Acute myeloid leukemia

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Section editor
AK.JPG
 Ashwin Kishtagari, MD
Vanderbilt University
Nashville, TN, USA
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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!

  • We have moved How I Treat articles to a dedicated page.

Note: regimens tested in specific populations are located on dedicated pages:

85 regimens on this page
141 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASH

ELN

ESMO

NCCN

SITC

Antifungal prophylaxis

Upfront induction therapy, standard and older "fit" patients

These are aggressive remission induction regimens given with curative intent.

7+3d (standard-dose)

7+3d: 7 days of cytarabine + 3 days of daunorubicin
AD: Ara-C (Cytarabine) & Daunorubicin
DA: Daunorubicin & Ara-C (Cytarabine)

Regimen variant #1, 700/120 (CI Ara-C)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jin et al. 2013 2007-2011 Phase 3 (C) 1. HAD Might have inferior EFS
2. HAA Inferior EFS

Note: this was the lower bound of the allowable daunorubicin dose in Jin et al. 2013; the manuscript does not explicitly state that the cytarabine is given as continuous infusion, but this is presumed to be the case. To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

7-day course


Regimen variant #2, 700/135 (CI Ara-C)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yates et al. 1973 NR in abstract Non-randomized, fewer than 20 pts (RT)
Rai et al. 1981 (CALGB 7421) 1974-04-25 to 1975-05-07 Phase 3 (E-esc) 1. 7+3d; bolus Ara-C Seems to have superior CR rate
2. 5+2d; CI Ara-C Superior CR rate
3. 5+2d; bolus Ara-C Superior CR rate
Omura et al. 1982 1974-05 to 1975-06 Phase 3 (E-de-esc) 1. AVML Not directly compared
2. TAD Superior time to CR
Yates et al. 1982 (CALGB 7721) 1977-1979 Phase 3 (C) 1. 7+3d (low-dose) Did not meet efficacy endpoints
2. 7+3a; 30 mg/m2 Did not meet efficacy endpoints
Vogler et al. 1984 1977-1981 Non-randomized part of RCT
Preisler et al. 1987 (CALGB 7921) 1979-1982 Phase 3 (C) 1. 10+3d Did not meet primary endpoint of CR rate
2. TAD Did not meet primary endpoint of CR rate
Stein et al. 1990 1982-1985 Phase 3 (C) MA Did not meet primary endpoint of CR rate
Arlin et al. 1990 NR in abstract Phase 3 (C) 7+3m Did not meet efficacy endpoints
Dillman et al. 1991 (CALGB 8321) 1982-1986 Phase 3 (C) 7+3d; higher-dose Ara-C Did not meet primary efficacy endpoints
Mandelli et al. 1991 1984-1987 Phase 3 (C) 7+3i Did not meet primary endpoint of FFS
Wiernik et al. 1992 1985-1989 Phase 3 (C) 7+3i Seems to have inferior OS
Vogler et al. 1992 1985-1989 Phase 3 (C) 7+3i Seems to have inferior CR rate
Rowe et al. 2004 (ECOG E3993) 1993-1997 Phase 3 (C) 1. 7+3d & GM-CSF
2. 7+3i
3. 7+3i & GM-CSF
4. 7+3m
5. 7+3m & GM-CSF 		Did not meet primary endpoint of CR rate
Latagliata et al. 2008 (GIMEMA GSI 103 AMLE) 2001-2004 Phase 3 (C) 7+3 (Daunoxome) Did not meet primary endpoint of CR rate
Cripe et al. 2010 (ECOG E3999) 2002-2005 Phase 3 (C) 7+3d & Zosuquidar Did not meet primary endpoint of OS
Fernandez et al. 2009 (ECOG E1900) 2002-2008 Phase 3 (C) 7+3d; high-dose Inferior OS
Jin et al. 2013 2007-2011 Phase 3 (C) 1. HAD Might have inferior EFS
2. HAA Inferior EFS
Dombret et al. 2015 (AZA-AML-001) 2010-2014 Phase 3 (C) Azacitidine Might have inferior OS

Note: this was the upper bound of the allowable daunorubicin dose in Jin et al. 2013, and the lower bound of the allowable daunorubicin dose in AZA-AML-001.

Chemotherapy

7-day course

Subsequent treatment

  • ECOG E3993, patients with persistent disease at day 14 (more than 5% blasts): underwent an identical second cycle of 7+3i re-induction


Regimen variant #3, 700/150 (CI Ara-C)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bishop et al. 1990 1984-1987 Phase 3 (C) ADE; standard-dose Did not meet endpoint of OS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

7-day course


Regimen variant #4, 1120/120 (intermittent Ara-C)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Masaoka et al. 1996 NR in abstract Randomized Phase 2 (E-switch-ic) 7+3i Seems to have inferior CR rate

Chemotherapy

7-day course


Regimen variant #5, 1400/135 (CI Ara-C)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Dillman et al. 1991 (CALGB 8321) 1982-1986 Phase 3 (E-esc) 7+3d; lower-dose Ara-C Did not meet primary efficacy endpoints
Weick et al. 1996 (SWOG S8600) 1986-1991 Phase 3 (C) HiDAC+3d Seems to have inferior RFS
Zittoun et al. 1996 (AML 8B) 1986-1993 Phase 3 (C) 7+3d & GM-CSF Did not meet primary efficacy endpoint
Moore et al. 2004 (CALGB 9222) 1992-1995 Non-randomized part of phase 3 RCT
Anderson et al. 2002 (SWOG S9333) 1995-1998 Phase 3 (C) ME Did not meet primary endpoint of CR rate
Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01) 2000-2006 Phase 3 (C) 7+3d; high-dose Inferior CR rate
Lee et al. 2011 (ADcomparison) 2001-2008 Phase 3 (C) 7+3d; high-dose Seems to have inferior OS
Stone et al. 2015 (ACCEDE) 2008-2010 Phase 3 (C) Amonafide & Cytarabine Did not meet primary endpoint of CR rate

Note: This variant is commonly used in Europe.

Chemotherapy

7-day course

Subsequent treatment

  • CALGB 9222: HiDAC versus multi-agent chemotherapy consolidation
  • HOVON 43 AML/SAKK 30/01: MiDAC consolidation
  • ACCEDE, day 14 bone marrow positive: a second course of 7+3d re-induction
  • ACCEDE, PR or better at time of count recovery, transplant-eligible: Allogeneic HSCT consolidation
  • ACCEDE, PR or better at time of count recovery, transplant-ineligible, younger than 60: HiDAC consolidation
  • ACCEDE, PR or better at time of count recovery, transplant-ineligible, 60 years old or older: MiDAC consolidation

References

  1. Yates JW, Wallace HJ Jr, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep. 1973 Nov-Dec;57(4):485-8. PubMed
  2. CALGB 7421: Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K, Obrecht JP, Preisler HD, Nawabi IW, Prager D, Carey RW, Cooper MR, Haurani F, Hutchison JL, Silver RT, Falkson G, Wiernik P, Hoagland HC, Bloomfield CD, James GW, Gottlieb A, Ramanan SV, Blom J, Nissen NI, Bank A, Ellison RR, Kung F, Henry P, McIntyre OR, Kaan SK. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood. 1981 Dec;58(6):1203-12. link to original article contains dosing details in manuscript PubMed
  3. Omura GA, Vogler WR, Lefante J, Silberman H, Knospe W, Gordon D, Jarrell R. Treatment of acute myelogenous leukemia: influence of three induction regimens and maintenance with chemotherapy or BCG immunotherapy. Cancer. 1982 Apr 15;49(8):1530-6. link to original article contains dosing details in manuscript PubMed
  4. CALGB 7721: Yates J, Glidewell O, Wiernik P, Cooper MR, Steinberg D, Dosik H, Levy R, Hoagland C, Henry P, Gottlieb A, Cornell C, Berenberg J, Hutchison JL, Raich P, Nissen N, Ellison RR, Frelick R, James GW, Falkson G, Silver RT, Haurani F, Green M, Henderson E, Leone L, Holland JF. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood. 1982 Aug;60(2):454-62. link to original article contains dosing details in manuscript PubMed
  5. Vogler WR, Winton EF, Gordon DS, Raney MR, Go B, Meyer L; SECSG. A randomized comparison of postremission therapy in acute myelogenous leukemia: a Southeastern Cancer Study Group trial. Blood. 1984 May;63(5):1039-45. link to original article contains dosing details in manuscript PubMed
  6. CALGB 7921: Preisler H, Davis RB, Kirshner J, Dupre E, Richards F 3rd, Hoagland HC, Kopel S, Levy RN, Carey R, Schulman P, Gottlieb AJ, McIntyre OR. Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a Cancer and Leukemia Group B study. Blood. 1987 May;69(5):1441-9. link to original article contains dosing details in manuscript PubMed
  7. Stein RS, Vogler WR, Winton EF, Cohen HJ, Raney MR, Bartolucci A; Southeastern Cancer Study Group. Therapy of acute myelogenous leukemia in patients over the age of 50: a randomized Southeastern Cancer Study Group trial. Leuk Res. 1990;14(10):895-903. link to original article contains dosing details in abstract PubMed
  8. Bishop JF, Lowenthal RM, Joshua D, Matthews JP, Todd D, Cobcroft R, Whiteside MG, Kronenberg H, Ma D, Dodds A, Herrmann R, Szer J, Wolf MM, Young G; Australian Leukemia Study Group. Etoposide in acute nonlymphocytic leukemia. Blood. 1990 Jan 1;75(1):27-32. link to original article contains dosing details in abstract PubMed
  9. Arlin Z, Case DC Jr, Moore J, Wiernik P, Feldman E, Saletan S, Desai P, Sia L, Cartwright K; Lederle Cooperative Group. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Leukemia. 1990 Mar;4(3):177-83. PubMed
  10. Mandelli F, Petti MC, Ardia A, Di Pietro N, Di Raimondo F, Ganzina F, Falconi E, Geraci E, Ladogana S, Latagliata R, Malleo C, Nobile F, Petti N, Rotoli B, Specchia G, Tabilio A, Resegotti L; GIMEMA. A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia: a multicentric study from the Italian Co-operative Group GIMEMA. Eur J Cancer. 1991;27(6):750-5. link to original article contains dosing details in manuscript PubMed
  11. CALGB 8321: Dillman RO, Davis RB, Green MR, Weiss RB, Gottlieb AJ, Caplan S, Kopel S, Preisler H, McIntyre OR, Schiffer C. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood. 1991 Nov 15;78(10):2520-6. link to original article contains dosing details in manuscript PubMed
  12. Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, Ritch PS, Enck RE, Weitberg AB. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992 Jan 15;79(2):313-9. link to original article contains dosing details in manuscript PubMed
  13. Vogler WR, Velez-Garcia E, Weiner RS, Flaum MA, Bartolucci AA, Omura GA, Gerber MC, Banks PL; Southeastern Cancer Study Group. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group study. J Clin Oncol. 1992 Jul;10(7):1103-11. link to original article contains dosing details in abstract PubMed
  14. ECOG E1490: Rowe JM, Andersen JW, Mazza JJ, Bennett JM, Paietta E, Hayes FA, Oette D, Cassileth PA, Stadtmauer EA, Wiernik PH. A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood. 1995 Jul 15;86(2):457-62. link to original article PubMed
  15. AML 8B: Zittoun R, Suciu S, Mandelli F, de Witte T, Thaler J, Stryckmans P, Hayat M, Peetermans M, Cadiou M, Solbu G, Petti MC, Willemze R. Granulocyte-macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: a randomized trial by the European Organization for Research and Treatment of Cancer Leukemia Cooperative Group. J Clin Oncol. 1996 Jul;14(7):2150-9. link to original article contains dosing details in manuscript PubMed NCT01324063
    1. Update: Hengeveld M, Suciu S, Karrasch M, Specchia G, Marie JP, Muus P, Petti MC, Rotoli B, Amadori S, Fioritoni G, Leoni P, Morra E, Thaler J, Resegotti L, Fazi P, Vignetti M, Mandelli F, Zittoun R, de Witte T; EORTC; GIMEMA. Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukaemia aged between 46 and 60 years: final results of the randomized phase III study (AML 8B) of the European Organisation for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. Ann Hematol. 2012 Jun;91(6):825-35. Epub 2012 Mar 31. link to original article link to PMC article contains dosing details in abstract PubMed
  16. Masaoka T, Ogawa M, Yamada K, Kimura K, Ohashi Y. A phase II comparative study of idarubicin plus cytarabine versus daunorubicin plus cytarabine in adult acute myeloid leukemia. Semin Hematol. 1996 Oct;33(4 Suppl 3):12-7. contains dosing details in abstract PubMed
  17. SWOG S8600: Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP, Bickers JN, Hynes HE, Welborn JL, Simon SR, Grever M; SWOG. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 1996 Oct 15;88(8):2841-51. link to original article contains dosing details in abstract PubMed
  18. SWOG S9126: List AF, Kopecky KJ, Willman CL, Head DR, Persons DL, Slovak ML, Dorr R, Karanes C, Hynes HE, Doroshow JH, Shurafa M, Appelbaum FR. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Blood. 2001 Dec 1;98(12):3212-20. link to original article PubMed
  19. SWOG S9333: Anderson JE, Kopecky KJ, Willman CL, Head D, O'Donnell MR, Luthardt FW, Norwood TH, Chen IM, Balcerzak SP, Johnson DB, Appelbaum FR. Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study. Blood. 2002 Dec 1;100(12):3869-76. Epub 2002 Aug 1. link to original article contains dosing details in abstract PubMed
  20. ECOG E3993: Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. link to original article contains dosing details in manuscript PubMed NCT04446052
  21. CALGB 9222: Moore JO, George SL, Dodge RK, Amrein PC, Powell BL, Kolitz JE, Baer MR, Davey FR, Bloomfield CD, Larson RA, Schiffer CA. Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222. Blood. 2005 May 1;105(9):3420-7. Epub 2004 Nov 30. link to original article link to PMC article contains dosing details in manuscript PubMed
  22. GIMEMA GSI 103 AMLE: Latagliata R, Breccia M, Fazi P, Iacobelli S, Martinelli G, Di Raimondo F, Sborgia M, Fabbiano F, Pirrotta MT, Zaccaria A, Amadori S, Caramatti C, Falzetti F, Candoni A, Mattei D, Morselli M, Alimena G, Vignetti M, Baccarani M, Mandelli F. Liposomal daunorubicin versus standard daunorubicin: long term follow-up of the GIMEMA GSI 103 AMLE randomized trial in patients older than 60 years with acute myelogenous leukaemia. Br J Haematol. 2008 Dec;143(5):681-9. Epub 2008 Oct 20. link to original article contains dosing details in manuscript PubMed
  23. HOVON 43 AML/SAKK 30/01: Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology; AMLSG; Swiss Group for Clinical Cancer Research. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. link to original article contains dosing details in manuscript PubMed ISRCTN77039377
  24. ECOG E1900: Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00049517
    1. Update: Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, Lazarus HM, Levine RL, Litzow MR, Paietta EM, Patel JP, Racevskis J, Rowe JM, Tallman MS, Sun Z, Luger SM. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016 Mar 24;127(12):1551-8. Epub 2016 Jan 11. link to original article link to PMC article PubMed
  25. ECOG E3999: Cripe LD, Uno H, Paietta EM, Litzow MR, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Luger S, Tallman MS. Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. Blood. 2010 Nov 18;116(20):4077-85. Epub 2010 Aug 17. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00046930
  26. ADcomparison: Lee JH, Joo YD, Kim H, Bae SH, Kim MK, Zang DY, Lee JL, Lee GW, Lee JH, Park JH, Kim DY, Lee WS, Ryoo HM, Hyun MS, Kim HJ, Min YJ, Jang YE, Lee KH; Cooperative Study Group A for Hematology. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood. 2011 Oct 6;118(14):3832-41. Epub 2011 Aug 9. link to original article contains dosing details in abstract PubMed NCT00474006
  27. Jin J, Wang JX, Chen FF, Wu DP, Hu J, Zhou JF, Hu JD, Wang JM, Li JY, Huang XJ, Ma J, Ji CY, Xu XP, Yu K, Ren HY, Zhou YH, Tong Y, Lou YJ, Ni WM, Tong HY, Wang HF, Mi YC, Du X, Chen BA, Shen Y, Chen Z, Chen SJ. Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2013 Jun;14(7):599-608. Epub 2013 May 9. link to original article contains dosing details in manuscript PubMed ChiCTR-TRC-06000054
  28. ACCEDE: Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, Wetzler M, Rizzieri D, Erba HP, Damon L, Jang JH, Tallman MS, Warzocha K, Masszi T, Sekeres MA, Egyed M, Horst HA, Selleslag D, Solomon SR, Venugopal P, Lundberg AS, Powell B. Phase III open-label randomized study of cytarabine in combination with amonafide l-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10;33(11):1252-7. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00715637
  29. AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01074047
    1. Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article PubMed

7+3d (intermediate-dose)

7+3d: 7 days of cytarabine + 3 days of daunorubicin

Regimen variant #1, CI Ara-C (100 mg/m2)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Büchner et al. 2012 (OSHO 061) 2002-2008 Phase 3 (C) See paper for details Did not meet primary endpoint of EFS
Schaich et al. 2013 (AML2003) 2003-2009 Non-randomized part of phase 3 RCT
Walker et al. 2021 (CALGB 10201) 2004-2006 Phase 3 (C) 7+3d & Oblimersen Did not meet primary endpoint of OS
Petersdorf et al. 2013 (SWOG S0106) 2004-2009 Phase 3 (C) 7+3d & GO Did not meet co-primary endpoint of CR rate
Serve et al. 2013 (AML2006) 2006-2008 Randomized Phase 2 (C) 7+3d & Sorafenib Did not meet primary endpoint of EFS
Lancet et al. 2014 (CLTR0308-204) 2008-11 to 2009-10 Randomized Phase 2 (C) CPX-351 Might have inferior composite CR/CRi rate
Röllig et al. 2015 (SORAML) 2009-2011 Randomized Phase 2 (C) 7+3d & Sorafenib Seems to have inferior EFS
Müller-Tidow et al. 2015 (AML-AZA) 2010-2012 Phase 3 (C) 7+3d & Azacitidine Did not meet primary endpoint of EFS
Dombret et al. 2015 (AZA-AML-001) 2010-2014 Phase 3 (C) Azacitidine Might have inferior OS
Lancet et al. 2018 (CLTR0310-301) 2012-12 to 2014-11 Phase 3 (C) CPX-351 Inferior OS
Sekeres et al. 2023 (BRIGHT AML 1019) 2018-04 to 2020-01 Phase 3 (C) 7+3d & Glasdegib Did not meet primary endpoint of OS

Note: this was the upper bound of the allowable daunorubicin dose in AZA-AML-001. Dombret et al. 2015 did not specify which days the daunorubicin is administered; some protocols give daunorubicin on days 3 to 5

Chemotherapy

7-day course

Subsequent treatment

  • AML2003: HiDAC versus MAC/MAMAC/MAC consolidation
  • CALGB 10201: IDAC consolidation x 2
  • SWOG S0106: HiDAC consolidation x 3
  • CLTR0310-301: 5+2d consolidation
  • BRIGHT AML 1019, younger than 60 years old: HiDAC consolidation x 4
  • BRIGHT AML 1019, 60 years old or older: IDAC consolidation x 4


Regimen variant #2, CI Ara-C (200 mg/m2)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Holowiecki et al. 2004 (PALG AML1/1999) 1999-2002 Phase 3 (C) DAC Inferior CR rate after first induction
Chevallier et al. 2010 (LAM-2001) 2001-2005 Phase 3 (C) 7+5i Did not meet primary endpoint of LFS
Holowiecki et al. 2012 (PALG AML1/2004) 2004-2008 Phase 3 (C) 1. DAC Inferior OS
2. DAF Did not meet primary endpoint of OS
Castaigne et al. 2012 (ALFA-0701) 2008-2010 Phase 3 (C) 7+3d & GO Inferior EFS
Lübbert et al. 2023 (EORTC-1301) 2014-12-01 to 2019-08-20 Phase 3 (C) Decitabine Did not meet primary endpoint of OS

Chemotherapy

Supportive therapy

  • "According to commonly accepted guidelines with no prophylactic IV antibiotics"
  • Granulocyte colony-stimulating factor recommended only for patients older than 50 years old whose leukemic blasts were negative for CD114 expression

7-day course

Subsequent treatment

  • PALG AML1/1999 & PALG AML1/2004, remission: HAM, then HiDAC consolidation
  • PALG AML1/1999 & PALG AML1/2004, partial remission: 7+3d re-induction.
  • PALG AML1/1999, non-responders: CLAG salvage
  • ALFA-0701, CR or CRp: Cytarabine & daunorubicin consolidation
  • EORTC-1301: Allogeneic HSCT consolidation, if possible

