After 3 to 4 weeks, patients proceed to ATRA, 6-MP, MTX maintenance.

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 contains verified protocol PubMed
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
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 link to supplementary appendix link to protocol contains verified protocol PubMed
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
Powell et al. 2010 (C9710)	Phase III	Arsenic trioxide -> ATRA & Daunorubicin

Treatment preceded by ATRA, cytarabine, daunorubicin induction. Consolidation therapy starts within 2 to 4 weeks of hematologic remission.

Chemotherapy

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID, starting days 1 to 7
Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1 to 3

7-day cycle for 2 cycles

Treatment followed by randomization to ATRA maintenance versus ATRA, 6-MP, MTX maintenance.

References

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

Cytarabine & Daunorubicin

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Regimen

Study	Evidence	Comparator
Adès et al. 2006 (APL 2000)	Phase III	Daunorubicin

Treatment preceded by ATRA, cytarabine, daunorubicin induction.

Chemotherapy

Cytarabine (Cytosar) as follows:
- Cycle 1: 200 mg/m²/day IV continuous infusion on days 1 to 7
- Cycle 2 as follows:
  - Younger (<60) low-risk (WBC <10k) or older (>60) high-risk (WBC >10k): 1000 mg/m² IV every 12 hours on days 1 to 4 (8 total doses)
  - Younger (<60) high-risk (WBC >10k): 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 >10k) patients

5 doses of intrathecal chemotherapy with Methotrexate (MTX) 15 mg IT, Cytarabine (Cytosar) 50 mg IT, and corticosteroids given during consolidation

Treatment followed by ATRA, 6-MP, MTX maintenance.

References

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

Cytarabine & Idarubicin

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Regimen

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

Treatment preceded by ATRA & idarubicin induction. This consolidation protocol was intended for patients older than 60.

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

Treatment is followed by ATRA maintenance.

References

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 -> Etoposide & Mitoxantrone -> Cytarabine, Idarubicin, Thioguanine

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Regimen

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

Treatment in LAP 0389 preceded by idarubicin induction versus cytarabine & idarubicin induction (neither with ATRA; no longer standard of care). Treatment in AIDA 0493 preceded by ATRA & idarubicin induction; note that the consolidation portion of the protocol is described in Avvisati et al. 1996.

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

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

Etoposide (Vepesid) 100 mg/m² IV over 45 to 60 minutes oncer 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

One course

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

Cytarabine (Cytosar) 150 mg/m² SC every 8 hours on days 1 to 5
Idarubicin (Idamycin) as follows:
- LAP 0389 protocol: 5 mg/m² IV once on day 1
- AIDA 0493 protocol: 12 mg/m² IV once on day 1
Thioguanine (Tabloid) 70 mg/m² PO every 8 hours on days 1 to 5

One course

Treatment in LAP 0389 followed by 6-MP & MTX maintenance versus no further treatment. Treatment in AIDA 0493 followed by ATRA maintenance versus ATRA, 6-MP, MTX maintenance versus 6-MP & MTX maintenance versus no further treatment.

References

Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood. 1996 Aug 15;88(4):1390-8. link to full article contains verified protocol PubMed
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. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. 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
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
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 -> Etoposide & Mitoxantrone -> Cytarabine, Idarubicin, Thioguanine, with ATRA

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AIDA: ATRA, IDArubicin

Regimen

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

Treatment preceded by ATRA & idarubicin induction. 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.

Chemotherapy

All-trans retinoic acid (ATRA) 45 mg/m²/day PO for a total of 15 days
Cytarabine (Cytosar) 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

4-day course of therapy, followed by:

All-trans retinoic acid (ATRA) 45 mg/m²/day PO for a total of 15 days
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

5-day course of therapy, followed by:

All-trans retinoic acid (ATRA) 45 mg/m²/day PO for a total of 15 days
Cytarabine (Cytosar) 150 mg/m² SC every 8 hours (450 mg/m²/day total dosage) on days 1 to 5
Idarubicin (Idamycin) 12 mg/m² IV once on day 1
Thioguanine (Tabloid) 70 mg/m² PO every 8 hours (210 mg/m²/day total dosage) on days 1 to 5

5-day course of therapy

CNS prophylaxis

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

"Total of 3 cycles"

Treatment followed by ATRA alternating with 6-MP, MTX maintenance.

References

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

Cytarabine & Idarubicin -> Mitoxantrone -> Cytarabine & Idarubicin, with ATRA

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PETHEMA: Programa Español de Tratamientos en HEMAtología

Regimen

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

Treatment preceded by ATRA & idarubicin induction. This is risk-adapted therapy for high-risk younger than 60 patients in PETHEMA LPA2005.

Chemotherapy

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID, days 1 to 15
Idarubicin (Idamycin) 5 mg/m² IV once per day on days 1 to 4
Cytarabine (Cytosar) 1000 mg/m² IV once per day on days 1 to 4

1-month cycle, followed by:

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID, days 1 to 15
Mitoxantrone (Novantrone) 10 mg/m² IV once per day on days 1 to 5

1-month cycle, followed by:

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID, days 1 to 15
Idarubicin (Idamycin) 12 mg/m² IV once on day 1
Cytarabine (Cytosar) 150 mg/m², IV every 8 hours (total dose of 450 mg/m²/day) on days 1 to 4 (12 total doses)

1-month cycle

Treatment followed by ATRA, 6-MP, MTX maintenance.

References

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 (Cerubidine)

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Regimen

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

Treatment preceded by ATRA & daunorubicin induction. This consolidation arm was a randomization for younger (<60), low-risk (WBC <10k) patients. Low-risk (WBC <10k) older (>60) patients received this regimen in a non-randomized fashion.

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

Treatment followed by ATRA, 6-MP, MTX maintenance.

References

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

Idarubicin -> Mitoxantrone -> Idarubicin

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PETHEMA: Programa Español de Tratamientos en HEMAtología

Regimen

Study	Evidence
Sanz et al. 2004 (PETHEMA LPA96/LPA99)	Non-randomized

Treatment preceded by ATRA & idarubicin induction therapy. This was the low-risk treatment arm of PETHEMA LPA99; all patients on PETHEMA LPA96 underwent this consolidation protocol.

Chemotherapy

Idarubicin (Idamycin) 5 mg/m² IV once per day on days 1 to 4

1-month cycle, followed by:

Mitoxantrone (Novantrone) 10 mg/m² IV once per day on days 1 to 5

1-month cycle, followed by:

Idarubicin (Idamycin) 12 mg/m² IV once on day 1

1-month cycle

Treatment followed by ATRA, 6-MP, MTX maintenance.

