Acute promyelocytic leukemia

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31 regimens on this page 48 variants on this page

Guidelines

ELN

• 2009: Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet PubMed

ESMO

• 2013: Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

NCCN

• NCCN Guidelines - Acute Myeloid Leukemia

Upfront induction therapy

Arsenic trioxide monotherapy

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Regimen #1

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

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

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

Arsenic trioxide & ATRA

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Regimen #1

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

Chemotherapy

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

Treatment followed by arsenic trioxide & ATRA consolidation.

Regimen #2

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

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

Chemotherapy

• Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 2 hours once per day, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days.
• All-trans retinoic acid (ATRA) 45 mg/m²/day, divided into two equal doses PO BID, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days.

Supportive medications

• Prednisone (Sterapred) 0.5 mg/kg PO once per day from days 1 until the end of induction or the onset of differentiation syndrome
  • Patients who develop differentiation syndrome then received: Dexamethasone (Decadron) 10 mg IV every 12 hours until signs and symptoms resolve, and for a minimum of 3 days
• Hemostatic support: Transfusions to keep platelet count greater than 30 x 10⁹/L for the first 10 days of induction and greater than 20 x 10⁹/L for the remainder of induction
• Hydroxyurea (Hydrea) as follows:
  • Patients with WBC count greater than 10 x 10⁹/L and less than 50 x 10⁹/L after the start of therapy received: 500 mg PO four times per day, given until WBC count is less than 10 x 10⁹/L
  • Patients with WBC count greater than 50 x 10⁹/L after the start of therapy received: 1000 mg PO four times per day, given until WBC count is less than 10 x 10⁹/L

One course, to remission

Treatment followed by arsenic trioxide & ATRA consolidation.

Regimen #3

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

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 greater than 30 x 10⁹/L for any patient in the first four weeks of therapy.

Chemotherapy

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

Supportive medications

• "Prophylactic and therapeutic antibiotics and transfusion of blood products to maintain platelet counts more than 30 x 10⁹/L, fibrinogen more than 150 mg/dL, and the international normalized ratio for prothrombin time less than 1.5" per institutional guidelines
• Heparin or Tranexamic acid (Cyklokapron) used if clinically indicated
• Patients in Estey et al. 2006 received: "Oral solumedrol" 20 mg PO once per day for 10 days to decrease risk of differentiation syndrome
• Patients in Ravandi et al. 2009 recieved: Methylprednisolone 50 mg PO once per day for 5 days to decrease risk of differentiation syndrome

Treatment followed by arsenic trioxide & ATRA consolidation.

References

1. Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De Thé H, Wang ZY, Chen SJ, Chen Z. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5328-35. Epub 2004 Mar 24. link to original article contains verified protocol link to PMC article PubMed
2. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article contains verified protocol PubMed
3. Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009 Feb 1;27(4):504-10. Epub 2008 Dec 15. link to original article contains verified protocol link to PMC article PubMed
4. Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WL, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3342-7. Epub 2009 Feb 18. link to original article contains verified protocol link to PMC article PubMed content property of HemOnc.org
5. 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
   1. Update: Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. link to original article link to PMC article PubMed
6. Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. link to SD article contains protocol PubMed

Arsenic trioxide, ATRA, Idarubicin

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Regimen

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

Chemotherapy

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

Supportive medications

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

36-day course

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

References

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

ATRA monotherapy

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Regimen

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

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

Chemotherapy

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

Treatment followed by ATRA consolidation, then cytarabine & daunorubicin consolidation.

References

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

ATRA, Cytarabine, Daunorubicin

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Regimen #1

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

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

Chemotherapy

• 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 RCT

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, then ATRA & daunorubicin consolidation versus ATRA & daunorubicin consolidation.

References

1. Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood. 1993 Dec 1;82(11):3241-9. link to original article PubMed
2. 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
3. Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains verified protocol link to PMC article PubMed

ATRA & Daunorubicin

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Regimen

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

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

Chemotherapy

• 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

1. 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	Efficacy
Avvisati et al. 1996	Pilot
Mandelli et al. 1997 (AIDA 0493)	Non-randomized portion of RCT
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	Inferior OS (*)
Burnett et al. 2015 (NCRI AML17)	Phase III	Arsenic trioxide & ATRA	Seems not superior

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

Chemotherapy

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

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

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

• Patients in PETHEMA LPA96 proceeded to receive idarubicin, then mitoxantrone, then idarubicin consolidation.
• Patients in AIDA 0493 proceeded to receive cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation.
• Patients in PETHEMA LPA99 proceeded to receive risk-adapted therapy:
  • Low-risk patients received idarubicin, then mitoxantrone, then idarubicin consolidation.
  • Intermediate- and high-risk patients received idarubicin, then mitoxantrone, then idarubicin, with ATRA consolidation.
• Patients in PETHEMA LPA2005 proceeded to receive risk-adapted therapy:
  • High-risk patients received cytarabine & idarubicin, then mitoxantrone, then cytarabine & idarubicin, with ATRA consolidation.
  • Intermediate- and low-risk patients received idarubicin, then mitoxantrone, then idarubicin, with ATRA consolidation.
• Patients in AIDA 2000 proceeded to receive risk-adapted therapy:
  • High-risk patients received cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine, with ATRA consolidation.
  • Intermediate- and low-risk patients received idarubicin, then mitoxantrone, then 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, then mitoxantrone, then idarubicin, with ATRA consolidation.