References

  1. PALG AML1/1999: Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, Skotnicki A, Jedrzejczak WW, Konopka L, Kuliczkowski K, Zdziarska B, Dmoszyńska A, Marianska B, Pluta A, Zawilska K, Komarnicki M, Kloczko J, Sulek K, Haus O, Stella-Holowiecka B, Baran W, Jakubas B, Paluszewska M, Wierzbowska A, Kielbinski M, Jagoda K; Polish Adult Leukemia Group. Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia: multicenter, phase III study. Leukemia. 2004 May;18(5):989-97. link to original article contains dosing details in manuscript PubMed
  2. LAM-2001: Chevallier P, Fornecker L, Lioure B, Béné MC, Pigneux A, Recher C, Witz B, Fegueux N, Bulabois CE, Daliphard S, Bouscary D, Vey N, Delain M, Bay JO, Turlure P, Bernard M, Himberlin C, Luquet I, Ifrah N, Harousseau JL; GOELAMS. Tandem versus single autologous peripheral blood stem cell transplantation as post-remission therapy in adult acute myeloid leukemia patients under 60 in first complete remission: results of the multicenter prospective phase III GOELAMS LAM-2001 trial. Leukemia. 2010 Jul;24(7):1380-5. Epub 2010 May 27. link to original article contains dosing details in abstract PubMed
    1. Update: Récher C, Béné MC, Lioure B, Pigneux A, Vey N, Delaunay J, Luquet I, Hunault M, Guyotat D, Bouscary D, Fegueux N, Jourdan E, Lissandre S, Escoffre-Barbe M, Bonmati C, Randriamalala E, Guièze R, Ojeda-Uribe M, Dreyfus F, Harousseau JL, Cahn JY, Ifrah N, Guardiola P; Groupe Ouest-Est d’ étude des Leucé mies Aiguës et autres. Long-term results of a randomized phase 3 trial comparing idarubicin and daunorubicin in younger patients with acute myeloid leukaemia. Leukemia. 2014 Feb;28(2):440-3. Epub 2013 Oct 9. link to original article PubMed
  3. PALG AML1/2004: Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. link to original article contains dosing details in manuscript PubMed
  4. ALFA-0701: Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. Epub 2012 Apr 5. link to original article contains dosing details in manuscript PubMed NCT00927498
    1. Update: Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. link to original article link to PMC article PubMed
  5. OSHO 061: Büchner T, Schlenk RF, Schaich M, Döhner K, Krahl R, Krauter J, Heil G, Krug U, Sauerland MC, Heinecke A, Späth D, Kramer M, Scholl S, Berdel WE, Hiddemann W, Hoelzer D, Hehlmann R, Hasford J, Hoffmann VS, Döhner H, Ehninger G, Ganser A, Niederwieser DW, Pfirrmann M. Acute Myeloid Leukemia (AML): different treatment strategies versus a common standard arm--combined prospective analysis by the German AML Intergroup. J Clin Oncol. 2012 Oct 10;30(29):3604-10. Epub 2012 Sep 10. link to original article contains dosing details in manuscript PubMed NCT01414231
  6. AML2003: Schaich M, Parmentier S, Kramer M, Illmer T, Stölzel F, Röllig C, Thiede C, Hänel M, Schäfer-Eckart K, Aulitzky W, Einsele H, Ho AD, Serve H, Berdel WE, Mayer J, Schmitz N, Krause SW, Neubauer A, Baldus CD, Schetelig J, Bornhäuser M, Ehninger G. High-dose cytarabine consolidation with or without additional amsacrine and mitoxantrone in acute myeloid leukemia: results of the prospective randomized AML2003 trial. J Clin Oncol. 2013 Jun 10;31(17):2094-102. Epub 2013 Apr 29. link to original article contains dosing details in manuscript PubMed NCT00180102
  7. AML2006: Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, Schaich M, Ottmann O, Duyster J, Wandt H, Fischer T, Giagounidis A, Neubauer A, Reichle A, Aulitzky W, Noppeney R, Blau I, Kunzmann V, Stuhlmann R, Krämer A, Kreuzer KA, Brandts C, Steffen B, Thiede C, Müller-Tidow C, Ehninger G, Berdel WE. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013 Sep 1;31(25):3110-8. Epub 2013 Jul 29. link to original article contains dosing details in abstract PubMed NCT00373373
  8. SWOG S0106: Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. Epub 2013 Apr 16. link to original article link to PMC article contains dosing details in abstract PubMed NCT00085709
  9. CLTR0308-204: Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, Komrokji R, Solomon SR, Kolitz JE, Cooper M, Yeager AM, Louie AC, Feldman EJ. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014 May 22;123(21):3239-46. Epub 2014 Mar 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00788892
  10. AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01074047
    1. Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article PubMed
  11. AML-AZA: Müller-Tidow C, Tschanter P, Röllig C, Thiede C, Koschmieder A, Stelljes M, Koschmieder S, Dugas M, Gerss J, Butterfaß-Bahloul T, Wagner R, Eveslage M, Thiem U, Krause SW, Kaiser U, Kunzmann V, Steffen B, Noppeney R, Herr W, Baldus CD, Schmitz N, Götze K, Reichle A, Kaufmann M, Neubauer A, Schäfer-Eckart K, Hänel M, Peceny R, Frickhofen N, Kiehl M, Giagounidis A, Görner M, Repp R, Link H, Kiani A, Naumann R, Brümmendorf TH, Serve H, Ehninger G, Berdel WE, Krug U; Study Alliance Leukemia Group. Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia. Leukemia. 2016 Mar;30(3):555-61. Epub 2015 Nov 2. link to original article contains dosing details in manuscript PubMed NCT00915252
  12. SORAML: Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Schäfer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghanß C, Repp R, Heits F, Dürk H, Hase J, Klut IM, Illmer T, Bornhäuser M, Schaich M, Parmentier S, Görner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, Ehninger G; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015 Dec;16(16):1691-9. Epub 2015 Nov 6. link to original article PubMed NCT00893373
  13. CLTR0310-301: Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. link to original article contains dosing details in abstract link to PMC article PubMed NCT01696084
    1. Update: Lancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Faderl S, Cortes JE. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2021 Jul;8(7):e481-e491. link to original article PubMed
  14. CALGB 10201: Walker AR, Marcucci G, Yin J, Blum W, Stock W, Kohlschmidt J, Mrózek K, Carroll AJ, Eisfeld AK, Wang ES, Jacobson S, Kolitz JE, Thakuri M, Sutamtewagul G, Vij R, Stuart RK, Byrd JC, Bloomfield CD, Stone RM, Larson RA. Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance). Blood Adv. 2021 Jul 13;5(13):2775-2787. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00085124.
  15. BRIGHT AML 1019: Sekeres MA, Montesinos P, Novak J, Wang J, Jeyakumar D, Tomlinson B, Mayer J, Jou E, Robak T, Taussig DC, Dombret H, Merchant A, Shaik N, O'Brien T, Roh W, Liu X, Ma W, DiRienzo CG, Chan G, Cortes JE. Glasdegib plus intensive or non-intensive chemotherapy for untreated acute myeloid leukemia: results from the randomized, phase 3 BRIGHT AML 1019 trial. Leukemia. 2023 Oct;37(10):2017-2026. Epub 2023 Aug 21. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03416179
  16. EORTC-1301: Lübbert M, Wijermans PW, Kicinski M, Chantepie S, Van der Velden WJFM, Noppeney R, Griškevičius L, Neubauer A, Crysandt M, Vrhovac R, Luppi M, Fuhrmann S, Audisio E, Candoni A, Legrand O, Foà R, Gaidano G, van Lammeren-Venema D, Posthuma EFM, Hoogendoorn M, Giraut A, Stevens-Kroef M, Jansen JH, de Graaf AO, Efficace F, Ammatuna E, Vilque JP, Wäsch R, Becker H, Blijlevens N, Dührsen U, Baron F, Suciu S, Amadori S, Venditti A, Huls G; EORTC Leukemia Group, GIMEMA, and German MDS Study Group. 10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial. Lancet Haematol. 2023 Nov;10(11):e879-e889. link to original article contains dosing details in supplement PubMed NCT02172872
  17. AMLSG31-19: NCT04628026
  18. ECOG E2906: NCT02085408
  19. ENHANCE-2: NCT04778397

7+3d (high-dose)

7+3d: 7 days of cytarabine + 3 days of daunorubicin

Regimen variant #1, 700/270

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fernandez et al. 2009 (ECOG E1900) 2002-2008 Phase 3 (E-esc) 7+3d; standard-dose Superior OS (primary endpoint)
Median OS: 23.7 vs 15.7 mo
(HR 0.74, 95% CI 0.60-0.90)
Zeidner et al. 2015 (JHOC-J1101) 2011-2013 Randomized Phase 2 (C) FLAM Inferior CR rate
Garcia-Manero et al. 2023 (SWOG S1203) 2013-04 to 2015-11 Phase 3 (C) 1. HiDAC & Idarubicin
2. HiDAC, Idarubicin, Vorinostat 		Did not meet primary endpoint of EFS

Chemotherapy

7-day course

Subsequent treatment

  • JHOC-J1101: Patients with residual leukemia at day 14 underwent 5+2d salvage


Regimen variant #2, 1400/240

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Castaigne et al. 2004 (ALFA 9000) 1990-1996 Phase 3 (C) 1. 7+3d x 2
2. Timed sequential induction 		Did not meet primary endpoint of RFI

Chemotherapy

7-day course


Regimen variant #3, 1400/270

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01) 2000-2006 Phase 3 (E-esc) 7+3d; standard-dose Superior CR rate (secondary endpoint)
Lee et al. 2011 (ADcomparison) 2001-2008 Phase 3 (E-esc) 7+3d; standard-dose Seems to have superior OS (secondary endpoint)
OS60: 46.8% vs 34.6%
(HR 0.74, 95% CI 0.58-0.97)

Seems to have superior EFS (primary endpoint)
Lee et al. 2017 (COSAH C-022) 2010-2014 Phase 3 (E-switch-ic) 7+3i Inconclusive whether non-inferior CR rate

Chemotherapy

7-day course

Subsequent treatment

  • HOVON 43 AML/SAKK 30/01: MiDAC consolidation
  • COSAH C-022, with CR, good- or intermediate-risk cytogenetics: HiDAC consolidation
  • COSAH C-022, with CR, high-risk cytogenetics: Cytarabine & etoposide consolidation

References

  1. ALFA 9000: Castaigne S, Chevret S, Archimbaud E, Fenaux P, Bordessoule D, Tilly H, de Revel T, Simon M, Dupriez B, Renoux M, Janvier M, Micléa JM, Thomas X, Bastard C, Preudhomme C, Bauters F, Degos L, Dombret H. Randomized comparison of double induction and timed-sequential induction to a "3 + 7" induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study. Blood. 2004 Oct 15;104(8):2467-74. Epub 2004 May 13. link to original article contains dosing details in manuscript PubMed
  2. HOVON 43 AML/SAKK 30/01: Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; HOVON; AMLSG; SAKK. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. link to original article contains dosing details in manuscript PubMed ISRCTN77039377
  3. ECOG E1900: Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00049517
    1. Update: Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, Lazarus HM, Levine RL, Litzow MR, Paietta EM, Patel JP, Racevskis J, Rowe JM, Tallman MS, Sun Z, Luger SM. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016 Mar 24;127(12):1551-8. Epub 2016 Jan 11. link to original article link to PMC article PubMed
  4. ADcomparison: Lee JH, Joo YD, Kim H, Bae SH, Kim MK, Zang DY, Lee JL, Lee GW, Lee JH, Park JH, Kim DY, Lee WS, Ryoo HM, Hyun MS, Kim HJ, Min YJ, Jang YE, Lee KH; Cooperative Study Group A for Hematology. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood. 2011 Oct 6;118(14):3832-41. Epub 2011 Aug 9. link to original article contains dosing details in abstract PubMed NCT00474006
  5. JHOC-J1101: Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, Lancet JE, Bose P, Levy MY, Tibes R, Gojo I, Gocke CD, Rosner GL, Little RF, Wright JJ, Doyle LA, Smith BD, Karp JE. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015 Sep;100(9):1172-9. Epub 2015 May 28. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01349972
  6. COSAH C-022: Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. link to original article contains dosing details in manuscript PubMed NCT01145846
  7. SWOG S1203: Garcia-Manero G, Podoltsev NA, Othus M, Pagel JM, Radich JP, Fang M, Rizzieri DA, Marcucci G, Strickland SA, Litzow MR, Savoie ML, Medeiros BC, Sekeres MA, Lin TL, Uy GL, Powell BL, Kolitz JE, Larson RA, Stone RM, Claxton D, Essell J, Luger SM, Mohan SR, Moseley A, Appelbaum FR, Erba HP. A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML. Leukemia. 2024 Jan;38(1):58-66. Epub 2023 Nov 7. link to original article contains dosing details in manuscript PubMed NCT01802333

7+3d & GO

7+3d & GO: 7 days of Cytarabine, 3 days of daunorubicin, Gemtuzumab Ozogamicin

Regimen variant #1, split GO dosing

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Castaigne et al. 2012 (ALFA-0701) 2008-2010 Phase 3 (E-RT-esc) 7+3d; intermediate-dose Superior EFS (primary endpoint)
EFS24: 40.8% vs 17.1%
(HR 0.58, 95% CI 0.43-0.78)

Seems to have superior OS (secondary endpoint)
OS24: 53.2% vs 41.9%
(HR 0.69, 95% CI 0.49-0.98)

Chemotherapy

Antibody-drug conjugate therapy

7-day course

Subsequent treatment


Regimen variant #2, single-day GO

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Petersdorf et al. 2013 (SWOG S0106) 2004-2009 Phase 3 (E-esc) 7+3d; intermediate-dose Did not meet co-primary endpoint of CR rate

Note: this was a failed confirmatory study which led to the withdrawal of the FDA indication in 2010. The FDA indication was later reinstated in 2017.

Chemotherapy

Antibody-drug conjugate therapy

7-day course

Subsequent treatment

References

  1. ALFA-0701: Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. Epub 2012 Apr 5. link to original article contains dosing details in manuscript PubMed NCT00927498
    1. Update: Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. link to original article link to PMC article PubMed
  2. SWOG S0106: Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. Epub 2013 Apr 16. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00085709

7+3i

7+3i: 7 days of cytarabine + 3 days of idarubicin
AI: Ara-C (Cytarabine) & Idarubicin
IA: Idarubicin & Ara-C (Cytarabine)

Regimen variant #1, 80/12, intermittent Ara-C

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Masaoka et al. 1996 NR in abstract Randomized Phase 2 (E-switch-ic) 7+3d; standard-dose Seems to have superior CR rate

Chemotherapy

7-day course


Regimen variant #2, 100/12, CI Ara-C

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mandelli et al. 1991 1984-1987 Phase 3 (E-RT-switch-ic) 7+3d Did not meet primary endpoint of FFS
Vogler et al. 1992 1985-1989 Phase 3 (E-RT-switch-ic) 7+3d Seems to have superior CR rate
Haas et al. 1993 1989-NR Non-randomized
Rowe et al. 2004 (ECOG E3993) 1993-1997 Phase 3 (E-switch-ic) 1. 7+3d; standard-dose
2. 7+3d + GM-CSF
3. 7+3i + GM-CSF
4. 7+3m
5. 7+3m + GM-CSF 		Did not meet primary endpoint of CR rate
Ohtake et al. 2010 (JALSG AML95) 1995-1997 Phase 3 (C) Individualized chemotherapy Did not meet efficacy endpoints
Miyawaki et al. 2005 (JALSG AML97) 1997-2001 Non-randomized part of RCT
Ohtake et al. 2010 (JALSG AML201) 2001-2005 Phase 3 (C) 7+5d Inconclusive whether non-inferior CR rate

Note: Patients in ECOG E3993 with persistent disease at day 14 (more than 5% blasts) underwent an identical second cycle of 7+3i.

Chemotherapy

7-day course (see note)


Regimen variant #3, 100/13, CI Ara-C

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wiernik et al. 1992 1985-1989 Phase 3 (E-RT-switch-ic) 7+3d; standard-dose Seems to have superior OS

Chemotherapy

7-day course


Regimen variant #4, 200/12, CI Ara-C

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Löwenberg et al. 2003 (HOVON/SAKK AML 29) 1995-1999 Phase 3 (C) 7+3i & G-CSF Seems to have inferior DFS
Pautas et al. 2010 (ALFA-9801) 1999-2006 Phase 3 (C) 1. 7+3d; high-dose
2. 7+4i 		Did not meet primary endpoint of EFS
Löwenberg et al. 2011 (HOVON/SAKK AML 42) 2001-2006 Phase 3 (C) HiDAC+3i Did not meet primary endpoint of EFS
Löwenberg et al. 2017 (HOVON-102) 2010-2013 Phase 3 (C) 7+3i & Clofarabine Did not meet primary endpoint of EFS
Lee et al. 2017 (COSAH C-022) 2010-2014 Phase 3 (C) 7+3d; high-dose Inconclusive whether non-inferior CR rate
Löwenberg et al. 2021 (HOVON/SAKK-132) 2015-2017 Phase 3 (C) 7+3i & Lenalidomide Did not meet primary endpoint of EFS

Note: in HOVON/SAKK AML 29 & HOVON/SAKK AML 42, idarubicin was given on days 5 to 7.

Chemotherapy

7-day course

Subsequent treatment

  • HOVON/SAKK AML 29 & HOVON/SAKK AML 42: Amsacrine & Cytarabine consolidation
  • ALFA-9801, patients achieiving CR: cytarabine & idarubicin consolidation
  • COSAH C-022, patients achieving CR, good- or intermediate-risk cytogenetics: HiDAC consolidation
  • COSAH C-022, patients achieving CR, high-risk cytogenetics: CYVE consolidation
  • HOVON/SAKK-132: Daunorubicin & IDAC (remission induction cycle II)


Regimen variant #5, with range

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Dombret et al. 2015 (AZA-AML-001) 2010-2014 Phase 3 (C) Azacitidine Might have inferior OS

Chemotherapy

7-day course

References

  1. Mandelli F, Petti MC, Ardia A, Di Pietro N, Di Raimondo F, Ganzina F, Falconi E, Geraci E, Ladogana S, Latagliata R, Malleo C, Nobile F, Petti N, Rotoli B, Specchia G, Tabilio A, Resegotti L; GIMEMA. A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia: a multicentric study from the Italian Co-operative Group GIMEMA. Eur J Cancer. 1991;27(6):750-5. link to original article PubMed
  2. Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, Ritch PS, Enck RE, Weitberg AB. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992 Jan 15;79(2):313-9. link to original article contains dosing details in manuscript PubMed
  3. Vogler WR, Velez-Garcia E, Weiner RS, Flaum MA, Bartolucci AA, Omura GA, Gerber MC, Banks PL; Southeastern Cancer Study Group. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group study. J Clin Oncol. 1992 Jul;10(7):1103-11. link to original article contains dosing details in abstract PubMed
  4. Haas R, Ho AD, Del Valle F, Fischer JT, Ehrhardt R, Döhner H, Witt B, Huberts H, Kaplan E, Hunstein W. Idarubicin/cytosine arabinoside and mitoxantrone/etoposide for the treatment of de novo acute myelogenous leukemia. Semin Oncol. 1993 Dec;20(6 Suppl 8):20-6. PubMed
  5. Masaoka T, Ogawa M, Yamada K, Kimura K, Ohashi Y. A phase II comparative study of idarubicin plus cytarabine versus daunorubicin plus cytarabine in adult acute myeloid leukemia. Semin Hematol. 1996 Oct;33(4 Suppl 3):12-7. contains dosing details in abstract PubMed
  6. HOVON/SAKK AML 29: Löwenberg B, van Putten W, Theobald M, Gmür J, Verdonck L, Sonneveld P, Fey M, Schouten H, de Greef G, Ferrant A, Kovacsovics T, Gratwohl A, Daenen S, Huijgens P, Boogaerts M; Dutch-Belgian Hemato-Oncology Cooperative Group; Swiss Group for Clinical Cancer Research. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med. 2003 Aug 21;349(8):743-52. link to original article contains dosing details in manuscript PubMed
  7. ECOG E3993: Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. link to original article contains dosing details in manuscript PubMed NCT04446052
  8. JALSG AML97: Miyawaki S, Sakamaki H, Ohtake S, Emi N, Yagasaki F, Mitani K, Matsuda S, Kishimoto Y, Miyazaki Y, Asou N, Matsushima T, Takahashi M, Ogawa Y, Honda S, Ohno R; Japan Adult Leukemia Study Group. A randomized, postremission comparison of four courses of standard-dose consolidation therapy without maintenance therapy versus three courses of standard-dose consolidation with maintenance therapy in adults with acute myeloid leukemia: the Japan Adult Leukemia Study Group AML 97 study. Cancer. 2005 Dec 15;104(12):2726-34. link to original article contains dosing details in abstract PubMed
  9. ALFA-9801: Pautas C, Merabet F, Thomas X, Raffoux E, Gardin C, Corm S, Bourhis JH, Reman O, Turlure P, Contentin N, de Revel T, Rousselot P, Preudhomme C, Bordessoule D, Fenaux P, Terré C, Michallet M, Dombret H, Chevret S, Castaigne S. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol. 2010 Feb 10;28(5):808-14. Epub 2010 Jan 4. link to original article contains dosing details in manuscript PubMed NCT00931138
  10. JALSG AML95: Ohtake S, Miyawaki S, Kiyoi H, Miyazaki Y, Okumura H, Matsuda S, Nagai T, Kishimoto Y, Okada M, Takahashi M, Handa H, Takeuchi J, Kageyama S, Asou N, Yagasaki F, Maeda Y, Ohnishi K, Naoe T, Ohno R. Randomized trial of response-oriented individualized versus fixed-schedule induction chemotherapy with idarubicin and cytarabine in adult acute myeloid leukemia: the JALSG AML95 study. Int J Hematol. 2010 Mar;91(2):276-83. link to original article contains dosing details in abstract PubMed
  11. JALSG AML201: Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 2011 Feb 24;117(8):2358-65. Epub 2010 Aug 6. link to original article PubMed C000000157
  12. HOVON/SAKK AML 42: Löwenberg B, Pabst T, Vellenga E, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Biemond BJ, Gratwohl A, de Greef GE, Verdonck LF, Schaafsma MR, Gregor M, Theobald M, Schanz U, Maertens J, Ossenkoppele GJ; HOVON; SAKK. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011 Mar 17;364(11):1027-36. link to original article contains dosing details in manuscript PubMed NTR230
  13. AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article contains dosing details in abstract link to PMC article PubMed NCT01074047
    1. Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article PubMed
  14. HOVON-102: Löwenberg B, Pabst T, Maertens J, van Norden Y, Biemond BJ, Schouten HC, Spertini O, Vellenga E, Graux C, Havelange V, de Greef GE, de Weerdt O, Legdeur MJ, Kuball J, Kooy MV, Gjertsen BT, Jongen-Lavrencic M, van de Loosdrecht AA, van Lammeren-Venema D, Hodossy B, Breems DA, Chalandon Y, Passweg J, Valk PJ, Manz MG, Ossenkoppele GJ; HOVON; SAKK. Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML. Blood. 2017 Mar 23;129(12):1636-1645. Epub 2017 Jan 3. link to original article contains dosing details in manuscript PubMed NTR2187
  15. COSAH C-022: Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. link to original article contains dosing details in manuscript PubMed NCT01145846
  16. HOVON/SAKK-132: Löwenberg B, Pabst T, Maertens J, Gradowska P, Biemond BJ, Spertini O, Vellenga E, Griskevicius L, Tick LW, Jongen-Lavrencic M, van Marwijk Kooy M, Vekemans MC, van der Velden WJFM, Beverloo B, Michaux L, Graux C, Deeren D, de Weerdt O, van Esser JWJ, Bargetzi M, Klein SK, Gadisseur A, Westerweel PE, Veelken H, Gregor M, Silzle T, van Lammeren-Venema D, Moors I, Breems DA, Hoogendoorn M, Legdeur MJC, Fischer T, Kuball J, Cornelissen J, Porkka K, Juliusson G, Meyer P, Höglund M, Gjertsen BT, Janssen JJWM, Huls G, Passweg J, Cloos J, Valk PJM, van Elssen CHMJ, Manz MG, Floisand Y, Ossenkoppele GJ. Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial. Blood Adv. 2021 Feb 23;5(4):1110-1121. link to original article contains dosing details in manuscript link to PMC article PubMed

7+3i & Sorafenib

Regimen

Study Dates of enrollment Evidence
Ravandi et al. 2010 (BAY43-9006) 2007-2009 Phase 1/2

Note: Regimen details are from the phase 2 part of the published phase 1/2 trial.

Chemotherapy

  • Cytarabine (Ara-C) by the following age-based criteria:
    • 60 years old or younger: 1500 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose: 6000 mg/m2)
    • Older than 60 years old: 1500 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose: 4500 mg/m2)
  • Idarubicin (Idamycin) 12 mg/m2 IV over 60 minutes once per day on days 1 to 3

Targeted therapy

7-day course

Subsequent treatment

References

  1. BAY43-9006: Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce SR, Brandt M, Byrd A, Bekele BN, Pratz K, Luthra R, Levis M, Andreeff M, Kantarjian HM. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010 Apr 10;28(11):1856-62. Epub 2010 Mar 8. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00542971
    1. Update: Ravandi F, Arana Yi C, Cortes JE, Levis M, Faderl S, Garcia-Manero G, Jabbour E, Konopleva M, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce S, Brandt M, Pratz K, Luthra R, Andreeff M, Kantarjian H. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014 Jul;28(7):1543-5. Epub 2014 Feb 3. link to original article link to PMC article PubMed

7+3d & Glasdegib

Regimen

Study Dates of enrollment Evidence
Cortes et al. 2018 (BRIGHT AML 1003 phase 2) 2012-NR Phase 2

Note: glasdegib is continued beyond induction; see paper for details.

Chemotherapy

Targeted therapy

28-day course

Subsequent treatment

References

  1. BRIGHT AML 1003 phase 2: Cortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, DeAngelo DJ, Pollyea DA, Sekeres MA, Robak T, Ma WW, Zeremski M, Naveed Shaik M, Douglas Laird A, O'Connell A, Chan G, Schroeder MA. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol. 2018 Nov;93(11):1301-1310. Epub 2018 Sep 9. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01546038

7+3m

7+3m: 7 days of cytarabine + 3 days of mitoxantrone
MAC: Mitoxantrone & Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Arlin et al. 1990 NR in abstract Phase 3 (E-RT-switch-ic) 7+3d Did not meet efficacy endpoints
Rowe et al. 2004 (ECOG E3993) 1993-1997 Phase 3 (E-switch-ic) 1. 7+3d; standard-dose
2. 7+3d + GM-CSF
3. 7+3i
4. 7+3i + GM-CSF
5. 7+3m + GM-CSF 		Did not meet primary endpoint of CR rate

Chemotherapy

7-day course

Subsequent treatment

  • ECOG E3993, patients with persistent disease at day 14 (more than 5% blasts): underwent an identical second cycle of 7+3m re-induction

References

  1. Arlin Z, Case DC Jr, Moore J, Wiernik P, Feldman E, Saletan S, Desai P, Sia L, Cartwright K; Lederle Cooperative Group. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Leukemia. 1990 Mar;4(3):177-83. PubMed
  2. ECOG E3993: Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. link to original article contains dosing details in manuscript PubMed NCT04446052

ADE (standard-dose Ara-C)

ADE: Ara-C (Cytarabine), Daunorubicin, Etoposide
7-3-7: 7 days of Cytarabine, 3 days of Daunorubicin, 7 days of Etoposide
8-3-5: 8 days of Cytarabine, 3 days of Daunorubicin, 5 days of Etoposide
10-3-5: 10 days of Cytarabine, 3 days of Daunorubicin, 5 days of Etoposide

Regimen variant #1, 7-3-7, 700/150/525

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bishop et al. 1996 1987-1991 Phase 3 (C) ADE (high-dose Ara-C) Inferior DFS

Chemotherapy

7-day course; can be repeated up to 3 times if CR not achieved

Subsequent treatment

  • ADE; 5-2-5 consolidation x 2


Regimen variant #2, 7-3-3, 700/180/300

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Baer et al. 2002 (CALGB 9720) 1998-03 to NR Phase 3 (C) ADEP Did not meet primary endpoint of CR rate

Chemotherapy

7-day course

Subsequent treatment


Regimen variant #3, 7-3-3, 700/270/300

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kolitz et al. 2010 (CALGB 19808) 2001-2003 Phase 3 (C) ADEP Did not meet co-primary endpoints of DFS/OS

Chemotherapy

7-day course

Subsequent treatment


Regimen variant #4, 10-3-5, 1000/150/250, CI Ara-C

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Willemze et al. 2013 (EORTC-GIMEMA AML-12) 1999-2008 Phase 3 (C) ADE (high-dose Ara-C) Seems to have inferior OS

Chemotherapy

10-day course


Regimen variant #5, 10-3-5, 1025/150/500, CI Ara-C

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mandelli et al. 2009 (EORTC-GIMEMA AML-10) 1993-1999 Phase 3 (C) 1. AIE
2. AME 		Did not meet primary endpoint of OS

Chemotherapy

10-day course


Regimen variant #6, 8-3-5, 1600/150/500, intermittent Ara-C

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hann et al. 1997 (UK MRC AML10) 1988-1995 Phase 3 (E-switch-ic) DAT 3+8 Did not meet efficacy endpoints
Burnett et al. 2010 (UK MRC AML15) 2002-2006 Phase 3 (C) See link See link

Note: these trials have complicated treatment schemas; see papers for details.

