Acute promyelocytic leukemia
31 regimens on this page
48 variants on this page
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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
Upfront induction therapy
Arsenic trioxide monotherapy
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Variant #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Shen et al. 2004 | Randomized (C) | 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.
Variant #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)
Subsequent treatment
- Patients in CR: Arsenic trioxide consolidation
References
- Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De Thé H, Wang ZY, Chen SJ, Chen Z. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5328-35. Epub 2004 Mar 24. link to original article contains verified protocol link to PMC article PubMed
- Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006 Apr 1;107(7):2627-32. Epub 2005 Dec 13. link to original article contains verified protocol PubMed
- Update: Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P,Viswabandya A, Thirugnanam R, Abraham A, Shaji RV, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010 Aug 20;28(24):3866-71. Epub 2010 Jul 19. link to original article PubMed
Arsenic trioxide & ATRA
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Variant #1, 0.15/45
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Estey et al. 2006 | Phase II | ||
Ravandi et al. 2008 | Phase II | ||
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) | Phase III (E) | ATRA & Idarubicin | Superior OS (*) |
Note: In Estey et al. 2006, arsenic trioxide was started on day 11, but was later modified to start on day 1 after a death due to hyperleukocytosis and intracranial hemorrhage during induction. GIMEMA/DSIL APL0406: Patients with low- or intermediate-risk APL (white blood cell count at presentation less than or equal to 10 x 109/L) were eligible; 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 (GIMEMA/DSIL APL0406) or 90 days (Estey et al. 2006 & Ravandi et al. 2008).
Supportive medications
- As described in GIMEMA/DSIL APL0406:
- Prednisone (Sterapred) 0.5 mg/kg PO once per day from days 1 until the end of induction or the onset of differentiation syndrome
- Patients who develop differentiation syndrome then received: Dexamethasone (Decadron) 10 mg IV every 12 hours until signs and symptoms resolve, and for a minimum of 3 days
- Hemostatic support: Transfusions to keep platelet count greater than 30 x 109/L for the first 10 days of induction and greater than 20 x 109/L for the remainder of induction
- Hydroxyurea (Hydrea) as follows:
- Patients with WBC count greater than 10 x 109/L and less than 50 x 109/L after the start of therapy received: 500 mg PO four times per day, given until WBC count is less than 10 x 109/L
- Patients with WBC count greater than 50 x 109/L after the start of therapy received: 1000 mg PO four times per day, given until WBC count is less than 10 x 109/L
One course, to remission
Subsequent treatment
Variant #2, 0.16/25
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Shen et al. 2004 | Randomized (E) | Arsenic trioxide ATRA |
Seems to have superior DFS |
Chemotherapy
- Arsenic trioxide (Trisenox) 0.16 mg/kg IV once per day, starting day 1 and continuing until remission
- 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.
One course
All patients achieving CR went on to receive chemotherapy-based consolidation and maintenance. These details are available in the original paper but are omitted here.
Variant #3, 0.3/45
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Burnett et al. 2015 (AML17) | Phase III (E) | ATRA & Idarubicin | Seems not superior |
Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.
Chemotherapy
- Arsenic trioxide (Trisenox) 0.3 mg/kg IV once per day on days 1 to 5, then 0.25 mg/kg IV twice per week on weeks 2 to 8
- All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID, starting on day 1 and continuing until hematologic complete remission or maximum of 60 days
Subsequent treatment
References
- Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De Thé H, Wang ZY, Chen SJ, Chen Z. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5328-35. Epub 2004 Mar 24. link to original article contains verified protocol link to PMC article PubMed
- 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 link to PMC article PubMed content property of HemOnc.org
- Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article contains verified protocol PubMed
- Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009 Feb 1;27(4):504-10. Epub 2008 Dec 15. link to original article contains verified protocol link to PMC article PubMed
- Update: Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. link to full article contains verified protocol PubMed
- GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains verified protocol PubMed
- HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
- 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
- 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, Gemtuzumab ozogamicin
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Variant #1, GO 6 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Burnett et al. 2015 (AML17) | Phase III (E) | 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
- Gemtuzumab ozogamicin (Mylotarg) 6 mg/m2 on day 1 if WBC count greater than 10 x 109/L
Subsequent treatment
Variant #2, GO 9 mg/m2
Study | Evidence |
---|---|
Estey et al. 2005 | Phase II |
Ravandi et al. 2008 | Phase II |
Note: in some protocols, if GO was unavailable, Idarubicin 12mg/m2 given instead. The original protocol was modified between Estey et al. 2006 and Ravandi et al. 2008. 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. 2008 so arsenic trioxide was started on day 1, and gemtuzumab ozogamicin was given if WBC count went greater than 30 x 109/L for any patient in the first four weeks of therapy.
