Acute myeloid leukemia

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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:
*AML, FLT3-positive
*AML, IDH-mutated
*AML, NPM1-mutated
*Acute promyelocytic leukemia
*Pediatric AML
Last updated on 2024-09-06:90 regimens on this page
154 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==
*2020: Sekeres et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults link to PMC article EuroPMC
==ELN==
*2024: Döhner et al. Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations EuroPMC
*2022: Döhner et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN EuroPMC
**2017: Döhner et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel link to PMC article EuroPMC
**2010: Döhner et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet EuroPMC
==ESMO==
*2020: Heuser et al. Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2013: Fey et al. Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Fey & Dreyling. Acute myeloblastic leukemia in adult patients: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2008: Fey & Dreyling. Acute myeloblastic leukemia in adult patients: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2007: Fey. Acute myeloblastic leukemia in adult patients: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2005: Fey et al. ESMO Minimum Clinical Recommendations for the diagnosis, treatment and follow-up of acute myeloblastic leukemia (AML) in adult patients EuroPMC
**2003: Fey. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of acute myeloblastic leukaemia (AML) in adult patients EuroPMC
*2010: Fey & Dreyling. Acute myeloblastic leukaemias and myelodysplastic syndromes in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
==NCCN==
*NCCN Guidelines - Acute Myeloid Leukemia
*2019: Tallman et al. Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. EuroPMC
*2017: O'Donnell et al. Acute Myeloid Leukemia, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology EuroPMC
*2013: O'Donnell et al. Acute myeloid leukemia, version 2.2013 link to PMC article EuroPMC
*2006: O'Donnell et al. Acute myeloid leukemia clinical practice guidelines in oncology. EuroPMC
*2003: Unknown et al. Acute myeloid leukemia. Clinical practice guidelines in oncology. EuroPMC
==SITC==
*2020: Boyiadzis et al. The Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of acute leukemia EuroPMC
**2016: Boyiadzis et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies: multiple myeloma, lymphoma, and acute leukemia EuroPMC
==Antifungal prophylaxis==
*2022: Stemler et al. Antifungal prophylaxis in adult patients with acute myeloid leukaemia treated with novel targeted therapies: a systematic review and expert consensus recommendation from the European Hematology Association EuroPMC
*2015: Halpern et al. Primary antifungal prophylaxis during curative-intent therapy for acute myeloid leukemia EuroPMC
=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 shorter EFS
Jin et al. 2013	2007-2011 	Phase 3 (C)	2. HAA 	Shorter 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====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Daunorubicin (Cerubidine) 40 mg/m2 IV once per day on days 1 to 3
7-day course
===Regimen variant #2, 700/135 (CI Ara-C)===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Yates et al. 1973 	Not reported 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 higher CR rate
Rai et al. 1981 (CALGB 7421) 	1974-04-25 to 1975-05-07	Phase 3 (E-esc) 	2. 5+2d; CI Ara-C 	Higher CR rate
Rai et al. 1981 (CALGB 7421) 	1974-04-25 to 1975-05-07	Phase 3 (E-esc) 	3. 5+2d; bolus Ara-C 	Higher CR rate
Omura et al. 1982 	1974-05 to 1975-06 	Phase 3 (E-de-esc) 	1. AVML 	Not directly compared
Omura et al. 1982 	1974-05 to 1975-06 	Phase 3 (E-de-esc) 	2. TAD 	Longer time to CR
Yates et al. 1982 (CALGB 7721) 	1977-1979 	Phase 3 (C) 	1. 7+3d (low-dose) 	Did not meet efficacy endpoints
Yates et al. 1982 (CALGB 7721) 	1977-1979 	Phase 3 (C) 	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
Preisler et al. 1987 (CALGB 7921) 	1979-1982 	Phase 3 (C) 	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 	Not reported 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 shorter OS (co-primary endpoint)Median OS: 8.7 vs 12.9 mo(HR not reported, p=0.038)
Vogler et al. 1992 	1985-1989 	Phase 3 (C) 	7+3i 	Seems to have lower CR rate
Rowe et al. 2004 (ECOG E3993) 	1993-1997 	Phase 3 (C) 	1. 7+3d & GM-CSF2. 7+3i3. 7+3i & GM-CSF4. 7+3m5. 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 OSMedian OS: 9.4 vs 7.2 mo
Fernandez et al. 2009 (ECOG E1900) 	2002-2008 	Phase 3 (C) 	7+3d; high-dose 	Shorter OSMedian OS: 15.7 vs 23.7 mo(HR 1.35, 95% CI 1.11-1.67)
Jin et al. 2013 	2007-2011 	Phase 3 (C) 	1. HAD 	Might have shorter EFS
Jin et al. 2013 	2007-2011 	Phase 3 (C) 	2. HAA 	Shorter EFS
Dombret et al. 2015 (AZA-AML-001) 	2010-2014 	Phase 3 (C) 	Azacitidine 	Might have shorter OSMedian OS: 6.5 vs 10.4 mo(HR 1.18, 95% CI 0.97-1.45)
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. The full manuscripts of Yates et al. 1973 and Arlin et al. 1990 were not available for review.
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Daunorubicin (Cerubidine) 45 mg/m2 IV bolus once per day on days 1 to 3
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+3d 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====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Daunorubicin (Cerubidine) 50 mg/m2 IV bolus once per day on days 1 to 3
7-day course
===Regimen variant #4, 1120/120 (intermittent Ara-C)===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Masaoka et al. 1996	Not reported in abstract	Randomized Phase 2 (E-switch-ic)	7+3i 	Seems to have lower CR rate
Note: The full manuscript was not available for review.
====Chemotherapy====
*Cytarabine (Ara-C) 80 mg/m2 IV over 2 hours every 12 hours on days 1 to 7
*Daunorubicin (Cerubidine) 40 mg/m2 IV bolus once per day on days 1 to 3
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 shorter RFS (secondary endpoint)
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 rateCR rate: 43% vs 34%
Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01)	2000-2006 	Phase 3 (C) 	7+3d; high-dose 	Lower CR rate
Stone et al. 2015 (ACCEDE) 	2008-2010 	Phase 3 (C) 	Amonafide & Cytarabine	Did not meet primary endpoint of CR rateCR rate: 45% vs 46%
Note: This variant is commonly used in Europe.
====Chemotherapy====
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
*Daunorubicin (Cerubidine) 45 mg/m2 IV push once per day on days 1 to 3 or days 5 to 7
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
===Regimen variant #6, 1400/135 (CI Ara-C/CI daunorubicin)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lee et al. 2011 (ADcomparison)	2001-2008 	Phase 3 (C)	7+3d; high-dose	Seems to have shorter OS (secondary endpoint)OS60: 34.6% vs 46.8%(HR 1.35, 95% CI 1.03-1.72)Seems to have shorter EFS (primary endpoint)EFS60: 28.4% vs 40.8%(aHR 1.30, 95% CI 1.00-1.67)
====Chemotherapy====
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
*Daunorubicin (Cerubidine) 45 mg/m2/day IV continuous infusion over 3 days, started on day 1 (total dose: 135 mg/m2)
7-day course
===References===
#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. EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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. dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01324063
##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 dosing details in abstract have been reviewed by our editors EuroPMC
#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. dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT04446052
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN77039377
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00049517
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00046930
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00474006
#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 dosing details in manuscript have been reviewed by our editors EuroPMC ChiCTR-TRC-06000054
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00715637
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01074047
##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 EuroPMC
##HRQoL analysis: Roboz GJ, Döhner H, Pocock C, Dombret H, Ravandi F, Jang JH, Selleslag D, Mayer J, Martens UM, Liesveld J, Bernal T, Wang MC, Yu P, Shi L, Guo S, La Torre I, Skikne B, Dong Q, Braverman J, Nehme SA, Beach CL, Wei AH. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Dec 1;106(12):3240-3244. Epub 2021 Sep 23. link to original article link to PMC article EuroPMC
==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 OSOS12: 40% vs 43%
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 EFSMedian EFS: 7 vs 5 mo(HR 0.79, 95% CI 0.59-1.06)
Lancet et al. 2014 (CLTR0308-204) 	2008-11 to 2009-10 	Randomized Phase 2 (C) 	CPX-351 	Might have lower composite CR/CRi rate
Röllig et al. 2015 (SORAML) 	2009-2011 	Randomized Phase 2 (C) 	7+3d & Sorafenib 	Shorter EFS (primary endpoint)Median EFS: 9 vs 21 mo(HR 1.56, 95% CI 1.10-2.22)
Müller-Tidow et al. 2015 (AML-AZA) 	2010-2012 	Phase 3 (C) 	7+3d & Azacitidine 	Did not meet primary endpoint of EFSMedian EFS: 6 vs 6 mo
Dombret et al. 2015 (AZA-AML-001) 	2010-2014 	Phase 3 (C) 	Azacitidine 	Might have shorter OSMedian OS: 6.5 vs 10.4 mo(HR 1.18, 95% CI 0.97-1.45)
Lancet et al. 2018 (CLTR0310-301) 	2012-12 to 2014-11 	Phase 3 (C) 	CPX-351 	Shorter OS1Median OS: 6 vs 9.3 mo(HR 1.43, 95% CI 1.1-1.82)
Sekeres et al. 2023 (BRIGHT AML 1019)	2018-04 to 2020-01 	Phase 3 (C) 	7+3d & Glasdegib 	Did not meet primary endpoint of OSMedian OS: 20 vs 17.2 mo(HR 0.95, 95% CI 0.71-1.28)
1Reported efficacy for CLTR0310-301 is based on the 2021 update.
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.