References

Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains verified protocol PubMed

Idarubicin -> Mitoxantrone -> Idarubicin, with ATRA

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AIDA: ATRA, IDArubicin
PETHEMA: Programa Español de Tratamientos en HEMAtología

Regimen #1

Study	Evidence	Comparator
Lo-Coco et al. 2010 (AIDA-2000)	Non-randomized
Sanz et al. 2010 (PETHEMA LPA2005)	Non-randomized
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406)	Phase III	No consolidation

Treatment preceded by ATRA & idarubicin induction. 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.

Chemotherapy

All-trans retinoic acid (ATRA) 45 mg/m²/day PO for a total of 15 days
Idarubicin (Idamycin) 5 mg/m² IV once per day on days 1 to 4

1-month cycle, followed by:

All-trans retinoic acid (ATRA) 45 mg/m²/day PO for a total of 15 days
Mitoxantrone (Novantrone) as follows:
- 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, followed by:

All-trans retinoic acid (ATRA) 45 mg/m²/day PO for a total of 15 days
Idarubicin (Idamycin) 12 mg/m² IV once on day 1

1-month cycle

Treatment in AIDA-2000 and GIMEMA/DSIL APL0406 followed by ATRA alternating with 6-MP, MTX maintenance. Treatment in PETHEMA LPA2005 followed by ATRA, 6-MP, MTX maintenance.

Regimen #2

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

Treatment preceded by ATRA & idarubicin induction. 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.

Chemotherapy

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID, days 1 to 15
Idarubicin (Idamycin) 7 mg/m² IV once per day on days 1 to 4

1-month cycle, followed by:

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID, days 1 to 15
Mitoxantrone (Novantrone) as follows:
- 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, followed by:

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID, days 1 to 15
Idarubicin (Idamycin) 12 mg/m² IV once per day on days 1 & 2

1-month cycle

Treatment followed by ATRA, 6-MP, MTX maintenance.

References

Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains verified protocol PubMed
Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA and HOVON Groups. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. link to original article contains verified protocol PubMed
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
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

Maintenance therapy

Arsenic trioxide (Trisenox)

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Regimen

Study	Evidence
Mathews et al. 2006	Non-randomized

Treatment preceded by arsenic trioxide consolidation.

Chemotherapy

Arsenic trioxide (Trisenox) 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day

10 consecutive days of each month for 6 months

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 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

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Regimen #1

Study	Evidence	Comparator
Powell et al. 2010 (C9710)	Phase III	ATRA, 6-MP, MTX

Treatment preceded by arsenic trioxide -> ATRA & daunorubicin consolidation versus ATRA & daunorubicin consolidation. Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.

Chemotherapy

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID for 7 days every other week

1 year of therapy

Regimen #2

Study	Evidence	Comparator
Mandelli et al. 1997 (AIDA 0493)	Phase III	ATRA, 6-MP, MTX 6-MP & MTX No further treatment
Fenaux et al. 1999 (APL93)	Phase III	ATRA, 6-MP, MTX 6-MP & MTX No further treatment

Treatment in AIDA 0493 preceded by cytarabine & idarubicin -> etoposide & mitoxantrone -> cytarabine, idarubicin, thioguanine consolidation. Treatment in APL 93 preceded by cytarabine & daunorubicin consolidation.

Chemotherapy

All-trans retinoic acid (ATRA) 45 mg/m²/day for 15 days every 3 months

2 year course of therapy

References

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. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. 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
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
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 PubMed

ATRA, Mercaptopurine, Methotrexate

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Regimen #1

Study	Evidence	Comparator
Powell et al. 2010 (C9710)	Phase III	ATRA

Treatment preceded by arsenic trioxide -> ATRA & daunorubicin consolidation versus ATRA & daunorubicin consolidation. Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.

Chemotherapy

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID for 7 days every other week
Mercaptopurine (Purinethol) 60 mg/m² PO once per day
Methotrexate (MTX) 20 mg/m² PO once per week

1 year of therapy

Regimen #2

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

Treatment preceded by cytarabine & daunorubicin consolidation versus daunorubicin consolidation.

Chemotherapy

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID on days 1 to 15
Mercaptopurine (Purinethol) 50 to 90 mg/m² PO once per day
Methotrexate (MTX) 15 mg/m² PO once per week

90-day cycle for 2 years

Regimen #3

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

Treatment preceded by arsenic trioxide & ATRA consolidation. Maintenance starts 3 to 4 weeks after completion of consolidation cycle 2.

Chemotherapy

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID on days 1 to 14
Mercaptopurine (Purinethol) 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

Dose adjustments

Methotrexate (MTX) and Mercaptopurine (Purinethol) doses titrated to ANC 1 to 2 x 10⁹/L (1,000 to 2,000/uL) and minimizing hepatotoxicity

90-day cycle for 8 cycles

Regimen #4

Treatment preceded by PETHEMA LPA99 or PETHEMA LPA2005 consolidation therapy.

Chemotherapy

All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID on days 1 to 15
Mercaptopurine (Purinethol) 50 mg/m² PO once per day
Methotrexate (MTX) 15 mg/m² IM once per week

Dose adjustments:

Methotrexate (MTX) and Mercaptopurine (Purinethol) decreased by 50% if WBC count <3.5 × 10⁹/L
Methotrexate (MTX) and Mercaptopurine (Purinethol) stopped if WBC count <2.5 × 10⁹/L

90-day cycle for 2 years

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

Study	Evidence	Comparator
Mandelli et al. 1997 (AIDA 0493)	Phase III	ATRA 6-MP & MTX No further treatment
Fenaux et al. 1999 (APL93)	Phase III	ATRA 6-MP & MTX No further treatment

Treatment in AIDA 0493 preceded by cytarabine & idarubicin -> etoposide & mitoxantrone -> cytarabine, idarubicin, thioguanine consolidation. Treatment in APL 93 preceded by cytarabine & daunorubicin consolidation.

Chemotherapy

Mercaptopurine (Purinethol) 90 mg/m² PO once per day
Methotrexate (MTX) 15 mg/m² IM once per week

3-month cycle, alternating with

All-trans retinoic acid (ATRA) 45 mg/m²/day for 15 days

2 year course of therapy

References

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. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. 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
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
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
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
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
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
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 PubMed
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

Mercaptopurine & Methotrexate

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Regimen #1

Study	Evidence	Comparator
Avvisati et al. 2002 (LAP 0389)	Phase III	No further treatment

Treatment preceded by cytarabine & idarubicin -> etoposide & mitoxantrone -> cytarabine, idarubicin, thioguanine consolidation.