Preceding treatment

Chemotherapy

8-day course

Subsequent treatment

  • UK MRC AML10: MACE consolidation
  • UK MRC AML15: Consolidation (see paper for details)


Regimen variant #7, 10-3-5, 2000/150/500, intermittent Ara-C

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hann et al. 1997 (UK MRC AML10) 1988-1995 Phase 3 (E-switch-ic) DAT 3+10 Did not meet efficacy endpoints
Burnett et al. 1999 (UK MRC AML12) 1993-1997 Phase 3 (C) See link See link
Burnett et al. 2010 (UK MRC AML15) 2002-2006 Phase 3 (C) See link See link

Note: these trials have complicated treatment schemas; see papers for details.

Chemotherapy

10-day course

Subsequent treatment

References

  1. Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Herrmann R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja S. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996 Mar 1;87(5):1710-7. link to original article contains dosing details in abstract PubMed
  2. UK MRC AML10: Hann IM, Stevens RF, Goldstone AH, Rees JK, Wheatley K, Gray RG, Burnett AK; Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia: results of the Medical Research Council's 10th AML trial (MRC AML10). Blood. 1997 Apr 1;89(7):2311-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG, Wheatley K; UK Medical Research Council Adult and Children's Leukaemia Working Parties. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet. 1998 Mar 7;351(9104):700-8. link to original article PubMed
  3. UK MRC AML12: Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the randomized MRC trial. Blood. 1999 Jun 15;93(12):4131-43. link to original article PubMed NCT00002658
    1. Update: Burnett AK, Hills RK, Milligan DW, Goldstone AH, Prentice AG, McMullin MF, Duncombe A, Gibson B, Wheatley K. Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol. 2010 Feb 1;28(4):586-95. Epub 2009 Dec 28. link to original article PubMed
  4. CALGB 9720: Baer MR, George SL, Dodge RK, O'Loughlin KL, Minderman H, Caligiuri MA, Anastasi J, Powell BL, Kolitz JE, Schiffer CA, Bloomfield CD, Larson RA. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood. 2002 Aug 15;100(4):1224-32. link to original article contains dosing details in abstract PubMed NCT00003190
    1. Update: Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrózek K, Kolitz JE, Powell BL, Moore JO, Stone RM, Anastasi J, Bloomfield CD, Larson RA. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720. J Clin Oncol. 2008 Oct 20;26(30):4934-9. Epub 2008 Jun 30. link to original article link to PMC article PubMed
  5. EORTC-GIMEMA AML-10: Mandelli F, Vignetti M, Suciu S, Stasi R, Petti MC, Meloni G, Muus P, Marmont F, Marie JP, Labar B, Thomas X, Di Raimondo F, Willemze R, Liso V, Ferrara F, Baila L, Fazi P, Zittoun R, Amadori S, de Witte T; EORTC; GIMEMA. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol. 2009 Nov 10;27(32):5397-403. Epub 2009 Oct 13. Erratum in: J Clin Oncol. 2010 Mar 10;28(8):1438. link to original article link to PMC article PubMed
    1. Update: Baron F, Efficace F, Cannella L, Muus P, Trisolini S, Halkes CJM, Fazi P, Vignetti M, Marie JP, Chiusolo P, van der Velden W, La Sala E, Vitolo U, Thomas X, Lefrère F, Di Raimondo F, Bourhis JH, Specchia G, Guimarães JE, Allione B, Vrhovac R, Ferrara F, Stevens-Kroef M, Meert L, de Witte T, Willemze R, Amadori S, Suciu S. Impact of the type of anthracycline and of stem cell transplantation in younger patients with acute myeloid leukaemia: Long-term follow up of a phase III study. Am J Hematol. 2020 Jul;95(7):749-758. Epub 2020 Apr 17. link to original article PubMed
  6. CALGB 19808: Kolitz JE, George SL, Marcucci G, Vij R, Powell BL, Allen SL, DeAngelo DJ, Shea TC, Stock W, Baer MR, Hars V, Maharry K, Hoke E, Vardiman JW, Bloomfield CD, Larson RA; Cancer and Leukemia Group B. P-glycoprotein inhibition using valspodar (PSC-833) does not improve outcomes for patients younger than age 60 years with newly diagnosed acute myeloid leukemia: Cancer and Leukemia Group B study 19808. Blood. 2010 Sep 2;116(9):1413-21. Epub 2010 Jun 3. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00006363
  7. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed ISRCTN17161961
    1. Update: Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. link to original article PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed
  8. EORTC-GIMEMA AML-12: Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, Muus P, Mistrik M, Amadori S, Specchia G, Fabbiano F, Nobile F, Sborgia M, Camera A, Selleslag DL, Lefrère F Sr, Magro D, Sica S, Cantore N, Beksac M, Berneman Z, Thomas X, Melillo L, Guimaraes JE, Leoni P, Luppi M, Mitra ME, Bron D, Fillet G, Marijt EW, Venditti A, Hagemeijer A, Mancini M, Jansen J, Cilloni D, Meert L, Fazi P, Vignetti M, Trisolini SM, Mandelli F, de Witte T. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: Results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2014 Jan 20;32(3):219-28. Epub 2013 Dec 2. link to original article contains dosing details in manuscript PubMed NCT00004128

ADE (high-dose Ara-C)

ADE: Ara-C (Cytarabine), Daunorubicin, Etoposide
HIDAC-3-5: HIgh-Dose Ara-C (Cytarabine), 3 days of Daunorubicin, 5 days of Etoposide
HIDAC-3-7: HIgh-Dose Ara-C (Cytarabine), 3 days of Daunorubicin, 7 days of Etoposide

Regimen variant #1, HIDAC-3-5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Willemze et al. 2013 (EORTC-GIMEMA AML-12) 1999-2008 Phase 3 (E-esc) ADE (standard-dose Ara-C) Seems to have superior OS (primary endpoint)
OS72: 42.5% vs 38.7%
(HR 0.89, 95% CI 0.79-1.00)

Chemotherapy

7-day course


Regimen variant #2, HIDAC-3-7

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bishop et al. 1996 1987-1991 Phase 3 (E-esc) ADE (standard-dose Ara-C) Superior DFS

Chemotherapy

7-day course; can be repeated up to 3 times if CR not achieved

Subsequent treatment

  • ADE; 5-2-5 consolidation x 2

References

  1. Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Herrmann R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja S. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996 Mar 1;87(5):1710-7. link to original article contains dosing details in abstract PubMed
  2. EORTC-GIMEMA AML-12: Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, Muus P, Mistrik M, Amadori S, Specchia G, Fabbiano F, Nobile F, Sborgia M, Camera A, Selleslag DL, Lefrère F Sr, Magro D, Sica S, Cantore N, Beksac M, Berneman Z, Thomas X, Melillo L, Guimaraes JE, Leoni P, Luppi M, Mitra ME, Bron D, Fillet G, Marijt EW, Venditti A, Hagemeijer A, Mancini M, Jansen J, Cilloni D, Meert L, Fazi P, Vignetti M, Trisolini SM, Mandelli F, de Witte T. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: Results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2014 Jan 20;32(3):219-28. Epub 2013 Dec 2. link to original article contains dosing details in manuscript PubMed NCT00004128

AIE

AIE: Ara-C (Cytarabine), Idarubicin, Etoposide
ICE: Idarubicin, Cytarabine, Etoposide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bradstock et al. 2004 (ALLG M7) 1995-2000 Non-randomized part of RCT
de Witte et al. 2010 (CRIANT) 1996-2003 Non-randomized part of phase 3 RCT
Schlenk et al. 2004 1998-2001 Phase 3 (C) A-ICE Inferior OS
Russo et al. 2005 1999-2002 Phase 3 (C) FLAI Inferior CR rate
Bassan et al. 2019 (NILG AML 02/06) 2007-2012 Phase 3 (C) Sequential high-dose therapy Did not meet primary endpoint of CR rate

Chemotherapy

7-day course

Subsequent treatment

  • ALLG M7: ICE versus IcE consolidation
  • NILG AML 02/06, early CR: IC consolidation

References

  1. ALLG M7: Bradstock KF, Matthews JP, Lowenthal RM, Baxter H, Catalano J, Brighton T, Gill D, Eliadis P, Joshua D, Cannell P, Schwarer AP, Durrant S, Gillett A, Koutts J, Taylor K, Bashford J, Arthur C, Enno A, Dunlop L, Szer J, Leahy M, Juneja S, Young GA; Australasian Leukaemia and Lymphoma Group. A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. Blood. 2005 Jan 15;105(2):481-8. Epub 2004 Jun 22. link to original article PubMed
  2. Schlenk RF, Fröhling S, Hartmann F, Fischer JT, Glasmacher A, del Valle F, Grimminger W, Götze K, Waterhouse C, Schoch R, Pralle H, Mergenthaler HG, Hensel M, Koller E, Kirchen H, Preiss J, Salwender H, Biedermann HG, Kremers S, Griesinger F, Benner A, Addamo B, Döhner K, Haas R, Döhner H; AML Study Group Ulm. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia. 2004 Nov;18(11):1798-803. link to original article PubMed
  3. Russo D, Malagola M, de Vivo A, Fiacchini M, Martinelli G, Piccaluga PP, Damiani D, Candoni A, Michielutti A, Castelli M, Testoni N, Ottaviani E, Rondoni M, Pricolo G, Mazza P, Zuffa E, Zaccaria A, Raspadori D, Bocchia M, Lauria F, Bonini A, Avanzini P, Gugliotta L, Visani G, Fanin R, Baccarani M. Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients. Br J Haematol. 2005 Oct;131(2):172-9. Erratum in: Br J Haematol. 2006 Mar;132(6):804. link to original article PubMed
  4. CRIANT: de Witte T, Hagemeijer A, Suciu S, Belhabri A, Delforge M, Kobbe G, Selleslag D, Schouten HC, Ferrant A, Biersack H, Amadori S, Muus P, Jansen JH, Hellström-Lindberg E, Kovacsovics T, Wijermans P, Ossenkoppele G, Gratwohl A, Marie JP, Willemze R. Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: final results of a prospective randomized European Intergroup Trial. Haematologica. 2010 Oct;95(10):1754-61. Epub 2010 May 21. link to original article link to PMC article PubMed NCT00002926
  5. NILG AML 02/06: Bassan R, Intermesoli T, Masciulli A, Pavoni C, Boschini C, Gianfaldoni G, Marmont F, Cavattoni I, Mattei D, Terruzzi E, De Paoli L, Cattaneo C, Borlenghi E, Ciceri F, Bernardi M, Scattolin AM, Todisco E, Campiotti L, Corradini P, Cortelezzi A, Ferrero D, Zanghì P, Oldani E, Spinelli O, Audisio E, Cortelazzo S, Bosi A, Falini B, Pogliani EM, Rambaldi A. Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML. Blood Adv. 2019 Apr 9;3(7):1103-1117. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00495287

CIA

CIA: Clofarabine, Idarubicin, Ara-C (Cytarabine)

Regimen variant #1, 15/10/1000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jabbour et al. 2017 (MDACC 2010-0788) 2011-2016 Randomized Phase 2 (E-switch-ic) FIA Did not meet primary endpoint of EFS

Chemotherapy

5-day course

Subsequent treatment

  • MDACC 2010-0788, patients not achieving CR or CRp: Optional second CIA induction
  • MDACC 2010-0788, patients achieving CR or CRp: CIA consolidation


Regimen variant #2, 20/10/1000

Study Dates of enrollment Evidence
Nazha et al. 2013 2010-2012 Phase 2

Chemotherapy

Supportive therapy

5-day course

Subsequent treatment

  • Nazha et al. 2013, patients with PR: a second course of CIA with the same drugs, doses, and schedule.
  • Nazha et al. 2013, patients achieving CR or CRi: CIA consolidation

References

  1. Nazha A, Kantarjian H, Ravandi F, Huang X, Choi S, Garcia-Manero G, Jabbour E, Borthakur G, Kadia T, Konopleva M, Cortes J, Ferrajoli A, Kornblau S, Daver N, Pemmaraju N, Andreeff M, Estrov Z, Du M, Brandt M, Faderl S. Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia. Am J Hematol. 2013 Nov;88(11):961-6. Epub 2013 Sep 9. [ https://doi.org/10.1002/ajh.23544 long link to original article] contains dosing details in manuscript link to PMC article PubMed
  2. MDACC 2010-0788: Jabbour E, Short NJ, Ravandi F, Huang X, Xiao L, Garcia-Manero G, Plunkett W, Gandhi V, Sasaki K, Pemmaraju N, Daver NG, Borthakur G, Jain N, Konopleva M, Estrov Z, Kadia TM, Wierda WG, DiNardo CD, Brandt M, O'Brien SM, Cortes JE, Kantarjian H. A randomized phase 2 study of idarubicin and cytarabine with clofarabine or fludarabine in patients with newly diagnosed acute myeloid leukemia. Cancer. 2017 Nov 15;123(22):4430-4439. Epub 2017 Jul 14. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01289457

DA 3 + 10

DA 3 + 10: Daunorubicin & Ara-C (Cytarabine), 3 days of daunorubicin + 10 days of cytarabine

Regimen variant #1, 50 mg/m2 dauno

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2010 (UK MRC AML15) 2002-2006 Phase 3 (C) See link See link
Burnett et al. 2012 (UK NCRI AML16) 2006-2010 Phase 3 (C) DA 3 + 10, GO Seems to have inferior OS

Note: this regimen is very similar to 7+3d; standard-dose; however, 1) there is slightly more cytarabine given, in an intermittent schedule, and 2) the daunorubicin is given intermittently over 5 days, not 3. Both trials have complicated treatment schemas; see papers for details.

Chemotherapy

10-day course

Subsequent treatment

  • See papers for details (to be completed).


Regimen variant #2, 60 mg/m2 dauno

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2015 (UK NCRI AML17) 2009-2014 Phase 3 (C) DA 3 + 10; high-dose Did not meet primary endpoint of OS

Note: this regimen is very similar to 7+3d; intermediate-dose; however, 1) there is slightly more cytarabine given, in an intermittent schedule, and 2) the daunorubicin is given intermittently over 5 days, not 3.

Chemotherapy

10-day course

Subsequent treatment

References

  1. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed ISRCTN17161961
    1. Update: Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. link to original article PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed
  2. UK NCRI AML16: Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. link to original article contains dosing details in manuscript PubMed ISRCTN11036523
    1. Update: Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. link to original article contains dosing details in manuscript PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. link to original article link to PMC article PubMed
  3. UK NCRI AML17: Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 Jun 18;125(25):3878-85. Epub 2015 Apr 1. link to original article contains dosing details in manuscript link to PMC article PubMed ISRCTN55675535
    1. Update: Burnett AK, Das Gupta E, Knapper S, Khwaja A, Sweeney M, Kjeldsen L, Hawkins T, Betteridge SE, Cahalin P, Clark RE, Hills RK, Russell NH; UK NCRI AML Study Group. Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial. Haematologica. 2018 Oct;103(10):1654-1661. Epub 2018 Jul 5. link to original article link to PMC article PubMed

DA 3 + 10, GO

DA 3 + 10, GO: Daunorubicin & Ara-C (Cytarabine), 3 days of daunorubicin + 10 days of cytarabine, Gemtuzumab Ozogamicin

Regimen variant #1, 50 mg/m2 dauno

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2010 (UK MRC AML15) 2002-2006 Phase 3 (E-esc) See link See link
Burnett et al. 2012 (UK NCRI AML16) 2006-2010 Phase 3 (E-esc) DA 3 + 10 Seems to have superior OS (primary endpoint)
OS36: 25% vs 20%
(HR 0.87, 95% CI 0.76-1.00)

Note: Both trials have complicated treatment schemas; see papers for details.

Chemotherapy

Antibody-drug conjugate therapy

10-day course

Subsequent treatment

  • See paper for details (to be completed).


Regimen variant #2, 60 mg/m2 dauno

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Freeman et al. 2023 (UK NCRI AML18) 2014-11-04 to 2019-03-12 Phase 3 (C) DA 3 + 10, GO; GO2 Did not meet primary endpoint of OS

Eligibility criteria

  • 60 years old or older and fit for intensive chemotherapy

Chemotherapy

Antibody-drug conjugate therapy

10-day course

Subsequent treatment

References

  1. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed ISRCTN17161961
    1. Update: Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. link to original article PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed
  2. UK NCRI AML16: Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. link to original article contains dosing details in manuscript PubMed ISRCTN11036523
    1. Update: Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. link to original article contains dosing details in manuscript PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. link to original article link to PMC article PubMed
  3. UK NCRI AML18: Freeman SD, Thomas A, Thomas I, Hills RK, Vyas P, Gilkes A, Metzner M, Jakobsen NA, Kennedy A, Moore R, Almuina NM, Burns S, King S, Andrew G, Gallagher KME, Sellar RS, Cahalin P, Weber D, Dennis M, Mehta P, Knapper S, Russell NH. Fractionated vs single-dose gemtuzumab ozogamicin with determinants of benefit in older patients with AML: the UK NCRI AML18 trial. Blood. 2023 Nov 16;142(20):1697-1707. link to original article link to PMC article contains dosing details in manuscript PubMed ISRCTN31682779

DAC

DAC: Daunorubicin, Ara-C (Cytarabine), Cladribine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Holowiecki et al. 2004 (PALG AML1/1999) 1999-2002 Phase 3 (E-esc) DA Superior CR rate after first induction
Holowiecki et al. 2012 (PALG AML1/2004) 2004-2008 Phase 3 (E-esc) 1. DA Superior OS (primary endpoint)
Median OS: 24 vs 14 mo
(HR 0.69, 97.5% CI 0.5-0.96)
2. DAF Not reported

Chemotherapy

Supportive therapy

  • "According to commonly accepted guidelines with no prophylactic IV antibiotics"
  • Granulocyte colony-stimulating factor recommended only for patients older than 50 years old whose leukemic blasts were negative for CD114 expression

7-day course

Subsequent treatment

  • PALG AML1/1999 & PALG AML1/2004, partial remission: DAC re-induction with the same drugs, doses, and schedule.
  • PALG AML1/1999, no response: CLAG salvage
  • PALG AML1/1999 & PALG AML1/2004, remission: HAM, then HiDAC consolidation

References

  1. PALG AML1/1999: Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, Skotnicki A, Jedrzejczak WW, Konopka L, Kuliczkowski K, Zdziarska B, Dmoszyńska A, Marianska B, Pluta A, Zawilska K, Komarnicki M, Kloczko J, Sulek K, Haus O, Stella-Holowiecka B, Baran W, Jakubas B, Paluszewska M, Wierzbowska A, Kielbinski M, Jagoda K; Polish Adult Leukemia Group. Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia: multicenter, phase III study. Leukemia. 2004 May;18(5):989-97. link to original article contains dosing details in manuscript PubMed
  2. PALG AML1/2004: Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. link to original article contains dosing details in manuscript PubMed

FLAG-Ida

FLAG-Ida: FLudarabine, Ara-C (Cytarabine), G-CSF (Lenograstim), Idarubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2010 (UK MRC AML15) 2002-2006 Phase 3 (C) 1. ADE 10+3+5
2. DA 3+10
3. DA 3+10 & GO
4. FLAG-Ida & GO 		Did not meet primary endpoint of OS1

1While this was a negative trial, a predefined analysis by cytogenetics showed a significant survival benefit for GO in patients with favorable cytogenetics.

Chemotherapy

Growth factor therapy

7-day course

Subsequent treatment

  • See paper for details

References

  1. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed ISRCTN17161961
    1. Update: Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. link to original article PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed

HAA

HAA: Homoharringtonine (Omacetaxine), Ara-C (Cytarabine), Aclarubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jin et al. 2013 2007-2011 Phase 3 (E-esc) 1. DA Superior EFS (co-primary endpoint)
EFS36: 35.4% vs 23.1%
2. HAD Not reported

Note: There were significantly more deaths in this arm, despite a superior primary efficacy endpoint.

Chemotherapy

7-day course

Subsequent treatment

  • Jin et al. 2013, CR: IDAC consolidation x 2

References

  1. Jin J, Wang JX, Chen FF, Wu DP, Hu J, Zhou JF, Hu JD, Wang JM, Li JY, Huang XJ, Ma J, Ji CY, Xu XP, Yu K, Ren HY, Zhou YH, Tong Y, Lou YJ, Ni WM, Tong HY, Wang HF, Mi YC, Du X, Chen BA, Shen Y, Chen Z, Chen SJ. Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2013 Jun;14(7):599-608. Epub 2013 May 9. link to original article contains dosing details in abstract PubMed ChiCTR-TRC-06000054

ICL

ICL: Idarubicin, Cytarabine, Lomustine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pigneux et al. 2017 (LAM-SA 2007) 2008-2011 Phase 3 (E-esc) IA Seems to have superior OS (primary endpoint)
OS24: 56% vs 48%
(HR 0.73, 95% CI 0.54-0.99)

Chemotherapy

7-day course

Subsequent treatment

References

  1. LAM-SA 2007: Pigneux A, Béné MC, Salmi LR, Dumas PY, Delaunay J, Bonmati C, Guièze R, Luquet I, Cornillet-Lefebvre P, Delabesse E, Ianotto JC, Ojeda-Uribe M, Hunault M, Banos A, Fornecker LM, Bernard M, Jourdan E, Vey N, Zerazhi H, Hishri Y, Mineur A, Asselineau J, Delepine R, Cahn JY, Ifrah N, Récher C; French Innovative Leukemia Organization. Improved survival by adding lomustine to conventional chemotherapy for elderly patients with aml without unfavorable cytogenetics: results of the LAM-SA 2007 FILO trial. J Clin Oncol. 2018 36:32, 3203-3210. Epub 2018 Sep 27. link to original article contains dosing details in manuscript PubMed NCT00590837

MEC

MEC: Mitoxantrone, Etoposide, Cytarabine
MICE: MItoxantrone, Cytarabine, Etoposide
MAE: Mitoxantrone, Ara-C (Cytarabine), Etoposide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Amadori et al. 2005 (EORTC/GIMEMA AML-13) 1995-2001 Phase 3 (C) MICE & G-CSF Inferior CR rate
Amadori et al. 2013 (EORTC/GIMEMA AML-17) 2002-2007 Phase 3 (C) GO, then MICE Might have superior OS (primary endpoint)
Median OS: 10 vs 7.1 mo
(HR 0.83, 95% CI 0.69-1.01)

Chemotherapy

7-day course

References

  1. EORTC/GIMEMA AML-13: Amadori S, Suciu S, Jehn U, Stasi R, Thomas X, Marie JP, Muus P, Lefrère F, Berneman Z, Fillet G, Denzlinger C, Willemze R, Leoni P, Leone G, Casini M, Ricciuti F, Vignetti M, Beeldens F, Mandelli F, De Witte T; EORTC; GIMEMA. Use of glycosylated recombinant human G-CSF (lenograstim) during and/or after induction chemotherapy in patients 61 years of age and older with acute myeloid leukemia: final results of AML-13, a randomized phase-3 study. Blood. 2005 Jul 1;106(1):27-34. Epub 2005 Mar 10. link to original article link to PMC article PubMed NCT00002719
    1. Update: Jehn U, Suciu S, Thomas X, Lefrère F, Muus P, Berneman Z, Marie JP, Adamo F, Fillet G, Nobile F, Ricciuti F, Leone G, Rizzoli V, Montanaro M, Beeldens F, Fazi P, Mandelli F, Willemze R, de Witte T, Amadori S. Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial. Leukemia. 2006 Oct;20(10):1723-30. Epub 2006 Aug 17. link to original article PubMed
  2. EORTC/GIMEMA AML-17: Amadori S, Suciu S, Stasi R, Salih HR, Selleslag D, Muus P, De Fabritiis P, Venditti A, Ho AD, Lübbert M, Thomas X, Latagliata R, Halkes CJ, Falzetti F, Magro D, Guimaraes JE, Berneman Z, Specchia G, Karrasch M, Fazi P, Vignetti M, Willemze R, de Witte T, Marie JP. Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17). J Clin Oncol. 2013 Dec 10;31(35):4424-30. Epub 2013 Oct 14. link to original article contains dosing details in manuscript PubMed NCT00052299

Subsequent induction therapy, standard and older "fit" patients

Note: these are aggressive remission induction regimens given with curative intent, as part of a pre-planned protocol of therapy. They are less common in adults in the United States, but are often called "Course 2", "re-induction", or similar in other countries. These are to be distinguished from salvage therapy, which is outlined below.