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Daunorubicin (Cerubidine) 60 mg/m2 IV push once per day on days 1 to 3 or days 3 to 5
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 	Lower CR rate after first induction (primary endpoint)CR rate: 47% vs 64%
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 	Shorter OS
Holowiecki et al. 2012 (PALG AML1/2004)	2004-2008 	Phase 3 (C)	2. DAF 	Did not meet primary endpoint of OS
Castaigne et al. 2012 (ALFA-0701) 	2008-2010 	Phase 3 (C)	7+3d & GO 	Shorter EFS (primary endpoint)EFS24: 17.1% vs 40.8%(HR 1.72, 95% CI 1.28-2.33)Seems to have shorter OS (secondary endpoint)OS24: 41.9% vs 53.2%(HR 1.45, 95% CI 1.02-2.04)
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====
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
*Daunorubicin (Cerubidine) 60 mg/m2 IV over 5 to 30 minutes once per day on days 1 to 3
====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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00927498
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01414231
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00180102
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00373373
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00085709
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00788892
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01074047
##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 EuroPMC
##HRQoL analysis: Roboz GJ, Döhner H, Pocock C, Dombret H, Ravandi F, Jang JH, Selleslag D, Mayer J, Martens UM, Liesveld J, Bernal T, Wang MC, Yu P, Shi L, Guo S, La Torre I, Skikne B, Dong Q, Braverman J, Nehme SA, Beach CL, Wei AH. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Dec 1;106(12):3240-3244. Epub 2021 Sep 23. link to original article link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00915252
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00893373
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01696084
##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 EuroPMC
##Q-TWiST analysis: Cortes JE, Lin TL, Uy GL, Ryan RJ, Faderl S, Lancet JE. Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML. J Hematol Oncol. 2021 Jul 13;14(1):110. link to original article link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00085124.
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03416179
#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 dosing details in supplement have been reviewed by our editors EuroPMC NCT02172872
##HRQoL analysis: Efficace F, Kicinski M, Coens C, Suciu S, van der Velden WJFM, Noppeney R, Chantepie S, Griskevicius L, Neubauer A, Audisio E, Luppi M, Fuhrmann S, Foà R, Crysandt M, Gaidano G, Vrhovac R, Venditti A, Posthuma EFM, Candoni A, Baron F, Legrand O, Mengarelli A, Fazi P, Vignetti M, Giraut A, Wijermans PW, Huls G, Lübbert M. Decitabine in older patients with AML: quality of life results of the EORTC-GIMEMA-GMDS-SG randomized phase 3 trial. Blood. 2024 Aug 1;144(5):541-551. link to original article EuroPMC
#AMLSG31-19: NCT04628026
#ECOG E2906: NCT02085408
#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 	Longer 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 	Lower CR rate
Garcia-Manero et al. 2023 (SWOG S1203)	2013-04 to 2015-11 	Phase 3 (C) 	1. HiDAC & Idarubicin2. HiDAC, Idarubicin, Vorinostat	Did not meet primary endpoint of EFS
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Daunorubicin (Cerubidine) 90 mg/m2 IV once per day on days 1 to 3
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 22. Timed sequential induction	Did not meet primary endpoint of RFI
====Chemotherapy====
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
*Daunorubicin (Cerubidine) 80 mg/m2 IV once per day on days 1 to 3
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	Higher CR rate (secondary endpoint)
Lee et al. 2017 (COSAH C-022) 	2010-2014 	Phase 3 (E-switch-ic)	7+3i 	Inconclusive whether non-inferior CR rate
====Chemotherapy====
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
*Daunorubicin (Cerubidine) 90 mg/m2 IV once per day on days 1 to 3
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
===Regimen variant #4, 1400/270 (CI daunorubicin)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lee et al. 2011 (ADcomparison)	2001-2008 	Phase 3 (E-esc)	7+3d; standard-dose	Seems to have longer OS (secondary endpoint)OS60: 46.8% vs 34.6%(HR 0.74, 95% CI 0.58-0.97)Seems to have longer EFS (primary endpoint)EFS60: 40.8% vs 28.4%(aHR 0.77, 95% CI 0.60-0.998)
====Chemotherapy====
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
*Daunorubicin (Cerubidine) 90 mg/m2/day IV continuous infusion over 3 days, started on day 1 (total dose: 270 mg/m2)
7-day course
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN77039377
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00049517
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00474006
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01349972
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01145846
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01802333
==7+3d & GO==
7+3d & GO: 7 days of Cytarabine, 3 days of daunorubicin, Gemtuzumab Ozogamicin
===Regimen variant #1, split GO dosing ("GO-147")===
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	Longer EFS (primary endpoint)EFS24: 40.8% vs 17.1%(HR 0.58, 95% CI 0.43-0.78)Seems to have longer OS (secondary endpoint)OS24: 53.2% vs 41.9%(HR 0.69, 95% CI 0.49-0.98)
Jaramillo et al. 2024 (GnG) 	2021-04 to 2022-05-05	Phase 3 (C) 	7+3d + GO; "GO-1" 	Did not meet co-primary endpoints of MRD-/EFS
Note: GnG was closed early due to low enrollment; no conclusions should be drawn from the results.
====Chemotherapy====
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
*Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1 to 3
====Antibody-drug conjugate therapy====
*Gemtuzumab ozogamicin (Mylotarg) 3 mg/m2 (maximum dose of 5 mg) IV over 2 hours once per day on days 1, 4, 7
7-day course
====Subsequent treatment====
*ALFA-0701, patients in CR or CRp and platelet count at least 100 x 109 by day 45 after the initiation of chemotherapy: Cytarabine, Daunorubicin, Gemtuzumab ozogamicin consolidation
*ALFA-0701, patients in CR or CRp and platelet count less than 100 x 109 by day 45 after the initiation of chemotherapy: Cytarabine & Daunorubicin consolidation
===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====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Daunorubicin (Cerubidine) 45 mg/m2 IV once per day on days 1 to 3
====Antibody-drug conjugate therapy====
*Gemtuzumab ozogamicin (Mylotarg) 6 mg/m2 IV over 2 hours once on day 4
7-day course
====Subsequent treatment====
*HiDAC consolidation x 3
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00927498
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00085709
#GnG: Jaramillo S, Krisam J, Le Cornet L, Kratzmann M, Baumann L, Eissymont O, Crysandt M, Görner M, Kayser S, Krause S, Schliemann C, Gaska T, Kaufmann M, Chemnitz J, Schaich M, Hoellein A, Platzbecker U, Kieser M, Müller-Tidow C, Schlenk RF. Randomized phase III GnG study on two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and double-blinded intensive postremission therapy with or without glasdegib in patients with newly diagnosed acute myeloid leukemia. Haematologica. 2024 Jun 1;109(6):1973-1976. link to original article link to PMC article does not contain dosing details in manuscript or supplement EuroPMC NCT04093505
==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	Not reported in abstract	Randomized Phase 2 (E-switch-ic)	7+3d; standard-dose	Seems to have higher CR rate
Note: The full manuscript was not available for review.
====Chemotherapy====
*Cytarabine (Ara-C) 80 mg/m2 IV over 2 hours every 12 hours on days 1 to 7
*Idarubicin (Idamycin) 12 mg/m2 IV bolus once per day on days 1 to 3
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 higher CR rate
Haas et al. 1993 	1989 to not reported	Non-randomized 	 	
Rowe et al. 2004 (ECOG E3993) 	1993-1997 	Phase 3 (E-switch-ic) 	1. 7+3d; standard-dose2. 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
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Idarubicin (Idamycin) 12 mg/m2 IV bolus once per day on days 1 to 3
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, 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 longer OS (co-primary endpoint)Median OS: 12.9 vs 8.7 mo(HR not reported, p=0.038)
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Idarubicin (Idamycin) 13 mg/m2 IV once per day on days 1 to 3
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 shorter DFS (co-primary endpoint)DFS48: 33% vs 42%(HR 1.30, 95% CI 1.01-1.64)
Pautas et al. 2010 (ALFA-9801) 	1999-2006 	Phase 3 (C)	1. 7+3d; high-dose2. 4i+7	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 EFSEFS60: 34% vs 35%(HR 1.11, 95% CI 0.93-1.33)
Löwenberg et al. 2017 (HOVON-102) 	2010-2013 	Phase 3 (C)	7+3i & Clofarabine 	Did not meet primary endpoint of EFSEFS48: 35% vs 38%
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 EFSEFS48: 44% vs 44%(HR 1.01, 95% CI 0.83-1.22)
Note: in HOVON/SAKK AML 29 & HOVON/SAKK AML 42, idarubicin was given on days 5 to 7.
====Chemotherapy====
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
*Idarubicin (Idamycin) 12 mg/m2 IV over 3 hours once per day on days 1 to 3
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 shorter OSMedian OS: 6.5 vs 10.4 mo(HR 1.18, 95% CI 0.97-1.45)
====Chemotherapy====
*Cytarabine (Ara-C) 100 to 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 to 1400 mg/m2)
*Idarubicin (Idamycin) 9 to 12 mg/m2 IV once per day on days 1 to 3
7-day course
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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. EuroPMC
#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. dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT04446052
#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 dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00931138
#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 dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC C000000157
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NTR230
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01074047
##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 EuroPMC
##HRQoL analysis: Roboz GJ, Döhner H, Pocock C, Dombret H, Ravandi F, Jang JH, Selleslag D, Mayer J, Martens UM, Liesveld J, Bernal T, Wang MC, Yu P, Shi L, Guo S, La Torre I, Skikne B, Dong Q, Braverman J, Nehme SA, Beach CL, Wei AH. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Dec 1;106(12):3240-3244. Epub 2021 Sep 23. link to original article link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NTR2187
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01145846
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==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====
*Sorafenib (Nexavar) 400 mg PO twice per day on days 1 to 7
7-day course
====Subsequent treatment====
*Cytarabine, idarubicin, sorafenib consolidation
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00542971
##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 EuroPMC
==7+3d & Glasdegib==
===Regimen===
Study 	Dates of enrollment 	Evidence
Cortes et al. 2018 (BRIGHT AML 1003 phase 2)	2012 to not reported	Phase 2
Note: glasdegib was continued beyond induction; see paper for details.