Chemotherapy

Mercaptopurine (Purinethol) 1 mg/kg PO once per day
Methotrexate (MTX) 0.25 mg/kg IM once per week

2-year course of therapy

Regimen #2

Study	Evidence	Comparator
Mandelli et al. 1997 (AIDA 0493)	Phase III	ATRA ATRA, 6-MP, MTX No further treatment
Fenaux et al. 1999 (APL93)	Phase III	ATRA ATRA, 6-MP, MTX No further treatment

Treatment in AIDA 0493 preceded by cytarabine & idarubicin -> etoposide & mitoxantrone -> cytarabine, idarubicin, thioguanine consolidation. Treatment in APL 93 preceded by cytarabine & daunorubicin consolidation. Note that this arm was dropped from AIDA 0493 from February 1997.

Chemotherapy

Mercaptopurine (Purinethol) 90 mg/m² PO once per day
Methotrexate (MTX) 15 mg/m² IM once per week

2-year course of therapy

References

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. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. 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
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
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
Mandelli et al. 1997 (AIDA 0493)	Phase III	ATRA ATRA, 6-MP, MTX 6-MP & MTX
Fenaux et al. 1999 (APL93)	Phase III	ATRA ATRA, 6-MP, MTX 6-MP & MTX
Avvisati et al. 2002 (LAP 0389)	Phase III	6-MP & MTX

Preceded by cytarabine & daunorubicin consolidation in APL 93. Preceded by cytarabine & idarubicin -> etoposide & mitoxantrone -> cytarabine, idarubicin, thioguanine consolidation in AIDA 0493 and LAP 0389. No further treatment given after consolidation. Note that this arm was dropped from AIDA 0493 from February 1997.

References

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. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. 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
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
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/refractory

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

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
Idarubicin (Idamycin) 12 mg/m² IV over 30 minutes once per day on days 1 & 2 (Idarubicin was added under special conditions; see text for details)
Intrathecal therapy given once after platelet recovery, consisting of:
- Methotrexate (MTX) 15 mg IT,
- Cytarabine (Cytosar) 40 mg IT, and
- Corticosteroids: (Prednisolone (Millipred) 10 mg IT or Dexamethasone (Decadron) 4 mg IT

Consolidation #1 and #2

Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 2 hours once per day, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days
Intrathecal therapy given once after platelet recovery, consisting of:
- Methotrexate (MTX) 15 mg IT,
- Cytarabine (Cytosar) 40 mg IT, and
- Corticosteroids: (Prednisolone (Millipred) 10 mg IT or Dexamethasone (Decadron) 4 mg IT

Consolidation #3

Cytarabine (Cytosar) 2 g/m² IV over 3 hours twice per day on days 1 to 4 (8 doses total)
Filgrastim (Neupogen) starting on day 6 (dose, frequency not specified)

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

Busulfan (Myleran) & Melphalan (Alkeran) -> autologous stem cell transplant; see transplant conditioning regimens

References

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

Investigational agents

Tamibarotene (Amnoid)