Chemotherapy
- Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 2 hours once per day on days 1 to 28 or until CR
- All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 28 or until CR
- Gemtuzumab Ozogamicin (Mylotarg) 9 mg/m2 IV once on day 1 if WBC count greater than 10 x 109/L
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
- Methylprednisolone (Solumedrol) as follows:
- Estey et al. 2006: 20 mg PO once per day for 10 days to decrease risk of differentiation syndrome
- Ravandi et al. 2008: 50 mg PO once per day for 5 days to decrease risk of differentiation syndrome
One course
Subsequent treatment
References
- Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article contains verified protocol PubMed
- Update: Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. link to full article contains verified protocol PubMed
- Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009 Feb 1;27(4):504-10. Epub 2008 Dec 15. link to original article contains verified protocol link to PMC article PubMed
- Update: Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. link to full article contains verified protocol PubMed
- NCRI AML17: Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. link to original article PubMed
Arsenic trioxide, ATRA, Idarubicin
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Regimen
Study | Evidence |
---|---|
Iland et al. 2012 (ALLG APML4) | Phase II |
Chemotherapy
- Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 2 hours once per day on days 9 to 36
- All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID on days 1 to 36
- Idarubicin (Idamycin) as follows:
- Patients up to age 61: 12 mg/m2 IV once per day on days 2, 4, 6, 8
- Patients 61 to 70 years old: 9 mg/m2 IV once per day on days 2, 4, 6, 8
- Patients greater than 70 years old: 6 mg/m2 IV once per day on days 2, 4, 6, 8
Supportive medications
- Prednisone (Sterapred) 1 mg/kg PO once per day on days 1 to 10, or until WBC count falls below 1 x 109/L, or until resolution of differentiation syndrome (whichever occurs last)
- Hemostatic support : Values checked and products transfused once or twice per day to keep platelet count greater than 30 x 109/L, fibrinogen greater than 1.5 g/L (150 mg/dL), normal PT and PTT
- Electrolyte support while on Arsenic trioxide (Trisenox): supplemental potassium and magnesium given to keep levels in the upper half of their normal ranges
36-day course
Subsequent treatment
- Arsenic trioxide & ATRA consolidation, in 3 to 4 weeks
References
- ALLG APML4: Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. link to original article contains verified protocol PubMed
ATRA monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Warrell et al. 1991 | Pilot, <20 pts | ||
Fenaux et al. 1993 (EAPLG APL 91) | Phase III (E) | 7+3d | Superior EFS |
Tallman et al. 1997 (ECOG E2491) | Phase III (E) | Cytarabine & Daunorubicin | Superior OS |
These obsolete regimens are here for historical reference; ATRA is no longer used as monotherapy for induction; some patients in EAPLG APL 91 received concurrent chemotherapy (see paper for details)
Chemotherapy
- All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID, starting day 1 and continuing until remission or maximum of 90 days.