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1 to 3
====Targeted therapy====
*Glasdegib (Daurismo) 100 mg PO once per day, started on day -3
28-day course
====Subsequent treatment====
*IDAC consolidation
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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 	Not reported 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-dose2. 7+3d + GM-CSF3. 7+3i4. 7+3i + GM-CSF5. 7+3m + GM-CSF	Did not meet primary endpoint of CR rate
Note: The full manuscript for Arlin et al. 1990 was not available for review.
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Mitoxantrone (Novantrone) 12 mg/m2 IV once per day on days 1 to 3
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===
#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. dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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)	Did not meet primary endpoint of CR rateCR rate: 74% vs 71%
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3
*Etoposide (Vepesid) 75 mg/m2 IV once per day on days 1 to 7
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 not reported	Phase 3 (C)	ADEP 	Did not meet primary endpoint of CR rateCR rate: 46% vs 39%(p=0.47)
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Daunorubicin (Cerubidine) 60 mg/m2 IV bolus once per day on days 1 to 3
*Etoposide (Vepesid) 100 mg/m2 IV over 2 hours once per day on days 1 to 3
7-day course
====Subsequent treatment====
*CALGB 9720, patients achieving CR1: Observation versus low-dose IL-2 maintenance
===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====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Daunorubicin (Cerubidine) 90 mg/m2 IV once per day on days 1 to 3
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
7-day course
====Subsequent treatment====
*CALGB 19808, patients achieving CR1: Observation versus low-dose IL-2 maintenance
===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 shorter OSOS72: 38.70% vs 42.50%(HR 1.12, 95% CI 1.00-1.27)
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 10 days, started on day 1 (total dose: 1000 mg/m2)
*Daunorubicin (Cerubidine) 50 mg/m2 IV over 5 minutes once per day on days 1, 3, 5
*Etoposide (Vepesid) 50 mg/m2 IV over 60 minutes once per day on days 1 to 5
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. AIE2. AME	Did not meet primary endpoint of OS
====Chemotherapy====
*Cytarabine (Ara-C) 25 mg/m2 IV bolus once on day 1, then 100 mg/m2/day IV continuous infusion over 10 days (total dose: 1025 mg/m2)
*Daunorubicin (Cerubidine) 50 mg/m2 IV over 5 minutes 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
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====
*UK MRC AML10: ADE 10-3-5 induction
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2/day IV every 12 hours on days 1 to 8
*Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1, 3, 5
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
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====
*Cytarabine (Ara-C) 100 mg/m2/day IV every 12 hours on days 1 to 10
*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
10-day course
====Subsequent treatment====
*ADE 8-3-5 re-induction
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
##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 EuroPMC
#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 EuroPMC NCT00002658
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003190
##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 EuroPMC
#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 EuroPMC
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00006363
#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 EuroPMC ISRCTN17161961
## 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 EuroPMC
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 longer OS (primary endpoint)OS72: 42.5% vs 38.7%(HR 0.89, 95% CI 0.79-1.00)
====Chemotherapy====
*Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours every 12 hours on days 1, 3, 5, 7 (total dose: 24,000 mg/m2)
*Daunorubicin (Cerubidine) 50 mg/m2 IV over 5 minutes once per day on days 1, 3, 5
*Etoposide (Vepesid) 50 mg/m2 IV over 60 minutes once per day on days 1 to 5
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)	Did not meet primary endpoint of CR rateCR rate: 71% vs 74%
====Chemotherapy====
*Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours every 12 hours on days 1, 3, 5, 7 (total dose per cycle: 24,000 mg/m2)
*Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3
*Etoposide (Vepesid) 75 mg/m2 IV once per day on days 1 to 7
7-day course; can be repeated up to 3 times if CR not achieved
====Subsequent treatment====
*ADE; 5-2-5 consolidation x 2
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Lower CR rate (primary endpoint)CR rate: 39% vs 52%
Russo et al. 2005 	1999-2002 	Phase 3 (C) 	FLAI 	Lower 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====
*Cytarabine (Ara-C) 100 mg/m2 IV over 30 minutes twice per day on days 1 to 7 (total dose: 1400 mg/m2)
*Idarubicin (Idamycin) 12 mg/m2 IV over 30 minutes once per day on days 1 to 3
*Etoposide (Vepesid) 100 mg/m2 IV over 60 minutes once per day on days 1 to 5
7-day course
====Subsequent treatment====
*ALLG M7: ICE versus IcE consolidation
*NILG AML 02/06, early CR: IC consolidation
===References===
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC NCT00002926
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 EFSMedian EFS: 13 vs 12 mo(HR not reported)
====Chemotherapy====
*Clofarabine (Clolar) 15 mg/m2 IV once per day on days 1 to 5, given 4 hours before cytarabine
*Idarubicin (Idamycin) 10 mg/m2 IV once per day on days 1 to 3
*Cytarabine (Ara-C) 1000 mg/m2 IV over 2 hours once per day on days 1 to 5
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====
*Clofarabine (Clolar) 20 mg/m2 IV over 60 minutes once per day on days 1 to 5
*Idarubicin (Idamycin) 10 mg/m2 IV over 30 minutes once per day on days 1 to 3
*Cytarabine (Ara-C) 1000 mg/m2 IV over 2 hours once per day on days 1 to 5
====Supportive therapy====
*Levofloxacin (Levaquin)
*Itraconazole (Sporanox)
*Valacyclovir (Valtrex)
*Granulocyte colony-stimulating factor neither mandated nor forbidden and given per physician discretion
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===
#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] dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 shorter OS (primary endpoint)OS36: 20% vs 25%(HR 1.15, 95% CI 1.00-1.32)
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====
*Cytarabine (Ara-C) 100 mg/m2 IV every 12 hours on days 1 to 10
*Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1, 3, 5
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====
*Cytarabine (Ara-C) 100 mg/m2 IV every 12 hours on days 1 to 10
*Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1, 3, 5
10-day course
====Subsequent treatment====
*UK NCRI AML17, CBF+: DA 3+8 & GO consolidation
*UK NCRI AML17, non-CBF, no FLT3 mutation, not poor risk: DA 3+8 versus DA 3+8 & Everolimus consolidation
*UK NCRI AML17, poor risk other than FLT3 mutation: Clofarabine & Daunorubicin versus FLAG-Ida consolidation
===References===
#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 EuroPMC ISRCTN17161961
## 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 EuroPMC
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN11036523
##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 dosing details in manuscript have been reviewed by our editors EuroPMC
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ISRCTN55675535
##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 EuroPMC
==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 longer 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====
*Cytarabine (Ara-C) 100 mg/m2 IV every 12 hours on days 1 to 10
*Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1, 3, 5
====Antibody-drug conjugate therapy====
*Gemtuzumab ozogamicin (Mylotarg) 3 mg/m2 IV once on day 1
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====
*Cytarabine (Ara-C) 100 mg/m2 IV every 12 hours on days 1 to 10
*Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1, 3, 5
====Antibody-drug conjugate therapy====
*Gemtuzumab ozogamicin (Mylotarg) 3 mg/m2 IV once on day 1
10-day course
====Subsequent treatment====
*DA 3 + 8 consolidation
===References===
#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 EuroPMC ISRCTN17161961
## 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 EuroPMC
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN11036523
##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 dosing details in manuscript have been reviewed by our editors EuroPMC
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN31682779
#UK NCRI AML19: Russell NH, Wilhelm-Benartzi C, Othman J, Dillon R, Knapper S, Batten LM, Canham J, Hinson EL, Betteridge S, Overgaard UM, Gilkes A, Potter N, Mehta P, Kottaridis P, Cavenagh J, Hemmaway C, Arnold C, Freeman SD, Dennis M; PORTEC Study Group. Fludarabine, Cytarabine, Granulocyte Colony-Stimulating Factor, and Idarubicin With Gemtuzumab Ozogamicin Improves Event-Free Survival in Younger Patients With Newly Diagnosed AML and Overall Survival in Patients With NPM1 and FLT3 Mutations. J Clin Oncol. 2024 Apr 1;42(10):1158-1168. Epub 2024 Jan 12. link to original article EuroPMC ISRCTN78449203
==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 	Higher CR rate after first induction (primary endpoint)CR rate: 64% vs 47%
Holowiecki et al. 2012 (PALG AML1/2004)	2004-2008 	Phase 3 (E-esc)	1. DA 	Longer OS (primary endpoint)Median OS: 24 vs 14 mo(HR 0.69, 97.5% CI 0.5-0.96)
Holowiecki et al. 2012 (PALG AML1/2004)	2004-2008 	Phase 3 (E-esc)	2. DAF 	Not reported
====Chemotherapy====
*Daunorubicin (Cerubidine) 60 mg/m2 IV over 5 minutes once per day on days 1 to 3
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
*Cladribine (Leustatin) 5 mg/m2 IV over 3 hours once per day on days 1 to 5
====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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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+52. 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====
*Fludarabine (Fludara) 30 mg/m2 IV once per day on days 2 to 6
*Cytarabine (Ara-C) 2000 mg/m2 IV over 4 hours once per day on days 2 to 6, given 4 hours after fludarabine
*Idarubicin (Idamycin) 8 mg/m2 IV once per day on days 4 to 6
====Growth factor therapy====
*Lenograstim (Granocyte) 263 mcg SC once per day on days 1 to 7
7-day course
====Subsequent treatment====
*See paper for details
===References===
#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 EuroPMC ISRCTN17161961
## 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 EuroPMC
##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 EuroPMC
==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 	Longer EFS (co-primary endpoint)EFS36: 35.4% vs 23.1%
Jin et al. 2013	2007-2011 	Phase 3 (E-esc)	2. HAD 	Not reported
Note: There were significantly more deaths in this arm, despite a superior primary efficacy endpoint.