DA 3+8

DA 3+8: Daunorubicin & Ara-C (Cytarabine), 3 days of daunorubicin + 10 days of cytarabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2015 (UK NCRI AML17everolimus) 2009-2014 Phase 3 (C) DA 3+8 & Everolimus Did not meet primary endpoint of RFS

Note: UK NCRI AML17 can be considered as a platform RCT, and this subtrial is therefore denoted as UK NCRI AML17everolimus.

Biomarker eligibility criteria

  • Non-core-binding factor (CBF) AML, no FLT3 mutation, and not poor risk

Preceding treatment

Chemotherapy

10-day course

Subsequent treatment

References

  1. UK NCRI AML17everolimus: Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 Jun 18;125(25):3878-85. Epub 2015 Apr 1. link to original article contains dosing details in manuscript link to PMC article PubMed ISRCTN55675535
    1. Update: Burnett AK, Das Gupta E, Knapper S, Khwaja A, Sweeney M, Kjeldsen L, Hawkins T, Betteridge SE, Cahalin P, Clark RE, Hills RK, Russell NH; UK NCRI AML Study Group. Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial. Haematologica. 2018 Oct;103(10):1654-1661. Epub 2018 Jul 5. link to original article link to PMC article PubMed

DA 3+8 & GO

DA 3+8 & GO: Daunorubicin, Ara-C (Cytarabine), 3 days of daunorubicin + 8 days of cytarabine, Gemtuzumab Ozogamicin

Regimen

Study Dates of enrollment Evidence
Burnett et al. 2015 (UK NCRI AML17) 2009-2014 Non-randomized part of phase 3 RCT

Biomarker eligibility criteria

  • Core-binding factor (CBF) AML

Preceding treatment

Chemotherapy

Antibody-drug conjugate therapy

8-day course

Subsequent treatment

References

  1. UK NCRI AML17: Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 Jun 18;125(25):3878-85. Epub 2015 Apr 1. link to original article contains dosing details in manuscript link to PMC article PubMed ISRCTN55675535
    1. Update: Burnett AK, Das Gupta E, Knapper S, Khwaja A, Sweeney M, Kjeldsen L, Hawkins T, Betteridge SE, Cahalin P, Clark RE, Hills RK, Russell NH; UK NCRI AML Study Group. Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial. Haematologica. 2018 Oct;103(10):1654-1661. Epub 2018 Jul 5. link to original article link to PMC article PubMed

First-line induction therapy, older or "unfit" patients

Note: these regimens are generally considered to be part of a non-curative line of treatment.

Azacitidine monotherapy

Regimen variant #1, 7 days x 3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Vives et al. 2021 (FLUGAZA) 2014-10 to 2017-10 Phase 3 (E-switch-ooc) FLUGA Superior OS12 (primary endpoint)
OS12: 47% vs 27%

Chemotherapy

28-day cycle for 3 cycles

Subsequent treatment


Regimen variant #2, 7 days x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fenaux et al. 2009 (AZA PH GL 2003) 2003-2007 Phase 3 (E-esc) Investigator's choice of:
1a. Best supportive care
1b. LoDAC
1c. Intensive chemotherapy 		Superior OS (primary endpoint)
Median OS: 24.5 vs 16 mo
(HR 0.47, 95% CI 0.28-0.79)
Dombret et al. 2015 (AZA-AML-001) 2010-2014 Phase 3 (E-esc) Investigator's choice of:
1a. 7+3d; standard-dose
1b. 7+3d; intermediate-dose
1c. 7+3i
1d. Best supportive care
1e. LoDAC 		Might have superior OS (primary endpoint)
Median OS: 10.4 vs 6.5 mo
(HR 0.85, 95% CI 0.69-1.03)
Fenaux et al. 2023 (SGI-110-04) 2015-03-19 to 2016-11-25 Phase 3 (C) Guadecitabine Did not meet co-primary endpoints of CR rate/OS
DiNardo et al. 2020 (VIALE-A) 2017-02-06 to 2019-05-31 Phase 3 (C) Azacitidine & Venetoclax Inferior OS
Awaiting publication (PRAN-16-52) 2017-2020 Phase 3 (C) Azacitidine & Pracinostat TBD if different primary endpoint of OS
Sekeres et al. 2023 (BRIGHT AML 1019) 2018-04 to 2020-01 Phase 3 (C) Azacitidine & Glasdegib Did not meet primary endpoint of OS
Awaiting publication (PEVOLAM) 2019-ongoing Phase 3 (C) Azacitidine & Pevonedistat TBD if different primary endpoint of OS

Note: Patients in AZA PH GL 2003 had 20-30% blasts in the bone marrow.

Chemotherapy

28-day cycle for at least 6 cycles


Regimen variant #2, 5-2-2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (PEVOLAM) 2019-ongoing Phase 3 (C) Azacitidine & Pevonedistat TBD if different primary endpoint of OS

Note: This treatment approach is timed to start on a Monday.

Chemotherapy

28-day cycles

References

  1. AZA PH GL 2003: Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562-9. Epub 2009 Dec 21. link to original article PubMed NCT00071799
  2. AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01074047
    1. Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article PubMed
  3. VIALE-A: DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Döhner H, Letai A, Fenaux P, Koller E, Havelange V, Leber B, Esteve J, Wang J, Pejsa V, Hájek R, Porkka K, Illés Á, Lavie D, Lemoli RM, Yamamoto K, Yoon SS, Jang JH, Yeh SP, Turgut M, Hong WJ, Zhou Y, Potluri J, Pratz KW. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 13;383(7):617-629. link to original article contains dosing details in abstract PubMed NCT02993523
  4. FLUGAZA: Vives S, Martínez-Cuadrón D, Bergua Burgues J, Algarra L, Tormo M, Martínez-Sánchez MP, Serrano J, Herrera P, Ramos F, Salamero O, Lavilla E, López-Lorenzo JL, Gil C, Vidriales B, Falantes JF, Serrano A, Labrador J, Sayas MJ, Foncillas MÁ, Amador Barciela ML, Olave MT, Colorado M, Gascón A, Fernández MÁ, Simiele A, Pérez-Encinas MM, Rodríguez-Veiga R, García O, Martínez-López J, Barragán E, Paiva B, Sanz MÁ, Montesinos P; PETHEMA Group. A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia. Cancer. 2021 Jun 15;127(12):2003-2014. Epub 2021 Feb 24. link to original article contains dosing details in manuscript PubMed NCT02319135
  5. SGI-110-04: Fenaux P, Gobbi M, Kropf PL, Issa JJ, Roboz GJ, Mayer J, Krauter J, Robak T, Kantarjian H, Novak J, Jedrzejczak WW, Thomas X, Ojeda-Uribe M, Miyazaki Y, Min YH, Yeh SP, Brandwein J, Gercheva-Kyuchukova L, Demeter J, Griffiths E, Yee K, Döhner K, Hao Y, Keer H, Azab M, Döhner H. Guadecitabine vs treatment choice in newly diagnosed acute myeloid leukemia: a global phase 3 randomized study. Blood Adv. 2023 Sep 12;7(17):5027-5037. link to original article contains dosing details in manuscript PubMed NCT02348489
  6. BRIGHT AML 1019: Sekeres MA, Montesinos P, Novak J, Wang J, Jeyakumar D, Tomlinson B, Mayer J, Jou E, Robak T, Taussig DC, Dombret H, Merchant A, Shaik N, O'Brien T, Roh W, Liu X, Ma W, DiRienzo CG, Chan G, Cortes JE. Glasdegib plus intensive or non-intensive chemotherapy for untreated acute myeloid leukemia: results from the randomized, phase 3 BRIGHT AML 1019 trial. Leukemia. 2023 Oct;37(10):2017-2026. Epub 2023 Aug 21. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03416179
  7. PEVOLAM: NCT04090736
  8. PRAN-16-52: NCT03151408

Azacitidine & Venetoclax

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
DiNardo et al. 2018 (M14-358) 2014-11-19 to 2015-12-15 Phase 1b, >20 pts (RT)
DiNardo et al. 2020 (VIALE-A) 2017-02-06 to 2019-05-31 Phase 3 (E-RT-esc) Azacitidine Superior OS (primary endpoint)
Median OS: 14.7 vs 9.6 mo
(HR 0.66, 95% CI 0.52-0.85)

Note: Patients with WBC count more than 25 x 109/L at presentation were pre-treated with hydroxyurea or leukapheresis.

Chemotherapy

Targeted therapy

  • Venetoclax (Venclexta) as follows:
    • Cycle 1: 20 mg PO once on day 2, then 50 mg PO once on day 3, then 100 mg PO once on day 4, then 200 mg PO once on day 5, then 400 mg PO once per day on days 6 to 28
    • Cycle 2 onwards: 400 mg PO once per day on days 1 to 28

28-day cycles

References

  1. M14-358: DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 Feb;19(2):216-228. Epub 2018 Jan 12. link to original article contains dosing details in manuscript PubMed NCT02203773 NCT02203773]
    1. Update: DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019 Jan 3;133(1):7-17. Epub 2018 Oct 25. link to original article link to PMC article PubMed
  2. VIALE-A: DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Döhner H, Letai A, Fenaux P, Koller E, Havelange V, Leber B, Esteve J, Wang J, Pejsa V, Hájek R, Porkka K, Illés Á, Lavie D, Lemoli RM, Yamamoto K, Yoon SS, Jang JH, Yeh SP, Turgut M, Hong WJ, Zhou Y, Potluri J, Pratz KW. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 13;383(7):617-629. link to original article contains dosing details in abstract PubMed NCT02993523
  3. ENHANCE-2: NCT04778397

Azacitidine & Gemtuzumab ozogamicin

Study Dates of enrollment Evidence
Nand et al. 2008 2005-08 to 2007-08 Phase 2
Nand et al. 2013 (SWOG S0703) 2008-NR Phase 2

Note: Patients with WBC count more than 10 x 109/L at presentation were pre-treated with Hydrea. Leukapheresis was recommended for patients with WBC count more than x 109/L. Nand et al. 2008 did not describe the maintenance portion of the regimen, and used only SC azacitidine.

Pre-phase

Supportive therapy

Once WBC is less than 10 x 109/L, stop Hydrea and proceed:


Induction

Chemotherapy

Antibody-drug conjugate therapy

Supportive therapy

  • "Appropriate premedications" which were not specified

8-day course

Subsequent treatment

  • SWOG S0703, D14 bone marrow with 5% or more blasts: Azacitidine & GO re-induction identical to the first was administered
  • SWOG S0703, CR or CRi: Azacitidine & GO consolidation, within 60 days

References

  1. Nand S, Godwin J, Smith S, Barton K, Michaelis L, Alkan S, Veerappan R, Rychlik K, Germano E, Stiff P. Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial. Leuk Lymphoma. 2008 Nov;49(11):2141-7. link to original article contains dosing details in manuscript PubMed
  2. SWOG S0703: Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00658814

Clofarabine monotherapy

Regimen variant #1, 20 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2012 (UK NCRI AML16) 2006-2010 Phase 3 (E-switch-ic) LoDAC Did not meet primary endpoint of OS1

1Reported efficacy is based on the 2013 update.

Chemotherapy

4- to 6-week cycle for 4 cycles


Regimen variant #2, 30 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2010 (UWCM-001) 2003-2005 Phase 2
Faderl et al. 2008 (MDACC 2004-0183) 2004-NR Randomized Phase 2 (E-de-esc) Clofarabine & LoDAC Seems to have inferior EFS (secondary endpoint)
Burnett et al. 2010 (BIOV-121) 2004-2005 Phase 2

Chemotherapy

5-day course

Subsequent treatment

References

  1. MDACC 2004-0183: Faderl S, Ravandi F, Huang X, Garcia-Manero G, Ferrajoli A, Estrov Z, Borthakur G, Verstovsek S, Thomas DA, Kwari M, Kantarjian HM. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008 Sep 1;112(5):1638-45. Epub 2008 Jun 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00088218
  2. UWCM-001; BIOV-121: Burnett AK, Russell NH, Kell J, Dennis M, Milligan D, Paolini S, Yin J, Culligan D, Johnston P, Murphy J, McMullin MF, Hunter A, Das-Gupta E, Clark R, Carr R, Hills RK. European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy. J Clin Oncol. 2010 May 10;28(14):2389-95. Epub 2010 Apr 12. link to original article PubMed
  3. UK NCRI AML16: Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. link to original article contains dosing details in manuscript PubMed ISRCTN11036523
    1. Update: Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. link to original article contains dosing details in manuscript PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. link to original article link to PMC article PubMed

Clofarabine & LoDAC

Clofarabine & LoDAC: Clofarabine & Low Dose Ara-C (Cytarabine)

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Faderl et al. 2008 (MDACC 2004-0183) 2004-NR Randomized Phase 2 (E-esc) Clofarabine Seems to have superior EFS (secondary endpoint)

Chemotherapy

  • Clofarabine (Clolar) 30 mg/m2 IV over 60 minutes once per day on days 1 to 5, given first
  • Cytarabine (Ara-C) 20 mg SC once per day on days 1 to 14, given 4 hours after clofarabine on days 1 to 5

28- to 49-day cycle for up to 2 cycles

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence
Faderl et al. 2012 2008-10 to 2010-01 Phase 2

Chemotherapy

10-day course

Subsequent treatment

References

  1. MDACC 2004-0183: Faderl S, Ravandi F, Huang X, Garcia-Manero G, Ferrajoli A, Estrov Z, Borthakur G, Verstovsek S, Thomas DA, Kwari M, Kantarjian HM. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008 Sep 1;112(5):1638-45. Epub 2008 Jun 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00088218
  2. Faderl S, Ravandi F, Huang X, Wang X, Jabbour E, Garcia-Manero G, Kadia T, Ferrajoli A, Konopleva M, Borthakur G, Burger J, Feliu J, Kantarjian HM. Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients. Cancer. 2012 Sep 15;118(18):4471-7. Epub 2012 Jan 26. link to original article link to PMC article PubMed
    1. Update: Kadia TM, Faderl S, Ravandi F, Jabbour E, Garcia-Manero G, Borthakur G, Ferrajoli A, Konopleva M, Burger J, Huang X, Wang X, Pierce S, Brandt M, Feliu J, Cortes J, Kantarjian H. Final results of a phase 2 trial of clofarabine and low-dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia. Cancer. 2015 Jul 15;121(14):2375-82. Epub 2015 Mar 25. link to original article link to PMC article PubMed

CPX-351 monotherapy

CPX-351: Liposomal Cytarabine and Daunorubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lancet et al. 2014 (CLTR0308-204) 2008-11 to 2009-10 Randomized Phase 2 (E-switch-ic) 7+3d; intermediate-dose Might have superior composite CR/CRi rate (primary endpoint)
Lancet et al. 2018 (CLTR0310-301) 2012-12 to 2014-11 Phase 3 (E-RT-switch-ic) 7+3d; intermediate-dose Superior OS1 (primary endpoint)
Median OS: 9.3 vs 6.0 mo
(HR 0.70, 95% CI 0.55-0.91)

1Reported efficacy is based on the 2021 update.

Chemotherapy

  • CPX-351 (Vyxeos) as follows:
    • First induction: 100 units/m2 IV over 90 minutes once per day on days 1, 3, 5
    • Second induction (if needed): 100 units/m2 IV over 90 minutes once per day on days 1 & 3

One or two courses

Subsequent treatment

  • CLTR0310-301, CR/CRi: CPX-351 consolidation

References

  1. CLTR0308-204: Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, Komrokji R, Solomon SR, Kolitz JE, Cooper M, Yeager AM, Louie AC, Feldman EJ. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014 May 22;123(21):3239-46. Epub 2014 Mar 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00788892
  2. CLTR0310-301: Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. link to original article contains dosing details in abstract link to PMC article PubMed NCT01696084
    1. Update: Lancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Faderl S, Cortes JE. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2021 Jul;8(7):e481-e491. link to original article PubMed

Decitabine monotherapy

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Issa et al. 2014 NR Randomized Phase 2 (C) Decitabine & Valproate Did not meet primary endpoint

Chemotherapy

4- to 6-week cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kantarjian et al. 2012 (DACO-016) 2006-2009 Phase 3 (E-esc) Patient's choice of:
1a. LoDAC
1b. Best supportive care 		Might have superior OS (primary endpoint)
Median OS: 7.7 vs 5 mo
(HR 0.85, 95% CI 0.69-1.04)
Kantarjian et al. 2021 (SEAMLESS) 2011-2014 Phase 3 (C) Decitabine/Sapacitabine Did not meet primary endpoint of OS
Montesinos et al. 2020 (JNJ AML2002) 2015-2018 Phase 2/3 (C) Decitabine & Talacotuzumab Did not meet co-primary endpoints of CR/OS
Fenaux et al. 2023 (SGI-110-04) 2015-03-19 to 2016-11-25 Phase 3 (C) Guadecitabine Did not meet co-primary endpoints of CR rate/OS

Chemotherapy

Supportive therapy

28-day cycles


Regimen variant #3

Study Dates of enrollment Evidence
Blum et al. 2010 (OSU 07017) 2007-NR Phase 2
Welch et al. 2016 (Wash U 201210102) 2013-2015 Phase 2

Chemotherapy

Supportive therapy

28-day cycles

Subsequent treatment

  • OSU 07017, persistent AML (5% or more blasts): repeated cycles with 10 days of decitabine as described above
  • OSU 07017, no morphologic evidence of AML (less than 5% blasts): received 5 days of decitabine as described by decitabine maintenance

References

  1. OSU 07017: Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7473-8. Epub 2010 Apr 5. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00492401
  2. DACO-016: Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00260832
    1. Subgroup analysis: Wierzbowska A, Wawrzyniak E, Pluta A, Robak T, Mazur GJ, Dmoszynska A, Cermak J, Oriol A, Lysak D, Arthur C, Doyle M, Xiu L, Ravandi F, Kantarjian HM. Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial. Am J Hematol. 2018 May;93(5):E125-E127. Epub 2018 Feb 24. link to original article PubMed
  3. Issa JP, Garcia-Manero G, Huang X, Cortes J, Ravandi F, Jabbour E, Borthakur G, Brandt M, Pierce S, Kantarjian HM. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015 Feb 15;121(4):556-61. Epub 2014 Oct 21. link to original article contains dosing details in manuscript link to PMC article PubMed
  4. Wash U 201210102: Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, Wilson RK, Baty JD, Duncavage EJ, Tandon D, Lee Y, Wartman LD, Uy GL, Ghobadi A, Tomasson MH, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Cashen AF, Schroeder MA, Jacoby MA, Heath SE, Luber K, Janke MR, Hantel A, Khan N, Sukhanova MJ, Knoebel RW, Stock W, Graubert TA, Walter MJ, Westervelt P, Link DC, DiPersio JF, Ley TJ. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016 Nov 24;375(21):2023-2036. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01687400
  5. JNJ AML-2002: Montesinos P, Roboz GJ, Bulabois CE, Subklewe M, Platzbecker U, Ofran Y, Papayannidis C, Wierzbowska A, Shin HJ, Doronin V, Deneberg S, Yeh SP, Ozcan MA, Knapper S, Cortes J, Pollyea DA, Ossenkoppele G, Giralt S, Döhner H, Heuser M, Xiu L, Singh I, Huang F, Larsen JS, Wei AH. Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. Leukemia. 2021 Jan;35(1):62-74. Epub 2020 Mar 16. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02472145
  6. SEAMLESS: Kantarjian HM, Begna KH, Altman JK, Goldberg SL, Sekeres MA, Strickland SA, Arellano ML, Claxton DF, Baer MR, Gautier M, Berman E, Seiter K, Solomon SR, Schiller GJ, Luger SM, Butrym A, Gaidano G, Thomas XG, Montesinos P, Rizzieri DA, Quick DP, Venugopal P, Gaur R, Maness LJ, Kadia TM, Ravandi F, Buyse ME, Chiao JH. Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS). Cancer. 2021 Dec 1;127(23):4421-4431. Epub 2021 Aug 23. link to original article contains dosing details in abstract link to PMC article PubMed NCT01303796
  7. SGI-110-04: Fenaux P, Gobbi M, Kropf PL, Issa JJ, Roboz GJ, Mayer J, Krauter J, Robak T, Kantarjian H, Novak J, Jedrzejczak WW, Thomas X, Ojeda-Uribe M, Miyazaki Y, Min YH, Yeh SP, Brandwein J, Gercheva-Kyuchukova L, Demeter J, Griffiths E, Yee K, Döhner K, Hao Y, Keer H, Azab M, Döhner H. Guadecitabine vs treatment choice in newly diagnosed acute myeloid leukemia: a global phase 3 randomized study. Blood Adv. 2023 Sep 12;7(17):5027-5037. link to original article contains dosing details in manuscript PubMed NCT02348489

Decitabine & Venetoclax

Regimen variant #1, 5 days of decitabine

Study Dates of enrollment Evidence
DiNardo et al. 2018 (M14-358) 2014-11-19 to 2015-12-15 Phase 1b, >20 pts (RT)

Note: Patients with WBC count more than 25 x 109/L at presentation were pre-treated with hydroxyurea or leukapheresis.

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, 10 days of decitabine

Study Dates of enrollment Evidence
DiNardo et al. 2020 (DEC10-VEN) 2018-2019 Phase 2

Note: Therapy with hydroxyurea or one dose of cytarabine up to 2000 mg/m2 was allowed during cycle 1.

Chemotherapy

Targeted therapy

  • Venetoclax (Venclexta) as follows:
    • Cycle 1: 400 mg PO once per day on days 1 to 28
    • Cycle 2 onwards: 400 mg PO once per day on days 1 to 21

28-day cycles

References

  1. M14-358: DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 Feb;19(2):216-228. Epub 2018 Jan 12. link to original article contains dosing details in manuscript PubMed NCT02203773 NCT02203773]
    1. Update: DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019 Jan 3;133(1):7-17. Epub 2018 Oct 25. link to original article link to PMC article PubMed
  2. DEC10-VEN: DiNardo CD, Maiti A, Rausch CR, Pemmaraju N, Naqvi K, Daver NG, Kadia TM, Borthakur G, Ohanian M, Alvarado Y, Issa GC, Montalban-Bravo G, Short NJ, Yilmaz M, Bose P, Jabbour EJ, Takahashi K, Burger JA, Garcia-Manero G, Jain N, Kornblau SM, Thompson PA, Estrov Z, Masarova L, Sasaki K, Verstovsek S, Ferrajoli A, Wierda WG, Wang SA, Konoplev S, Chen Z, Pierce SA, Ning J, Qiao W, Ravandi F, Andreeff M, Welch JS, Kantarjian HM, Konopleva MY. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet Haematol. 2020 Oct;7(10):e724-e736. Epub 2020 Sep 5. link to original article link to PMC article PubMed NCT03404193

FLAG

FLAG: FLudarabine, Ara-C (Cytarabine), G-CSF
FLUGA: FLUdarabine, G-CSF, Ara-C (Cytarabine)

Regimen variant #1, IV

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Vives et al. 2021 (FLUGAZA) 2014-10 to 2017-10 Phase 3 (C) Azacitidine Inferior OS12

Note: This approach was used for hospitalized patients; filgrastim was not given if WBC count was more than 25 x 109/L.

