Acute promyelocytic leukemia

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Induction therapy

APL 2000 (EAPLG) induction

Regimen

Phase III

Induction for young and high-risk patients

• 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 on days 3 to 5
• Cytarabine (Cytosar) 200 mg/m2 IV on days 3 to 9

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

Induction for older low-risk patients

If >60 years old and WBC <10 x 10^9/L:

• 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 on days 3 to 5

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

To be followed by APL 2000 (EAPLG) consolidation therapy.

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
2. 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

APML4 induction

Regimen, Iland et al. 2012 (APML4)

Phase II

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

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

To be followed in 3 to 4 weeks by APML4 consolidation therapy

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

North American Leukemia Intergroup Study C9710 induction

Regimen

Phase III

• 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) 50 mg/m2 IV on days 3 to 6
• Cytarabine (Cytosar) 200 mg/m2/day IV continuous infusion on days 3 to 9

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

To be followed by North American Leukemia Intergroup Study C9710 consolidation therapy.

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 PubMed

AIDA 0493 & AIDA 2000 induction

AIDA: ATRA, IDArubicin

Regimen, Avvisati et al. 1996; Lo-Coco et al. 2010 (AIDA 2000); Latagliata et al. 2011 (AIDA 0493); Avvisati et al. 2011 (AIDA 0493); Lo-Coco et al. 2013

Phase III

• 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.
  • For patients <20 years old, All-trans retinoic acid (ATRA) dose was 25 mg/m2/day, divided into two equal doses PO BID
• Idarubicin (Idamycin) 12 mg/m2 IV once on days 2, 4, 6, 8

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

To be followed by AIDA 0493 consolidation or AIDA 2000 consolidation therapy.

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. 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
3. 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
4. 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
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 contains verified protocol PubMed

PETHEMA LPA99, LPA2005 induction

PETHEMA: Programa Español de Tratamientos en HEMAtología

Regimen

• 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.
  • For patients <20 years old, All-trans retinoic acid (ATRA) dose was 25 mg/m2/day, divided into two equal doses PO BID
• Idarubicin (Idamycin) 12 mg/m2 IV bolus on days 2, 4, 6, 8
  • For patients >70 years old, Idarubicin (Idamycin) 12 mg/m2 IV bolus on days 2, 4, 6 (day 8 dose omitted)

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

To be followed by PETHEMA LPA99 or PETHEMA LPA2005 consolidation therapy.

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
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

Arsenic trioxide (Trisenox)

Regimen

Phase III

• 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)

If in CR, wait 4 weeks, then:

• Arsenic trioxide (Trisenox) 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day x 28 days

28-day course

If in CR, wait 4 weeks, then:

• Arsenic trioxide (Trisenox) 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day x "10 days a month"

1-month cycles x 6 months

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 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
3. 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 & Arsenic

Regimen #1, Lo-Coco et al. 2013

Phase III

Lo-Coco et al. 2013 excluded patients with high-risk APML (white blood cell count at presentation ≥10 x 10⁹/L)

• 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.
• 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.

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

To be followed by ATRA & Arsenic consolidation therapy.

Regimen #2, Estey et al. 2006 & 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.

• 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 x 10 days to decrease risk of differentiation syndrome
• Patients in Ravandi et al. 2009 recieved: Methylprednisolone 50 mg PO once per day x 5 days to decrease risk of differentiation syndrome

To be followed by ATRA & Arsenic consolidation therapy.

Regimen #3, Shen et al. 2004

Phase II

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.

• 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

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 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 PubMed
4. Update: Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WL, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3342-7. Epub 2009 Feb 18. link to original article contains verified protocol PubMed
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

Consolidation therapy

APL 2000 (EAPLG) consolidation

Preceded by APL 2000 (EAPLG) induction therapy.

Regimen

Phase III

Consolidation regimen for patients ≤60 years old and WBC <10 x 10^9/L or age >60 and WBC >10 x 10^9/L

• Daunorubicin (Cerubidine) 60 mg/m2 IV on days 1 to 3
• Cytarabine (Cytosar) 200 mg/m2 IV on days 1 to 7

Followed by:

• Daunorubicin (Cerubidine) 45 mg/m2 IV on days 1 to 3
• Cytarabine (Cytosar) 1000 mg/m2 IV every 12 hours on days 1 to 4 (8 total doses)

Note: Adès et al. 2006 and Adès et al. 2008 both do not say that IT chemotherapy is used for patients with age >60 and WBC >10 x 10^9/L, but figure 1 in Adès et al. 2006 depicts IT chemotherapy in this patient group. I did not see a reference that clearly resolved this contradiction.