====Chemotherapy====
*Omacetaxine (Synribo) 2 mg/m2/day (route not specified) on days 1 to 7
*Cytarabine (Ara-C) 100 mg/m2 IV once per day on days 1 to 7
*Aclarubicin (Aclacinon) 20 mg IV once per day on days 1 to 7
7-day course
====Subsequent treatment====
*Jin et al. 2013, CR: IDAC consolidation x 2
===References===
#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 dosing details in abstract have been reviewed by our editors EuroPMC 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 longer OS (primary endpoint)OS24: 56% vs 48%(HR 0.73, 95% CI 0.54-0.99)
====Chemotherapy====
*Idarubicin (Idamycin) 8 mg/m2 IV once per day on days 1 to 5
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
*Lomustine (CCNU) 200 mg/m2 PO once on day 1
7-day course
====Subsequent treatment====
*IC and methotrexate/mercaptopurine with norethandrolone
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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	Lower CR rate
Amadori et al. 2013 (EORTC/GIMEMA AML-17)	2002-2007 	Phase 3 (C)	GO-MICE 	Might have longer OS (primary endpoint)Median OS: 10 vs 7.1 mo(HR 0.83, 95% CI 0.69-1.01)
====Chemotherapy====
*Mitoxantrone (Novantrone) 7 mg/m2 IV once per day on days 1, 3, 5
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
7-day course
===References===
#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 EuroPMC NCT00002719
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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====
*Induction DA 3+10 versus DA 3+10; high-dose
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2 IV every 12 hours on days 1 to 8
*Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1, 3, 5
10-day course
====Subsequent treatment====
*Consolidation HiDAC x 1 versus HiDAC x 2
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ISRCTN55675535
##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 EuroPMC
==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====
*Induction DA 3+10 versus DA 3+10; high-dose
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2 IV every 12 hours on days 1 to 8
*Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1, 3, 5
====Antibody-drug conjugate therapy====
*Gemtuzumab ozogamicin (Mylotarg) 3 mg/m2 IV once on day 1
8-day course
====Subsequent treatment====
*Consolidation HiDAC x 1 versus HiDAC x 2
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ISRCTN55675535
##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 EuroPMC
=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 	Higher OS12 (primary endpoint)OS12: 47% vs 27%
====Chemotherapy====
*Azacitidine (Vidaza) 75 mg/m2 SC once per day on days 1 to 7
28-day cycle for 3 cycles
====Subsequent treatment====
*FLUGAZA, SD or better: Azacitidine consolidation x 6
===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 care1b. LoDAC1c. 7+3d1d. 7+3i1e. 7+3m 	Longer 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-dose1b. 7+3d; intermediate-dose1c. 7+3i1d. Best supportive care1e. LoDAC	Might have longer 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 endpoint of OSMedian OS: 8.5 vs 7.1 mo(HR 1.03, 95% CI 0.88-1.20)Did not meet co-primary endpoint of CR rate
DiNardo et al. 2020 (VIALE-A) 	2017-02-06 to 2019-05-31	Phase 3 (C) 	Azacitidine & Venetoclax 	Shorter OSMedian OS: 9.6 vs 14.7 mo(HR 1.52, 95% CI 1.18-1.92)
Garcia-Manero et al. 2024 (PRIMULA) 	2017-07 to 2020-08 	Phase 3 (C) 	Azacitidine & Pracinostat 	Did not meet primary endpoint of OSMedian OS: 9.95 vs 9.95 mo(HR not reported)
Sekeres et al. 2023 (BRIGHT AML 1019)	2018-04 to 2020-01 	Phase 3 (C) 	Azacitidine & Glasdegib 	Did not meet primary endpoint of OSMedian OS: 12.2 vs 12.7 mo(HR 0.95, 95% CI 0.71-1.28)
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====
*Azacitidine (Vidaza) 75 mg/m2 IV or SC once per day on days 1 to 7
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====
*Azacitidine (Vidaza) 75 mg/m2 IV or SC once per day on days 1 to 5, 8, 9
28-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00071799
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01074047
##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 EuroPMC
##HRQoL analysis: Roboz GJ, Döhner H, Pocock C, Dombret H, Ravandi F, Jang JH, Selleslag D, Mayer J, Martens UM, Liesveld J, Bernal T, Wang MC, Yu P, Shi L, Guo S, La Torre I, Skikne B, Dong Q, Braverman J, Nehme SA, Beach CL, Wei AH. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Dec 1;106(12):3240-3244. Epub 2021 Sep 23. link to original article link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02993523
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02319135
#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 dosing details in manuscript have been reviewed by our editors EuroPMC link to PMC article NCT02348489
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03416179
# PRIMULA: Garcia-Manero G, Kazmierczak M, Wierzbowska A, Fong CY, Keng MK, Ballinari G, Scarci F, Adès L. Pracinostat combined with azacitidine in newly diagnosed adult acute myeloid leukemia (AML) patients unfit for standard induction chemotherapy: PRIMULA phase III study. Leuk Res. 2024 May;140:107480. Epub 2024 Mar 12. link to original article EuroPMC NCT03151408
# CASCADE: NCT02785900
# PEVOLAM: NCT04090736
==Azacitidine & Venetoclax==
===Regimen variant #1, slower ramp===
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====
*Azacitidine (Vidaza) 75 mg/m2 IV or SC once per day on days 1 to 7
====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
===Regimen variant #2, faster ramp===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
DiNardo et al. 2020 (VIALE-A)	2017-02-06 to 2019-05-31	Phase 3 (E-RT-esc)	Azacitidine	Longer OS (primary endpoint)Median OS: 14.7 vs 9.6 mo(HR 0.66, 95% CI 0.52-0.85)
====Chemotherapy====
*Azacitidine (Vidaza) 75 mg/m2 IV or SC once per day on days 1 to 7
====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 per day on days 3 to 28
**Cycle 2 onwards: 400 mg PO once per day on days 1 to 28
28-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02203773 NCT02203773]
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02993523
#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 to not reported	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====
*Hydroxyurea (Hydrea) 1500 mg PO twice per day or in higher doses if necessary
Once WBC is less than 10 x 109/L, stop Hydrea and proceed:
===Induction===
====Chemotherapy====
*Azacitidine (Vidaza) 75 mg/m2 IV or SC once per day on days 1 to 7
====Antibody-drug conjugate therapy====
*Gemtuzumab ozogamicin (Mylotarg) 3 mg/m2 IV once on day 8
====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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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====
*Clofarabine (Clolar) 20 mg/m2 IV over 60 minutes once per day on days 1 to 5
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 to not reported	Randomized Phase 2 (E-de-esc)	Clofarabine & LoDAC	Seems to have shorter EFS (secondary endpoint)Median EFS: 1.7 vs 7.1 mo(HR not reported, p=0.04)
Burnett et al. 2010 (BIOV-121) 	2004-2005 	Phase 2 	 	
====Chemotherapy====
*Clofarabine (Clolar) 30 mg/m2 IV over 60 minutes once per day on days 1 to 5
5-day course
====Subsequent treatment====
*A second induction was permitted for SD or better.