@@ Line 1: / Line 1: @@
 '''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
-Is there a regimen missing from this list?  Would you like to share a different dosage/schedule or an additional reference for a regimen?  Have you noticed an error?  Do you have an idea that will help the site grow to better meet your needs and the needs of many others?  You are [[How_to_contribute|invited to contribute to the site]].
+Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].
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-|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]]  |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
+|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
-<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]]  |?Variant |limit=10000|format=sum}} variants on this page</b></font></div>
+<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} variants on this page</b></font></div>
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 |}
+====Chemotherapy====
 *[[Arsenic trioxide (Trisenox)]] 0.16 mg/kg IV once per day
@@ Line 53: / Line 53: @@
 |-
 |}
+====Chemotherapy====
 *[[Arsenic trioxide (Trisenox)]] 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day
@@ Line 89: / Line 89: @@
 ====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
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days
 ''Treatment followed by [[#Arsenic_trioxide_.26_ATRA_2|arsenic trioxide & ATRA consolidation]].''
@@ Line 113: / Line 113: @@
 ====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.
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/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====
@@ Line 143: / Line 143: @@
 |}
 ====Chemotherapy====
-*[[All-trans retinoic acid (ATRA)]] 25 mg/m2/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
+*[[All-trans retinoic acid (ATRA)]] 25 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
 *[[Arsenic trioxide (Trisenox)]] 0.16 mg/kg IV once per day, starting day 1 and continuing until remission
@@ Line 171: / Line 171: @@
 |}
-''The original protocol was modified between Estey et al. 2006 and Ravandi et al. 2009.  Estey et al. 2006 covered part of the whole cohort.  In the initial protocol, arsenic trioxide was started on day 11, and gemtuzumab ozogamicin was only used for high risk patients.  After a death due to hyperleukocytosis and intracranial hemorrhage during induction, the protocol was modified as described in Ravandi et al. 2009 so arsenic trioxide was started on day 1, and gemtuzumab ozogamicin was given if WBC count went >30 x 10<sup>9</sup>/L for any patient in the first four weeks of therapy.''
+''The original protocol was modified between Estey et al. 2006 and Ravandi et al. 2009. Estey et al. 2006 covered part of the whole cohort. In the initial protocol, arsenic trioxide was started on day 11, and gemtuzumab ozogamicin was only used for high risk patients. After a death due to hyperleukocytosis and intracranial hemorrhage during induction, the protocol was modified as described in Ravandi et al. 2009 so arsenic trioxide was started on day 1, and gemtuzumab ozogamicin was given if WBC count went >30 x 10<sup>9</sup>/L for any patient in the first four weeks of therapy.''
 ====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.
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/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 1 hour 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 [[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV over 1 hour once per day, starting on day 1 and continuing until remission
-*Patients with high-risk disease (initial WBC =10 x 10<sup>9</sup>/L) received: [[Gemtuzumab ozogamicin (Mylotarg)]] 9 mg/m2 IV once on day 1
+*Patients with high-risk disease (initial WBC =10 x 10<sup>9</sup>/L) received: [[Gemtuzumab ozogamicin (Mylotarg)]] 9 mg/m<sup>2</sup> IV once on day 1
-**Patients who initially were not high-risk but subsequently developed WBC =10 x 10<sup>9</sup>/L during the first four weeks of therapy received: [[Gemtuzumab ozogamicin (Mylotarg)]] 9 mg/m2 IV once
+**Patients who initially were not high-risk but subsequently developed WBC =10 x 10<sup>9</sup>/L during the first four weeks of therapy received: [[Gemtuzumab ozogamicin (Mylotarg)]] 9 mg/m<sup>2</sup> IV once
 ====Supportive medications====
 *"Prophylactic and therapeutic antibiotics and transfusion of blood products to maintain platelet counts more than 30 x 10<sup>9</sup>/L, fibrinogen more than 150 mg/dL, and the international normalized ratio for prothrombin time less than 1.5" per institutional guidelines
 *[[Heparin]] or [[Tranexamic acid (Cyklokapron)]] used if clinically indicated
-*Patients in Estey et al. 2006 received: "Oral solumedrol" 20 mg PO once per day x 10 days to decrease risk of differentiation syndrome
+*Patients in 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 (Solumedrol)|Methylprednisolone]] 50 mg PO once per day x 5 days to decrease risk of differentiation syndrome
+*Patients in Ravandi et al. 2009 recieved: [[Methylprednisolone (Solumedrol)|Methylprednisolone]] 50 mg PO once per day for 5 days to decrease risk of differentiation syndrome
 ''Treatment followed by [[#Arsenic_trioxide_.26_ATRA_2|arsenic trioxide & ATRA consolidation]].''
@@ Line 214: / Line 214: @@
 |-
 |}
+====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
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/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 up to age 61: 12 mg/m<sup>2</sup> 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 61 to 70 years old: 9 mg/m<sup>2</sup> IV once per day on days 2, 4, 6, 8
-**Patients >70 years old: 6 mg/m2 IV once per day on days 2, 4, 6, 8
+**Patients >70 years old: 6 mg/m<sup>2</sup> IV once per day on days 2, 4, 6, 8
-Supportive medications:
+====Supportive medications====
 *[[Prednisone (Sterapred)]] 1 mg/kg PO once per day on days 1 to 10, or until WBC falls below 1 x 10<sup>9</sup>/L (1,000/uL), or until resolution of differentiation syndrome (whichever occurs last)
 *Hemostatic support : Values checked and products transfused once or twice per day to keep platelet count > 30 x 10<sup>9</sup>/L (30,000/uL), fibrinogen >1.5 g/L (150 mg/dL), normal PT and PTT
@@ Line 232: / Line 232: @@
 ===References===
-# Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R,Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80.  Epub 2012 Jun 19. [http://bloodjournal.hematologylibrary.org/content/120/8/1570.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22715121 PubMed]
+# Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R,Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. [http://bloodjournal.hematologylibrary.org/content/120/8/1570.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22715121 PubMed]
 ==ATRA, Cytarabine, Daunorubicin {{#subobject:dade93|Regimen=1}}==
@@ Line 258: / Line 258: @@
 ''This induction arm was a randomization for young (<60), low-risk (WBC <10k) patients. High-risk (WBC >10k) patients received this regimen in a non-randomized fashion, along with intrathecal therapy during consolidation.''
+====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.
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
-*[[Cytarabine (Cytosar)]] 200 mg/m2 IV continuous infusion on days 3 to 9
+*[[Cytarabine (Cytosar)]] 200 mg/m<sup>2</sup> IV continuous infusion on days 3 to 9
-*[[Daunorubicin (Cerubidine)]] 60 mg/m2 IV once per day on days 3 to 5
+*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 3 to 5
 '''9-day course of initial induction chemotherapy, with ongoing use of ATRA'''
@@ Line 281: / Line 281: @@
 |-
 |}
+====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.
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
-*[[Cytarabine (Cytosar)]] 200 mg/m2/day IV continuous infusion on days 3 to 9
+*[[Cytarabine (Cytosar)]] 200 mg/m<sup>2</sup>/day IV continuous infusion on days 3 to 9
-*[[Daunorubicin (Cerubidine)]] 50 mg/m2 IV once per day on days 3 to 6
+*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 3 to 6
 '''9-day initial induction chemotherapy, with ongoing use of ATRA'''
@@ Line 318: / Line 318: @@
 ''This induction arm was a randomization for young (<60), low-risk (WBC <10k) patients. Low-risk (WBC <10k) older (>60) patients received this regimen in a non-randomized fashion.''
+====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.
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
-*[[Daunorubicin (Cerubidine)]] 60 mg/m2 IV once per day on days 3 to 5
+*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 3 to 5
 '''9-day course of initial induction chemotherapy, with ongoing use of ATRA'''
@@ Line 420: / Line 420: @@