Consolidation regimen for patients ≤60 years old and WBC >10 x 10^9/L

• Daunorubicin (Cerubidine) 60 mg/m2 IV on days 1 to 3
• Cytarabine (Cytosar) 200 mg/m2 IV on days 1 to 7
• 3 doses of intrathecal chemotherapy with Methotrexate (MTX) 15 mg IT, Cytarabine (Cytosar) 50 mg IT, and corticosteroids

Followed by:

• Daunorubicin (Cerubidine) 45 mg/m2 IV on days 1 to 3
• If age <50 years old: Cytarabine (Cytosar) 2000 mg/m2 IV every 12 hours on days 1 to 5 (10 total doses)
• If age 50-60 years old: Cytarabine (Cytosar) 1500 mg/m2 IV every 12 hours on days 1 to 5 (10 total doses)
• 2 doses of intrathecal chemotherapy with Methotrexate (MTX) 15 mg IT, Cytarabine (Cytosar) 50 mg IT, and corticosteroids

Consolidation regimen for patients >60 years old and WBC <10 x 10^9/L

• Daunorubicin (Cerubidine) 60 mg/m2 IV on days 1 to 3

Followed by:

• Daunorubicin (Cerubidine) 45 mg/m2 IV on days 1 to 3

To be followed by APL 2000 (EAPLG) maintenance therapy.

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
2. 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

APML4 consolidation

Preceded by APML4 induction therapy.

Regimen, Iland et al. 2012 (APML4)

Phase II

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, proceed to APML4 maintenance

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

North American Leukemia Intergroup Study C9710 consolidation

Preceded by North American Leukemia Intergroup Study C9710 induction therapy.

Regimen

Phase III

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

• 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), THEN

• 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 cycles x 2 cycles

To be followed by North American Leukemia Intergroup Study C9710 maintenance therapy.

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 PubMed

AIDA 0493 consolidation

AIDA: ATRA, IDArubicin
Preceded by AIDA 0493 induction therapy.

Regimen

Phase III

As detailed in Avvisati, et al., 2002:

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

4-day course of therapy, THEN

• Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 to 5 (administered first)
• Etoposide (Vepesid) 100 mg/m2 IV over 45 to 60 minutes (administered second, 12 hours after start of mitoxantrone) days 1 to 5

5-day course of therapy, THEN

• Idarubicin (Idamycin) 12 mg/m2 IV day 1
• Cytarabine (Cytosar) 150 mg/m2 SC every 8 hours (450 mg/m2/day total dosage) days 1 to 5
• Thioguanine (Tabloid) 70 mg/m2 PO every 8 hours (210 mg/m2/day total dosage) days 1 to 5

5-day course of therapy

To be followed by AIDA 0493 maintenance therapy.

References

1. 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
2. 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
3. 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

AIDA 2000 consolidation

AIDA: ATRA, IDArubicin
Preceded by AIDA 0493 & AIDA 2000 induction therapy.

Regimen, Lo-Coco et al. 2010 (AIDA 2000)

Phase II

Low or intermediate risk

Patients with initial WBC <10 x 10⁹/L were considered to be low or intermediate risk. Lo-Coco et al. 2010 was unclear about how many days--if any--were between each part of consolidation therapy.

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

4-day course of therapy, THEN

• Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 to 5
• All-trans retinoic acid (ATRA) 45 mg/m2/day PO for a total of 15 days

5-day course of therapy, THEN

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

To be followed by AIDA 2000 maintenance therapy.

High risk

Patients with initial WBC >10 x 10⁹/L were considered to be high risk.

"Before the initiation of each consolidation cycle," high-risk patients received intracranial prophylaxis:

• Methotrexate (MTX) 12 mg IT once prior to each consolidation cycle
• Mercaptopurine (Purinethol) 40 mg IT once prior to each consolidation cycle

"total of 3 courses"

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

4-day course of therapy, THEN

• Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 to 5
• Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
• All-trans retinoic acid (ATRA) 45 mg/m2/day PO for a total of 15 days

5-day course of therapy, THEN

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

5-day course of therapy

To be followed by AIDA 2000 maintenance therapy.

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

PETHEMA LPA99 consolidation

PETHEMA: Programa Español de Tratamientos en HEMAtología
Preceded by PETHEMA LPA99, LPA2005 induction therapy.