*MDACC 2004-0183, responders: clofarabine & cytarabine consolidation
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00088218
#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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN11036523
##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 dosing details in manuscript have been reviewed by our editors EuroPMC
##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 EuroPMC
==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 to not reported	Randomized Phase 2 (E-esc)	Clofarabine	Seems to have longer EFS (secondary endpoint)Median EFS: 7.1 vs 1.7 mo(HR not reported, p=0.04)
====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====
*MDACC 2004-0183, CRi or better: Clofarabine & LoDAC consolidation
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Faderl et al. 2012	2008-10 to 2010-01 	Phase 2
====Chemotherapy====
*Clofarabine (Clolar) 20 mg/m2 IV once per day on days 1 to 5, given first
*Cytarabine (Ara-C) 20 mg SC twice per day on days 1 to 10
28-day course
====Subsequent treatment====
*Faderl et al. 2012, anything other than CR after first induction: Optional identical Clofarabine & LoDAC re-induction
*Faderl et al. 2012, anything other than CR after the second induction: Decitabine salvage
*Faderl et al. 2012, CR: Clofarabine & low-dose cytarabine alternating with decitabine consolidation
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00088218
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
##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 EuroPMC
==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 higher 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	Longer 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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00788892
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01696084
##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 EuroPMC
##Q-TWiST analysis: Cortes JE, Lin TL, Uy GL, Ryan RJ, Faderl S, Lancet JE. Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML. J Hematol Oncol. 2021 Jul 13;14(1):110. link to original article link to PMC article EuroPMC
==Decitabine monotherapy==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Issa et al. 2014	Not reported 	Randomized Phase 2 (C)	Decitabine & Valproate	Did not meet primary endpoint
====Chemotherapy====
*Decitabine (Dacogen) 20 mg/m2 IV over 60 minutes once per day on days 1 to 5
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. LoDAC1b. Best supportive care	Might have longer 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 endpoint of OSMedian OS: 8.5 vs 7.1 mo(HR 1.03, 95% CI 0.88-1.20)Did not meet co-primary endpoint of CR rate
====Chemotherapy====
*Decitabine (Dacogen) 20 mg/m2 IV over 60 minutes once per day on days 1 to 5
====Supportive therapy====
*Hydroxyurea (Hydrea) (dose not specified) could be used up until cycle 1 day 15
28-day cycles
===Regimen variant #3===
Study 	Dates of enrollment 	Evidence
Blum et al. 2010 (OSU 07017) 	2007 to not reported	Phase 2
Welch et al. 2016 (Wash U 201210102)	2013-2015 	Phase 2
====Chemotherapy====
*Decitabine (Dacogen) 20 mg/m2 IV over 60 minutes once per day on days 1 to 10
====Supportive therapy====
*Hydroxyurea (Hydrea) (dose not specified) allowed during and prior to cycle 1
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===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00492401
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00260832
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01687400
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02472145
#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 dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT01303796
#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 dosing details in manuscript have been reviewed by our editors EuroPMC link to PMC article NCT02348489
# CASCADE: NCT02785900
==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====
*Decitabine (Dacogen) 20 mg/m2 IV or SC once per day on days 1 to 5
====Targeted therapy====
*Venetoclax (Venclexta) 400, 800, or 1200 mg PO once per day on days 1 to 28
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====
*Decitabine (Dacogen) 20 mg/m2 IV or SC once per day on days 1 to 10
====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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02203773 NCT02203773]
##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 EuroPMC
#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 EuroPMC 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	Lower 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====
*Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 1 to 3
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	Lower 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====
*Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 1 to 3
28-day cycle for 3 cycles
====Subsequent treatment====
*FLUGAZA, SD or better: mini-FLUGA consolidation x 6
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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	Longer OS (primary endpoint)Median OS: 4.9 vs 3.6 mo(HR 0.69, 95% CI 0.53-0.90)
====Antibody-drug conjugate therapy====
*Gemtuzumab ozogamicin (Mylotarg) 6 mg/m2 IV once on day 1, then 3 mg/m2 IV once on day 8
8-day course
====Subsequent treatment====
*EORTC/GIMEMA AML-19, patients with benefit: Gemtuzumab ozogamicin maintenance
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 to not reported	Randomized Phase 2 (E-RT-esc)	LoDAC 	Longer 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====
*Cytarabine (Ara-C) 20 mg SC twice per day on days 1 to 10
====Targeted therapy====
*Glasdegib (Daurismo) 100 mg PO once per day on days 1 to 28
28-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01546038
##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 EuroPMC
==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 lower OCRR
Döhner et al. 2014 (BI 1230.4) 	2010-2011 	Randomized Phase 2 (C)	LoDAC & Volasertib	Seems to have lower ORR (primary endpoint)ORR: 13.3% vs 31%
Cortes et al. 2018 (BRIGHT AML 1003)	2014 to not reported 	Randomized Phase 2 (C)	Glasdegib & LoDAC 	Shorter OS1Median OS: 4.3 vs 8.3 mo(HR 2.02, 95% CI 1.33-3.08)
Fenaux et al. 2023 (SGI-110-04) 	2015-03-19 to 2016-11-25	Phase 3 (C) 	Guadecitabine 	Did not meet co-primary endpoint of OSMedian OS: 8.5 vs 7.1 mo(HR 1.03, 95% CI 0.88-1.20)Did not meet co-primary endpoint of CR rate
1Reported efficacy for BRIGHT AML 1003 is based on the 2021 update.
====Chemotherapy====
*Cytarabine (Ara-C) 20 mg SC twice per day on days 1 to 10
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 OSMedian OS: 5.1 vs 4.7 mo(HR 1.04, 95% CI 0.78-1.39)
Burnett et al. 2015 	2010-2012 	Randomized (C) 	Sapacitabine 	Might have lower CR rate
Dombret et al. 2015 (AZA-AML-001) 	2010-2014 	Phase 3 (C) 	Azacitidine 	Might have shorter OSMedian OS: 6.5 vs 10.4 mo(HR 1.18, 95% CI 0.97-1.45)
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
Dennis et al. 2015 (UK NCRI LI-1) 	2012-2013 	Randomized (C) 	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====
*Cytarabine (Ara-C) 20 mg/m2 SC twice per day on days 1 to 10
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 shorter OSMedian OS: 5 vs 7.7 mo(HR 1.18, 95% CI 0.96-1.45)
Wei et al. 2020 (VIALE-C) 	2017-05 to 2018-11 	Phase 3 (C)	LoDAC & Venetoclax	Seems to have shorter OS1Median OS: 4.1 vs 8.4 mo(HR 1.43, 95% CI 1.01-2.00)
1Reported efficacy for VIALE-C is based on the 2021 update.
====Chemotherapy====
*Cytarabine (Ara-C) 20 mg/m2 SC once per day on days 1 to 10
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	Shorter OSMedian OS: 16 vs 24.5 mo(HR 2.13, 95% CI 1.27-3.57)
====Chemotherapy====
*Cytarabine (Ara-C) 20 mg/m2 SC once per day on days 1 to 14
28-day cycle for at least 4 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00071799
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00260832
##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 EuroPMC
#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 EuroPMC NCT00528333
#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 dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN11036523
##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 dosing details in manuscript have been reviewed by our editors EuroPMC
##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 EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC NCT00952588
#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 EuroPMC NCT00804856
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ISRCTN40571019
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01074047
##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 EuroPMC
##HRQoL analysis: Roboz GJ, Döhner H, Pocock C, Dombret H, Ravandi F, Jang JH, Selleslag D, Mayer J, Martens UM, Liesveld J, Bernal T, Wang MC, Yu P, Shi L, Guo S, La Torre I, Skikne B, Dong Q, Braverman J, Nehme SA, Beach CL, Wei AH. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Dec 1;106(12):3240-3244. Epub 2021 Sep 23. link to original article link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01546038
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03069352
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC link to PMC article NCT02348489
#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 longer 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====
*Cytarabine (Ara-C) 20 mg/m2 SC once per day on days 1 to 10
====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===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02287233
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03069352
##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 EuroPMC
==Temozolomide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Brandwein et al. 2014	Not reported 	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===
#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 dosing details in abstract have been reviewed by our editors EuroPMC
=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 lower OS24
Note: Patients were first randomized to daunorubicin or idarubicin beginning with induction, and continued the same agent in consolidation.
====Preceding treatment====
*4d+7 induction
====Chemotherapy====
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
*Daunorubicin (Cerubidine) 45 mg/m2 IV once per day on days 1 to 4
One course
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 lower OS24
Note: Patients were first randomized to daunorubicin or idarubicin beginning with induction, and continued the same agent in consolidation.
====Preceding treatment====
*4i+7 induction
====Chemotherapy====
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
*Idarubicin (Idamycin) 9 mg/m2 IV once per day on days 1 to 4
One course
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose: 500 mg/m2)
*Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1 & 2
5-day course
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01696084
##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 EuroPMC
##Q-TWiST analysis: Cortes JE, Lin TL, Uy GL, Ryan RJ, Faderl S, Lancet JE. Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML. J Hematol Oncol. 2021 Jul 13;14(1):110. link to original article link to PMC article EuroPMC
==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====
*7+3i induction
====Chemotherapy====
*Cytarabine (Ara-C) 25 mg/m2 IV once on day 1, then 100 mg/m2/day IV continuous infusion over 120 hours (total dose: 525 mg/m2)
*Idarubicin (Idamycin) 12 mg/m2 IV once per day on days 1 & 2
5-day course
====Subsequent treatment====
*Consolidation HiDAC versus BuCy, then auto HSCT or BuCy, then allo HSCT
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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, 1 cycle of 2000 mg/m2 every 12 hours x 6 (HDAC-135)===
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====
*Cytarabine & Mitoxantrone consolidation
====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====
*Induction BHAC-MMV
====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====
*A-VVV consolidation
===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)	BuCy, then auto HSCT	Seems to have longer OS (secondary endpoint)Median OS: 60 vs 27 mo(HR not reported, p=0.05)
Note: This trial had a third treatment group for patients with bone marrow donors; this group was not randomized.