References

1. Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood. 1996 Aug 15;88(4):1390-8. link to full article contains verified protocol PubMed
2. 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
3. Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains verified protocol PubMed
   1. Update: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains verified protocol PubMed
4. Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA and HOVON Groups. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. link to original article contains verified protocol PubMed
5. Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; Italian GIMEMA Cooperative Group. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. link to original article contains verified protocol PubMed
6. Latagliata R, Breccia M, Fazi P, Vignetti M, Di Raimondo F, Sborgia M, Vincelli D, Candoni A, Salvi F, Rupoli S, Martinelli G, Kropp MG, Tonso A, Venditti A, Melillo L, Cimino G, Petti MC, Avvisati G, Lo-Coco F, Mandelli F; GIMEMA Acute Leukaemia Working Party. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia. Long-term results and prognostic factors. Br J Haematol. 2011 Sep;154(5):564-8. Epub 2011 Jul 14. link to full article contains verified protocol PubMed
7. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains verified protocol PubMed
   1. Update: Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. link to original article link to PMC article PubMed
8. Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. link to original article PubMed

Consolidation after upfront therapy

Arsenic trioxide monotherapy

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Regimen

Study	Evidence
Mathews et al. 2006	Non-randomized

Preceding treatment

• 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

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

Arsenic trioxide, then ATRA & Daunorubicin

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Regimen

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

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

Preceding treatment

• ATRA, cytarabine, daunorubicin induction.

Chemotherapy, part 1

• 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:

Chemotherapy, part 2

• 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

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

Arsenic trioxide & ATRA

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Regimen #1

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

Preceding treatment

• 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

Consolidation starts 3 to 4 weeks after completion of induction.

Preceding treatment

• Arsenic trioxide, ATRA, idarubicin induction

Chemotherapy, part 1

• 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

Chemotherapy, part 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

1. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article contains verified protocol PubMed
2. Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R,Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. link to original article contains verified protocol PubMed
3. 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
   1. Update: Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. link to original article link to PMC article PubMed
4. Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. link to SD article PubMed

ATRA & Daunorubicin

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Regimen

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

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

Preceding treatment

• ATRA, cytarabine, daunorubicin induction

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

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

Cytarabine & Daunorubicin

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Regimen

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

Preceding treatment

• 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 (less than 60) low-risk (WBC count less than 10 x 10⁹/L) or older (greater than 60) high-risk (WBC count greater than 10 x 10⁹/L): 1000 mg/m² IV every 12 hours on days 1 to 4 (8 total doses)
    • Younger (less than 60) high-risk (WBC count greater than 10 x 10⁹/L): 2000 mg/m² IV every 12 hours on days 1 to 5 (10 total doses)
• Daunorubicin (Cerubidine) as follows:
  • Cycle 1: 60 mg/m² IV once per day on days 1 to 3
  • Cycle 2: 45 mg/m² IV once per day on days 1 to 3

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

• 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

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

Cytarabine & Idarubicin

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Regimen

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

This consolidation protocol was intended for patients older than 60.

Preceding treatment

• ATRA & idarubicin induction

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

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

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

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Regimen

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

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

Preceding treatment

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

Chemotherapy, part 1

• Cytarabine (Cytosar) 1000 mg/m² IV over 6 hours once per day on days 1 to 4, given first
• Idarubicin (Idamycin) 5 mg/m² IV once per day on days 1 to 4, given second, 3 hours after cytarabine infusion complete

One course

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

Chemotherapy, part 2

• 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/uL or more and platelets numbered 100 x 10⁹/L or more."