 ====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
+**21 or older: 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID
-**<20 years old: 25 mg/m2/day, divided into two equal doses PO BID
+**<20 years old: 25 mg/m<sup>2</sup>/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
+**Up to age 70: 12 mg/m<sup>2</sup> IV bolus once per day on days 2, 4, 6, 8
-**>70 years old: 12 mg/m2 IV bolus once per day on days 2, 4, 6
+**>70 years old: 12 mg/m<sup>2</sup> IV bolus once per day on days 2, 4, 6
 '''8-day initial induction chemotherapy, with ongoing use of ATRA as described'''
@@ Line 478: / Line 478: @@
 ''Treatment preceded by [[Acute_promyelocytic_leukemia#Arsenic_trioxide_.28Trisenox.29|arsenic trioxide induction]].''
+====Chemotherapy====
 *[[Arsenic trioxide (Trisenox)]] 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day
@@ Line 512: / Line 512: @@
 ''Treatment preceded by [[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin induction]]. Consolidation therapy starts within 2 to 4 weeks of hematologic remission.''
+====Chemotherapy====
 *[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
 '''7-week cycles (5 weeks of therapy, then 2 weeks off), followed by:'''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting days 1 to 7
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, starting days 1 to 7
-*[[Daunorubicin (Cerubidine)]] 50 mg/m2 IV once per day on days 1 to 3
+*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3
-'''7-day cycle x 2 cycles'''
+'''7-day cycle for 2 cycles'''
 ''Treatment followed by [[#ATRA|ATRA maintenance]] versus [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX maintenance]].''
@@ Line 560: / Line 560: @@
 ''Treatment preceded by [[#Arsenic_trioxide_.26_ATRA|Arsenic trioxide & ATRA induction]].''
+====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
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/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'''
@@ Line 587: / Line 587: @@
 ====Consolidation cycle 1====
 ''Given 3 to 4 weeks after completion of induction.''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 28
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID on days 1 to 28
 *[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV once per day on days 1 to 28
@@ Line 594: / Line 594: @@
 ====Consolidation cycle 2====
 ''Given 3 to 4 weeks after completion of consolidation cycle 1.''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 7, 15 to 21, 29 to 35
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID on days 1 to 7, 15 to 21, 29 to 35
 *[[Arsenic trioxide (Trisenox)]] 0.15 mg/kg IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
@@ Line 603: / Line 603: @@
 ===References===
 # Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. [http://www.bloodjournal.org/content/107/9/3469.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16373661 PubMed]
-# Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R,Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80.  Epub 2012 Jun 19. [http://www.bloodjournal.org/content/120/8/1570.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22715121 PubMed]
+# Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R,Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. [http://www.bloodjournal.org/content/120/8/1570.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22715121 PubMed]
 # Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. [http://www.nejm.org/doi/full/10.1056/NEJMoa1300874 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1300874/suppl_file/nejmoa1300874_protocol.pdf link to supplementary appendix] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1300874/suppl_file/nejmoa1300874_protocol.pdf link to protocol] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23841729 PubMed]
 # 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00193-X/fulltext link to SD article] [http://www.ncbi.nlm.nih.gov/pubmed/26384238 PubMed]
@@ Line 630: / Line 630: @@
 ''Treatment preceded by [[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin induction]]. Consolidation therapy starts within 2 to 4 weeks of hematologic remission.''
+====Chemotherapy====
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, starting days 1 to 7
+*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, starting days 1 to 7
+'''7-day cycle for 2 cycles'''
-*[[Daunorubicin (Cerubidine)]] 50 mg/m2 IV once per day on days 1 to 3
-'''7-day cycle x 2 cycles'''
+''Treatment followed by randomization to [[#ATRA|ATRA maintenance]] versus [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX maintenance]].''
-''Treatment followed by [[#ATRA|ATRA maintenance]] versus [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX maintenance]].''
 ===References===
@@ Line 665: / Line 665: @@
 ''Treatment preceded by [[#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, cytarabine, daunorubicin induction]].''
+====Chemotherapy====
 *[[Cytarabine (Cytosar)]] as follows:
-**Cycle 1: 200 mg/m2/day IV continuous infusion on days 1 to 7
+**Cycle 1: 200 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 7
 **Cycle 2 as follows:
-***Younger (<60) low-risk (WBC <10k) or older (>60) high-risk (WBC >10k): 1000 mg/m2 IV every 12 hours on days 1 to 4 (8 total doses)
+***Younger (<60) low-risk (WBC <10k) or older (>60) high-risk (WBC >10k): 1000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 4 (8 total doses)
-***Younger (<60) high-risk (WBC >10k): 2000 mg/m2 IV every 12 hours on days 1 to 5 (10 total doses)
+***Younger (<60) high-risk (WBC >10k): 2000 mg/m<sup>2</sup> 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 1: 60 mg/m<sup>2</sup> IV once per day on days 1 to 3
-**Cycle 2: 45 mg/m2 IV once per day on days 1 to 3
+**Cycle 2: 45 mg/m<sup>2</sup> IV once per day on days 1 to 3
 ====Intrathecal for high-risk (WBC >10k) patients====
@@ Line 705: / Line 705: @@
 |}
 ''Treatment preceded by [[#ATRA_.26_Idarubicin|ATRA & idarubicin induction]]. This consolidation protocol was intended for patients older than 60.''
+====Chemotherapy====
-*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV over 6 hours once per day on days 1 to 4, '''given first'''
+*[[Cytarabine (Cytosar)]] 1000 mg/m<sup>2</sup> 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'''
+*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4, '''given second, 3 hours after cytarabine infusion complete'''
 '''One course'''
@@ Line 746: / Line 746: @@
 ''Treatment in '''LAP 0389''' preceded by idarubicin induction versus cytarabine & idarubicin induction (neither with ATRA; no longer standard of care). Treatment in '''AIDA 0493''' preceded by [[#ATRA_.26_Idarubicin|ATRA & idarubicin induction]]; note that the consolidation portion of the protocol is described in Avvisati et al. 1996.''
+====Chemotherapy====
-*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV over 6 hours once per day on days 1 to 4, '''given first'''
+*[[Cytarabine (Cytosar)]] 1000 mg/m<sup>2</sup> 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'''
+*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4, '''given second, 3 hours after cytarabine infusion complete'''
 '''One course'''
@@ Line 754: / Line 754: @@
 ''Next course to begin "at recovery from the previous one, when polymorphonuclear cells numbered 1500/μL or more and platelets numbered 100k/μL or more."''
-*[[Etoposide (Vepesid)]] 100 mg/m2 IV over 45 to 60 minutes oncer per day on days 1 to 5, '''given second, 12 hours after start of mitoxantrone'''
+*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 45 to 60 minutes oncer 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'''
+*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given first'''
 '''One course'''
@@ Line 761: / Line 761: @@
 ''Next course to begin "at recovery from the previous one, when polymorphonuclear cells numbered 1500/μL or more and platelets numbered 100k/μL or more."''
-*[[Cytarabine (Cytosar)]] 150 mg/m2 SC every 8 hours on days 1 to 5
+*[[Cytarabine (Cytosar)]] 150 mg/m<sup>2</sup> SC every 8 hours on days 1 to 5
 *[[Idarubicin (Idamycin)]] as follows:
-**LAP 0389 protocol: 5 mg/m2 IV once on day 1
+**LAP 0389 protocol: 5 mg/m<sup>2</sup> IV once on day 1
-**AIDA 0493 protocol: 12 mg/m2 IV once on day 1
+**AIDA 0493 protocol: 12 mg/m<sup>2</sup> IV once on day 1
-*[[Thioguanine (Tabloid)]] 70 mg/m2 PO every 8 hours on days 1 to 5
+*[[Thioguanine (Tabloid)]] 70 mg/m<sup>2</sup> PO every 8 hours on days 1 to 5
 '''One course'''
@@ Line 778: / Line 778: @@
 # Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F; GIMEMA (Gruppo Italiano Malattie Ematologische dell'Adulto) Italian Cooperative Group. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. [http://www.bloodjournal.org/content/100/9/3141.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12384411 PubMed]