High risk patients=

• 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, THEN

• 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, THEN

• 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 days 1 & 2

1-month cycle

Intermediate risk patients

• 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, THEN

• 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, THEN

• 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 days 1 & 2

1-month cycle

Low risk patients

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

1-month cycle, THEN

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

1-month cycle, THEN

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

1-month cycle

To be followed by PETHEMA LPA99, LPA2005 maintenance therapy.

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
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

PETHEMA LPA2005 consolidation

PETHEMA: Programa Español de Tratamientos en HEMAtología
Preceded by PETHEMA LPA99, LPA2005 induction therapy.

Regimen

High risk patients

• 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, THEN

• 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, THEN

• 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 day 1
• Cytarabine (Cytosar) 150 mg/m2, IV every 8 hours (total dose of 450 mg/m2/day), days 1 to 4 (12 total doses)

1-month cycle

Intermediate risk patients

• 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, THEN

• 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 3

1-month cycle, THEN

• 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 days 1 & 2

1-month cycle

Low risk patients

• 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

1-month cycle, THEN

• 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 3

1-month cycle, THEN

• 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

1-month cycle

To be followed by PETHEMA LPA99, LPA2005 maintenance therapy.

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
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

ATRA & Arsenic - consolidation

Preceded by ATRA & Arsenic induction therapy.

Regimen, Estey et al. 2006 & Lo-Coco et al. 2013

Phase II

• 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
• 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

28 weeks of therapy

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. 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

Maintenance therapy

APL 2000 (EAPLG) maintenance

Preceded by APL 2000 (EAPLG) consolidation therapy.

Regimen

Phase III

• Mercaptopurine (Purinethol) 50 to 90 mg/m2 PO once per day
• Methotrexate (MTX) 15 mg/m2 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 cycles x 2 years

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
2. 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

APML4 maintenance

Preceded by APML4 consolidation therapy.

Regimen, Iland et al. 2012 (APML4)

Phase II

Given 3 to 4 weeks after completion of consolidation cycle 2.

• All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 14
• Methotrexate (MTX) 5 to 15 mg/m2/week PO on days 15 to 90
• Mercaptopurine (Purinethol) 50 to 90 mg/m2 PO once per day on days 15 to 90
• 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 cycles x 8 cycles

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

North American Leukemia Intergroup Study C9710 maintenance

Preceded by North American Leukemia Intergroup Study C9710 consolidation therapy.

Regimen

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

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

With or without:

• Mercaptopurine (Purinethol) 60 mg/m2 PO once per day
• Methotrexate (MTX) 20 mg/m2 PO once per week

1 year of therapy

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 PubMed

AIDA 0493 maintenance

Preceded by AIDA 0493 consolidation therapy.

Regimen

Phase III

See Avvisati et al. 2011 for details about outcomes with or without maintenance therapy. Treatment options investigated included only using Part A, only using Part B, or alternating between the two, in all cases for a total of 2 years.

Part A

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

90-day course of therapy, alternating with part B, given for a total of 2 years

Part B

• All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 15

90-day course of therapy, alternating with part A, given for a total of 2 years

Alternate regimen (Avvisati et al. 2002)

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

2-year course of therapy

References

1. 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
2. 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. 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 original article contains verified protocol PubMed

AIDA 2000 maintenance

Preceded by AIDA 2000 consolidation therapy.

Regimen, Lo-Coco et al. 2010 (AIDA 2000)

Phase II

Patients RT-PCR negative for PML/RARA after consolidation received maintenance therapy. Patients who were RT-PCR positive for PML/RARA after consolidation were considered to have resistant disease and were given salvage therapy.

Part A

• Mercaptopurine (Purinethol) 50 mg/m2 PO once per day
• Methotrexate (MTX) 15 mg/m2 IM once per week

90-day course of therapy, alternating with part B, given for a total of 2 years

Part B

Lo-Coco et al. 2010 did not list details about ATRA; this is how it was given in Avvisati et al. 2011 (AIDA 0493).

• All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 15

90-day course of therapy, alternating with part A, given for a total of 2 years

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

PETHEMA LPA99, LPA2005 maintenance

PETHEMA: Programa Español de Tratamientos en HEMAtología
Preceded by PETHEMA LPA99 or PETHEMA LPA2005 consolidation therapy.

Regimen

• 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

90-day cycles x 2 years

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
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 PubMed

Relapsed/refractory

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

Regimen, 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

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