Subsequent treatment
- EAPLG APL 91: Cytarabine & daunorubicin consolidation
- ECOG E2491: ATRA consolidation, then cytarabine & daunorubicin consolidation
References
- Warrell RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri LM, Hittelman WN, Vyas R, Andreeff M, Tafuri A, Jakubowski A, Gabrilove J, Gordon MS, Dmitrovsky E. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991 May 16;324(20):1385-93. link to original article PubMed
- EAPLG APL 91: Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D, Huebner G, Bauters F, Fegueux N, Fey M, Sanz M, Lowenberg B, Maloisel F, Auzanneau G, Sadoun A, Gardin C, Bastion Y, Ganser A, Jacky E, Dombret H, Chastang C, Degos L; European APL 91 Group. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. Blood. 1993 Dec 1;82(11):3241-9. link to original article contains protocol PubMed
- Update: Fenaux P, Chevret S, Guerci A, Fegueux N, Dombret H, Thomas X, Sanz M, Link H, Maloisel F, Gardin C, Bordessoule D, Stoppa AM, Sadoun A, Muus P, Wandt H, Mineur P, Whittaker JA, Fey M, Daniel MT, Castaigne S, Degos L; European APL group. Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. Leukemia. 2000 Aug;14(8):1371-7. PubMed
- ECOG E2491: Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997 Oct 9;337(15):1021-8. Erratum in: N Engl J Med 1997 Nov 27;337(22):1639. link to original article contains verified protocol PubMed
- Update: Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, Ogden A, Weinstein H, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002 Dec 15;100(13):4298-302. Epub 2002 Aug 15. link to original article PubMed
ATRA, Cytarabine, Daunorubicin
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Variant #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Adès et al. 2006 (EAPLG APL 2000) | Phase III (C) | 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
Subsequent treatment
Variant #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
Subsequent treatment
References
- EAPLG APL 2000: Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; 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
- 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
- C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains verified protocol link to PMC article PubMed
ATRA & Daunorubicin
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Adès et al. 2006 (EAPLG APL 2000) | Phase III (E) | 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
Subsequent treatment
References
- EAPLG APL 2000: Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; 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
- Update: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains verified protocol PubMed
ATRA & Idarubicin
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AIDA: ATRA, IDArubicin
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Avvisati et al. 1996 (GIMEMA AIDA) | Pilot | ||
Mandelli et al. 1997 (GIMEMA AIDA 0493) | Non-randomized portion of RCT | ||
Sanz et al. 2003 (PETHEMA LPA96/LPA99) | Non-randomized | ||
Sanz et al. 2010 (PETHEMA LPA2005) | Non-randomized | ||
Lo-Coco et al. 2010 (GIMEMA AIDA 2000) | Non-randomized | ||
Latagliata et al. 2011 (GIMEMA AIDA 0493 amended protocol) | Non-randomized | ||
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) | Phase III (C) | Arsenic trioxide & ATRA | Inferior OS (*) |
Burnett et al. 2015 (NCRI AML17) | Phase III (C) | Arsenic trioxide & ATRA | Seems not superior |
Note: this is the same induction used in multiple protocols. Consolidation and maintenance differ, follow the appropriate links below. Efficacy in APL0406 is based on the 2016 update.
Chemotherapy
- All-trans retinoic acid (ATRA) as follows, starting day 1 and continuing until remission or maximum of 90 days:
- 21 or older: 45 mg/m2/day, divided into two equal doses PO BID
- Less than 20 years old: 25 mg/m2/day, divided into two equal doses PO BID
- Idarubicin (Idamycin) as follows:
- Up to age 70: 12 mg/m2 IV bolus once per day on days 2, 4, 6, 8
- Older than 70 years old: 12 mg/m2 IV bolus once per day on days 2, 4, 6
8-day initial induction chemotherapy, with ongoing use of ATRA as described
Subsequent treatment
Once CR was achieved, patients proceeded to consolidation as follows:
- PETHEMA LPA96: Idarubicin, then mitoxantrone, then idarubicin consolidation
- GIMEMA AIDA 0493: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
- PETHEMA LPA99: risk-adapted therapy as follows:
- Low-risk patients: Idarubicin, then mitoxantrone, then idarubicin consolidation
- Intermediate- and high-risk patients: Idarubicin, then mitoxantrone, then idarubicin, with ATRA consolidation
- PETHEMA LPA2005: risk-adapted therapy as follows:
- High-risk patients: Cytarabine & idarubicin, then mitoxantrone, then cytarabine & idarubicin, with ATRA consolidation
- Intermediate- and low-risk patients: Idarubicin, then mitoxantrone, then idarubicin, with ATRA consolidation
- AIDA 2000: risk-adapted therapy as follows:
- High-risk patients: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine, with ATRA consolidation
- Intermediate- and low-risk patients: Idarubicin, then mitoxantrone, then idarubicin, with ATRA consolidation
- GIMEMA AIDA 0493 amended protocol: Cytarabine & idarubicin consolidation
- GIMEMA/DSIL APL0406 and NCRI AML17: Idarubicin, then mitoxantrone, then idarubicin, with ATRA consolidation
References
- GIMEMA AIDA: Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood. 1996 Aug 15;88(4):1390-8. link to full article contains verified protocol PubMed
- GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
- 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