Chemotherapy, part 3

• 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

1. Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood. 1996 Aug 15;88(4):1390-8. link to full article contains verified protocol PubMed
2. 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
3. Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains verified protocol PubMed
   1. Update: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains verified protocol PubMed
4. Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F; GIMEMA (Gruppo Italiano Malattie Ematologische dell'Adulto) Italian Cooperative Group. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. link to original article contains verified protocol PubMed

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

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AIDA: ATRA, IDArubicin

Regimen

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

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

Preceding treatment

• ATRA & idarubicin induction

Chemotherapy, part 1

• 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:

Chemotherapy, part 2

• 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:

Chemotherapy, part 3

• 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

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

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

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PETHEMA: Programa Español de Tratamientos en HEMAtología

Regimen

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

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

Preceding treatment

• ATRA & idarubicin induction

Chemotherapy, consolidation #1

• 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:

Chemotherapy, consolidation #2

• 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:

Chemotherapy, consolidation #3

• 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/SC 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

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

Daunorubicin monotherapy

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Regimen

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

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

Preceding treatment

• ATRA & daunorubicin induction

Chemotherapy

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

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

References

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

Idarubicin, then Mitoxantrone, then Idarubicin

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PETHEMA: Programa Español de Tratamientos en HEMAtología

Regimen

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

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

Preceding treatment

• ATRA & idarubicin induction

Chemotherapy, part 1

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

1-month cycle, followed by:

Chemotherapy, part 2

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

1-month cycle, followed by:

Chemotherapy, part 3

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

1-month cycle

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

References

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

Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA

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

Regimen #1

Study	Evidence
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)	Non-randomized portion of RCT

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

Preceding treatment

• ATRA & idarubicin induction

Chemotherapy, part 1

• 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:

Chemotherapy, part 2

• 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:

Chemotherapy, part 3

• 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

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

Preceding treatment

• ATRA & idarubicin induction

Chemotherapy, part 1

• 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:

Chemotherapy, part 2

• 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:

Chemotherapy, part 3

• 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

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

Maintenance after upfront therapy

Arsenic trioxide monotherapy

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Regimen

Study	Evidence
Mathews et al. 2006	Non-randomized

====Preceding treatment==== *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

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

ATRA monotherapy

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Regimen #1

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

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

Preceding treatment

• Arsenic trioxide, then ATRA & daunorubicin consolidation versus ATRA & daunorubicin consolidation

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	Efficacy
Mandelli et al. 1997 (AIDA 0493)	Phase III	ATRA, 6-MP, MTX	Seems not superior
		6-MP & MTX	Seems not superior
		No further treatment	Seems not superior
Fenaux et al. 1999 (APL93)	Phase III	ATRA, 6-MP, MTX	Inferior 2-year relapse rate
		6-MP & MTX No further treatment	Seems to have superior 2-year relapse rate

Preceding treatment

• AIDA 0493: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
• APL 93: 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

1. 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
2. Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999 Aug 15;94(4):1192-200. link to original article PubMed
   1. Update: Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, Recher C, Thomas X, Rayon C, Castaigne S, Tournilhac O, de Botton S, Ifrah N, Cahn JY, Solary E, Gardin C, Fegeux N, Bordessoule D, Ferrant A, Meyer-Monard S, Vey N, Dombret H, Degos L, Chevret S, Fenaux P; European APL Group. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010 Mar 4;115(9):1690-6. Epub 2009 Dec 17. link to original article PubMed
3. Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains verified protocol link to PMC article PubMed

ATRA, Mercaptopurine, Methotrexate

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Regimen #1

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

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

Preceding treatment

• Arsenic trioxide, then ATRA & daunorubicin consolidation versus ATRA & daunorubicin consolidation

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 RCT

Preceding treatment

• 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

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

Preceding treatment

• Arsenic trioxide & ATRA consolidation

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 1000 to 2000/uL and minimizing hepatotoxicity

90-day cycle for 8 cycles

Regimen #4

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

Preceding treatment

• PETHEMA LPA99, low-risk: Idarubicin, then Mitoxantrone, then Idarubicin consolidation
• PETHEMA LPA99, intermediate- and high-risk and PETHEMA LPA2005, low- and intermediate-risk Idarubicin, then Mitoxantrone, then Idarubicin, with ATRA consolidation
• PETHEMA LPA2005, high-risk: Cytarabine & Idarubicin, then Mitoxantrone, then Cytarabine & Idarubicin, with ATRA consolidation

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 less than 3.5 × 10⁹/L
• Methotrexate (MTX) and Mercaptopurine (Purinethol) stopped if WBC count less than 2.5 × 10⁹/L

90-day cycle for 2 years

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

Study	Evidence	Comparator	Efficacy
Mandelli et al. 1997 (AIDA 0493)	Phase III	ATRA	Seems not superior
		6-MP & MTX	Seems not superior
		No further treatment	Seems not superior
Fenaux et al. 1999 (APL93)	Phase III	6-MP & MTX	Seems to have superior 2-year relapse rate
		ATRA No further treatment	Superior 2-year relapse rate

Preceding treatment

• AIDA 0493: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
• APL 93: 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