====Preceding treatment====
*5+2i consolidation
====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 (HDAC-135)===
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 DFSMedian DFS: 1.1 vs 1 years(HR not reported, p=0.66)
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 	Shorter EFS (primary endpoint)Median EFS: 9 vs 21 mo(HR 1.56, 95% CI 1.10-2.22)
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====
*CALGB 9222: Induction 7+3d; standard-dose
*SWOG S0106: Induction 7+3d; intermediate-dose versus 7+3d & GO
*AML2003: Induction 7+3d; intermediate-dose x 2
*ACCEDE: Induction Amonafide & Cytarabine versus 7+3d; standard-dose
*SORAML: Induction 7+3d; intermediate-dose versus 7+3d & Sorafenib
*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)
3 cycles of varying durations
====Subsequent treatment====
*SWOG S0106: GO maintenance versus no further 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====
*Induction 7+5d or 7+3i
====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 x 109/L, and 100 x 109/L
===Regimen variant #6, 4 cycles of 3000 mg/m2 every 12 hours x 6 (HDAC-135)===
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 longer 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====
*ALFA-9802: Cytarabine & Daunorubicin consolidation
===Regimen variant #7, 1 to 3 cycles of 3000 mg/m2 every 12 hours x 6 (HDAC-123)===
Study 	Dates of enrollment 	Evidence
Dumas et al. 2020 	2008-01-01 to 2017-06-30	Retrospective
Nedumannil et al. 2023	2018-06 to 2023-06 	Retrospective
====Chemotherapy====
*Cytarabine (Ara-C) 3000 mg/m2 IV every 12 hours on days 1 to 3 (total dose per cycle: 18,000 mg/m2)
1 to 3 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC C000000157
##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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00880243
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00085709
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00180102
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00715637
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00893373
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01145846
#Retrospective: Dumas PY, Bertoli S, Bérard E, Leguay T, Tavitian S, Galtier J, Alric C, Bidet A, Delabesse E, Rieu JB, Vial JP, Vergez F, Lechevalier N, Luquet I, Klein E, Sarry A, Rey H, de Grande AC, Despas F, Pigneux A, Récher C. Delivering HDAC over 3 or 5 days as consolidation in AML impacts health care resource consumption but not outcome. Blood Adv. 2020 Aug 25;4(16):3840-3849. link to original article link to PMC article EuroPMC
#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 EuroPMC NCT01246752
#Retrospective: Nedumannil R, Batterham E, Harding E, Ritchie D, Wei A, Bajel A. Consecutive day dosing of high-dose cytarabine consolidation over 3 days is resource-efficient and safe in older adult patients with acute myeloid leukemia. Leuk Lymphoma. 2023 Dec;64(13):2123-2132. Epub 2023 Sep 1. link to original article EuroPMC
==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====
*Induction Amonafide & Cytarabine versus 7+3d; standard-dose
====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====
*Induction BHAC-MMV
====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====
*A-VVV consolidation
===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====
*HOVON 43 AML/SAKK 30/01, transplant eligible patients: allogeneic HSCT consolidation
*HOVON 43 AML/SAKK 30/01, transplant ineligible patients: Gemtuzumab ozogamicin maintenance versus no further treatment
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN77039377
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 shorter RFS (primary endpoint)RFS24: 46.5% vs 58.5%(aHR 1.54, 95% CI 1.02-2.33)
====Preceding treatment====
*Cytarabine, Daunorubicin, G-CSF induction
====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====
*Filgrastim (Neupogen) 5 mcg/kg IV once per day on days 1 to 5
35-day cycle for 3 cycles
===References===
#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 dosing details in supplement have been reviewed by our editors EuroPMC NCT00932412
==Azacitidine monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Nand et al. 2013 (SWOG S0703)	2008 to not reported	Phase 2
====Preceding treatment====
*Azacitidine & Gemtuzumab ozogamicin consolidation
====Chemotherapy====
*Azacitidine (Vidaza) 75 mg/m2 SC once on day 1
28-day cycle for 4 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00658814
==Azacitidine & Gemtuzumab ozogamicin==
===Regimen===
Study 	Dates of enrollment 	Evidence
Nand et al. 2013 (SWOG S0703)	2008 to not reported	Phase 2
====Preceding treatment====
*Azacitidine & Gemtuzumab ozogamicin induction
====Chemotherapy====
*Azacitidine (Vidaza) 75 mg/m2 IV or SC once per day on days 1 to 7
====Antibody-drug conjugate therapy====
*Gemtuzumab ozogamicin (Mylotarg) 3 mg/m2 IV once on day 8
====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===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00658814
==Busulfan & Cyclophosphamide, 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
===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 RFSRFS60: 38% vs 29%(HR 0.82, 95% CI 0.66-1.10)
====Preceding treatment====
*Induction 7+3i, then Amsacrine & Cytarabine consolidation
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 EuroPMC 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	 	
Beelen et al. 2019 (MC-FludT.14/L)	2013-2016 	Phase 3 (C) 	Fludarabine & Treosulfan	Non-inferior EFS24
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00070135
#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 EuroPMC NCT01339910
#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 dosing details in abstract have been reviewed by our editors EuroPMC NCT00822393
#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 EuroPMC NCT01471444
==CIA==
CIA: Clofarabine, Idarubicin, Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment	Evidence
Nazha et al. 2013	2010-2012 	Phase 2
====Preceding treatment====
*CIA induction
====Chemotherapy====
*Clofarabine (Clolar) 15 mg/m2 IV once per day on days 1 to 3
*Idarubicin (Idamycin) 8 mg/m2 IV once per day on days 1 & 2
*Cytarabine (Ara-C) 750 mg/m2 IV once per day on days 1 to 3
21- to 28-day cycle for up to 6 cycles; exact timing depends on disease response and recovery from regimen toxicity
===References===
#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] dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==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 longer RFS (primary endpoint)RFS24: 58.5% vs 46.5%(aHR 0.65, 95% CI 0.43-0.98)
====Preceding treatment====
*Cytarabine, Daunorubicin, G-CSF induction
====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====
*Filgrastim (Neupogen) 5 mcg/kg IV once per day on days 1 to 6
35-day cycle for 3 cycles
===References===
#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 dosing details in supplement have been reviewed by our editors EuroPMC 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)====
*Clofarabine (Clolar) 20 mg/m2 IV once per day on days 1 to 3
*Cytarabine (Ara-C) 20 mg SC twice per day on days 1 to 7
====Chemotherapy, decitabine portion (cycles 4 to 6, 10 to 12, 16 to 18)====
*Decitabine (Dacogen) 20 mg/m2 IV once per day on days 1 to 5
4- to 7-week cycle for 18 cycles, interval depending on count recovery
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
##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 EuroPMC
==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====
*CPX-351 induction
====Chemotherapy====
*CPX-351 (Vyxeos) 65 units/m2 IV over 90 minutes once per day on days 1 & 3
5- to 8-week cycle for 2 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01696084
##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 EuroPMC
##Q-TWiST analysis: Cortes JE, Lin TL, Uy GL, Ryan RJ, Faderl S, Lancet JE. Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML. J Hematol Oncol. 2021 Jul 13;14(1):110. link to original article link to PMC article EuroPMC
==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====
*7+3d; intermediate-dose or 7+3d & GO induction
====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 higher OS24 (primary endpoint)
====Preceding treatment====
*4d+7 induction
====Chemotherapy====
*Cytarabine (Ara-C) 60 mg/m2 SC every 12 hours on days 1 to 5 (total dose per cycle: 600 mg/m2)
*Daunorubicin (Cerubidine) 45 mg/m2 IV once on day 1
1-month cycle for up to 6 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00363025
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00927498
##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 EuroPMC
==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====
*7+3d & GO induction
====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====
*Gemtuzumab ozogamicin (Mylotarg) 3 mg/m2 (maximum dose of 5 mg) IV once on day 1
2 cycles (length not specified)
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00927498
##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 EuroPMC
==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====
*Induction 7+3d; high-dose versus 7+3i
====Chemotherapy====
*Cytarabine (Ara-C) 1000 mg/m2 IV once per day on days 1 to 6
*Etoposide (Vepesid) 150 mg/m2 IV once per day on days 1 to 3
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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 higher OS24 (primary endpoint)
====Preceding treatment====
*4i+7 induction
====Chemotherapy====
*Cytarabine (Ara-C) 60 mg/m2 SC every 12 hours on days 1 to 5 (total dose per cycle: 600 mg/m2)
*Idarubicin (Idamycin) 9 mg/m2 IV once on day 1
1-month cycle for up to 6 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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====
*7+3i & Sorafenib induction
====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====
*Sorafenib (Nexavar) 400 mg PO twice per day for up to 28 days
4- to 6-week cycle for up to 5 cycles
====Subsequent treatment====
*Sorafenib maintenance
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00542971
##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 EuroPMC
==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 	Longer 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====
*Zittoun et al. 1995: Induction 7+3d with CR, then Amsacrine & IDAC consolidation
===References===
#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 EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC NCT00150878
#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 EuroPMC
#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	TBD if different primary endpoint of EFS
Note: this dosing was intended for patients older than 60. Dosing information is from CT.gov.
====Preceding treatment====
*7+3d induction
====Chemotherapy====
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
*Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 to 3
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====
*Induction 7+3i, then Amsacrine & Cytarabine consolidation
====Chemotherapy====
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
*Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 to 5
One course
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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
===Regimen variant #2, low-dose TBI===
Study 	Dates of enrollment	Evidence
Gyukocza et al. 2010	1998-2008 	Non-randomized
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC 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====
*Cytarabine (Ara-C) 1500 mg/m2 IV once per day on days 1 to 3
*Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 3 to 5
One course
====Subsequent treatment====
*HiDAC consolidation
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC content property of HemOnc.org
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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	Longer OS (secondary endpoint)OS60: 26.3% vs 17.2%
====Preceding treatment====
*Induction 7+3i & Lomustine
====Chemotherapy, reinduction portion (cycles 1, 3, 5)====
*Idarubicin (Idamycin) 8 mg/m2 IV once on day 1
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 500 mg/m2)
====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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
=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	Longer DFS (primary endpoint)DFS12: 64% vs 42%(aHR 0.62, 95% CI 0.41-0.95)
====Preceding treatment====
*At least 2 cycles of intensive chemotherapy induction
====Chemotherapy====
*Azacitidine (Vidaza) 50 mg/m2 SC once per day on days 1 to 5
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====
*Induction 7+2d
====Chemotherapy====
*Azacitidine (Vidaza) 60 mg/m2 SC once per day on days 1 to 5
28-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC NTR1810
==Decitabine monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Blum et al. 2010 (OSU 07017)	2007 to not reported	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====
*Decitabine induction
====Chemotherapy====
*Decitabine (Dacogen) 20 mg/m2 IV over 60 minutes once per day on days 1 to 5
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===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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	Longer OS (primary endpoint)Median OS: 24.7 vs 14.8 mo(HR not reported1, p<0.001)
1The proportional hazards assumption was violated, so hazard ratios were not reported.