- PETHEMA LPA96/LPA99: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains verified protocol PubMed
- 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
- PETHEMA LPA2005: Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA and HOVON Groups. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. link to original article contains verified protocol PubMed
- GIMEMA AIDA-2000: Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; Italian GIMEMA Cooperative Group. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. link to original article contains verified protocol PubMed
- GIMEMA AIDA 0493 amended protocol: Latagliata R, Breccia M, Fazi P, Vignetti M, Di Raimondo F, Sborgia M, Vincelli D, Candoni A, Salvi F, Rupoli S, Martinelli G, Kropp MG, Tonso A, Venditti A, Melillo L, Cimino G, Petti MC, Avvisati G, Lo-Coco F, Mandelli F; GIMEMA Acute Leukaemia Working Party. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia: long-term results and prognostic factors. Br J Haematol. 2011 Sep;154(5):564-8. Epub 2011 Jul 14. link to full article contains verified protocol PubMed
- GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains verified protocol PubMed
- HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
- 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
- NCRI AML17: Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. Epub 2015 Sep 14. link to original article PubMed
Consolidation after upfront therapy
Arsenic trioxide monotherapy
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Regimen
Study | Evidence |
---|---|
Mathews et al. 2006 | Non-randomized |
Preceding treatment
Chemotherapy
- Arsenic trioxide (Trisenox) 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day
28-day course
Subsequent treatment
- Patients remaining in CR: Arsenic trioxide maintenance
References
- Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006 Apr 1;107(7):2627-32. Epub 2005 Dec 13. link to original article contains verified protocol PubMed
- 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 (E) | ATRA & Daunorubicin | Superior EFS |
Consolidation therapy starts within 2 to 4 weeks of hematologic remission.
Preceding treatment
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
Subsequent treatment
References
- C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains verified protocol link to PMC article PubMed
Arsenic trioxide & ATRA
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Variant #1
Study | Evidence |
---|---|
Estey et al. 2006 | Phase II |
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
- Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 1 to 2 hours once per day, 5 consecutive days per week, on weeks 1 to 4, 9 to 12, 17 to 20, 25 to 28
- All-trans retinoic acid (ATRA) 45 mg/m2/day, divided into two equal doses PO BID, 7 days per week on weeks 1 to 2, 5 to 6, 9 to 10, 13 to 14, 17 to 18, 21 to 22, 25 to 26
28 week course of therapy
There is no maintenance in this protocol.
Variant #2
Study | Evidence |
---|---|
Iland et al. 2012 (ALLG APML4) | Phase II |
Consolidation starts 3 to 4 weeks after completion of induction.
Preceding treatment
Chemotherapy, part 1
- 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
Subsequent treatment
- ATRA, 6-MP, MTX maintenance, after 3 to 4 weeks
References
- Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006 May 1;107(9):3469-73. Epub 2005 Dec 22. link to original article contains verified protocol PubMed
- ALLG APML4: Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. link to original article contains verified protocol PubMed
- GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains verified protocol PubMed
- HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
- 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
- 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 (C) | Arsenic trioxide, then ATRA & Daunorubicin | Inferior EFS |
Consolidation therapy starts within 2 to 4 weeks of hematologic remission.
Preceding treatment
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
Subsequent treatment
References
- C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains verified protocol link to PMC article PubMed
Cytarabine & Daunorubicin
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Adès et al. 2006 (EAPLG APL 2000) | Phase III (C) | Daunorubicin | Superior OS |
Preceding treatment
Chemotherapy
- Cytarabine (Cytosar) as follows:
- Cycle 1: 200 mg/m2/day IV continuous infusion on days 1 to 7
- Cycle 2 as follows:
- Younger (less than 60) low-risk (WBC count less than 10 x 109/L) or older (greater than 60) high-risk (WBC count greater than 10 x 109/L): 1000 mg/m2 IV every 12 hours on days 1 to 4 (8 total doses)
- Younger (less than 60) high-risk (WBC count greater than 10 x 109/L): 2000 mg/m2 IV every 12 hours on days 1 to 5 (10 total doses)
- Daunorubicin (Cerubidine) as follows:
- Cycle 1: 60 mg/m2 IV once per day on days 1 to 3
- Cycle 2: 45 mg/m2 IV once per day on days 1 to 3
Intrathecal for high-risk (WBC count greater than 10 x 109/L) patients
- 5 doses of intrathecal chemotherapy with Methotrexate (MTX) 15 mg IT, Cytarabine (Cytosar) 50 mg IT, and corticosteroids given during consolidation
Subsequent treatment
References
- EAPLG APL 2000: Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; 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
- Update: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains verified protocol PubMed
Cytarabine & Idarubicin
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Regimen
Study | Evidence |
---|---|
Latagliata et al. 2011 (GIMEMA AIDA 0493 amended protocol) | Non-randomized |
This consolidation protocol was intended for patients older than 60.