-==Cytarabine & Idarubicin -> Etoposide  & Mitoxantrone -> Cytarabine, Idarubicin, Thioguanine, with ATRA {{#subobject:632192|Regimen=1}}==
+==Cytarabine & Idarubicin -> Etoposide & Mitoxantrone -> Cytarabine, Idarubicin, Thioguanine, with ATRA {{#subobject:632192|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
@@ Line 801: / Line 801: @@
 ''Treatment preceded by [[#ATRA_.26_Idarubicin|ATRA & idarubicin induction]]. This is risk-adapted therapy for <u>high-risk</u> patients in '''AIDA-2000'''. The authors were unclear about how many days were between each part of consolidation therapy.''
+====Chemotherapy====
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
-*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV once per day on days 1 to 4
+*[[Cytarabine (Cytosar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 4
-*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once per day on days 1 to 4
+*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
 '''4-day course of therapy, followed by:'''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
-*[[Etoposide (Vepesid)]] 100 mg/m2 IV once per day on days 1 to 5
+*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 5
+*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
 '''5-day course of therapy, followed by:'''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
-*[[Cytarabine (Cytosar)]] 150 mg/m2 SC every 8 hours (450 mg/m2/day total dosage) on days 1 to 5
+*[[Cytarabine (Cytosar)]] 150 mg/m<sup>2</sup> SC every 8 hours (450 mg/m<sup>2</sup>/day total dosage) on days 1 to 5
-*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on day 1
+*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1
-*[[Thioguanine (Tabloid)]] 70 mg/m2 PO every 8 hours (210 mg/m2/day total dosage) on days 1 to 5
+*[[Thioguanine (Tabloid)]] 70 mg/m<sup>2</sup> PO every 8 hours (210 mg/m<sup>2</sup>/day total dosage) on days 1 to 5
 '''5-day course of therapy'''
@@ Line 855: / Line 855: @@
 ''Treatment preceded by [[#ATRA_.26_Idarubicin|ATRA & idarubicin induction]]. This is risk-adapted therapy for <u>high-risk younger than 60</u> patients in '''PETHEMA LPA2005'''.''
+====Chemotherapy====
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, days 1 to 15
-*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once per day on days 1 to 4
+*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
-*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV once per day on days 1 to 4
+*[[Cytarabine (Cytosar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 4
 '''1-month cycle, followed by:'''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, days 1 to 15
-*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 5
+*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
 '''1-month cycle, followed by:'''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, days 1 to 15
-*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on day 1
+*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1
-*[[Cytarabine (Cytosar)]] 150 mg/m2, IV every 8 hours (total dose of 450 mg/m2/day) on days 1 to 4 (12 total doses)
+*[[Cytarabine (Cytosar)]] 150 mg/m<sup>2</sup>, IV every 8 hours (total dose of 450 mg/m<sup>2</sup>/day) on days 1 to 4 (12 total doses)
 '''1-month cycle'''
@@ Line 901: / Line 901: @@
 |}
 ''Treatment preceded by [[#ATRA_.26_Daunorubicin|ATRA & daunorubicin induction]]. This consolidation arm was a randomization for younger (<60), low-risk (WBC <10k) patients. Low-risk (WBC <10k) older (>60) patients received this regimen in a non-randomized fashion.''
+====Chemotherapy====
 *[[Daunorubicin (Cerubidine)]] as follows:
-**Cycle 1: 60 mg/m2 IV once per day on days 1 to 3
+**Cycle 1: 60 mg/m<sup>2</sup> IV once per day on days 1 to 3
-**Cycle 2: 45 mg/m2 IV once per day on days 1 to 3
+**Cycle 2: 45 mg/m<sup>2</sup> IV once per day on days 1 to 3
 ''Treatment followed by [[#ATRA.2C_Mercaptopurine.2C_Methotrexate|ATRA, 6-MP, MTX maintenance]].''
@@ Line 934: / Line 934: @@
 ''Treatment preceded by [[#ATRA_.26_Idarubicin|ATRA & idarubicin induction]] therapy. This was the <u>low-risk</u> treatment arm of '''PETHEMA LPA99'''; <u>all patients</u> on '''PETHEMA LPA96''' underwent this consolidation protocol.''
+====Chemotherapy====
-*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once per day on days 1 to 4
+*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
 '''1-month cycle, followed by:'''
-*[[Mitoxantrone (Novantrone)]] 10 mg/m2 IV once per day on days 1 to 5
+*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
 '''1-month cycle, followed by:'''
-*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on day 1
+*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1
 '''1-month cycle'''
@@ Line 996: / Line 996: @@
 ''Treatment preceded by [[#ATRA_.26_Idarubicin|ATRA & idarubicin induction]]. This is risk-adapted therapy for <u>intermediate- and low-risk</u> patients in '''AIDA-2000''' and for <u>low-risk</u> patients in '''PETHEMA LPA2005'''; all patients assigned to the chemotherapy arm of '''GIMEMA/DSIL APL0406''' received this treatment. Note that the number of mitoxantrone doses differs between the protocols.''
+====Chemotherapy====
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
-*[[Idarubicin (Idamycin)]] 5 mg/m2 IV once per day on days 1 to 4
+*[[Idarubicin (Idamycin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 4
 '''1-month cycle, followed by:'''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
 *[[Mitoxantrone (Novantrone)]] as follows:
-**'''AIDA-2000 & GIMEMA/DSIL APL0406''': 10 mg/m2 IV once per day on days 1 to 5
+**'''AIDA-2000 & GIMEMA/DSIL APL0406''': 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
-**'''PETHEMA LPA2005''': 10 mg/m2 IV once per day on days 1 to 3
+**'''PETHEMA LPA2005''': 10 mg/m<sup>2</sup> IV once per day on days 1 to 3
 '''1-month cycle, followed by:'''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day PO for a total of 15 days
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day PO for a total of 15 days
-*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once on day 1
+*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once on day 1
 '''1-month cycle'''
@@ Line 1,040: / Line 1,040: @@
 ''Treatment preceded by [[#ATRA_.26_Idarubicin|ATRA & idarubicin induction]]. This is risk-adapted therapy for <u>intermediate-</u> and <u>high-risk</u> patients in '''PETHEMA LPA99''' and for <u>intermediate-risk</u> and <u>high-risk older than 60</u> patients in '''PETHEMA LPA2005'''. Note that the number of mitoxantrone doses differs between the two protocols.''
+====Chemotherapy====
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, days 1 to 15
-*[[Idarubicin (Idamycin)]] 7 mg/m2 IV once per day on days 1 to 4
+*[[Idarubicin (Idamycin)]] 7 mg/m<sup>2</sup> IV once per day on days 1 to 4
 '''1-month cycle, followed by:'''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, days 1 to 15
 *[[Mitoxantrone (Novantrone)]] as follows:
-**'''PETHEMA LPA99''': 10 mg/m2 IV once per day on days 1 to 5
+**'''PETHEMA LPA99''': 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
-**'''PETHEMA LPA2005''': 10 mg/m2 IV once per day on days 1 to 3
+**'''PETHEMA LPA2005''': 10 mg/m<sup>2</sup> IV once per day on days 1 to 3
 '''1-month cycle, followed by:'''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID, days 1 to 15
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID, days 1 to 15
-*[[Idarubicin (Idamycin)]] 12 mg/m2 IV once per day on days 1 & 2
+*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once per day on days 1 & 2
 '''1-month cycle'''
@@ Line 1,090: / Line 1,090: @@
 ''Treatment preceded by [[Acute_promyelocytic_leukemia#Arsenic_trioxide_.28Trisenox.29_2|arsenic trioxide consolidation]].''
+====Chemotherapy====
 *[[Arsenic trioxide (Trisenox)]] 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day
-'''10 consecutive days of each month x 6 months'''
+'''10 consecutive days of each month for 6 months'''
 ===References===
@@ Line 1,121: / Line 1,121: @@
 |}
 ''Treatment preceded by [[#Arsenic_trioxide_-.3E_ATRA_.26_Daunorubicin|arsenic trioxide -> ATRA & daunorubicin consolidation]] versus [[#ATRA_.26_Daunorubicin|ATRA & daunorubicin consolidation]]. Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.''
+====Chemotherapy====
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID x 7 days every other week
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID for 7 days every other week
 '''1 year of therapy'''
@@ Line 1,152: / Line 1,152: @@
 |}