====Preceding treatment====
*Induction chemotherapy
====Chemotherapy====
*Azacitidine oral (Onureg) 300 mg PO once per day on days 1 to 14
28-day cycles
===References===
#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 dosing details in abstract have been reviewed by our editors EuroPMC NCT01757535
##Update: Wei AH, Döhner H, Sayar H, Ravandi F, Montesinos P, Dombret H, Selleslag D, Porkka K, Jang JH, Skikne B, Beach CL, Prebet T, Zhang G, Risueño A, Ugidos M, See WL, Menezes D, Roboz GJ. Long-term survival with oral azacitidine for patients with acute myeloid leukemia in first remission after chemotherapy: Updated results from the randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial. Am J Hematol. 2023 Apr;98(4):E84-E87. Epub 2023 Feb 6. link to original article EuroPMC
==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====
*Gemtuzumab ozogamicin induction, with clinical benefit
====Antibody-drug conjugate therapy====
*Gemtuzumab ozogamicin (Mylotarg) 2 mg/m2 IV once on day 1
1-month cycle for up to 8 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 longer DFS
====Preceding treatment====
*HiDAC, then amsacrine induction
====Chemotherapy====
*Cytarabine (Ara-C) 10 mg/m2 SC twice per day on days 1 to 21
8-week cycles
===References===
#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 dosing details in abstract have been reviewed by our editors EuroPMC
==Sorafenib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Ravandi et al. 2010 (BAY43-9006)	2007-2009 	Phase 1/2
====Preceding treatment====
*Cytarabine, Idarubicin, Sorafenib consolidation
====Targeted therapy====
*Sorafenib (Nexavar) 400 mg PO twice per day
Up to one year course, including consolidation
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00542971
##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 EuroPMC
=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====
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose: 500 mg/m2)
*Daunorubicin (Cerubidine) 45 mg/m2 IV once per day on days 1 & 2
5-day course
===References===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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 longer 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===
#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 EuroPMC 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)
One course
====Subsequent treatment====
*Robak et al. 2000, PR: Repeat CLAG re-induction
*Robak et al. 2000, CR: Cladribine, Cytarabine, Idarubicin consolidation
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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. EuroPMC
==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====
*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
*Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 to 3
====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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC content property of HemOnc.org
#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. EuroPMC
==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 to not reported	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===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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====
*Clofarabine (Clolar) 20 mg PO once per day on days 1 to 5
*Cytarabine (Ara-C) 20 mg/m2 SC twice per day on days 1 to 10
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====
*Clofarabine (Clolar) 20 mg PO once per day on days 1 to 5
*Cytarabine (Ara-C) 20 mg/m2 SC once per day on days 1 to 14
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====
*Clofarabine (Clolar) 30 mg/m2 IV once per day on days 1 to 5
*Cytarabine (Ara-C) 1000 mg/m2 IV once per day on days 1 to 5
At least one cycle
====Subsequent treatment====
*BRIDGE, chemo-responsive patients: Clofarabine & Melphalan, then allo HSCT consolidation
===Regimen variant #4, 40/1000===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Faderl et al. 2004 	Not reported 	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====
*Best described in Agura et al. 2011
*Dexamethasone (Decadron) 10 mg IV once per day
*5-HT3 antagonists on each day of chemotherapy
*Hydration at 150 mL/m2/H "to prevent tumor lysis syndrome" during chemotherapy
*Bumetanide (Bumex) 2 to 4 mg IV push once to twice per day as needed to keep weight within 1 kg of patient's initial weight
*Levofloxacin (Levaquin) 500 mg IV or PO once per day
*Acyclovir (Zovirax) 500 mg IV Q12H
*One of the following antifungals:
**Caspofungin (Cancidas) 50 mg IV once per day
**Voriconazole (Vfend) 200 mg (route not specified) twice per day
*Parenteral nutrition allowed
*No routine use of growth factors
28-day cycle for 1 to 4 cycles 
====Subsequent treatment====
*See individual papers for details
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00334074
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00317642
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC
==Etoposide & Mitoxantrone==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Ho et al. 1988	1984-1987 	Phase 2 	ORR: 54%
====Chemotherapy====
*Etoposide (Vepesid) 100 mg/m2 IV over 30 minutes once per day on days 1 to 5
*Mitoxantrone (Novantrone) 10 mg/m2 IV over 15 minutes once per day on days 1 to 5
21-day course
====Subsequent treatment====
*MEC consolidation
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#ASTRAL-2: Roboz GJ, Sanz G, Griffiths EA, Yee K, Kantarjian H, Récher C, Byrne MT, Patkowska E, Kim HJ, Thomas X, Moors I, Stock W, Illés Á, Fenaux P, Miyazaki Y, Yamauchi T, O'Connell CL, Hao Y, Keer HN, Azab M, Döhner H. Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial. Blood Adv. 2024 Apr 23;8(8):2020-2029. link to original article link to PMC article EuroPMC NCT02920008
==FLAG-Ida==
FLAG-Ida: FLudarabine, Ara-C (Cytarabine), G-CSF (Filgrastim), Idarubicin
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Parker et al. 1997	1995-1997 	Phase 2, fewer than 20 patients
Note: G-CSF was given both as antineoplastic priming and as supportive therapy in this regimen variant.
====Chemotherapy====
*Fludarabine (Fludara) by the following laboratory-based criteria:
**CrCl greater than 70 mL/min/1.73m2: 30 mg/m2 IV over 30 minutes once per day on days 1 to 5, given first
**CrCl 30 to 70 mL/min/1.73m2: 15 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 fludarabine
*Idarubicin (Idamycin) 10 mg/m2 IV once per day on days 1 to 3
====Growth factor therapy====
*Filgrastim (Neupogen) 300 mcg/m2 IV over 2 hours once per day on days -1 to 5
====Supportive therapy====
*Filgrastim (Neupogen) (dose not specified) SC once per day, starting on day 12, to continue until ANC greater than 500/uL
One course
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
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====
*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 fludarabine
*Idarubicin (Idamycin) 10 mg/m2 IV once per day on days 1 to 3
====Supportive therapy====
*Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6, to continue until ANC greater than 500/uL
5-day course
===Regimen variant #3===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Roboz et al. 2024 (ASTRAL-2)	Not reported to 2018-09	Phase 3 (C)	Guadecitabine	Did not meet primary endpoint of OSMedian OS: 5.4 vs 6.4 mo(HR 1.14, 95% CI 0.88-1.49)
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. The dose of cytarabine reported in Roboz et al. 2024 is 12 g/m2/day, which appears to be an error - the authors were contacted for clarification on July 7, 2024 and confirmed that this was an error; the standard 2 g/m2/day is shown here.
====Chemotherapy====
*Fludarabine (Fludara) 25 to 30 mg/m2 IV once per day on days 1 to 5
*Cytarabine (Ara-C) 2000 mg/m2 IV once per day on days 1 to 5, given 4 hours after fludarabine
*Idarubicin (Idamycin) 8 mg/m2 IV once per day on days 3 to 5
====Supportive therapy====
*Filgrastim (Neupogen) (dose not specified) SC once per day, starting on day 6, to continue until WBC count recovery
5-day course
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#ASTRAL-2: Roboz GJ, Sanz G, Griffiths EA, Yee K, Kantarjian H, Récher C, Byrne MT, Patkowska E, Kim HJ, Thomas X, Moors I, Stock W, Illés Á, Fenaux P, Miyazaki Y, Yamauchi T, O'Connell CL, Hao Y, Keer HN, Azab M, Döhner H. Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial. Blood Adv. 2024 Apr 23;8(8):2020-2029. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02920008
==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	Not reported 	Phase 3 (E-esc)	SHAI 	Seems to have longer TTF (primary endpoint)Median TTF: 3.38 vs 2.04 mo
====Chemotherapy====
*Fludarabine (Fludara) 15 mg/m2 IV twice per day on days 1, 2, 8, 9, given 4 hours prior to each cytarabine dose
*Cytarabine (Ara-C) 1000 mg/m2 IV twice per day on days 1, 2, 8, 9
*Idarubicin (Idamycin) 10 mg/m2 IV once per day on days 3, 4, 10, 11
====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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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====
*Gemtuzumab ozogamicin (Mylotarg) 3 mg/m2 IV once per day on days 1, 4, 7
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====
*Gemtuzumab ozogamicin (Mylotarg) 9 mg/m2 IV over 2 hours once on day 1
14- to 28-day cycle for up to 3 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==HAM==
HAM: High-dose Ara-C (Cytarabine), Mitoxantrone
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Stelljes et al. 2024 (ASAP)	2015-09-17 to 2022-01-12	Phase 3 (C)	Immediate allogeneic HSCT consolidation	Inconclusive whether non-inferior treatment success (primary endpoint)
====Chemotherapy====
*Cytarabine (Ara-C) by the following criteria:
**60 years old or younger AND no substantial comorbidity: 3000 mg/m2 IV twice per day on days 1 to 3
**Older than 60 years old OR substantial comorbidity: 1000 mg/m2 IV twice per day on days 1 to 3
*Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 3 to 5
One course
====Subsequent treatment====
*Allogeneic HSCT consolidation
===References===