Preceding treatment
Chemotherapy
- Cytarabine (Cytosar) 1000 mg/m2 IV over 6 hours once per day on days 1 to 4, given first
- Idarubicin (Idamycin) 5 mg/m2 IV once per day on days 1 to 4, given second, 3 hours after cytarabine infusion complete
One course
Subsequent treatment
References
- GIMEMA AIDA 0493 amended protocol: Latagliata R, Breccia M, Fazi P, Vignetti M, Di Raimondo F, Sborgia M, Vincelli D, Candoni A, Salvi F, Rupoli S, Martinelli G, Kropp MG, Tonso A, Venditti A, Melillo L, Cimino G, Petti MC, Avvisati G, Lo-Coco F, Mandelli F; GIMEMA Acute Leukaemia Working Party. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia: long-term results and prognostic factors. Br J Haematol. 2011 Sep;154(5):564-8. Epub 2011 Jul 14. link to full article contains verified protocol PubMed
Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine
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Regimen
Study | Evidence |
---|---|
Mandelli et al. 1997 (GIMEMA AIDA 0493) | Non-randomized portion of RCT |
Avvisati et al. 2002 (GIMEMA LAP 0389) | Non-randomized portion of RCT |
Note that the consolidation portion of the AIDA 0493 protocol is described in Avvisati et al. 1996.
Preceding treatment
- GIMEMA LAP 0389: Idarubicin induction versus cytarabine & idarubicin induction (neither with ATRA; no longer standard of care)
- GIMEMA AIDA 0493: ATRA & idarubicin induction
Chemotherapy, part 1
- Cytarabine (Cytosar) 1000 mg/m2 IV over 6 hours once per day on days 1 to 4, given first
- Idarubicin (Idamycin) 5 mg/m2 IV once per day on days 1 to 4, given second, 3 hours after cytarabine infusion complete
One course
Next course to begin "at recovery from the previous one, when polymorphonuclear cells numbered 1500/uL or more and platelets numbered 100 x 109/L or more."
Chemotherapy, part 2
- 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:
- GIMEMA LAP 0389: 5 mg/m2 IV once on day 1
- GIMEMA AIDA 0493: 12 mg/m2 IV once on day 1
- Thioguanine (Tabloid) 70 mg/m2 PO every 8 hours on days 1 to 5
One course
Subsequent treatment
- GIMEMA LAP 0389: 6-MP & MTX maintenance versus no further treatment
- GIMEMA AIDA 0493: ATRA maintenance versus ATRA, 6-MP, MTX maintenance versus 6-MP & MTX maintenance versus no further treatment
References
- 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
- GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
- 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
- PETHEMA LPA96/LPA99: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains verified protocol PubMed
- 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
- GIMEMA LAP 0389: Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F; GIMEMA (Gruppo Italiano Malattie Ematologische dell'Adulto) Italian Cooperative Group. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. link to original article contains verified protocol PubMed
Cytarabine & Idarubicin, then Etoposide & Mitoxantrone, then Cytarabine, Idarubicin, Thioguanine, with ATRA
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Regimen
Study | Evidence |
---|---|
Lo-Coco et al. 2010 (GIMEMA AIDA-2000) | Non-randomized |
This is risk-adapted therapy for high-risk patients in AIDA-2000. The authors were unclear about how many days were between each part of consolidation therapy.
Preceding treatment
Chemotherapy, part 1
- 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"
Subsequent treatment
References
- GIMEMA AIDA-2000: Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; Italian GIMEMA Cooperative Group. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. link to original article contains verified protocol PubMed
Cytarabine & Idarubicin, then Mitoxantrone, then Cytarabine & Idarubicin, with ATRA
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Regimen
Study | Evidence |
---|---|
Sanz et al. 2010 (PETHEMA LPA2005) | Non-randomized |
This is risk-adapted therapy for high-risk younger than 60 patients in PETHEMA LPA2005. Note that it is unclear from the paper which route the cytarabine is given in the third consolidation; this dose can be given by IV or SC routes.