1. 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
2. Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999 Aug 15;94(4):1192-200. link to original article PubMed
   1. Update: Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, Recher C, Thomas X, Rayon C, Castaigne S, Tournilhac O, de Botton S, Ifrah N, Cahn JY, Solary E, Gardin C, Fegeux N, Bordessoule D, Ferrant A, Meyer-Monard S, Vey N, Dombret H, Degos L, Chevret S, Fenaux P; European APL Group. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010 Mar 4;115(9):1690-6. Epub 2009 Dec 17. link to original article PubMed
3. Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains verified protocol PubMed
   1. Update: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains verified protocol PubMed
4. Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; European Acute Promyelocytic Leukemia Group. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. link to original article contains verified protocol PubMed
   1. Update: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains verified protocol PubMed
5. Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA and HOVON Groups. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. link to original article PubMed
6. Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains verified protocol link to PMC article PubMed
7. Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R,Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. link to original article contains verified protocol PubMed
8. 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

Mercaptopurine & Methotrexate

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Regimen #1

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

Preceding treatment

• Cytarabine & idarubicin, then etoposide & mitoxantrone, then 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	Efficacy
Mandelli et al. 1997 (AIDA 0493)	Phase III	ATRA	Seems not superior
		ATRA, 6-MP, MTX	Seems not superior
		No further treatment	Seems not superior
Fenaux et al. 1999 (APL93)	Phase III	ATRA ATRA, 6-MP, MTX	Seems to have inferior 2-year relapse rate
		No further treatment	Superior 2-year relapse rate

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

Preceding treatment

• AIDA 0493: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
• APL 93: Cytarabine & daunorubicin consolidation

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

1. 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
2. Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999 Aug 15;94(4):1192-200. link to original article PubMed
   1. Update: Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, Recher C, Thomas X, Rayon C, Castaigne S, Tournilhac O, de Botton S, Ifrah N, Cahn JY, Solary E, Gardin C, Fegeux N, Bordessoule D, Ferrant A, Meyer-Monard S, Vey N, Dombret H, Degos L, Chevret S, Fenaux P; European APL Group. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010 Mar 4;115(9):1690-6. Epub 2009 Dec 17. link to original article PubMed
3. Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F; GIMEMA (Gruppo Italiano Malattie Ematologische dell'Adulto) Italian Cooperative Group. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. link to original article contains verified protocol PubMed

No further treatment

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Regimen

Study	Evidence	Comparator	Efficacy
Mandelli et al. 1997 (AIDA 0493)	Phase III	ATRA	Seems not superior
		ATRA, 6-MP, MTX	Seems not superior
		6-MP & MTX	Seems not superior
Fenaux et al. 1999 (APL93)	Phase III	ATRA	Seems to have inferior 2-year relapse rate
		ATRA, 6-MP, MTX 6-MP & MTX	Inferior 2-year relapse rate
Avvisati et al. 2002 (LAP 0389)	Phase III	6-MP & MTX	Seems not superior

Preceded by Cytarabine & daunorubicin consolidation in APL 93. Preceded by Cytarabine & idarubicin, then etoposide & mitoxantrone, then 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

1. 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
2. Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999 Aug 15;94(4):1192-200. link to original article PubMed
   1. Update: Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, Recher C, Thomas X, Rayon C, Castaigne S, Tournilhac O, de Botton S, Ifrah N, Cahn JY, Solary E, Gardin C, Fegeux N, Bordessoule D, Ferrant A, Meyer-Monard S, Vey N, Dombret H, Degos L, Chevret S, Fenaux P; European APL Group. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010 Mar 4;115(9):1690-6. Epub 2009 Dec 17. link to original article PubMed
3. Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F; GIMEMA (Gruppo Italiano Malattie Ematologische dell'Adulto) Italian Cooperative Group. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. link to original article contains verified protocol PubMed

Relapsed or refractory, salvage therapy

Arsenic trioxide monotherapy

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Regimen

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

Chemotherapy

• Arsenic trioxide (Trisenox) 10 mg IV over 2 to 3 hours once per day

Given until complete remission (CR)

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

References

1. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma J, Zhang P, Zhang TD, Chen SJ, Chen Z, Wang ZY. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997 May 1;89(9):3354-60. link to original article PubMed
2. Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, Corso D, DeBlasio A, Gabrilove J, Scheinberg DA, Pandolfi PP, Warrell RP Jr. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998 Nov 5;339(19):1341-8. link to original article PubMed
3. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers EL, Coutré S, Dahlberg S, Ellison R, Warrell RP Jr. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001 Sep 15;19(18):3852-60. link to original article PubMed

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

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Regimen

Study	Evidence
Yanada et al. 2013	Phase II

Induction

• 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 count recovery, followed by:

• Busulfan (Myleran) & Melphalan (Alkeran), then autologous stem cell transplant; see transplant conditioning regimens

References

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

Investigational agents

• Tamibarotene (Amnoid)