#ASAP: Stelljes M, Middeke JM, Bug G, Wagner-Drouet EM, Müller LP, Schmid C, Krause SW, Bethge W, Jost E, Platzbecker U, Klein SA, Schubert J, Niederland J, Kaufmann M, Schäfer-Eckart K, Schaich M, Baldauf H, Stölzel F, Petzold C, Röllig C, Alakel N, Steffen B, Hauptrock B, Schliemann C, Sockel K, Lang F, Kriege O, Schaffrath J, Reicherts C, Berdel WE, Serve H, Ehninger G, Schmidt AH, Bornhäuser M, Mikesch JH, Schetelig J; Study Alliance Leukemia and the German Cooperative Transplant Study Group. Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial. Lancet Haematol. 2024 May;11(5):e324-e335. Epub 2024 Apr 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02461537
==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 longer 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====
*Cytarabine (Ara-C) 3000 mg/m2 IV every 12 hours on days 1 to 6 (total dose: 36,000 mg/m2)
6-day course
===References===
#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 EuroPMC
#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 dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00112554
#ASTRAL-2: Roboz GJ, Sanz G, Griffiths EA, Yee K, Kantarjian H, Récher C, Byrne MT, Patkowska E, Kim HJ, Thomas X, Moors I, Stock W, Illés Á, Fenaux P, Miyazaki Y, Yamauchi T, O'Connell CL, Hao Y, Keer HN, Azab M, Döhner H. Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial. Blood Adv. 2024 Apr 23;8(8):2020-2029. link to original article link to PMC article EuroPMC NCT02920008
==Intermediate-dose Cytarabine monotherapy (IDAC)==
IDAC: Intermediate Dose Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Konopleva et al. 2022 (MIRROS)	2015-12-31 to 2020-01-13	Phase 3 (C)	IDAC & Idasanutlin	Did not meet primary endpoint of OSMedian OS: 9.1 vs 8.3 mo(sHR 0.93, 95% CI 0.69-1.23)
====Chemotherapy====
*Cytarabine (Ara-C) 1000 mg/m2 IV once per day on days 1 to 5
28-day cycle for up to 3 cycles
===References===
#ASTRAL-2: Roboz GJ, Sanz G, Griffiths EA, Yee K, Kantarjian H, Récher C, Byrne MT, Patkowska E, Kim HJ, Thomas X, Moors I, Stock W, Illés Á, Fenaux P, Miyazaki Y, Yamauchi T, O'Connell CL, Hao Y, Keer HN, Azab M, Döhner H. Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial. Blood Adv. 2024 Apr 23;8(8):2020-2029. link to original article link to PMC article EuroPMC NCT02920008
#MIRROS: Konopleva MY, Röllig C, Cavenagh J, Deeren D, Girshova L, Krauter J, Martinelli G, Montesinos P, Schäfer JA, Ottmann O, Petrini M, Pigneux A, Rambaldi A, Recher C, Rodriguez-Veiga R, Taussig D, Vey N, Yoon SS, Ott M, Muehlbauer S, Beckermann BM, Catalani O, Genevray M, Mundt K, Jamois C, Fenaux P, Wei AH. Idasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial. Blood Adv. 2022 Jul 26;6(14):4147-4156. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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====
*Mitoxantrone (Novantrone) 5 mg/m2 IV bolus once per day on days 1 to 5
*Cytarabine (Ara-C) 500 mg/m2 IV over 90 minutes every 12 hours on days 1 to 6 (total dose: 6000 mg/m2)
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====
*Mitoxantrone (Novantrone) 12 mg/m2 IV bolus once per day on days 2 to 5
*Cytarabine (Ara-C) 1000 mg/m2 IV every 12 hours on days 1 to 5 (total dose: 10,000 mg/m2)
5-day course
===References===
#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 dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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====
*Mitoxantrone (Novantrone) 6 mg/m2 IV bolus once per day on days 1 to 6
*Etoposide (Vepesid) 80 mg/m2 IV over 60 minutes once per day on days 1 to 6
*Cytarabine (Ara-C) 1000 mg/m2 IV over 6 hours once per day on days 1 to 6
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====
*Mitoxantrone (Novantrone) 8 mg/m2 IV once per day on days 1 to 6
*Etoposide (Vepesid) 80 mg/m2 IV once per day on days 1 to 6
*Cytarabine (Ara-C) 1000 mg/m2 IV once per day on days 1 to 6
6-day course
===Regimen variant #3, 8/100/1000===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Greenberg et al. 2004 (ECOG E2995)	Not reported to 1999 	Phase 3 (C) 	MEC & Valspodar	Did not meet primary endpoint of CR rate
Cortes et al. 2014 (CLTR0308-205) 	2009 to not reported 	Randomized Phase 2 (C)	CPX-351 	Did not meet primary endpoint of OS12
Roboz et al. 2024 (ASTRAL-2) 	Not reported to 2018-09	Phase 3 (C) 	Guadecitabine 	Did not meet primary endpoint of OSMedian OS: 5.4 vs 6.4 mo(HR 1.14, 95% CI 0.88-1.49)
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. This was the recommended dosing for MEC in ASTRAL-2, which also provided ranges (see paper for details).
====Chemotherapy====
*Mitoxantrone (Novantrone) 8 mg/m2 IV push once per day on days 1 to 5, given third
*Etoposide (Vepesid) 100 mg/m2 IV over 2 hours once per day on days 1 to 5, given first
*Cytarabine (Ara-C) 1000 mg/m2 IV once per day on days 1 to 5, given second
28-day cycle for 1 to 2 cycles
===References===
#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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 EuroPMC NCT00822094
#ASTRAL-2: Roboz GJ, Sanz G, Griffiths EA, Yee K, Kantarjian H, Récher C, Byrne MT, Patkowska E, Kim HJ, Thomas X, Moors I, Stock W, Illés Á, Fenaux P, Miyazaki Y, Yamauchi T, O'Connell CL, Hao Y, Keer HN, Azab M, Döhner H. Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial. Blood Adv. 2024 Apr 23;8(8):2020-2029. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02920008
#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 	Longer 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 lower NRM12
Scott et al. 2017 (BMT CTN 0901) 	2011-2014 	Phase 3 (C) 	1a. BuFlu, then allo HSCT1b. FluMel, then allo HSCT	Seems to have longer 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 	Lower CIR24
===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 lower TRM12
===Regimen variant #3, 16/200===
Study 	Dates of enrollment	Evidence
Santos et al. 1983	1975-1982 	Non-randomized
===References===
#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 dosing details in abstract have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00774280
#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 EuroPMC NCT01191957
#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 EuroPMC NCT01339910
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02487069
#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 dosing details in abstract have been reviewed by our editors EuroPMC 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 higher TRMM12 (primary endpoint)
===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 higher NRM12 (primary endpoint)
===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
===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	Shorter OS (secondary endpoint)
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00774280
#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 EuroPMC NCT01191957
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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====
*Clofarabine & Cytarabine salvage
===References===
#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 dosing details in abstract have been reviewed by our editors EuroPMC
=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
Roboz et al. 2024 (ASTRAL-2)	Not reported to 2018-09	Phase 3 (C)	Guadecitabine	Did not meet primary endpoint of OSMedian OS: 5.4 vs 6.4 mo(HR 1.14, 95% CI 0.88-1.49)
Note: Roboz et al. 2014 does not contain precise dosing information for the control arm regimens.
====Chemotherapy====
*Azacitidine (Vidaza) 75 mg/m2 IV or SC once per day on days 1 to 7
28-day cycle for at least 4 cycles
===References===
#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 EuroPMC
#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 EuroPMC NCT01147939
#ASTRAL-2: Roboz GJ, Sanz G, Griffiths EA, Yee K, Kantarjian H, Récher C, Byrne MT, Patkowska E, Kim HJ, Thomas X, Moors I, Stock W, Illés Á, Fenaux P, Miyazaki Y, Yamauchi T, O'Connell CL, Hao Y, Keer HN, Azab M, Döhner H. Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial. Blood Adv. 2024 Apr 23;8(8):2020-2029. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02920008
==Decitabine monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Roboz et al. 2024 (ASTRAL-2)	Not reported to 2018-09	Phase 3 (C)	Guadecitabine	Did not meet primary endpoint of OSMedian OS: 5.4 vs 6.4 mo(HR 1.14, 95% CI 0.88-1.49)
====Chemotherapy====
*Decitabine (Dacogen) 20 mg/m2 IV once per day on days 1 to 5
28-day cycles
===References===
#ASTRAL-2: Roboz GJ, Sanz G, Griffiths EA, Yee K, Kantarjian H, Récher C, Byrne MT, Patkowska E, Kim HJ, Thomas X, Moors I, Stock W, Illés Á, Fenaux P, Miyazaki Y, Yamauchi T, O'Connell CL, Hao Y, Keer HN, Azab M, Döhner H. Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial. Blood Adv. 2024 Apr 23;8(8):2020-2029. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02920008
==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
Roboz et al. 2024 (ASTRAL-2)	Not reported to 2018-09	Phase 3 (C)	Guadecitabine	Did not meet primary endpoint of OSMedian OS: 5.4 vs 6.4 mo(HR 1.14, 95% CI 0.88-1.49)
====Chemotherapy====
*Cytarabine (Ara-C) 20 mg/m2 IV or SC twice per day on days 1 to 10
28-day cycles
===References===
#ASTRAL-2: Roboz GJ, Sanz G, Griffiths EA, Yee K, Kantarjian H, Récher C, Byrne MT, Patkowska E, Kim HJ, Thomas X, Moors I, Stock W, Illés Á, Fenaux P, Miyazaki Y, Yamauchi T, O'Connell CL, Hao Y, Keer HN, Azab M, Döhner H. Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial. Blood Adv. 2024 Apr 23;8(8):2020-2029. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02920008
==Ruxolitinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Eghtedar et al. 2012 (MDACC 2007-0925)	2008-2010 	Phase 2
====Targeted therapy====
*Ruxolitinib (Jakafi) 25 mg PO twice per day on days 1 to 28
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===
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
=Response criteria=
==NCI-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia (1990)==
#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 EuroPMC
==Revised International Working Group recommendations (2003)==
#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 EuroPMC
=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===
#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 EuroPMC
==Prognosis in cytogenetically normal AML==
#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 EuroPMC
#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 EuroPMC
==Whole genome sequencing==
#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 link to PMC article EuroPMC
Category:Acute myeloid leukemia regimens
Category:Disease-specific pages
Category:Acute leukemias
Category:Myeloid neoplasms