Preceding treatment
Chemotherapy, consolidation #1
- 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
Subsequent treatment
References
- PETHEMA LPA2005: Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA and HOVON Groups. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. link to original article contains verified protocol PubMed
Daunorubicin monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Adès et al. 2006 (EAPLG APL 2000) | Phase III (E) | Cytarabine & Daunorubicin | Inferior OS |
This consolidation arm was a randomization for younger (less than 60), low-risk (WBC count less than 10 x 109/L) patients. Low-risk (WBC count less than 10 x 109/L) older (greater than 60) patients received this regimen in a non-randomized fashion.
Preceding treatment
Chemotherapy
- Daunorubicin (Cerubidine) as follows:
- Cycle 1: 60 mg/m2 IV once per day on days 1 to 3
- Cycle 2: 45 mg/m2 IV once per day on days 1 to 3
Subsequent treatment
References
- EAPLG APL 2000: Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; European Acute Promyelocytic Leukemia Group. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. link to original article contains verified protocol PubMed
- Update: Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;111(3):1078-84. Epub 2007 Nov 1. link to original article contains verified protocol PubMed
Idarubicin, then Mitoxantrone, then Idarubicin
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Regimen
Study | Evidence |
---|---|
Sanz et al. 2003 (PETHEMA LPA96/LPA99) | Non-randomized |
This was the low-risk treatment arm of PETHEMA LPA99; all patients on PETHEMA LPA96 underwent this consolidation protocol.
Preceding treatment
Chemotherapy, part 1
- 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
Subsequent treatment
References
- PETHEMA LPA96/LPA99: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains verified protocol PubMed
- 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
back to top |
Variant #1
Study | Evidence |
---|---|
Lo-Coco et al. 2010 (GIMEMA AIDA-2000) | Non-randomized |
Sanz et al. 2010 (PETHEMA LPA2005) | Non-randomized |
Lo-Coco et al. 2013 (GIMEMA/DSIL APL0406) | Non-randomized portion of RCT |
This is risk-adapted therapy for intermediate- and low-risk patients in AIDA-2000 and for low-risk patients in PETHEMA LPA2005; all patients assigned to the chemotherapy arm of GIMEMA/DSIL APL0406 received this treatment. Note that the number of mitoxantrone doses differs between the protocols.
Preceding treatment
Chemotherapy, part 1
- 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
Subsequent treatment
- AIDA-2000 and GIMEMA/DSIL APL0406: ATRA alternating with 6-MP, MTX maintenance
- PETHEMA LPA2005: ATRA, 6-MP, MTX maintenance
Variant #2
Study | Evidence |
---|---|
Sanz et al. 2003 (PETHEMA LPA99) | Non-randomized |
Sanz et al. 2010 (PETHEMA LPA2005) | Non-randomized |
This is risk-adapted therapy for intermediate- and high-risk patients in PETHEMA LPA99 and for intermediate-risk and high-risk older than 60 patients in PETHEMA LPA2005. Note that the number of mitoxantrone doses differs between the two protocols.
Preceding treatment
Chemotherapy, part 1
- 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
Subsequent treatment
References
- PETHEMA LPA99: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains verified protocol PubMed
- 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
- PETHEMA LPA2005: Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA and HOVON Groups. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. link to original article contains verified protocol PubMed
- GIMEMA AIDA-2000: Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; Italian GIMEMA Cooperative Group. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. link to original article contains verified protocol PubMed
- GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains verified protocol PubMed
- HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
- 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
back to top |
Regimen
Study | Evidence |
---|---|
Mathews et al. 2006 | Non-randomized |
Preceding treatment
Chemotherapy
- Arsenic trioxide (Trisenox) 10 mg (0.15 mg/kg for pediatric patients) IV over 2 to 3 hours once per day
10 consecutive days of each month for 6 months
References
- Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006 Apr 1;107(7):2627-32. Epub 2005 Dec 13. link to original article contains verified protocol PubMed
- 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
back to top |
Variant #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Powell et al. 2010 (C9710) | Phase III (E) | ATRA, 6-MP, MTX | Might have inferior DFS |
Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.