 ''Treatment in '''AIDA 0493''' preceded by [[#Cytarabine_.26_Idarubicin_-.3E_Etoposide_.26_Mitoxantrone_-.3E_Cytarabine.2C_Idarubicin.2C_Thioguanine|cytarabine & idarubicin -> etoposide & mitoxantrone -> cytarabine, idarubicin, thioguanine consolidation]]. Treatment in '''APL 93''' preceded by [[#Cytarabine_.26_Daunorubicin|cytarabine & daunorubicin consolidation]].''
+====Chemotherapy====
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day for 15 days every 3 months
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day for 15 days every 3 months
 '''2 year course of therapy'''
@@ Line 1,185: / Line 1,185: @@
 |}
 ''Treatment preceded by [[#Arsenic_trioxide_-.3E_ATRA_.26_Daunorubicin|arsenic trioxide -> ATRA & daunorubicin consolidation]] versus [[#ATRA_.26_Daunorubicin_2|ATRA & daunorubicin consolidation]]. Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.''
+====Chemotherapy====
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID x 7 days every other week
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID for 7 days every other week
-*[[Mercaptopurine (Purinethol)]] 60 mg/m2 PO once per day
+*[[Mercaptopurine (Purinethol)]] 60 mg/m<sup>2</sup> PO once per day
-*[[Methotrexate (MTX)]] 20 mg/m2 PO once per week
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per week
 '''1 year of therapy'''
@@ Line 1,208: / Line 1,208: @@
 ''Treatment preceded by [[#Cytarabine_.26_Daunorubicin|cytarabine & daunorubicin consolidation]] versus [[#Daunorubicin_.28Cerubidine.29|daunorubicin consolidation]].''
+====Chemotherapy====
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID on days 1 to 15
+*[[Mercaptopurine (Purinethol)]] 50 to 90 mg/m<sup>2</sup> PO once per day
+*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> PO once per week
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 15
+'''90-day cycle for 2 years'''
-*[[Mercaptopurine (Purinethol)]] 50 to 90 mg/m2 PO once per day
-*[[Methotrexate (MTX)]] 15 mg/m2 PO once per week
-'''90-day cycles x 2 years'''
 ===Regimen #3 {{#subobject:ac797|Variant=1}}===
@@ Line 1,231: / Line 1,231: @@
 ''Treatment preceded by [[#Arsenic_trioxide_.26_ATRA_2|arsenic trioxide & ATRA consolidation]]. Maintenance starts 3 to 4 weeks after completion of consolidation cycle 2.''
+====Chemotherapy====
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID on days 1 to 14
+*[[Mercaptopurine (Purinethol)]] 50 to 90 mg/m<sup>2</sup> PO once per day on days 15 to 90
+*[[Methotrexate (MTX)]] 5 to 15 mg/m<sup>2</sup>/week PO on days 15 to 90
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 14
+====Dose adjustments====
-*[[Mercaptopurine (Purinethol)]] 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
-Dose adjustments:
 *[[Methotrexate (MTX)]] and [[Mercaptopurine (Purinethol)]] doses titrated to ANC 1 to 2 x 10<sup>9</sup>/L (1,000 to 2,000/uL) and minimizing hepatotoxicity
-'''90-day cycle x 8 cycles'''
+'''90-day cycle for 8 cycles'''
 ===Regimen #4 {{#subobject:80d40a|Variant=1}}===
 ''Treatment preceded by [[#PETHEMA_LPA99_consolidation|PETHEMA LPA99]] or [[#PETHEMA_LPA2005_consolidation|PETHEMA LPA2005]] consolidation therapy.''
+====Chemotherapy====
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 15
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day, divided into two equal doses PO BID on days 1 to 15
-*[[Mercaptopurine (Purinethol)]] 50 mg/m2 PO once per day
+*[[Mercaptopurine (Purinethol)]] 50 mg/m<sup>2</sup> PO once per day
-*[[Methotrexate (MTX)]] 15 mg/m2 IM once per week
+*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IM once per week
 Dose adjustments:
@@ Line 1,252: / Line 1,252: @@
 *[[Methotrexate (MTX)]] and [[Mercaptopurine (Purinethol)]] stopped if WBC count <2.5 × 10<sup>9</sup>/L
-'''90-day cycle x 2 years'''
+'''90-day cycle for 2 years'''
 ===Regimen #5, ATRA alternating with 6-MP, MTX {{#subobject:1d7cb5|Variant=1}}===
@@ Line 1,280: / Line 1,280: @@
 |}
 ''Treatment in '''AIDA 0493''' preceded by [[#Cytarabine_.26_Idarubicin_-.3E_Etoposide_.26_Mitoxantrone_-.3E_Cytarabine.2C_Idarubicin.2C_Thioguanine|cytarabine & idarubicin -> etoposide & mitoxantrone -> cytarabine, idarubicin, thioguanine consolidation]]. Treatment in '''APL 93''' preceded by [[#Cytarabine_.26_Daunorubicin|cytarabine & daunorubicin consolidation]].''
+====Chemotherapy====
-*[[Mercaptopurine (Purinethol)]] 90 mg/m2 PO once per day
+*[[Mercaptopurine (Purinethol)]] 90 mg/m<sup>2</sup> PO once per day
-*[[Methotrexate (MTX)]] 15 mg/m2 IM once per week
+*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IM once per week
 '''3-month cycle, alternating with'''
-*[[All-trans retinoic acid (ATRA)]] 45 mg/m2/day for 15 days
+*[[All-trans retinoic acid (ATRA)]] 45 mg/m<sup>2</sup>/day for 15 days
 '''2 year course of therapy'''
@@ Line 1,299: / Line 1,299: @@
 # Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA and HOVON Groups. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. [http://bloodjournal.hematologylibrary.org/content/115/25/5137.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/20393132 PubMed]
 # Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. [http://bloodjournal.hematologylibrary.org/content/116/19/3751.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20705755 PubMed]
-# Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R,Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80.  Epub 2012 Jun 19. [http://bloodjournal.hematologylibrary.org/content/120/8/1570.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22715121 PubMed]
+# Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R,Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. [http://bloodjournal.hematologylibrary.org/content/120/8/1570.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22715121 PubMed]
 ==Mercaptopurine & Methotrexate {{#subobject:a29183|Regimen=1}}==
@@ Line 1,325: / Line 1,325: @@
 ''Treatment preceded by [[#Cytarabine_.26_Idarubicin_-.3E_Etoposide_.26_Mitoxantrone_-.3E_Cytarabine.2C_Idarubicin.2C_Thioguanine|cytarabine & idarubicin -> etoposide & mitoxantrone -> cytarabine, idarubicin, thioguanine consolidation]].''
+====Chemotherapy====
 *[[Mercaptopurine (Purinethol)]] 1 mg/kg PO once per day
 *[[Methotrexate (MTX)]] 0.25 mg/kg IM once per week
@@ Line 1,358: / Line 1,358: @@
 ''Treatment in '''AIDA 0493''' preceded by [[#Cytarabine_.26_Idarubicin_-.3E_Etoposide_.26_Mitoxantrone_-.3E_Cytarabine.2C_Idarubicin.2C_Thioguanine|cytarabine & idarubicin -> etoposide & mitoxantrone -> cytarabine, idarubicin, thioguanine consolidation]]. Treatment in '''APL 93''' preceded by [[#Cytarabine_.26_Daunorubicin|cytarabine & daunorubicin consolidation]]. Note that this arm was dropped from '''AIDA 0493''' from February 1997.''
+====Chemotherapy====
-*[[Mercaptopurine (Purinethol)]] 90 mg/m2 PO once per day
+*[[Mercaptopurine (Purinethol)]] 90 mg/m<sup>2</sup> PO once per day
-*[[Methotrexate (MTX)]] 15 mg/m2 IM once per week
+*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IM once per week
 '''2-year course of therapy'''
@@ Line 1,443: / Line 1,443: @@
 ====Induction====
 *[[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
-*[[Idarubicin (Idamycin)]] 12 mg/m2 IV over 30 minutes once per day on days 1 & 2 (Idarubicin was added under special conditions; see text for details)
+*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 (Idarubicin was added under special conditions; see text for details)
 *Intrathecal therapy given once after platelet recovery, consisting of:
 **[[Methotrexate (MTX)]] 15 mg IT,
@@ Line 1,457: / Line 1,457: @@
 ====Consolidation #3====
-*[[Cytarabine (Cytosar)]] 2 g/m2 IV over 3 hours twice per day on days 1 to 4 (8 doses total)
+*[[Cytarabine (Cytosar)]] 2 g/m<sup>2</sup> IV over 3 hours twice per day on days 1 to 4 (8 doses total)
 *[[Filgrastim (Neupogen)]] starting on day 6 (dose, frequency not specified)
 '''Peripheral blood stem cells collected upon WBC recovery, followed by:'''
-*[[Busulfan (Myleran)]] & [[Melphalan (Alkeran)]] autologous stem cell transplant; see [[Transplant_conditioning_regimens#Busulfan_.26_Melphalan|transplant conditioning regimens]]
+*[[Busulfan (Myleran)]] & [[Melphalan (Alkeran)]] -> autologous stem cell transplant; see [[Transplant_conditioning_regimens#Busulfan_.26_Melphalan|transplant conditioning regimens]]
 ===References===
 # Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. [http://bloodjournal.hematologylibrary.org/content/121/16/3095.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23412094 PubMed]
-[[Category:Malignant hematology regimens]]
-[[Category:Chemotherapy regimens]]
 =Investigational agents=
 *[[Tamibarotene (Amnoid)]]
+[[Category:Chemotherapy regimens]]
+[[Category:Malignant hematology regimens]]
+[[Category:Leukemia regimens]]