Chemotherapy

  • Fludarabine (Fludara) by the following age-based criteria:
    • Younger than 75 years old: 25 mg/m2 IV once per day on days 2 to 6
    • 75 years old or older: 25 mg/m2 IV once per day on days 2 to 5
  • Cytarabine (Ara-C) by the following age-based criteria:
    • Younger than 75 years old: 75 mg/m2 IV over 6 hours once per day on days 2 to 6
    • 75 years old or older: 75 mg/m2 IV over 6 hours once per day on days 2 to 5

Growth factor therapy

28-day cycle for 3 cycles

Subsequent treatment

  • FLUGAZA, SD or better: mini-FLUGA consolidation x 6


Regimen variant #2, SC

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Vives et al. 2021 (FLUGAZA) 2014-10 to 2017-10 Phase 3 (C) Azacitidine Inferior OS12

Note: This approach was used for outpatients; filgrastim was not given if WBC count was more than 25 x 109/L.

Chemotherapy

  • Fludarabine (Fludara) by the following age-based criteria:
    • Younger than 75 years old: 40 mg/m2 PO once per day on days 2 to 6
    • 75 years old or older: 40 mg/m2 PO once per day on days 2 to 5
  • Cytarabine (Ara-C) by the following age-based criteria:
    • Younger than 75 years old: 75 mg/m2 SC once per day on days 2 to 6
    • 75 years old or older: 75 mg/m2 SC once per day on days 2 to 5

Growth factor therapy

28-day cycle for 3 cycles

Subsequent treatment

  • FLUGAZA, SD or better: mini-FLUGA consolidation x 6

References

  1. FLUGAZA: Vives S, Martínez-Cuadrón D, Bergua Burgues J, Algarra L, Tormo M, Martínez-Sánchez MP, Serrano J, Herrera P, Ramos F, Salamero O, Lavilla E, López-Lorenzo JL, Gil C, Vidriales B, Falantes JF, Serrano A, Labrador J, Sayas MJ, Foncillas MÁ, Amador Barciela ML, Olave MT, Colorado M, Gascón A, Fernández MÁ, Simiele A, Pérez-Encinas MM, Rodríguez-Veiga R, García O, Martínez-López J, Barragán E, Paiva B, Sanz MÁ, Montesinos P; PETHEMA Group. A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia. Cancer. 2021 Jun 15;127(12):2003-2014. Epub 2021 Feb 24. link to original article contains dosing details in manuscript PubMed NCT02319135

Gemtuzumab ozogamicin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Amadori et al. 2016 (EORTC/GIMEMA AML-19) 2004-2013 Phase 3 (E-RT-esc) Best supportive care Superior OS (primary endpoint)
Median OS: 4.9 vs 3.6 mo
(HR 0.69, 95% CI 0.53-0.90)

Antibody-drug conjugate therapy

8-day course

Subsequent treatment

References

  1. EORTC/GIMEMA AML-19: Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F; EORTC; GIMEMA. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016 Mar 20;34(9):972-9. Epub 2016 Jan 25. link to original article contains dosing details in manuscript PubMed NCT00091234

Glasdegib & LoDAC

Glasdegib & LoDAC: Glasdegib & Low Dose Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2018 (BRIGHT AML 1003) 2014-NR Randomized Phase 2 (E-RT-esc) LoDAC Superior OS1 (primary endpoint)
Median OS: 8.3 vs 4.3 mo
(HR 0.495, 95% CI 0.325-0.75)

1Reported efficacy is based on the 2021 update.

Chemotherapy

Targeted therapy

28-day cycles

References

  1. BRIGHT AML 1003: Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, Pollyea DA, DesJardins P, Ottmann O, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Heuser M. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019 Feb;33(2):379-389. Epub 2018 Dec 16. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01546038
    1. Update: Heuser M, Smith BD, Fiedler W, Sekeres MA, Montesinos P, Leber B, Merchant A, Papayannidis C, Pérez-Simón JA, Hoang CJ, O'Brien T, Ma WW, Zeremski M, O'Connell A, Chan G, Cortes JE. Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial. Ann Hematol. 2021 May;100(5):1181-1194. Epub 2021 Mar 19. Erratum in: Ann Hematol. 2021 Jul;100(7):1917-1918. link to original article link to PMC article PubMed

Low-dose Cytarabine monotherapy (LoDAC)

LoDAC: Low Dose Ara-C (Cytarabine)
LDAC: Low-dose Ara-C (Cytarabine)

Regimen variant #1, 20 mg twice per day, indefinite duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kantarjian et al. 2013 (SPARK-AML1) 2009-2010 Randomized Phase 2 (C) Barasertib & LoDAC Seems to have inferior OCRR
Döhner et al. 2014 (BI 1230.4) 2010-2011 Randomized Phase 2 (C) LoDAC & Volasertib Seems to have inferior OS
Cortes et al. 2018 (BRIGHT AML 1003) 2014-NR Randomized Phase 2 (C) Glasdegib & LoDAC Inferior OS
Fenaux et al. 2023 (SGI-110-04) 2015-03-19 to 2016-11-25 Phase 3 (C) Guadecitabine Did not meet co-primary endpoints of CR rate/OS

Chemotherapy

28-day cycles


Regimen variant #2, 20 mg/m2 twice per day, limited duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2012 (UK NCRI AML16) 2006-2010 Phase 3 (C) Clofarabine Did not meet primary endpoint of OS1
Sekeres et al. 2012 (SG033-0003) 2007-2010 Randomized Phase 2 (C) LoDAC & Lintuzumab Did not meet primary endpoint of OS
Burnett et al. 2015 2010-2012 Randomized (C) Sapacitabine Might have inferior CR rate
Dombret et al. 2015 (AZA-AML-001) 2010-2014 Phase 3 (C) Azacitidine Might have inferior OS
Dennis et al. 2015 (UK NCRI LI-1) 2012-2013 Randomized (C) 1. LDAC & Vosaroxin Did not meet composite primary endpoint of CR/CRi rate
2. Vosaroxin Did not meet composite primary endpoint of CR/CRi rate

1Reported efficacy for UK NCRI AML16 is based on the 2016 update.

Chemotherapy

4- to 6-week cycle for up to 4 cycles


Regimen variant #3, 20 mg/m2 once per day, 10 out of 28 days, indefinite duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kantarjian et al. 2012 (DACO-016) 2006-2009 Phase 3 (C) Decitabine Might have inferior OS
Wei et al. 2020 (VIALE-C) 2017-05 to 2018-11 Phase 3 (C) LoDAC & Venetoclax Seems to have inferior OS1

1Reported efficacy for VIALE-C is based on an unplanned follow-up analysis described in the initial paper.

Chemotherapy

28-day cycles


Regimen variant #4, 20 mg/m2 once per day, 14 out of 28 days, indefinite duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fenaux et al. 2009 (AZA PH GL 2003) 2003-2007 Phase 3 (C) Azacitidine Inferior OS

Chemotherapy

28-day cycle for at least 4 cycles

References

  1. AZA PH GL 2003: Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562-9. Epub 2009 Dec 21. link to original article contains dosing details in manuscript PubMed NCT00071799
  2. DACO-016: Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00260832
    1. Subgroup analysis: Wierzbowska A, Wawrzyniak E, Pluta A, Robak T, Mazur GJ, Dmoszynska A, Cermak J, Oriol A, Lysak D, Arthur C, Doyle M, Xiu L, Ravandi F, Kantarjian HM. Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial. Am J Hematol. 2018 May;93(5):E125-E127. Epub 2018 Feb 24. link to original article PubMed
  3. SG033-0003: Sekeres MA, Lancet JE, Wood BL, Grove LE, Sandalic L, Sievers EL, Jurcic JG. Randomized phase IIb study of low-dose cytarabine and lintuzumab versus low-dose cytarabine and placebo in older adults with untreated acute myeloid leukemia. Haematologica. 2013 Jan;98(1):119-28. Epub 2012 Jul 16. link to original article link to PMC article PubMed NCT00528333
  4. UK NCRI AML16: Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. link to original article contains dosing details in manuscript PubMed ISRCTN11036523
    1. Update: Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. link to original article contains dosing details in manuscript PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. link to original article link to PMC article PubMed
  5. SPARK-AML1: Kantarjian HM, Martinelli G, Jabbour EJ, Quintás-Cardama A, Ando K, Bay JO, Wei A, Gröpper S, Papayannidis C, Owen K, Pike L, Schmitt N, Stockman PK, Giagounidis A; SPARK-AML1 Investigators. Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer. 2013 Jul 15;119(14):2611-9. Epub 2013 Apr 19. link to original article link to PMC article contains dosing details in abstract PubMed NCT00952588
  6. BI 1230.4: Döhner H, Lübbert M, Fiedler W, Fouillard L, Haaland A, Brandwein JM, Lepretre S, Reman O, Turlure P, Ottmann OG, Müller-Tidow C, Krämer A, Raffoux E, Döhner K, Schlenk RF, Voss F, Taube T, Fritsch H, Maertens J. Randomized, phase 2 trial comparing low-dose cytarabine with or without volasertib in AML patients not suitable for intensive induction therapy. Blood. 2014 Aug 28;124(9):1426-33. Epub 2014 Jul 8. link to original article link to PMC article PubMed NCT00804856
  7. Burnett AK, Russell N, Hills RK, Panoskaltsis N, Khwaja A, Hemmaway C, Cahalin P, Clark RE, Milligan D. A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia. Leukemia. 2015 Jun;29(6):1312-9. Epub 2015 Feb 13. link to original article contains dosing details in manuscript PubMed
  8. UK NCRI LI-1: Dennis M, Russell N, Hills RK, Hemmaway C, Panoskaltsis N, McMullin MF, Kjeldsen L, Dignum H, Thomas IF, Clark RE, Milligan D, Burnett AK. Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia. Blood. 2015 May 7;125(19):2923-32. Epub 2015 Mar 24. link to original article contains dosing details in manuscript link to PMC article PubMed ISRCTN40571019
  9. AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01074047
    1. Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article PubMed
  10. BRIGHT AML 1003: Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, Pollyea DA, DesJardins P, Ottmann O, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Heuser M. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019 Feb;33(2):379-389. Epub 2018 Dec 16. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01546038
    1. Update: Heuser M, Smith BD, Fiedler W, Sekeres MA, Montesinos P, Leber B, Merchant A, Papayannidis C, Pérez-Simón JA, Hoang CJ, O'Brien T, Ma WW, Zeremski M, O'Connell A, Chan G, Cortes JE. Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial. Ann Hematol. 2021 May;100(5):1181-1194. Epub 2021 Mar 19. Erratum in: Ann Hematol. 2021 Jul;100(7):1917-1918. link to original article link to PMC article PubMed
  11. VIALE-C: Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, Kim I, Stevens DA, Fiedler W, Pagoni M, Samoilova O, Hu Y, Anagnostopoulos A, Bergeron J, Hou JZ, Murthy V, Yamauchi T, McDonald A, Chyla B, Gopalakrishnan S, Jiang Q, Mendes W, Hayslip J, Panayiotidis P. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020 Jun 11;135(24):2137-2145. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03069352
    1. Update: Wei AH, Panayiotidis P, Montesinos P, Laribi K, Ivanov V, Kim I, Novak J, Stevens DA, Fiedler W, Pagoni M, Bergeron J, Ting SB, Hou JZ, Anagnostopoulos A, McDonald A, Murthy V, Yamauchi T, Wang J, Chyla B, Sun Y, Jiang Q, Mendes W, Hayslip J, DiNardo CD. 6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150). Blood Cancer J. 2021 Oct 1;11(10):163. Erratum in: Blood Cancer J. 2021 Oct 26;11(10):171. link to original article link to PMC article PubMed
  12. SGI-110-04: Fenaux P, Gobbi M, Kropf PL, Issa JJ, Roboz GJ, Mayer J, Krauter J, Robak T, Kantarjian H, Novak J, Jedrzejczak WW, Thomas X, Ojeda-Uribe M, Miyazaki Y, Min YH, Yeh SP, Brandwein J, Gercheva-Kyuchukova L, Demeter J, Griffiths E, Yee K, Döhner K, Hao Y, Keer H, Azab M, Döhner H. Guadecitabine vs treatment choice in newly diagnosed acute myeloid leukemia: a global phase 3 randomized study. Blood Adv. 2023 Sep 12;7(17):5027-5037. link to original article contains dosing details in manuscript PubMed NCT02348489
  13. POLO-AML-2: NCT01721876

LoDAC & Venetoclax

LoDAC & Venetoclax: Low Dose Ara-C (Cytarabine) & Venetoclax

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wei et. al. 2019 (M14-387) 2015-2017 Phase 1b/2 (RT)
Wei et al. 2020 (VIALE-C) 2017-05 to 2018-11 Phase 3 (E-RT-esc) LoDAC Seems to have superior OS1 (primary endpoint)
Median OS: 8.4 vs 4.1 mo
(HR 0.70, 95% CI 0.50-0.99)

1Reported efficacy for VIALE-C is based on the 2021 update.

Chemotherapy

Targeted therapy

  • Venetoclax (Venclexta) as follows:
    • Cycle 1: 100 mg PO once on day 1, then 200 mg PO once on day 2, then 400 mg PO once on day 3, then 600 mg PO once per day on days 4 to 28
    • Cycle 2 onwards: 600 mg PO once per day on days 1 to 28

28-day cycles

Dose and schedule modifications

  • M14-387: The dose of venetoclax was reduced by 50% for moderate CYP3A inhibitors and approximately 75% to 90% for strong inhibitors.

References

  1. M14-387: Wei AH, Strickland SA Jr, Hou JZ, Fiedler W, Lin TL, Walter RB, Enjeti A, Tiong IS, Savona M, Lee S, Chyla B, Popovic R, Salem AH, Agarwal S, Xu T, Fakouhi KM, Humerickhouse R, Hong WJ, Hayslip J, Roboz GJ. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019 May 20;37(15):1277-1284. Epub 2019 Mar 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02287233
  2. VIALE-C: Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, Kim I, Stevens DA, Fiedler W, Pagoni M, Samoilova O, Hu Y, Anagnostopoulos A, Bergeron J, Hou JZ, Murthy V, Yamauchi T, McDonald A, Chyla B, Gopalakrishnan S, Jiang Q, Mendes W, Hayslip J, Panayiotidis P. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020 Jun 11;135(24):2137-2145. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03069352
    1. Update: Wei AH, Panayiotidis P, Montesinos P, Laribi K, Ivanov V, Kim I, Novak J, Stevens DA, Fiedler W, Pagoni M, Bergeron J, Ting SB, Hou JZ, Anagnostopoulos A, McDonald A, Murthy V, Yamauchi T, Wang J, Chyla B, Sun Y, Jiang Q, Mendes W, Hayslip J, DiNardo CD. 6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150). Blood Cancer J. 2021 Oct 1;11(10):163. Erratum in: Blood Cancer J. 2021 Oct 26;11(10):171. link to original article link to PMC article PubMed

Temozolomide monotherapy

Regimen

Study Dates of enrollment Evidence
Brandwein et al. 2014 NR Phase 2

Note: Patient selection was based on MGMT expression by Western blot. See article for details.

Chemotherapy

  • Temozolomide (Temodar) 200 mg/m2/day PO on days 1 to 7
    • Complete responders could receive: 200 mg/m2/day PO on days 1 to 5

28-day cycle for up to 12 cycles

References

  1. Brandwein JM, Kassis J, Leber B, Hogge D, Howson-Jan K, Minden MD, Galarneau A, Pouliot JF. Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high-risk myelodysplastic syndrome patients pre-screened for low O(6) -methylguanine DNA methyltransferase expression. Br J Haematol. 2014 Dec;167(5):664-70. Epub 2014 Aug 27. link to original article contains dosing details in abstract PubMed

Consolidation after upfront therapy

4d + 7

4d + 7: 4 days of daunorubicin + 7 days of cytarabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gardin et al. 2007 (ALFA 9803) 1999-2006 Phase 3 (C) Cytarabine & Daunorubicin x 6 Seems to have inferior OS24

Note: Patients were first randomized to daunorubicin or idarubicin beginning with induction, and continued the same agent in consolidation.

Preceding treatment

Chemotherapy

One course

References

  1. ALFA 9803: Gardin C, Turlure P, Fagot T, Thomas X, Terre C, Contentin N, Raffoux E, de Botton S, Pautas C, Reman O, Bourhis JH, Fenaux P, Castaigne S, Michallet M, Preudhomme C, de Revel T, Bordessoule D, Dombret H. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007 Jun 15;109(12):5129-35. Epub 2007 Mar 6. link to original article contains dosing details in manuscript PubMed NCT00363025

4i + 7

4i + 7: 4 days of idarubicin + 7 days of cytarabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gardin et al. 2007 (ALFA 9803) 1999-2006 Phase 3 (C) Cytarabine & Idarubicin x 6 Seems to have inferior OS24

Note: Patients were first randomized to daunorubicin or idarubicin beginning with induction, and continued the same agent in consolidation.

Preceding treatment

Chemotherapy

One course

References

  1. ALFA 9803: Gardin C, Turlure P, Fagot T, Thomas X, Terre C, Contentin N, Raffoux E, de Botton S, Pautas C, Reman O, Bourhis JH, Fenaux P, Castaigne S, Michallet M, Preudhomme C, de Revel T, Bordessoule D, Dombret H. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007 Jun 15;109(12):5129-35. Epub 2007 Mar 6. link to original article contains dosing details in manuscript PubMed NCT00363025

5+2d

Regimen

Study Dates of enrollment Evidence
Lancet et al. 2018 (CLTR0310-301) 2012-12 to 2014-11 Non-randomized part of phase 3 RCT

Preceding treatment

  • Induction 7+3d; intermediate-dose

Chemotherapy

5-day course

References

  1. CLTR0310-301: Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. link to original article contains dosing details in abstract link to PMC article PubMed NCT01696084

5+2i

Regimen

Study Dates of enrollment Evidence
Cassileth et al. 1998 1990-02 to 1995-02 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

5-day course

Subsequent treatment

References

  1. Cassileth PA, Harrington DP, Appelbaum FR, Lazarus HM, Rowe JM, Paietta E, Willman C, Hurd DD, Bennett JM, Blume KG, Head DR, Wiernik PH. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. 1998 Dec 3;339(23):1649-56. link to original article contains dosing details in manuscript PubMed

High-dose Cytarabine monotherapy (HiDAC)

HiDAC: High Dose Ara-C (Cytarabine)
HDAC: High Dose Ara-C (Cytarabine)
HDAraC: High Dose AraC (Cytarabine)

Regimen variant #1, 2000 mg/m2 every 12 hours x 6

Study Dates of enrollment Evidence
Holowiecki et al. 2012 (PALG AML1/2004) 2004-2008 Non-randomized part of phase 3 RCT

Details in the text are scant.

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 2000 mg/m2 IV every 12 hours on days 1, 3, 5 (total dose: 12,000 mg/m2)

5-day course


Regimen variant #2, 2 cycles of 2000 mg/m2 every 12 hours x 10

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Fukushima et al. 2012 2002-2006 Randomized, fewer than 20 pts in this arm (C) mIDAC Seems to be more toxic

Note: length of cycle was not specified in the manuscript; 28-day cycle is typical for this regimen.

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 2000 mg/m2 IV over 60 minutes every 12 hours on days 1 to 5 (total dose: 20,000 mg/m2)

28-day cycle for 2 cycles

Subsequent treatment


Regimen variant #3, 1 cycle of 3000 mg/m2 every 12 hours x 12

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cassileth et al. 1998 1990-02 to 1995-02 Phase 3 (C) 1a. BuCy, then auto HSCT
1b. BuCy, then allo HSCT 		Seems to have superior OS (co-primary endpoint)

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours every 12 hours on days 1 to 6 (total dose: 36,000 mg/m2)

6-day course


Regimen variant #4, 3 cycles of 3000 mg/m2 every 12 hours x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moore et al. 2004 (CALGB 9222) 1992-1995 Phase 3 (C) HiDAC, then CYVE, then AZQ & Mitoxantrone Did not meet primary endpoint of DFS
Schaich et al. 2013 (AML2003) 2003-2009 Phase 3 (C) MAC/MAMAC/MAC Did not meet primary endpoint of DFS
Petersdorf et al. 2013 (SWOG S0106) 2004-2009 Non-randomized part of phase 3 RCT
Stone et al. 2015 (ACCEDE) 2008-2010 Non-randomized part of phase 3 RCT
Röllig et al. 2015 (SORAML) 2009-2011 Randomized Phase 2 (C) HiDAC & Sorafenib Seems to have inferior EFS
Stone et al. 2015 (COSAH C-022) 2010-2014 Non-randomized part of phase 3 RCT
Bornhäuser et al. 2023 (ETAL-1) 2011-02-02 to 2018-07-01 Phase 3 (C) Allogeneic HSCT Did not meet primary endpoint of OS

Note: CALGB 9222 specified that each cycle begins within 2 weeks after hematopoietic recovery from the preceding cycle. SORAML specified a 28-day (minimum) cycle or 1 week after marrow recovery, whichever comes later.

Eligibility criteria

  • ETAL-1: First CR/CRi, age 18 to 60 years, intermediate-risk AML, available donor

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours every 12 hours on days 1, 3, 5 (total dose per cycle: 18,000 mg/m2)

3 cycles of varying durations

Subsequent treatment


Regimen variant #5, 3 cycles of 2000 mg/m2 every 12 hours x 10

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ohtake et al. 2010 (JALSG AML201) 2001-2005 Phase 3 (E-de-esc) Multiagent chemotherapy Did not meet primary endpoint of DFS

Note: this was considered an experimental arm in Japan, given the timing of HiDAC approval. Reported efficacy is based on the 2010 update by Miyawaki et al.

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on days 1 to 5 (total dose per cycle: 10,000 mg/m2)

3 cycles, started 1 week after neutrophils, WBCs, and platelets recovered to more than 1500/μL, 3 × 109/L, and 100 × 109/L


Regimen variant #6, 4 cycles of 3000 mg/m2 every 12 hours x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mayer et al. 1994 (CALGB 8525) 1985-1990 Phase 3 (E-esc) Low-dose continuous infusion cytarabine Seems to have superior OS
Thomas et al. 2011 (ALFA-9802) 1999-2006 Phase 3 (C) Timed sequential chemotherapy (TSC) Did not meet primary endpoint of EFS
Lee et al. 2017 (COSAH C-022) 2010-2014 Non-randomized part of phase 3 RCT

Note: cycle length of HiDAC is not specified; 28-day cycle is often used in clinical practice. Both arms of CALGB 8525 were experimental.