Preceding treatment
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
Variant #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mandelli et al. 1997 (GIMEMA AIDA 0493) | Phase III (E) | ATRA, 6-MP, MTX | Seems not superior |
6-MP & MTX | Seems not superior | ||
No further treatment | Seems not superior | ||
Fenaux et al. 1999 (EAPLG APL 93) | Phase III (E) | 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
- GIMEMA AIDA 0493: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
- EAPLG 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
- GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
- 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
- EAPLG APL 93: Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia; The European APL Group. Blood. 1999 Aug 15;94(4):1192-200. link to original article PubMed
- 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
- C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains verified protocol link to PMC article PubMed
ATRA, Mercaptopurine, Methotrexate
back to top |
Variant #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Powell et al. 2010 (C9710) | Phase III (E) | ATRA | Might have superior DFS |
Maintenance therapy starts 2 to 4 weeks after recovery from consolidation therapy.
Preceding treatment
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
Variant #2
Study | Evidence |
---|---|
Adès et al. 2006 (EAPLG APL 2000) | Non-randomized portion of RCT |
Preceding treatment
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
Variant #3
Study | Evidence |
---|---|
Iland et al. 2012 (ALLG APML4) | Phase II |
Maintenance starts 3 to 4 weeks after completion of consolidation cycle 2.
Preceding treatment
Chemotherapy
- 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
Variant #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
Variant #5, ATRA alternating with 6-MP, MTX
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mandelli et al. 1997 (GIMEMA AIDA 0493) | Phase III (E) | ATRA | Seems not superior |
6-MP & MTX | Seems not superior | ||
No further treatment | Seems not superior | ||
Fenaux et al. 1999 (EAPLG APL 93) | Phase III (E) | 6-MP & MTX | Seems to have superior 2-year relapse rate |
ATRA No further treatment |
Superior 2-year relapse rate |
Preceding treatment
- GIMEMA AIDA 0493: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
- EAPLG APL 93: Cytarabine & daunorubicin consolidation
Chemotherapy
- Mercaptopurine (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
- GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
- 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
- EAPLG APL 93: Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia; The European APL Group. Blood. 1999 Aug 15;94(4):1192-200. link to original article PubMed
- 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
- PETHEMA LPA99: Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatías Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. Epub 2003 Oct 23. link to original article contains verified protocol PubMed
- 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
- EAPLG APL 2000: Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P; European Acute Promyelocytic Leukemia Group. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006 Dec 20;24(36):5703-10. Epub 2006 Nov 20. link to original article contains verified protocol PubMed
- 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
- PETHEMA LPA2005: Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B; PETHEMA and HOVON Groups. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. Epub 2010 Apr 14. link to original article PubMed
- C9710: Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains verified protocol link to PMC article PubMed
- ALLG APML4: Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80. Epub 2012 Jun 19. link to original article contains verified protocol PubMed
- GIMEMA/DSIL APL0406: Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. link to original article contains verified protocol PubMed
- HRQoL analysis: Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, Lo-Coco F. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes. J Clin Oncol. 2014 Oct 20;32(30):3406-12. Epub 2014 Sep 22. link to original article PubMed
- Update: Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. Epub 2016 Oct 31. link to original article link to PMC article PubMed
Mercaptopurine & Methotrexate
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Variant #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Avvisati et al. 2002 (GIMEMA LAP 0389) | Phase III (C) | No further treatment | Seems not superior |
Preceding treatment
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
Variant #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mandelli et al. 1997 (GIMEMA AIDA 0493) | Phase III (C) | ATRA | Seems not superior |
ATRA, 6-MP, MTX | Seems not superior | ||
No further treatment | Seems not superior | ||
Fenaux et al. 1999 (EAPLG APL 93) | Phase III (C) | 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
- GIMEMA AIDA 0493: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
- EAPLG 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
- GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
- 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
- EAPLG APL 93: Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia; The European APL Group. Blood. 1999 Aug 15;94(4):1192-200. link to original article PubMed
- 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
- GIMEMA LAP 0389: Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F; GIMEMA (Gruppo Italiano Malattie Ematologische dell'Adulto) Italian Cooperative Group. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. link to original article contains verified protocol PubMed
No further treatment
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mandelli et al. 1997 (GIMEMA AIDA 0493) | Phase III (C) | ATRA | Seems not superior |
ATRA, 6-MP, MTX | Seems not superior | ||
6-MP & MTX | Seems not superior | ||
Fenaux et al. 1999 (EAPLG APL 93) | Phase III (C) | ATRA | Seems to have inferior 2-year relapse rate |
ATRA, 6-MP, MTX 6-MP & MTX |
Inferior 2-year relapse rate | ||
Avvisati et al. 2002 (GIMEMA LAP 0389) | Phase III (C) | 6-MP & MTX | Seems not superior |
No further treatment given after consolidation. Note that this arm was dropped from AIDA 0493 from February 1997.