Difference between revisions of "Acute promyelocytic leukemia"

Revision as of 18:09, 14 August 2016

Induction therapy

Arsenic trioxide (Trisenox)

Regimen #1

Chemotherapy

Regimen #2

Chemotherapy

References

Arsenic trioxide & ATRA

Regimen #1

Chemotherapy

Regimen #2

Chemotherapy

Supportive medications

Regimen #3

Chemotherapy

Regimen #4

Chemotherapy

Supportive medications

References

Arsenic trioxide, ATRA, Idarubicin

Regimen

Chemotherapy

Supportive medications

References

ATRA, Cytarabine, Daunorubicin

Regimen #1

Chemotherapy

Regimen #2

Chemotherapy

References

ATRA & Daunorubicin

Regimen

Chemotherapy

References

ATRA & Idarubicin

Regimen

Chemotherapy

References

Consolidation therapy

Arsenic trioxide (Trisenox)

Regimen

Chemotherapy

References

Arsenic trioxide -> ATRA & Daunorubicin

Regimen

Chemotherapy

References

Arsenic trioxide & ATRA

Regimen #1

Chemotherapy

Regimen #2

Consolidation cycle 1

Consolidation cycle 2

References

ATRA & Daunorubicin

Regimen

Chemotherapy

References

Cytarabine & Daunorubicin

Regimen

Chemotherapy

Intrathecal for high-risk (WBC >10k) patients

References

Cytarabine & Idarubicin

Regimen

Chemotherapy

References

Cytarabine & Idarubicin -> Etoposide & Mitoxantrone -> Cytarabine, Idarubicin, Thioguanine

Regimen

Chemotherapy

References

Cytarabine & Idarubicin -> Etoposide & Mitoxantrone -> Cytarabine, Idarubicin, Thioguanine, with ATRA

Regimen

Chemotherapy

CNS prophylaxis

References

Cytarabine & Idarubicin -> Mitoxantrone -> Cytarabine & Idarubicin, with ATRA

Regimen