Preceding treatment

  • ALFA-9802: Timed sequential therapy +/- GM-CSF priming
  • COSAH C-022: Induction 7+3d; high-dose versus 7+3i

Chemotherapy

  • Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours every 12 hours on days 1, 3, 5 (total dose per cycle: 18,000 mg/m2)

28-day cycle for up to 4 cycles

Subsequent treatment

References

  1. CALGB 8525: Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei E 3rd; CALGB. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med. 1994 Oct 6;331(14):896-903. link to original article contains dosing details in manuscript PubMed
  2. Cassileth PA, Harrington DP, Appelbaum FR, Lazarus HM, Rowe JM, Paietta E, Willman C, Hurd DD, Bennett JM, Blume KG, Head DR, Wiernik PH. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. 1998 Dec 3;339(23):1649-56. link to original article contains dosing details in manuscript PubMed
  3. CALGB 9222: Moore JO, George SL, Dodge RK, Amrein PC, Powell BL, Kolitz JE, Baer MR, Davey FR, Bloomfield CD, Larson RA, Schiffer CA. Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222. Blood. 2005 May 1;105(9):3420-7. Epub 2004 Nov 30. link to original article link to PMC article contains dosing details in manuscript PubMed
  4. JALSG AML201: Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 2011 Feb 24;117(8):2358-65. Epub 2010 Aug 6. link to original article PubMed C000000157
    1. Update: Miyawaki S, Ohtake S, Fujisawa S, Kiyoi H, Shinagawa K, Usui N, Sakura T, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R. A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood. 2011 Feb 24;117(8):2366-72. Epub 2010 Dec 29. link to original article contains dosing details in manuscript PubMed
  5. ALFA-9802: Thomas X, Elhamri M, Raffoux E, Renneville A, Pautas C, de Botton S, de Revel T, Reman O, Terré C, Gardin C, Chelghoum Y, Boissel N, Quesnel B, Hicheri Y, Bourhis JH, Fenaux P, Preudhomme C, Michallet M, Castaigne S, Dombret H. Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study. Blood. 2011 Aug 18;118(7):1754-62. Epub 2011 Jun 20. link to original article contains dosing details in manuscript PubMed NCT00880243
  6. Fukushima T, Urasaki Y, Yamaguchi M, Ueda M, Morinaga K, Haba T, Sugiyama T, Nakao S, Origasa H, Umehara H, Ueda T. A randomized comparison of modified intermediate-dose Ara-C versus high-dose ara-c in post-remission therapy for acute myeloid leukemia. Anticancer Res. 2012 Feb;32(2):643-7. link to original article contains dosing details in manuscript PubMed
  7. SWOG S0106: Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. Epub 2013 Apr 16. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00085709
  8. AML2003: Schaich M, Parmentier S, Kramer M, Illmer T, Stölzel F, Röllig C, Thiede C, Hänel M, Schäfer-Eckart K, Aulitzky W, Einsele H, Ho AD, Serve H, Berdel WE, Mayer J, Schmitz N, Krause SW, Neubauer A, Baldus CD, Schetelig J, Bornhäuser M, Ehninger G. High-dose cytarabine consolidation with or without additional amsacrine and mitoxantrone in acute myeloid leukemia: results of the prospective randomized AML2003 trial. J Clin Oncol. 2013 Jun 10;31(17):2094-102. Epub 2013 Apr 29. link to original article contains dosing details in manuscript PubMed NCT00180102
  9. ACCEDE: Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, Wetzler M, Rizzieri D, Erba HP, Damon L, Jang JH, Tallman MS, Warzocha K, Masszi T, Sekeres MA, Egyed M, Horst HA, Selleslag D, Solomon SR, Venugopal P, Lundberg AS, Powell B. Phase III open-label randomized study of cytarabine in combination with amonafide l-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10;33(11):1252-7. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00715637
  10. PALG AML1/2004: Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. link to original article contains dosing details in manuscript PubMed
  11. SORAML: Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Schäfer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghanß C, Repp R, Heits F, Dürk H, Hase J, Klut IM, Illmer T, Bornhäuser M, Schaich M, Parmentier S, Görner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, Ehninger G; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015 Dec;16(16):1691-9. Epub 2015 Nov 6. link to original article contains dosing details in abstract PubMed NCT00893373
  12. COSAH C-022: Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. link to original article contains dosing details in manuscript PubMed NCT01145846
  13. ETAL-1: Bornhäuser M, Schliemann C, Schetelig J, Röllig C, Kramer M, Glass B, Platzbecker U, Burchert A, Hänel M, Müller LP, Klein S, Bug G, Beelen D, Rösler W, Schäfer-Eckart K, Schmid C, Jost E, Lenz G, Tischer J, Spiekermann K, Pfirrmann M, Serve H, Stölzel F, Alakel N, Middeke JM, Thiede C, Ehninger G, Berdel WE, Stelljes M. Allogeneic Hematopoietic Cell Transplantation vs Standard Consolidation Chemotherapy in Patients With Intermediate-Risk Acute Myeloid Leukemia: A Randomized Clinical Trial. JAMA Oncol. 2023 Apr 1;9(4):519-526. link to original article link to PMC article PubMed NCT01246752

Intermediate-dose Cytarabine monotherapy (IDAC)

IDAC: Intermediate Dose Ara-C (Cytarabine)
mIDAC: modified Intermediate Dose Ara-C (Cytarabine)

Regimen variant #1, 1000 mg/m2 x 3

Study Dates of enrollment Evidence
Stone et al. 2015 (ACCEDE) 2008-2010 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 1000 mg/m2 IV over 3 hours once per day on days 1, 3, 5 (total dose per cycle: 3000 mg/m2)

3 cycles (length not specified)


Regimen variant #2, 1000 mg/m2 x 10

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Fukushima et al. 2012 2002-2006 Randomized, fewer than 20 pts in this arm (E-de-esc) HDAC Seems to be less toxic (primary endpoint)

Note: cycle length was not specified; 28-day cycles are frequently used in this setting.

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 1000 mg/m2 IV over 60 minutes every 12 hours on days 1 to 5 (total dose: 10,000 mg/m2)

28-day cycle for 2 cycles (see note)

Subsequent treatment


Regimen variant #3, 1000 mg/m2 x 12

Study Dates of enrollment Evidence
Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01) 2000-2006 Non-randomized part of phase 3 RCT

Preceding treatment

  • Induction 7+3d; standard-dose versus 7+3d; high-dose

Chemotherapy

  • Cytarabine (Ara-C) 1000 mg/m2 IV over 6 hours every 12 hours on days 1 to 6 (total dose: 12,000 mg/m2)

6-day course

Subsequent treatment

References

  1. HOVON 43 AML/SAKK 30/01: Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; HOVON; AMLSG; SAKK. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. link to original article contains dosing details in manuscript PubMed ISRCTN77039377
  2. Fukushima T, Urasaki Y, Yamaguchi M, Ueda M, Morinaga K, Haba T, Sugiyama T, Nakao S, Origasa H, Umehara H, Ueda T. A randomized comparison of modified intermediate-dose Ara-C versus high-dose ara-c in post-remission therapy for acute myeloid leukemia. Anticancer Res. 2012 Feb;32(2):643-7. link to original article contains dosing details in manuscript PubMed
  3. ACCEDE: Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, Wetzler M, Rizzieri D, Erba HP, Damon L, Jang JH, Tallman MS, Warzocha K, Masszi T, Sekeres MA, Egyed M, Horst HA, Selleslag D, Solomon SR, Venugopal P, Lundberg AS, Powell B. Phase III open-label randomized study of cytarabine in combination with amonafide l-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10;33(11):1252-7. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00715637

HiDAC & G-CSF

HiDAC & G-CSF: High Dose Ara-C (Cytarabine) & Granulocyte Colony Stimulating Factor

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thomas et al. 2017 (ALFA-0702) 2009-2013 Randomized Phase 2 (C) CLARA Seems to have inferior RFS

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours every 12 hours on days 1, 3, 5 (total dose per cycle: 18,000 mg/m2)

Growth factor therapy

35-day cycle for 3 cycles

References

  1. ALFA-0702: Thomas X, de Botton S, Chevret S, Caillot D, Raffoux E, Lemasle E, Marolleau JP, Berthon C, Pigneux A, Vey N, Reman O, Simon M, Recher C, Cahn JY, Hermine O, Castaigne S, Celli-Lebras K, Ifrah N, Preudhomme C, Terré C, Dombret H. Randomized phase II study of clofarabine-based consolidation for younger adults with acute myeloid leukemia in first remission. J Clin Oncol. 2017 Apr 10;35(11):1223-1230. Epub 2017 Feb 21. link to original article contains dosing details in supplement PubMed NCT00932412

Azacitidine monotherapy

Regimen

Study Dates of enrollment Evidence
Nand et al. 2013 (SWOG S0703) 2008-NR Phase 2

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

References

  1. SWOG S0703: Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00658814

Azacitidine & Gemtuzumab ozogamicin

Regimen

Study Dates of enrollment Evidence
Nand et al. 2013 (SWOG S0703) 2008-NR Phase 2

Preceding treatment

Chemotherapy

Antibody-drug conjugate therapy

Supportive therapy

  • "Appropriate premedications" which were not specified
  • Growth factors per physician discretion

8-day course

Subsequent treatment

  • Azacitidine maintenance, within 42 days of completion of consolidation

References

  1. SWOG S0703: Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00658814

BuCy, then auto HSCT

BuCy: Busulfan & Cyclophosphamide

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Liu et al. 2023 2016-01 to 2019-02 Phase 3 (C) Ida-BuCy Did not meet primary endpoint of RR

Chemotherapy

Supportive therapy

One course


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Vellenga et al. 2011 (HOVON-SAKK AML-29/AML-42) 1995-2006 Phase 3 (E-esc) Etoposide & Mitoxantrone Did not meet primary endpoint of RFS
RFS60: 38% vs 29%
(HR 0.82, 95% CI 0.66-1.10)

Preceding treatment

Chemotherapy

Supportive therapy

One course

References

  1. HOVON-SAKK AML-29/AML-42: Vellenga E, van Putten W, Ossenkoppele GJ, Verdonck LF, Theobald M, Cornelissen JJ, Huijgens PC, Maertens J, Gratwohl A, Schaafsma R, Schanz U, Graux C, Schouten HC, Ferrant A, Bargetzi M, Fey MF, Löwenberg B; HOVON; SAKK. Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood. 2011 Dec 1;118(23):6037-42. Epub 2011 Sep 27. link to original article contains dosing details in manuscript PubMed
  2. Liu H, Huang F, Zhang Y, Wu M, Xu N, Fan Z, Sun Z, Li X, Lin D, Xiong Y, Liu X, Lin R, Shi P, Xu J, Wang Z, Li X, Sun J, Liu Q, Xuan L. Idarubicin plus BuCy versus BuCy conditioning regimens for intermediate-risk acute myeloid leukemia in first complete remission undergoing auto-HSCT: An open-label, multicenter, randomized phase 3 trial. Am J Hematol. 2023 Mar;98(3):408-412. Epub 2023 Jan 1. link to original article PubMed NCT02671708

Busulfan & Fludarabine, then allo HSCT

BuFlu: Busulfan & Fludarabine

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Devine et al. 2015 (CALGB 100103) 2004-2011 Phase 2, fewer than 20 pts in subgroup
Nand et al. 2013 (SWOG S0703) 2008-NR Phase 2
Beelen et al. 2019 (MC-FludT.14/L) 2013-2016 Phase 3 (C) Fludarabine & Treosulfan Non-inferior EFS24

Chemotherapy

  • Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days -7 to -3
    • MC-FludT.14/L gave the doses on days -6 to -2
  • Busulfan (Myleran) 0.8 mg/kg IV over 2 hours every 6 hours on days -4 & -3 (total dose: 6.4 mg/kg)

Immunotherapy

GVHD prophylaxis

  • ATG (Rabbit) 2.5 mg/kg IV over 6 hours once per day on days -4 to -2
  • Tacrolimus (Prograf) with doses adjusted to maintain levels of 5 to 10 ng/mL, tapered on day +90 to off by day +180 (if no GVHD)
  • Methotrexate (MTX) 5 mg/m2 IV once per day on days +1, +3, +6, +11

One course

References

  1. SWOG S0703: Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. link to original article link to PMC article PubMed NCT00658814
  2. CALGB 100103: Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. Epub 2015 Nov 2. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00070135
  3. BMT CTN 0901: Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, Maziarz RT, Warlick ED, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt S, Geller NL, Leifer E, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-1161. Epub 2017 Feb 13. link to original article link to PMC article PubMed NCT01339910
  4. MC-FludT.14/L: Beelen DW, Trenschel R, Stelljes M, Groth C, Masszi T, Reményi P, Wagner-Drouet EM, Hauptrock B, Dreger P, Luft T, Bethge W, Vogel W, Ciceri F, Peccatori J, Stölzel F, Schetelig J, Junghanß C, Grosse-Thie C, Michallet M, Labussiere-Wallet H, Schaefer-Eckart K, Dressler S, Grigoleit GU, Mielke S, Scheid C, Holtick U, Patriarca F, Medeot M, Rambaldi A, Micò MC, Niederwieser D, Franke GN, Hilgendorf I, Winkelmann NR, Russo D, Socié G, Peffault de Latour R, Holler E, Wolff D, Glass B, Casper J, Wulf G, Menzel H, Basara N, Bieniaszewska M, Stuhler G, Verbeek M, Grass S, Iori AP, Finke J, Benedetti F, Pichlmeier U, Hemmelmann C, Tribanek M, Klein A, Mylius HA, Baumgart J, Dzierzak-Mietla M, Markiewicz M. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet Haematol. 2020 Jan;7(1):e28-e39. Epub 2019 Oct 9. link to original article contains dosing details in abstract PubMed NCT00822393
  5. MDACC 2011-0628: Andersson BS, Thall PF, Ma J, Valdez BC, Bassett R Jr, Chen J, Ahmed S, Alousi A, Bashir Q, Ciurea S, Gulbis A, Cool R, Kawedia J, Hosing C, Kebriaei P, Kornblau S, Myers A, Oran B, Rezvani K, Shah N, Shpall E, Parmar S, Popat UR, Nieto Y, Champlin RE. A randomized phase III study of pretransplant conditioning for AML/MDS with fludarabine and once daily IV busulfan ± clofarabine in allogeneic stem cell transplantation. Bone Marrow Transplant. 2022 Aug;57(8):1295-1303. Epub 2022 May 24. link to original article link to PMC article PubMed NCT01471444

CIA

CIA: Clofarabine, Idarubicin, Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence
Nazha et al. 2013 2010-2012 Phase 2

Preceding treatment

Chemotherapy

21- to 28-day cycle for up to 6 cycles; exact timing depends on disease response and recovery from regimen toxicity

References

  1. Nazha A, Kantarjian H, Ravandi F, Huang X, Choi S, Garcia-Manero G, Jabbour E, Borthakur G, Kadia T, Konopleva M, Cortes J, Ferrajoli A, Kornblau S, Daver N, Pemmaraju N, Andreeff M, Estrov Z, Du M, Brandt M, Faderl S. Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia. Am J Hematol. 2013 Nov;88(11):961-6. Epub 2013 Sep 9. [ https://doi.org/10.1002/ajh.23544 long link to original article] contains dosing details in manuscript link to PMC article PubMed

CLARA

CLARA: CLofarabine and ARA-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thomas et al. 2017 (ALFA-0702) 2009-2013 Randomized Phase 2 (E-esc) HiDAC & G-CSF Seems to have superior RFS (primary endpoint)
RFS24: 58.5% vs 46.5%
(aHR 0.65, 95% CI 0.43-0.98)

Preceding treatment

Chemotherapy

  • Clofarabine (Clolar) 30 mg/m2 IV over 2 hours once per day on days 2 to 6, given first
  • Cytarabine (Ara-C) 1000 mg/m2 IV over 2 hours once per day on days 1 to 5, given second, 4 hours after clofarabine, on days 2 to 5

Growth factor therapy

35-day cycle for 3 cycles

References

  1. ALFA-0702: Thomas X, de Botton S, Chevret S, Caillot D, Raffoux E, Lemasle E, Marolleau JP, Berthon C, Pigneux A, Vey N, Reman O, Simon M, Recher C, Cahn JY, Hermine O, Castaigne S, Celli-Lebras K, Ifrah N, Preudhomme C, Terré C, Dombret H. Randomized phase II study of clofarabine-based consolidation for younger adults with acute myeloid leukemia in first remission. J Clin Oncol. 2017 Apr 10;35(11):1223-1230. Epub 2017 Feb 21. link to original article contains dosing details in supplement PubMed NCT00932412

Clofarabine & LoDAC/Decitabine

Clofarabine & LoDAC/Decitabine: Clofarabine & Low Dose Ara-C (Cytarabine) alternating with Decitabine

Regimen

Study Dates of enrollment Evidence
Faderl et al. 2012 2008-10 to 2010-01 Phase 2

Preceding treatment

  • Induction Clofarabine & LoDAC, which is counted as "Cycle 1". Cycles are given every 4 to 7 weeks pending hematologic recovery and resolution of other toxicities.

Chemotherapy, clofarabine & LoDAC portion (cycles 2, 3, 7 to 9, 13 to 15)

Chemotherapy, decitabine portion (cycles 4 to 6, 10 to 12, 16 to 18)

4- to 7-week cycle for 18 cycles, interval depending on count recovery

References

  1. Faderl S, Ravandi F, Huang X, Wang X, Jabbour E, Garcia-Manero G, Kadia T, Ferrajoli A, Konopleva M, Borthakur G, Burger J, Feliu J, Kantarjian HM. Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients. Cancer. 2012 Sep 15;118(18):4471-7. Epub 2012 Jan 26. link to original article contains dosing details in manuscript link to PMC article PubMed
    1. Update: Kadia TM, Faderl S, Ravandi F, Jabbour E, Garcia-Manero G, Borthakur G, Ferrajoli A, Konopleva M, Burger J, Huang X, Wang X, Pierce S, Brandt M, Feliu J, Cortes J, Kantarjian H. Final results of a phase 2 trial of clofarabine and low-dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia. Cancer. 2015 Jul 15;121(14):2375-82. Epub 2015 Mar 25. link to original article link to PMC article PubMed

CPX-351 monotherapy

CPX-351: Liposomal Cytarabine and Daunorubicin

Regimen

Study Dates of enrollment Evidence
Lancet et al. 2018 (CLTR0310-301) 2012-12 to 2014-11 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

5- to 8-week cycle for 2 cycles

References

  1. CLTR0310-301: Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. link to original article contains dosing details in abstract link to PMC article PubMed NCT01696084

Cytarabine & Daunorubicin

Regimen variant #1

Study Dates of enrollment Evidence
Castaigne et al. 2012 (ALFA-0701) 2008-2010 Non-randomized part of phase 3 RCT

Note: the preceding treatment is not a true randomization because only patients in the gemtuzumab ozogamicin arm with platelet count less than 100 x 109 at day 45 from initiation of chemotherapy were assigned to this regimen.

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 1000 mg/m2 IV every 12 hours on days 1 to 4 (total dose per cycle: 8000 mg/m2)
  • Daunorubicin (Cerubidine) as follows:
    • Cycle 1: 60 mg/m2 IV once on day 1
    • Cycle 2: 60 mg/m2 IV once per day on days 1 & 2

2 cycles (length not specified)


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gardin et al. 2007 (ALFA 9803) 1999-2006 Phase 3 (E-esc) 4d + 7 Seems to have superior OS24 (primary endpoint)

Preceding treatment

Chemotherapy

1-month cycle for up to 6 cycles

References

  1. ALFA 9803: Gardin C, Turlure P, Fagot T, Thomas X, Terre C, Contentin N, Raffoux E, de Botton S, Pautas C, Reman O, Bourhis JH, Fenaux P, Castaigne S, Michallet M, Preudhomme C, de Revel T, Bordessoule D, Dombret H. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007 Jun 15;109(12):5129-35. Epub 2007 Mar 6. link to original article contains dosing details in manuscript PubMed NCT00363025
  2. ALFA-0701: Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. Epub 2012 Apr 5. link to original article contains dosing details in manuscript PubMed NCT00927498
    1. Update: Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. link to original article link to PMC article PubMed

Cytarabine, Daunorubicin, Gemtuzumab ozogamicin

Regimen

Study Dates of enrollment Evidence
Castaigne et al. 2012 (ALFA-0701) 2008-2010 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 1000 mg/m2 IV every 12 hours on days 1 to 4 (total dose per cycle: 8000 mg/m2)
  • Daunorubicin (Cerubidine) as follows:
    • Cycle 1: 60 mg/m2 IV once on day 1
    • Cycle 2: 60 mg/m2 IV once per day on days 1 & 2

Antibody-drug conjugate therapy

2 cycles (length not specified)

References

  1. ALFA-0701: Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. Epub 2012 Apr 5. link to original article contains dosing details in manuscript PubMed NCT00927498
    1. Update: Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. Epub 2018 Aug 3. link to original article link to PMC article PubMed

Cytarabine & Etoposide (CYVE)

CYVE: CYtarabine & VEpesid (Etoposide)

Regimen

Study Dates of enrollment Evidence
Lee et al. 2017 (COSAH C-022) 2010-2014 Non-randomized part of phase 3 RCT

Note: this consolidation regimen was for patients with high-risk cytogenetics.

Preceding treatment

Chemotherapy

4 courses

Subsequent treatment

  • COSAH C-022, transplant eligible patients with available donors: usually proceeded to allogeneic HSCT consolidation after 2 courses (details not specified)

References

  1. COSAH C-022: Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. link to original article contains dosing details in manuscript PubMed NCT01145846

Cytarabine & Idarubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gardin et al. 2007 (ALFA 9803) 1999-2006 Phase 3 (E-esc) 4i + 7 Seems to have superior OS24 (primary endpoint)

Preceding treatment

Chemotherapy

1-month cycle for up to 6 cycles

References

  1. ALFA 9803: Gardin C, Turlure P, Fagot T, Thomas X, Terre C, Contentin N, Raffoux E, de Botton S, Pautas C, Reman O, Bourhis JH, Fenaux P, Castaigne S, Michallet M, Preudhomme C, de Revel T, Bordessoule D, Dombret H. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007 Jun 15;109(12):5129-35. Epub 2007 Mar 6. link to original article contains dosing details in manuscript PubMed NCT00363025

Cytarabine, Idarubicin, Sorafenib

Regimen

Study Dates of enrollment Evidence
Ravandi et al. 2010 (BAY43-9006) 2007-2009 Phase 1/2

Regimen details are from the phase 2 part of the published phase 1/2 trial.

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 750 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 2250 mg/m2)
  • Idarubicin (Idamycin) 8 mg/m2 IV over 60 minutes once per day on days 1 & 2

Targeted therapy

4- to 6-week cycle for up to 5 cycles

Subsequent treatment

References

  1. BAY43-9006: Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce SR, Brandt M, Byrd A, Bekele BN, Pratz K, Luthra R, Levis M, Andreeff M, Kantarjian HM. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010 Apr 10;28(11):1856-62. Epub 2010 Mar 8. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00542971
    1. Update: Ravandi F, Arana Yi C, Cortes JE, Levis M, Faderl S, Garcia-Manero G, Jabbour E, Konopleva M, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce S, Brandt M, Pratz K, Luthra R, Andreeff M, Kantarjian H. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014 Jul;28(7):1543-5. Epub 2014 Feb 3. link to original article link to PMC article PubMed

Cyclophosphamide & TBI, then allo HSCT

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Non-relapse mortality
Blume et al. 1980 1976-1979 Non-randomized, fewer than 20 pts
Zittoun et al. 1995 1986-1993 Phase 3 (E-esc) Intensive chemotherapy Superior DFS
Bornhäuser et al. 2012 (9005-2003) 2004-2009 Phase 3 (C) Fludarabine & TBI, then allo HSCT Did not meet secondary efficacy endpoints Did not meet primary endpoint of NRM

Preceding treatment

Details in most of the manuscripts are limited.

Chemotherapy

Radiotherapy

  • Total body irradiation by the following study-specific criteria:
    • Zhang et al. 2023: 450 cGy once per day on days -5 & -4 (900 cGy total)
    • Other studies: 10 to 1200 cGy total

Immunotherapy

One course

References

  1. Blume KG, Beutler E, Bross KJ, Chillar RK, Ellington OB, Fahey JL, Farbstein MJ, Forman SJ, Schmidt GM, Scott EP, Spruce WE, Turner MA, Wolf JL. Bone-marrow ablation and allogeneic marrow transplantation in acute leukemia. N Engl J Med. 1980 May 8;302(19):1041-6. link to original article PubMed
  2. Zittoun RA, Mandelli F, Willemze R, de Witte T, Labar B, Resegotti L, Leoni F, Damasio E, Visani G, Papa G, Caronia F, Hayat M, Stryckmans P, Rotoli B, Leoni P, Peetermans ME, Dardenne M, Vegna ML, Petti MC, Solbu G, Suciu S; EORTC; GIMEMA. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 1995 Jan 26;332(4):217-23. link to original article contains dosing details in abstract PubMed
  3. 9005-2003: Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. Epub 2012 Sep 7. link to original article contains dosing details in abstract PubMed NCT00150878
  4. Retrospective: Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, Aljurf M, van Besien K, Bredeson C, Cahn JY, Costa LJ, de Lima M, Gale RP, Hale GA, Halter J, Hamadani M, Inamoto Y, Kamble RT, Litzow MR, Loren AW, Marks DI, Olavarria E, Roy V, Sabloff M, Savani BN, Seftel M, Schouten HC, Ustun C, Waller EK, Weisdorf DJ, Wirk B, Horowitz MM, Arora M, Szer J, Cortes J, Kalaycio ME, Maziarz RT, Saber W. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013 Dec 5;122(24):3863-70. Epub 2013 Sep 24. link to original article link to PMC article PubMed
  5. SWOG S9920: NCT00005866

Etoposide & Mitoxantrone

ME: Mitoxantrone & Etoposide

Regimen variant #1, 3 days

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (AMLSG31-19) 2021-ongoing Phase 3 (C) ME & Venetoclax In progress

Note: this dosing was intended for patients older than 60. Dosing information is from CT.gov.