Preceding treatment
- EAPLG APL 93: Cytarabine & daunorubicin consolidation
- GIMEMA AIDA 0493 & LAP 0389: Cytarabine & idarubicin, then etoposide & mitoxantrone, then cytarabine, idarubicin, thioguanine consolidation
References
- GIMEMA AIDA 0493: Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F; Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997 Aug 1;90(3):1014-21. link to original article contains partial protocol PubMed
- 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
- EAPLG APL 93: Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia; The European APL Group. Blood. 1999 Aug 15;94(4):1192-200. link to original article PubMed
- 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
- GIMEMA LAP 0389: Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F; GIMEMA (Gruppo Italiano Malattie Ematologische dell'Adulto) Italian Cooperative Group. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood. 2002 Nov 1;100(9):3141-6. link to original article contains verified protocol PubMed
Relapsed or refractory, salvage induction therapy
Arsenic trioxide monotherapy
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Variant #1, 0.15 mg/kg/d
Study | Evidence |
---|---|
Soignet et al. 1998 | Non-randomized, <20 pts |
Soignet et al. 2001 | Phase II |
Chemotherapy
- Arsenic trioxide (Trisenox) 0.15 mg/kg IV over 2 hours once per day
Given until complete remission (CR) or a maximum of 60 doses
Subsequent treatment
- Confirmed CR: Arsenic trioxide consolidation and optional maintenance
Variant #2, 10 mg/d
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
- 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
- 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 contains protocol PubMed
- 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 contains verified protocol PubMed
Arsenic trioxide & Idarubicin
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Regimen
Study | Evidence |
---|---|
Yanada et al. 2013 | Phase II |
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
- 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:
- Cytarabine (Cytosar) 40 mg IT, admixed with MTX & steroids
- Methotrexate (MTX) 15 mg IT, admixed with Ara-C & steroids
- ONE of the following corticosteroids:
- Prednisolone (Millipred) 10 mg IT, admixed with Ara-C & MTX
- Dexamethasone (Decadron) 4 mg IT, admixed with Ara-C & MTX
One course
Subsequent treatment
References
- Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. link to original article contains verified protocol PubMed
Tamibarotene monotherapy
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Regimen
Study | Evidence |
---|---|
Sanford et al. 2015 | Phase II, <20 pts |
Chemotherapy
- Tamibarotene (Amnoid) 6 mg/m2/d, divided into two daily doses
Up to 56-day course
Subsequent treatment
- Patients achieving CR: Tamibarotene consolidation, if not proceeding to transplant
References
- Sanford D, Lo-Coco F, Sanz MA, Di Bona E, Coutre S, Altman JK, Wetzler M, Allen SL, Ravandi F, Kantarjian H, Cortes JE. Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all-trans retinoic acid and arsenic trioxide. Br J Haematol. 2015 Nov;171(4):471-7. Epub 2015 Jul 24. link to original article link to PMC article contains verified protocol PubMed
Consolidation after salvage therapy
Arsenic trioxide monotherapy
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Regimen
Study | Evidence |
---|---|
Yanada et al. 2013 | Phase II |
Preceding treatment
Chemotherapy
- Arsenic trioxide (Trisenox) 0.15 mg/kg IV once per day on days 1 to 25
Intrathecal therapy
- Given at the conclusion of each cycle (3 doses total, including re-induction)
- Cytarabine (Cytosar) 40 mg IT, admixed with MTX & steroids
- Methotrexate (MTX) 15 mg IT, admixed with Ara-C & steroids
- ONE of the following corticosteroids:
- Prednisolone (Millipred) 10 mg IT, admixed with Ara-C & MTX
- Dexamethasone (Decadron) 4 mg IT, admixed with Ara-C & MTX
2 cycles
Susbsequent treatment
References
- Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. link to original article contains verified protocol PubMed
Busulfan & Melphalan, then auto HSCT
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Regimen
Study | Evidence |
---|---|
Yanada et al. 2013 | Phase II |
Preceding treatment
Chemotherapy
- Busulfan (Myleran) 1 mg/kg PO every 6 hours on days -6 to -4 (total dose of 12 mg/kg)
- Melphalan (Alkeran) 70 mg/m2 IV bolus once per day on days -3 & -2
Supportive therapy
- Autologous stem cells re-infused on day 0
One course
References
- Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. link to original article contains verified protocol PubMed