Preceding treatment

Chemotherapy

One course


Regimen variant #2, 5 days

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Vellenga et al. 2011 (HOVON-SAKK AML-29/AML-42) 1995-2006 Phase 3 (C) Bu/Cy, then auto HSCT Did not meet primary endpoint of RFS

Preceding treatment

Chemotherapy

One course

References

  1. HOVON-SAKK AML-29/AML-42: Vellenga E, van Putten W, Ossenkoppele GJ, Verdonck LF, Theobald M, Cornelissen JJ, Huijgens PC, Maertens J, Gratwohl A, Schaafsma R, Schanz U, Graux C, Schouten HC, Ferrant A, Bargetzi M, Fey MF, Löwenberg B; HOVON; SAKK. Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood. 2011 Dec 1;118(23):6037-42. Epub 2011 Sep 27. link to original article contains dosing details in manuscript PubMed
  2. AMLSG31-19: NCT04628026

Fludarabine & TBI, then allo HSCT

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy Non-relapse mortality
Bornhäuser et al. 2012 (9005-2003) 2004-2009 Phase 3 (E-switch-ic) Cyclophosphamide & TBI, then allo HSCT Did not meet secondary efficacy endpoints Did not meet primary endpoint of NRM

Chemotherapy

Radiotherapy

Immunotherapy

One course


Regimen variant #2, low-dose TBI

Study Dates of enrollment Evidence
Gyukocza et al. 2010 1998-2008 Non-randomized

Chemotherapy

Radiotherapy

Immunotherapy

GVHD prophylaxis

  • Cyclosporine 6.25 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 100 over 80 days (if no GVHD)
  • Mycophenolate mofetil (CellCept) 15 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 40 over 56 days (if no GVHD)

One course

References

  1. Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010 Jun 10;28(17):2859-67. Epub 2010 May 3. link to original article contains dosing details in manuscript link to PMC article PubMed
  2. 9005-2003: Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. Epub 2012 Sep 7. link to original article contains dosing details in abstract PubMed NCT00150878

HAM

HAM: High-dose Ara-C (Cytarabine), Mitoxantrone

Regimen

Study Dates of enrollment Evidence
Wierzbowska et al. 2007 2002-11 to 2006-11 Phase 2
Holowiecki et al. 2012 (PALG AML1/2004) 2004-2008 Non-randomized part of phase 3 RCT

Preceding treatment

  • Wierzbowska et al. 2007: Induction CLAG-M
  • PALG AML1/2004: Induction DA versus DAC versus DAF

Chemotherapy

Subsequent treatment

References

  1. Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Holowiecki J, Kyrcz-Krzemien S, Grosicki S, Giebel S, Skotnicki AB, Piatkowska-Jakubas B, Kuliczkowski K, Kielbinski M, Zawilska K, Kloczko J, Wrzesień-Kuś A; Polish Adult Leukemia Group. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008 Feb;80(2):115-26. Epub 2007 Dec 11. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
  2. PALG AML1/2004: Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. link to original article contains dosing details in manuscript PubMed

IC & Norethandrolone/6-MP, MTX, Norethandrolone

IC & Norethandrolone/6-MP, MTX, Norethandrolone: Idarubicin, Cytarabine, Norethandrolone alternating with 6-MP, MTX, Norethandrolone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pigneux et al. 2016 (GOELAMS LAM-SA2002) 2002-2005 Phase 3 (E-esc) IC/6-MP & MTX Superior OS (secondary endpoint)
OS60: 26.3% vs 17.2%

Preceding treatment

Chemotherapy, reinduction portion (cycles 1, 3, 5)

Endocrine therapy, reinduction portion (cycles 1, 3, 5)

  • Norethandrolone (Nilevar) by the following weight-based criteria:
    • Less than 60 kg: 10 mg PO once per day
    • More than 60 kg: 20 mg PO once per day

Chemotherapy, maintenance portion (cycles 2, 4, 6)

  • Methotrexate (MTX) by the following weight-based criteria:
    • Less than 60 kg: 20 mg PO once per day on days 1, 4, 8, 11
    • More than 60 kg: 25 mg PO once per day on days 1, 4, 8, 11
  • Mercaptopurine (6-MP) by the following weight-based criteria:
    • Less than 60 kg: 100 mg PO once per day on days 15 to 30
    • More than 60 kg: 150 mg PO once per day on days 15 to 30

Endocrine therapy, maintenance portion (cycles 2, 4, 6)

  • Norethandrolone (Nilevar) by the following weight-based criteria:
    • Less than 60 kg: 10 mg PO once per day
    • More than 60 kg: 20 mg PO once per day

3-month cycle for 6 cycles

References

  1. GOELAMS LAM-SA2002: Pigneux A, Béné MC, Guardiola P, Recher C, Hamel JF, Sauvezie M, Harousseau JL, Tournilhac O, Witz F, Berthou C, Escoffre-Barbe M, Guyotat D, Fegueux N, Himberlin C, Hunault M, Delain M, Lioure B, Jourdan E, Bauduer F, Dreyfus F, Cahn JY, Sotto JJ, Ifrah N. Addition of androgens improves survival in elderly patients with acute myeloid leukemia: a GOELAMS study. J Clin Oncol. 2017 Feb;35(4):387-393. Epub 2016 Oct 24. link to original article contains dosing details in manuscript PubMed NCT00700544

Low-dose TBI, then allo HSCT

TBI: Total Body Irradiation

Regimen

Study Dates of enrollment Evidence
Gyukocza et al. 2010 1998-2008 Non-randomized

Radiotherapy

Immunotherapy

GVHD prophylaxis

One course

References

  1. Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010 Jun 10;28(17):2859-67. Epub 2010 May 3. link to original article contains dosing details in manuscript link to PMC article PubMed

Maintenance after first-line therapy

Note: with a few exceptions, these regimens are given as part of a non-curative line of therapy.

Azacitidine monotherapy

Regimen variant #1, 12 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Huls et al. 2019 (HOVON97) 2009-2016 Phase 3 (E-esc) Observation Superior DFS (primary endpoint)
DFS12: 64% vs 42%
(aHR 0.62, 95% CI 0.41-0.95)

Preceding treatment

Chemotherapy

28-day cycle for up to 12 cycles


Regimen variant #2, indefinite

Study Dates of enrollment Evidence
Grövdal et al. 2010 2004-2006 Phase 2

Intended to be used for transformed MDS patients in remission after AML induction therapy.

Preceding treatment

Chemotherapy

28-day cycles

References

  1. Grövdal M, Karimi M, Khan R, Aggerholm A, Antunovic P, Astermark J, Bernell P, Engström LM, Kjeldsen L, Linder O, Nilsson L, Olsson A, Holm MS, Tangen JM, Wallvik J, Oberg G, Hokland P, Jacobsen SE, Porwit A, Hellström-Lindberg E. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol. 2010 Aug;150(3):293-302. Epub 2010 May 20. link to original article contains dosing details in manuscript PubMed
  2. HOVON97: Huls G, Chitu DA, Havelange V, Jongen-Lavrencic M, van de Loosdrecht AA, Biemond BJ, Sinnige H, Hodossy B, Graux C, Kooy RVM, de Weerdt O, Breems D, Klein S, Kuball J, Deeren D, Terpstra W, Vekemans MC, Ossenkoppele GJ, Vellenga E, Löwenberg B; Dutch-Belgian Hemato-Oncology Cooperative Group. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients. Blood. 2019 Mar 28;133(13):1457-1464. Epub 2019 Jan 10. link to original article contains dosing details in abstract PubMed NTR1810

Decitabine monotherapy

Regimen

Study Dates of enrollment Evidence
Blum et al. 2010 (OSU 07017) 2007-NR Phase 2

Blum et al. 2010 did not clearly state whether decitabine maintenance is at the same dosage/frequency as induction therapy. This is the inferred dosage from the paper.

Preceding treatment

Chemotherapy

28-day cycles

Dose and schedule modifications

  • Patients with no evidence of residual disease by flow cytometry or cytogenetics who had grade 4 neutropenia (ANC less than 500/μL) persisting greater than or equal to 14 days received 4 days instead of 5 days of decitabine starting with the following cycle. If neutropenia occurred again as above with 4 days of decitabine, patients received 3 days instead of 4 days of decitabine starting with the following cycle.

References

  1. OSU 07017: Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7473-8. Epub 2010 Apr 5. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00492401

Azacitidine oral monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wei et al. 2020 (QUAZAR AML-001) 2013-2017 Phase 3 (E-RT-esc) Observation Superior OS1 (primary endpoint)
Median OS: 24.7 vs 14.8 mo

1The proportional hazards assumption was violated, so hazard ratios are not reported.

Preceding treatment

Chemotherapy

28-day cycle

References

  1. QUAZAR AML-001: Wei AH, Döhner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, Ravandi F, Sayar H, Jang JH, Porkka K, Selleslag D, Sandhu I, Turgut M, Giai V, Ofran Y, Kizil Çakar M, Botelho de Sousa A, Rybka J, Frairia C, Borin L, Beltrami G, Čermák J, Ossenkoppele GJ, La Torre I, Skikne B, Kumar K, Dong Q, Beach CL, Roboz GJ; QUAZAR AML-001 Trial Investigators. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med. 2020 Dec 24;383(26):2526-2537. link to original article contains dosing details in abstract PubMed NCT01757535

Gemtuzumab ozogamicin monotherapy

Regimen

Study Dates of enrollment Evidence
Amadori et al. 2016 (EORTC/GIMEMA AML-19) 2004-2013 Non-randomized part of phase 3 RCT

Preceding treatment

Antibody-drug conjugate therapy

1-month cycle for up to 8 cycles

References

  1. EORTC/GIMEMA AML-19: Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F; EORTC; GIMEMA. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016 Mar 20;34(9):972-9. Epub 2016 Jan 25. link to original article contains dosing details in manuscript PubMed NCT00091234

Low-dose Cytarabine monotherapy (LoDAC)

LoDAC: Low Dose Ara-C (cytarabine)
LDAC: Low Dose Ara-C (cytarabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robles et al. 2000 (ECOG E5483) 1984-1988 Phase 3 (E-esc) Observation Might have superior DFS

Preceding treatment

Chemotherapy

8-week cycles

References

  1. ECOG E5483: Robles C, Kim KM, Oken MM, Bennett JM, Letendre L, Wiernik PH, O'Connell MJ, Cassileth PA. Low-dose cytarabine maintenance therapy vs observation after remission induction in advanced acute myeloid leukemia: an Eastern Cooperative Oncology Group Trial (E5483). Leukemia. 2000 Aug;14(8):1349-53. link to original article contains dosing details in abstract PubMed

Sorafenib monotherapy

Regimen

Study Dates of enrollment Evidence
Ravandi et al. 2010 (BAY43-9006) 2007-2009 Phase 1/2

Preceding treatment

Targeted therapy

Up to one year course, including consolidation

References

  1. BAY43-9006: Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce SR, Brandt M, Byrd A, Bekele BN, Pratz K, Luthra R, Levis M, Andreeff M, Kantarjian HM. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010 Apr 10;28(11):1856-62. Epub 2010 Mar 8. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00542971
    1. Update: Ravandi F, Arana Yi C, Cortes JE, Levis M, Faderl S, Garcia-Manero G, Jabbour E, Konopleva M, O'Brien S, Estrov Z, Borthakur G, Thomas D, Pierce S, Brandt M, Pratz K, Luthra R, Andreeff M, Kantarjian H. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014 Jul;28(7):1543-5. Epub 2014 Feb 3. link to original article link to PMC article PubMed

Relapsed or refractory, salvage therapy

Note: these are generally aggressive regimens intended to induce a second remission as part of a path towards pre-planned allogeneic HSCT.

5+2d

Regimen

Study Dates of enrollment Evidence
Zeidner et al. 2015 (JHOC-J1101) 2011-2013 Non-randomized part of phase 2 RCT

Preceding treatment

  • Induction 7+3d; high-dose

Chemotherapy

5-day course

References

  1. JHOC-J1101: Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, Lancet JE, Bose P, Levy MY, Tibes R, Gojo I, Gocke CD, Rosner GL, Little RF, Wright JJ, Doyle LA, Smith BD, Karp JE. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015 Sep;100(9):1172-9. Epub 2015 May 28. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01349972

ADE (standard-dose Ara-C)

ADE: Ara-C (Cytarabine), Daunorubicin, Etoposide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Milligan et al. 2006 (MRC AML-HR) 1998-12 to 2003-12 Phase 3 (C) FLA Seems to have superior OS (primary endpoint)
OS48: 27% vs 16%
(HR 0.75, 95% CI 0.56-0.99)

Chemotherapy

  • Cytarabine (Ara-C) as follows:
    • Course 1: 100 mg/m2 IV push every 12 hours on days 1 to 10 (total dose: 2000 mg/m2)
    • Course 2: 100 mg/m2 IV push every 12 hours on days 1 to 8 (total dose: 1600 mg/m2)
  • Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1, 3, 5
  • Etoposide (Vepesid) 100 mg/m2 IV over 60 minutes once per day on days 1 to 5

2 courses (length not specified)

References

  1. MRC AML-HR: Milligan DW, Wheatley K, Littlewood T, Craig JI, Burnett AK; NCRI Haematological Oncology Clinical Studies Group. Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood. 2006 Jun 15;107(12):4614-22. Epub 2006 Feb 16. link to original article PubMed NCT00005863

CLAG

CLAG: CLadribine, Ara-C (Cytarabine), G-CSF

Regimen

Study Dates of enrollment Evidence
Robak et al. 2000 1998-02 to 1999-09 Phase 2

Chemotherapy

  • Cladribine (Leustatin) 5 mg/m2 IV over 2 hours once per day on days 1 to 5, given first
  • Cytarabine (Ara-C) 2000 mg/m2 IV over 4 hours once per day on days 1 to 5, given second, 2 hours after cladribine

Growth factor therapy

  • Filgrastim (Neupogen) 300 mcg SC once per day on days -1 to 5 (first dose is given 24 hours before first dose of cladribine)

References

  1. Robak T, Wrzesień-Kuś A, Lech-Marańda E, Kowal M, Dmoszyńska A. Combination regimen of cladribine (2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma. 2000 Sep;39(1-2):121-9. link to original article contains dosing details in manuscript PubMed
  2. Retrospective: Martin MG, Welch JS, Augustin K, Hladnik L, DiPersio JF, Abboud CN. Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma. 2009 Aug;9(4):298-301. PubMed

CLAG-M

CLAG-M: CLadribine, Ara-C (Cytarabine), G-CSF, Mitoxantrone

Regimen

Study Dates of enrollment Evidence
Wierzbowska et al. 2007 2002-11 to 2006-11 Phase 2

Chemotherapy

Growth factor therapy

  • Filgrastim (Neupogen) by the following laboratory-based criteria:
    • WBC count 20 x 109/L or less: 300 mcg SC once per day on days 0 to 5, started 24 hours prior to chemotherapy
    • WBC count more than 20 x 109/L: 300 mcg SC once per day on days 1 to 5, started simultaneously to cladribine

6-day course

Subsequent treatment

  • Wierzbowska et al. 2007, PR: recommended to undergo a second course of salvage CLAG-M.
  • Wierzbowska et al. 2007, primary refractory patients achieving CR after 2nd CLAG-M: HAM consolidation
  • Wierzbowska et al. 2007, others: could receive another course of CLAG-M re-induction or HAM consolidation per investigator discretion

References

  1. Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Holowiecki J, Kyrcz-Krzemien S, Grosicki S, Giebel S, Skotnicki AB, Piatkowska-Jakubas B, Kuliczkowski K, Kielbinski M, Zawilska K, Kloczko J, Wrzesień-Kuś A; Polish Adult Leukemia Group. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008 Feb;80(2):115-26. Epub 2007 Dec 11. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
  2. Retrospective: Martin MG, Welch JS, Augustin K, Hladnik L, DiPersio JF, Abboud CN. Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma. 2009 Aug;9(4):298-301. PubMed

CLARA

CLARA: CLofarabine and ARA-C (Cytarabine)
GCLAC: G-CSF, Clofarabine, Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence
Becker et al. 2011 (UW 6562) 2007-NR Phase 2

Chemotherapy

  • Clofarabine (Clolar) 25 mg/m2 IV over 60 minutes once per day on days 1 to 5, given first
  • Cytarabine (Ara-C) 2000 mg/m2 IV over 4 hours once per day on days 1 to 5, given second, 4 hours after start of clofarabine infusion

Growth factor therapy

  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting day -1, continuing until ANC at least 2000/μL for 2 consecutive days

6-day course

Subsequent treatment

  • UW 6562, patients with more than 5% blasts at day 21: CLARA re-induction x 1
  • UW 6562, CR: Optional CLARA consolidation for up to 2 cycles

References

  1. UW 6562: Becker PS, Kantarjian HM, Appelbaum FR, Petersdorf SH, Storer B, Pierce S, Shan J, Hendrie PC, Pagel JM, Shustov AR, Stirewalt DL, Faderl S, Harrington E, Estey EH. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol. 2011 Oct;155(2):182-9. Epub 2011 Aug 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00602225

Clofarabine & Cytarabine

Regimen variant #1, 20/20 variant 1

Study Dates of enrollment Evidence
Buckley et al. 2015 (FHCRC 2302.00) 2009-2013 Phase 1/2

Note: The dose of clofarabine is the one reported as the MTD. Note that the doses of both drugs are much lower than the other variants here.

Chemotherapy

Cycle duration not explicitly defined; presumably 28 days


Regimen variant #2, 20/20 variant 2

Study Dates of enrollment Evidence
Buckley et al. 2015 (FHCRC 2302.00) 2009-2013 Phase 1/2

Note: The dose of clofarabine is the one reported as the MTD. Note that the doses of both drugs are much lower than the other variants here.

Chemotherapy

Cycle duration not explicitly defined; presumably 28 days


Regimen variant #3, 30/1000

Study Dates of enrollment Evidence
Middeke et al. 2015 (BRIDGE) 2012-2013 Phase 2

Chemotherapy

At least one cycle

Subsequent treatment


Regimen variant #4, 40/1000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Faderl et al. 2004 NR Phase 1/2
Agura et al. 2011 (Baylor 004-145) 2005-2006 Phase 2
Faderl et al. 2012 (CLASSIC I) 2006-2009 Phase 3 (E-esc) IDAC Did not meet primary endpoint of OS

Note: length of cycles was not specified; 28-day cycle is typical for this regimen. In Faderl et al. 2004, clofarabine was given on days 2 to 6.

Chemotherapy

  • Clofarabine (Clolar) 40 mg/m2 IV over 60 minutes once per day on days 1 to 5, given first
  • Cytarabine (Ara-C) 1000 mg/m2 IV over 2 hours once per day on days 1 to 5, given second, 3 to 4 hours after completion of clofarabine infusion

Supportive therapy

28-day cycle for 1 to 4 cycles

Subsequent treatment

  • See individual papers for details

References

  1. Faderl S, Gandhi V, O'Brien S, Bonate P, Cortes J, Estey E, Beran M, Wierda W, Garcia-Manero G, Ferrajoli A, Estrov Z, Giles FJ, Du M, Kwari M, Keating M, Plunkett W, Kantarjian H. Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005 Feb 1;105(3):940-7. Epub 2004 Oct 14. link to original article contains dosing details in manuscript PubMed
  2. Baylor 004-145: Agura E, Cooper B, Holmes H, Vance E, Berryman RB, Maisel C, Li S, Saracino G, Tadic-Ovcina M, Fay J. Report of a phase II study of clofarabine and cytarabine in de novo and relapsed and refractory AML patients and in selected elderly patients at high risk for anthracycline toxicity. Oncologist. 2011;16(2):197-206. Epub 2011 Jan 27. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00334074
  3. CLASSIC I: Faderl S, Wetzler M, Rizzieri D, Schiller G, Jagasia M, Stuart R, Ganguly S, Avigan D, Craig M, Collins R, Maris M, Kovacsovics T, Goldberg S, Seiter K, Hari P, Greiner J, Vey N, Recher C, Ravandi F, Wang ES, Vasconcelles M, Huebner D, Kantarjian HM. Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial. J Clin Oncol. 2012 Jul 10;30(20):2492-9. Epub 2012 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00317642
  4. FHCRC 2302.00: Buckley SA, Mawad R, Gooley TA, Becker PS, Sandhu V, Hendrie P, Scott BL, Wood BL, Walter RB, Smith K, Dean C, Estey EH, Pagel JM. A phase I/II study of oral clofarabine plus low-dose cytarabine in previously treated acute myeloid leukaemia and high-risk myelodysplastic syndrome patients at least 60 years of age. Br J Haematol. 2015 Aug;170(3):349-55. Epub 2015 Apr 8. link to original article contains dosing details in manuscript PubMed
  5. BRIDGE: Middeke JM, Herbst R, Parmentier S, Bug G, Hänel M, Stuhler G, Schäfer-Eckart K, Rösler W, Klein S, Bethge W, Bitz U, Büttner B, Knoth H, Alakel N, Schaich M, Morgner A, Kramer M, Sockel K, von Bonin M, Stölzel F, Platzbecker U, Röllig C, Thiede C, Ehninger G, Bornhäuser M, Schetelig J. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial. Leukemia. 2016 Feb;30(2):261-7. Epub 2015 Aug 18. link to original article contains dosing details in abstract PubMed

Etoposide & Mitoxantrone

Regimen

Study Dates of enrollment Evidence Efficacy
Ho et al. 1988 1984-1987 Phase 2 ORR: 54%

Chemotherapy

References

  1. Ho AD, Lipp T, Ehninger G, Illiger HJ, Meyer P, Freund M, Hunstein W. Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia--an active and well-tolerated regimen. J Clin Oncol. 1988 Feb;6(2):213-7. link to original article PubMed

FLAG

FLAG: FLudarabine, Ara-C (Cytarabine), G-CSF

Regimen

Study Dates of enrollment Evidence
Montillo et al. 1998 1994-1996 Phase 2

Chemotherapy

  • Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days 1 to 5, given first
  • Cytarabine (Ara-C) 2000 mg/m2 IV over 4 hours once per day on days 1 to 5, given second, 4 hours after the start of fludarabine

Growth factor therapy

  • G-CSF with one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day -1 (the paper described this as day 0), first dose given 24 hours before first dose of chemotherapy, to continue until neutrophil recovery
    • Lenograstim (Granocyte) 5 mcg/kg SC once per day, starting on day -1 (the paper described this as day 0), first dose given 24 hours before first dose of chemotherapy, to continue until neutrophil recovery

6-day course

References

  1. Montillo M, Mirto S, Petti MC, Latagliata R, Magrin S, Pinto A, Zagonel V, Mele G, Tedeschi A, Ferrara F. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol. 1998 Jun;58(2):105-9. link to original article contains dosing details in manuscript PubMed

FLAG-Ida

FLAG-Ida: FLudarabine, Ara-C (Cytarabine), G-CSF (Filgrastim), Idarubicin

Regimen

Study Dates of enrollment Evidence
Parker et al. 1997 1995-1997 Phase 2, fewer than 20 patients
Pastore et al. 2003 1998-2002 Phase 2

Note: although this regimen is described as FLAG-Ida, the G-CSF starts on day 6 and is therefore considered as a supportive medication, not an antineoplastic.

Chemotherapy

Supportive therapy

5-day course

References

  1. Parker JE, Pagliuca A, Mijovic A, Cullis JO, Czepulkowski B, Rassam SM, Samaratunga IR, Grace R, Gover PA, Mufti GJ. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol. 1997 Dec;99(4):939-44. link to original article PubMed
  2. Pastore D, Specchia G, Carluccio P, Liso A, Mestice A, Rizzi R, Greco G, Buquicchio C, Liso V. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol. 2003 Apr;82(4):231-5. Epub 2003 Mar 15. link to original article contains dosing details in abstract PubMed

F-SHAI

F-SHAI: Fludarabine, Sequential High-dose Ara-C (cytarabine), Idarubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fiegl et al. 2013 NR Phase 3 (E-esc) SHAI Seems to have superior TTF (primary endpoint)
Median TTF: 3.38 vs 2.04 mo

Chemotherapy

Supportive therapy

  • G-CSF 5 mcg/kg SC once per day, starting on day 14 and continuing until ANC greater than 1500/μL
    • Discontinued if the post-treatment bmbx had more than 5% bone marrow blasts

11-day course

Dose and schedule modifications

  • Cytarabine (Ara-C) dose increased to 3000 mg/m2 for patients 60 or younger with refractory AML or greater than or equal to 2nd relapse

References

  1. Fiegl M, Unterhalt M, Kern W, Braess J, Spiekermann K, Staib P, Grüneisen A, Wörmann B, Schöndube D, Serve H, Reichle A, Hentrich M, Schiel X, Sauerland C, Heinecke A, Rieger C, Beelen D, Berdel WE, Büchner T, Hiddemann W. Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG. Leukemia. 2014 May;28(5):1001-7. Epub 2013 Oct 22. link to original article contains dosing details in manuscript PubMed

Gemtuzumab ozogamicin monotherapy

Regimen variant #1, fractionated dosing

Study Dates of enrollment Evidence
Taksin et al. 2006 (MyloFrance-1) 2005 Phase 2 (RT)

Antibody-drug conjugate therapy

One course


Regimen variant #2, original dosing

Historic variant
Study Dates of enrollment Evidence
Sievers et al. 2001 (GO study 1) 1997-1999 Phase 2 (RT)
Sievers et al. 2001 (GO study 2) 1997-1999 Phase 2 (RT)
Sievers et al. 2001 (GO study 3) 1997-1999 Phase 2 (RT)

Note: Sievers et al. 2001 reports on 3 similarly designed phase 2 trials that led to FDA accelerated approval in 2000; a subsequent confirmatory trial was negative. Due to the high toxicities at this dosing level, this variant should be considered of historical interest, only.

Antibody-drug conjugate therapy

14- to 28-day cycle for up to 3 cycles

References

  1. GO study 1: Sievers EL, Larson RA, Stadtmauer EA, Estey E, Löwenberg B, Dombret H, Karanes C, Theobald M, Bennett JM, Sherman ML, Berger MS, Eten CB, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR; Mylotarg Study Group. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001 Jul 1;19(13):3244-54. link to original article contains dosing details in abstract PubMed
    1. Update: Larson RA, Boogaerts M, Estey E, Karanes C, Stadtmauer EA, Sievers EL, Mineur P, Bennett JM, Berger MS, Eten CB, Munteanu M, Loken MR, Van Dongen JJ, Bernstein ID, Appelbaum FR; Mylotarg Study Group. Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia. 2002 Sep;16(9):1627-36. link to original article PubMed
    2. Update: Larson RA, Sievers EL, Stadtmauer EA, Löwenberg B, Estey EH, Dombret H, Theobald M, Voliotis D, Bennett JM, Richie M, Leopold LH, Berger MS, Sherman ML, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer. 2005 Oct 1;104(7):1442-52. link to original article PubMed
  2. GO study 2: Sievers EL, Larson RA, Stadtmauer EA, Estey E, Löwenberg B, Dombret H, Karanes C, Theobald M, Bennett JM, Sherman ML, Berger MS, Eten CB, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR; Mylotarg Study Group. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001 Jul 1;19(13):3244-54. link to original article contains dosing details in abstract PubMed
    1. Update: Larson RA, Boogaerts M, Estey E, Karanes C, Stadtmauer EA, Sievers EL, Mineur P, Bennett JM, Berger MS, Eten CB, Munteanu M, Loken MR, Van Dongen JJ, Bernstein ID, Appelbaum FR; Mylotarg Study Group. Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia. 2002 Sep;16(9):1627-36. link to original article PubMed
    2. Update: Larson RA, Sievers EL, Stadtmauer EA, Löwenberg B, Estey EH, Dombret H, Theobald M, Voliotis D, Bennett JM, Richie M, Leopold LH, Berger MS, Sherman ML, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer. 2005 Oct 1;104(7):1442-52. link to original article PubMed
  3. GO study 3: Sievers EL, Larson RA, Stadtmauer EA, Estey E, Löwenberg B, Dombret H, Karanes C, Theobald M, Bennett JM, Sherman ML, Berger MS, Eten CB, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR; Mylotarg Study Group. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001 Jul 1;19(13):3244-54. link to original article contains dosing details in abstract PubMed
    1. Update: Larson RA, Boogaerts M, Estey E, Karanes C, Stadtmauer EA, Sievers EL, Mineur P, Bennett JM, Berger MS, Eten CB, Munteanu M, Loken MR, Van Dongen JJ, Bernstein ID, Appelbaum FR; Mylotarg Study Group. Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia. 2002 Sep;16(9):1627-36. link to original article PubMed
    2. Update: Larson RA, Sievers EL, Stadtmauer EA, Löwenberg B, Estey EH, Dombret H, Theobald M, Voliotis D, Bennett JM, Richie M, Leopold LH, Berger MS, Sherman ML, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer. 2005 Oct 1;104(7):1442-52. link to original article PubMed
  4. MyloFrance-1: Taksin AL, Legrand O, Raffoux E, de Revel T, Thomas X, Contentin N, Bouabdallah R, Pautas C, Turlure P, Reman O, Gardin C, Varet B, de Botton S, Pousset F, Farhat H, Chevret S, Dombret H, Castaigne S. High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia. 2007 Jan;21(1):66-71. Epub 2006 Oct 19. link to original article contains dosing details in manuscript PubMed

High-dose Cytarabine monotherapy (HiDAC)

HiDAC: High Dose Ara-C (Cytarabine)

Regimen variant #1, CI

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Giles et al. 2009 (VION-CLI-037) 2005-2007 Phase 3 (C) HiDAC & Laromustine Mixed response (see note)

Note: while the experimental arm of this trial met the primary endpoint of ORR, the control arm had superior PFS.

Chemotherapy

  • Cytarabine (Ara-C) 1500 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose: 7500 mg/m2)

3-day course


Regimen variant #2, intermittent

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Karanes et al. 1999 (SWOG-8326) 1985-1992 Phase 3 (C) HiDAC & Mitoxantrone Did not meet primary endpoint of CR rate

Chemotherapy

6-day course

References

  1. CALGB 8121: Capizzi RL, Davis R, Powell B, Cuttner J, Ellison RR, Cooper MR, Dillman R, Major WB, Dupre E, McIntyre OR. Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia--a Cancer and Leukemia Group B Study. J Clin Oncol. 1988 Mar;6(3):499-508. link to original article PubMed
  2. SWOG-8326: Karanes C, Kopecky KJ, Head DR, Grever MR, Hynes HE, Kraut EH, Vial RH, Lichtin A, Nand S, Samlowski WE, Appelbaum FR. A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia Southwest Oncology Group Study. Leuk Res. 1999 Sep;23(9):787-94. link to original article contains dosing details in abstract PubMed
  3. VION-CLI-037: Giles F, Vey N, DeAngelo D, Seiter K, Stock W, Stuart R, Boskovic D, Pigneux A, Tallman M, Brandwein J, Kell J, Robak T, Staib P, Thomas X, Cahill A, Albitar M, O'Brien S. Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse. Blood. 2009 Nov 5;114(19):4027-33. Epub 2009 Aug 26. link to original article contains dosing details in manuscript PubMed NCT00112554

Intermediate-dose Cytarabine monotherapy (IDAC)

IDAC: Intermediate Dose Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (MIRROS) 2015-2020 Phase 3 (C) IDAC & Idasanutlin TBD1

1This study was terminated for futility based on efficacy results at the interim analysis, per CT.gov.

Chemotherapy

28-day cycle for up to 3 cycles

References

  1. MIRROS: contains dosing details on CT.gov NCT02545283

MAC

MAC: Mitoxantrone & Ara-C (Cytarabine)
MIDAC: Mitoxantrone & Intermediate-Dose Ara-C (Cytarabine)

Regimen variant #1, 6000/25

Study Dates of enrollment Evidence
Sternberg et al. 2000 1990-1997 Phase 2

Chemotherapy

6-day course


Regimen variant #2, 10,000/48

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Solary et al. 1996 1992-1995 Phase 3 (C) Cytarabine, Mitoxantrone, Quinine Did not meet primary endpoint of CR rate

Chemotherapy

5-day course

References

  1. Solary E, Witz B, Caillot D, Moreau P, Desablens B, Cahn JY, Sadoun A, Pignon B, Berthou C, Maloisel F, Guyotat D, Casassus P, Ifrah N, Lamy Y, Audhuy B, Colombat P, Harousseau JL. Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study. Blood. 1996 Aug 15;88(4):1198-205. link to original article contains dosing details in abstract PubMed
  2. Sternberg DW, Aird W, Neuberg D, Thompson L, MacNeill K, Amrein P, Shulman LN. Treatment of patients with recurrent and primary refractory acute myelogenous leukemia using mitoxantrone and intermediate-dose cytarabine: a pharmacologically based regimen. Cancer. 2000 May 1;88(9):2037-41. link to original article contains dosing details in manuscript PubMed

MEC

MEC: Mitoxantrone, Etoposide, Cytarabine

Regimen variant #1, 6/80/1000

Study Dates of enrollment Evidence
Amadori et al. 1991 1988-1990 Phase 2

Chemotherapy

6-day course


Regimen variant #2, 8/80/1000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Feldman et al. 2005 1999-2001 Phase 3 (C) MEC & Lintuzumab Did not meet primary endpoint of ORR

Chemotherapy

6-day course


Regimen variant #3, 8/100/1000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Greenberg et al. 2004 (ECOG E2995) NR-1999 Phase 3 (C) MEC & Valspodar Did not meet primary endpoint of CR rate
Cortes et al. 2014 (CLTR0308-205) 2009-NR Randomized Phase 2 (C) CPX-351 Did not meet primary endpoint of OS12

Note: this was the most commonly used salvage regimen in the control arm of CLTR0308-205; exact dosing details were not described in the paper.

Chemotherapy

28-day cycle for 1 to 2 cycles

References

  1. Amadori S, Arcese W, Isacchi G, Meloni G, Petti MC, Monarca B, Testi AM, Mandelli F. Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol. 1991 Jul;9(7):1210-4. link to original article PubMed
  2. ECOG E2995: Greenberg PL, Lee SJ, Advani R, Tallman MS, Sikic BI, Letendre L, Dugan K, Lum B, Chin DL, Dewald G, Paietta E, Bennett JM, Rowe JM. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol. 2004 Mar 15;22(6):1078-86. Erratum in: J Clin Oncol. 2004 Jul 1;22(13):2747. link to original article link to PMC article contains dosing details in manuscript PubMed
  3. Feldman EJ, Brandwein J, Stone R, Kalaycio M, Moore J, O'Connor J, Wedel N, Roboz GJ, Miller C, Chopra R, Jurcic JC, Brown R, Ehmann WC, Schulman P, Frankel SR, De Angelo D, Scheinberg D. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J Clin Oncol. 2005 Jun 20;23(18):4110-6. link to original article contains dosing details in manuscript PubMed
  4. CLTR0308-205: Cortes JE, Goldberg SL, Feldman EJ, Rizzeri DA, Hogge DE, Larson M, Pigneux A, Recher C, Schiller G, Warzocha K, Kantarjian H, Louie AC, Kolitz JE. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer. 2015 Jan 15;121(2):234-42. Epub 2014 Sep 15. link to original article link to PMC article PubMed NCT00822094
  5. D18-11141: NCT03926624

Consolidation after salvage therapy

Busulfan & Cyclophosphamide, then allo HSCT

BuCy: Busulfan & Cyclophosphamide

Regimen variant #1, 3.2 x 4/120

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lee et al. 2012 (COSAH C-005) 2005-2009 Phase 3 (E-switch-ic) BuFlu, then allo HSCT Superior OS (secondary endpoint)
OS24: 67.4% vs 41.4%
(HR 0.48, 95% CI 0.27-0.86)
Rambaldi et al. 2015 (GITMO-AMLR2) 2008-2012 Phase 3 (C) BuFlu, then allo HSCT Seems to have inferior 1-year non-relapse mortality
Scott et al. 2017 (BMT CTN 0901) 2011-2014 Phase 3 (C) 1a. BuFlu, then allo HSCT
1b. FluMel, then allo HSCT 		Seems to have superior OS (primary endpoint)
OS18: 76.4% vs 63.4%
(HR 0.64, 95% CI 0.38-0.98)
Xuan et al. 2023 2016-04-18 to 2019-09-30 Phase 3 (C) Busulfan, Cyclophosphamide, Decitabine, G-CSF Inferior CIR24

Chemotherapy

Immunotherapy

GVHD prophylaxis

Supportive therapy

  • Filgrastim (Neupogen) 450 mcg SC once per day, starting on day +5 and continued until ANC greater than 3000/μL

One course


Regimen variant #2, 0.8 x 16/120

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ling et al. 2023 2015-11-20 to 2019-09-30 Phase 3 (C) BuFlu, then haplo HSCT Seems to have inferior TRM12

Chemotherapy

Immunotherapy

One course


Regimen variant #3, 16/200

Study Dates of enrollment Evidence
Santos et al. 1983 1975-1982 Non-randomized

Note: the day of allogeneic stem cell transplant is not specified in the protocol.

Chemotherapy

Immunotherapy

One course

References

  1. Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, Braine HG, Burns WH, Elfenbein GJ, Kaizer H, Mellits D, Sensenbrenner LL, Stuart RK, Yeager AM. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med. 1983 Dec 1;309(22):1347-53. link to original article contains dosing details in abstract PubMed
  2. COSAH C-005: Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, Lee JH, Lee WS, Park JH, Bae SH, Hyun MS, Kim DY, Kim SD, Min YJ, Lee KH. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013 Feb 20;31(6):701-9. Epub 2012 Nov 5. link to original article contains dosing details in manuscript PubMed NCT00774280
  3. GITMO-AMLR2: Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. link to original article PubMed NCT01191957
  4. BMT CTN 0901: Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, Maziarz RT, Warlick ED, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt S, Geller NL, Leifer E, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-1161. Epub 2017 Feb 13. link to original article link to PMC article PubMed NCT01339910
  5. Ling Y, Xuan L, Xu N, Huang F, Fan Z, Guo Z, Xu X, Liu H, Lin R, Yu S, Zhang H, Jin H, Wu M, Liu C, Liang X, Ou R, Zhang Y, Liu X, Qu H, Zhai X, Sun J, Zhao Y, Liu Q. Busulfan Plus Fludarabine Compared With Busulfan Plus Cyclophosphamide for AML Undergoing HLA-Haploidentical Hematopoietic Cell Transplantation: A Multicenter Randomized Phase III Trial. J Clin Oncol. 2023 Oct 10;41(29):4632-4642. Epub 2023 Jun 19. link to original article contains dosing details in manuscript PubMed NCT02487069
  6. Xuan L, Dai M, Jiang E, Wang Y, Huang F, Fan Z, Xu N, Nie D, Liang X, Chen H, Ye J, Shi P, Liu H, Jin H, Lin R, Yan C, Zhang Y, Sun J, Han M, Liu Q. The effect of granulocyte-colony stimulating factor, decitabine, and busulfan-cyclophosphamide versus busulfan-cyclophosphamide conditioning on relapse in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. 2023 Mar;10(3):e178-e190. Epub 2023 Jan 23. link to original article contains dosing details in abstract PubMed NCT02744742

Busulfan & Fludarabine, then allo HSCT

BuFlu: Busulfan & Fludarabine
Flu/Bu: Fludarabine & Busulfan

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Ling et al. 2023 2015-11-20 to 2019-09-30 Phase 3 (E-de-esc) Busulfan & Cyclophosphamide Seems to have superior TRMM12 (primary endpoint)

Chemotherapy

Immunotherapy

One course


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Rambaldi et al. 2015 (GITMO-AMLR2) 2008-2012 Phase 3 (E-switch-ic) BuCy, then allo HSCT Seems to have superior NRM12 (primary endpoint)

Chemotherapy

GVHD prophylaxis, pre-transplant

  • Antithymocyte globulin, rabbit ATG (Thymoglobulin) by the following donor-based criteria:
    • Matched unrelated donors: 0.5 mg/kg IV once on day -3, then 2 mg/kg IV once on day -2, then 2.5 mg/kg IV once on day -1
    • Mismatched donors: total ATG dose could be increased to 7.5 mg/kg

Immunotherapy

GVHD prophylaxis, post-transplant

One course


Regimen variant #3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Andersson et al. 2008 1997-2005 Non-randomized Suggested improved outcomes, but shorter follow up

Chemotherapy

  • Busulfan (Myleran) 130 mg/m2 IV over 3 hours once per day on days -6 to -3
    • Dosing targeted for optimal pharmacokinetics but different parameters each institution, please consult the original publication for optimal levels
  • Fludarabine (Fludara) 40 mg/m2 IV over 60 minutes once per day on days -6 to -3, given first

GVHD prophylaxis, pre-transplant

Immunotherapy

GVHD prophylaxis, post-transplant

#1 Tacrolimus & methotrexate based (Andersson et al.)

Supportive therapy

  • All patients received Filgrastim (Neupogen) SC once per day from day +7 until achieving an absolute neutrophil count (ANC) ≥1.5 × 109/L for three days
  • Phenytoin (Dilantin) prophylaxis used during and for one day after IV busulfan

#2 Post-Transplant Cy based (Kanakry et al. and FHCC 2541.00)

GVHD prophylaxis

  • Cyclophosphamide (Cytoxan) 50 mg/kg IV once per day on days +3 & +4 (used alone in Kanakry et al. when all patients received bone marrow grafts)
  • ± Cyclosporine intravenous loading dose of CSP was given on day 5, followed by subsequent twice per day dosing adjusted to maintain whole blood trough at 120 to 360 ng/mL. In abscence of GVHD Cyclosporine was tapered from day +56 through day +126 (used in FHCC 2541.00 with PBSCT grafts)

Supportive therapy

One course


Regimen variant #4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lee et al. 2012 (COSAH C-005) 2005-2009 Phase 3 (E-switch-ic) BuCy, then allo HSCT Inferior OS (secondary endpoint)

Chemotherapy

  • Busulfan (Myleran) 3.2 mg/kg IV once per day on days -7 to -4, given first on days overlapping with fludarabine (total dose: 12.8 mg/kg)
  • Fludarabine (Fludara) 30 mg/m2 IV once per day on days -6 to -2, given second on days overlapping with busulfan

Immunotherapy

GVHD prophylaxis

Supportive therapy

  • Filgrastim (Neupogen) 450 mcg SC once per day, starting on day +5 and continued until ANC greater than 3000/μL

One course

References

  1. Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M, Roberson S, Giralt S, Pierre B, Russell JA, Shpall EJ, Jones RB, Champlin RE. Once daily IV busulfan and fludarabine (IV Bu-Flu) compares favorably with IV busulfan and cyclophosphamide (IV BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant. 2008;14(6):672-84. link to original article link to PMC article contains dosing details in manuscript PubMed
  2. COSAH C-005: Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, Lee JH, Lee WS, Park JH, Bae SH, Hyun MS, Kim DY, Kim SD, Min YJ, Lee KH. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013 Feb 20;31(6):701-9. Epub 2012 Nov 5. link to original article contains dosing details in manuscript PubMed NCT00774280
  3. GITMO-AMLR2: Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. link to original article PubMed NCT01191957
  4. Ling Y, Xuan L, Xu N, Huang F, Fan Z, Guo Z, Xu X, Liu H, Lin R, Yu S, Zhang H, Jin H, Wu M, Liu C, Liang X, Ou R, Zhang Y, Liu X, Qu H, Zhai X, Sun J, Zhao Y, Liu Q. Busulfan Plus Fludarabine Compared With Busulfan Plus Cyclophosphamide for AML Undergoing HLA-Haploidentical Hematopoietic Cell Transplantation: A Multicenter Randomized Phase III Trial. J Clin Oncol. 2023 Oct 10;41(29):4632-4642. Epub 2023 Jun 19. link to original article contains dosing details in manuscript PubMed NCT02487069

Clofarabine & Melphalan, then allo HSCT

Regimen

Study Dates of enrollment Evidence
Middeke et al. 2015 (BRIDGE) 2012-2013 Phase 2

Limited details are available in the abstract. Treatment is meant to be given during aplasia.

Preceding treatment

Chemotherapy

Immunotherapy

One course

References

  1. BRIDGE: Middeke JM, Herbst R, Parmentier S, Bug G, Hänel M, Stuhler G, Schäfer-Eckart K, Rösler W, Klein S, Bethge W, Bitz U, Büttner B, Knoth H, Alakel N, Schaich M, Morgner A, Kramer M, Sockel K, von Bonin M, Stölzel F, Platzbecker U, Röllig C, Thiede C, Ehninger G, Bornhäuser M, Schetelig J. Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial. Leukemia. 2016 Feb;30(2):261-7. Epub 2015 Aug 18. link to original article contains dosing details in abstract PubMed

Relapsed or refractory, subsequent lines of therapy

Note: these regimens are generally intended to delay progression of disease and are of non-curative intent.

Azacitidine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thepot et al. 2010 2004-2009 Phase 2
Roboz et al. 2014 (CLAVELA) 2010-2012 Phase 3 (C) Elacytarabine Did not meet primary endpoint of OS

Note: CLAVELA does not contain precise dosing information for the control arm regimens.

Chemotherapy

28-day cycle for at least 4 cycles

References

  1. Thepot S, Itzykson R, Seegers V, Raffoux E, Quesnel B, Chait Y, Sorin L, Dreyfus F, Cluzeau T, Delaunay J, Sanhes L, Eclache V, Dartigeas C, Turlure P, Harel S, Salanoubat C, Kiladjian JJ, Fenaux P, Adès L; Groupe Francophone des Myelodysplasies. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood. 2010 Nov 11;116(19):3735-42. Epub 2010 Jul 27. link to original article PubMed
  2. CLAVELA: Roboz GJ, Rosenblat T, Arellano M, Gobbi M, Altman JK, Montesinos P, O'Connell C, Solomon SR, Pigneux A, Vey N, Hills R, Jacobsen TF, Gianella-Borradori A, Foss Ø, Vetrhusand S, Giles FJ. International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2014 Jun 20;32(18):1919-26. Epub 2014 May 19. link to original article does not contain dosing details PubMed NCT01147939

Ruxolitinib monotherapy

Regimen

Study Dates of enrollment Evidence
Eghtedar et al. 2012 (MDACC 2007-0925) 2008-2010 Phase 2

Targeted therapy

28-day cycles

Dose and schedule modifications

  • Patients with progression were allowed to increase Ruxolitinib (Jakafi) dose to 50 mg PO twice per day

References

  1. MDACC 2007-0925: Eghtedar A, Verstovsek S, Estrov Z, Burger J, Cortes J, Bivins C, Faderl S, Ferrajoli A, Borthakur G, George S, Scherle PA, Newton RC, Kantarjian HM, Ravandi F. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood. 2012 May 17;119(20):4614-8. Epub 2012 Mar 15. link to original article contains dosing details in manuscript link to PMC article PubMed

Response criteria

NCI-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia (1990)

  1. Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ, et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol. 1990 May;8(5):813-9. link to original article PubMed

Revised International Working Group recommendations (2003)

  1. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. Erratum in: J Clin Oncol. 2004 Feb 1;22(3):576. LoCocco, Francesco [corrected to Lo-Coco, Francesco]. link to original article PubMed

Prognosis

Prognostic Index for Adult Patients With Acute Myeloid Leukemia in First Relapse (2005)

  • Relapse-free interval from first complete remission
    • More than 18 months (0 points)
    • 7 to 18 months (3 points)
    • Less than or equal to 6 months (5 points)
  • Cytogenetics at diagnosis
    • t(16;16) or inv(16) with or without additional cytogenetic abnormalities (0 points)
    • t(8;21) with or without additional cytogenetic abnormalities (3 points)
    • Normal, intermediate, unfavorable, or unknown cytogenetics (5 points)
  • Age at time of first relapse
    • 35 years old or younger (0 points)
    • 36 to 45 years old (1 point)
    • Older than 45 years old (2 points)
  • Stem cell transplantation performed before first relapse
    • No (0 points)
    • Yes, autologous or allogeneic (2 points)

Risk stratification:

  • 1 to 6 points: Favorable risk (1-year OS of 70%; 5-year OS of 46%)
  • 7 to 9 points: Intermediate risk (1-year OS of 49%; 5-year OS of 18%)
  • 10 to 14 points: Poor risk (1-year OS of 16%; 5-year OS of 4%)

References

  1. Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF, Vellenga E, De Greef GE, Jacky E, Van der Lelie J, Boogaerts MA, Löwenberg B. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005 Mar 20;23(9):1969-78. Epub 2005 Jan 4. link to original article PubMed

Prognosis in cytogenetically normal AML

  1. Seminal paper comparing the mutational status of NPM1, FLT3, CEBPA, MLL, and NRAS with clinical outcome: Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008 May 1;358(18):1909-18. link to original article PubMed
  2. CEBPA double mutations: Wouters BJ, Löwenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood. 2009 Mar 26;113(13):3088-91. Epub 2009 Jan 26. link to original article link to PMC article PubMed

Whole genome sequencing

  1. Seminal paper comparing WGS to cytogenetic analysis: Duncavage EJ, Schroeder MC, O'Laughlin M, Wilson R, MacMillan S, Bohannon A, Kruchowski S, Garza J, Du F, Hughes AEO, Robinson J, Hughes E, Heath SE, Baty JD, Neidich J, Christopher MJ, Jacoby MA, Uy GL, Fulton RS, Miller CA, Payton JE, Link DC, Walter MJ, Westervelt P, DiPersio JF, Ley TJ, Spencer DH. Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers. N Engl J Med. 2021 Mar 11;384(10):924-935. link to original article PubMed

Additional information

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