Acute myeloid leukemia - historical

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? See the main AML page for current regimens.

30 regimens on this page
35 variants on this page


Upfront induction therapy

5+2d

5+2d: 5 days of cytarabine + 2 days of daunorubicin

Regimen variant #1, CI Ara-C

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rai et al. 1981 (CALGB 7421) 1974-04-25 to 1975-05-07 Phase 3 (C) 1. 7+3d; bolus Ara-C Inferior CR rate
2. 7+3d; CI Ara-C Inferior CR rate
3. 5+2d; bolus Ara-C Did not meet endpoint of CR rate

Chemotherapy

5-day course


Regimen variant #2, bolus Ara-C

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rai et al. 1981 (CALGB 7421) 1974-04-25 to 1975-05-07 Phase 3 (C) 1. 7+3d; bolus Ara-C Inferior CR rate
2. 7+3d; CI Ara-C Inferior CR rate
3. 5+2d; CI Ara-C Did not meet endpoint of CR rate

Chemotherapy

5-day course

References

  1. CALGB 7421: Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K, Obrecht JP, Preisler HD, Nawabi IW, Prager D, Carey RW, Cooper MR, Haurani F, Hutchison JL, Silver RT, Falkson G, Wiernik P, Hoagland HC, Bloomfield CD, James GW, Gottlieb A, Ramanan SV, Blom J, Nissen NI, Bank A, Ellison RR, Kung F, Henry P, McIntyre OR, Kaan SK. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood. 1981 Dec;58(6):1203-12. link to original article contains dosing details in manuscript PubMed

5+3d

5+3d: 5 days of cytarabine + 3 days of daunorubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Berman et al. 1991 (L-19 Protocol) 1984-1989 Phase 3 (C) 5+3i Inferior CR rate

Chemotherapy

5-day course

References

  1. L-19 Protocol: Berman E, Heller G, Santorsa J, McKenzie S, Gee T, Kempin S, Gulati S, Andreeff M, Kolitz J, Gabrilove J, Reich L, Mayer K, Keefe D, Trainor K, Schluger A, Penenberg D, Raymond V, O'Reilly R, Jhanwar S, Young C, Clarkson B. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood. 1991 Apr 15;77(8):1666-74. link to original article contains dosing details in manuscript PubMed

5+3i

5+3i: 5 days of cytarabine + 3 days of idarubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Berman et al. 1991 (L-19 Protocol) 1984-1989 Phase 3 (E-RT-switch-ic) 5+3d Superior CR rate

Chemotherapy

  • Cytarabine (Ara-C) 25 mg/m2 IV bolus once on day 1, then 200 mg/m2/day IV continuous infusion over 120 hours (total dose: 1025 mg/m2)
  • Idarubicin (Idamycin) 12 mg/m2 IV bolus once per day on days 1 to 3

5-day course

References

  1. L-19 Protocol: Berman E, Heller G, Santorsa J, McKenzie S, Gee T, Kempin S, Gulati S, Andreeff M, Kolitz J, Gabrilove J, Reich L, Mayer K, Keefe D, Trainor K, Schluger A, Penenberg D, Raymond V, O'Reilly R, Jhanwar S, Young C, Clarkson B. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood. 1991 Apr 15;77(8):1666-74. link to original article contains dosing details in manuscript PubMed

7+3d (low-dose)

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

Regimen variant #1, 700/90

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Löwenberg et al. 1998 (EORTC/HOVON AML-9) 1986-1993 Phase 3 (C) 7+3m; low-dose Might have inferior CR rate

Chemotherapy

Two courses


Regimen variant #2, 1400/90

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Löwenberg et al. 1997 (EORTC/HOVON AML-11) 1990-1994 Phase 3 (C) 7+3d & GM-CSF Did not meet primary endpoint of CR rate

Chemotherapy

7-day course

References

  1. EORTC/HOVON AML-11: Löwenberg B, Suciu S, Archimbaud E, Ossenkoppele G, Verhoef GE, Vellenga E, Wijermans P, Berneman Z, Dekker AW, Stryckmans P, Schouten H, Jehn U, Muus P, Sonneveld P, Dardenne M, Zittoun R; EORTC; HOVON. Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group. Blood. 1997 Oct 15;90(8):2952-61. link to original article contains dosing details in abstract PubMed
  2. EORTC/HOVON AML-9: Löwenberg B, Suciu S, Archimbaud E, Haak H, Stryckmans P, de Cataldo R, Dekker AW, Berneman ZN, Thyss A, van der Lelie J, Sonneveld P, Visani G, Fillet G, Hayat M, Hagemeijer A, Solbu G, Zittoun R; European Organization for the Research and Treatment of Cancer; Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. J Clin Oncol. 1998 Mar;16(3):872-81. link to original article PubMed

7+3i & Panobinostat

7+3i & Panobinostat: 7 days of cytarabine + 3 days of idarubicin, Panobinostat

Regimen

Study Dates of enrollment Evidence Efficacy
Ocio et al. 2015 (panobidara) NR Phase 1b/2 CR rate: 64%

Note: the dose of idarubicin is lower than that used in standard 7+3i. The panobinostat dose is the MTD in this phase 1b/2 study.

Chemotherapy

Targeted therapy

19-day course

Subsequent treatment

References

  1. panobidara: Ocio EM, Herrera P, Olave MT, Castro N, Pérez-Simón JA, Brunet S, Oriol A, Mateo M, Sanz MÁ, López J, Montesinos P, Chillón MC, Prieto-Conde MI, Díez-Campelo M, González M, Vidriales MB, Mateos MV, San Miguel JF; PETHEMA. Panobinostat as part of induction and maintenance for elderly patients with newly diagnosed acute myeloid leukemia: phase Ib/II panobidara study. Haematologica. 2015 Oct;100(10):1294-300. Epub 2015 Jul 9. link to original article contains dosing details in manuscript link to PMC article PubMed

7+3i & Vorinostat

Regimen

Study Dates of enrollment Evidence
Garcia-Manero et al. 2012 (MDACC 2007-0835) 2008-2010 Phase 2

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 4 (total dose: 6000 mg/m2)
    • Older than 60 years old: 1500 mg/m2/day IV continuous infusion over 72 hours, started on day 4 (total dose: 4500 mg/m2)
  • Idarubicin (Idamycin) 12 mg/m2 IV once per day on days 4 to 6

Targeted therapy

Supportive therapy

  • Methylprednisolone (Solumedrol) (note: the paper spelled this as "salumedrol"--it's assumed this is what they meant) 50 mg IV on days of cytarabine to prevent fever and rash

7-day course for 1 to 2 cycles

Subsequent treatment

References

  1. MDACC 2007-0835: Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, Borthakur G, Kadia TM, Konopleva MY, Faderl S, Cortes JE, Brandt M, Hu Y, McCue D, Newsome WM, Pierce SR, de Lima M, Kantarjian HM. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol. 2012 Jun 20;30(18):2204-10. Epub 2012 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00656617

7+5i

7+5i: 7 days of cytarabine + 5 days of idarubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Solary et al. 2003 1995-1999 Phase 3 (C) 7+5i & Quinine Did not meet primary endpoint of OS48

Chemotherapy

7-day course

References

  1. Solary E, Drenou B, Campos L, de Crémoux P, Mugneret F, Moreau P, Lioure B, Falkenrodt A, Witz B, Bernard M, Hunault-Berger M, Delain M, Fernandes J, Mounier C, Guilhot F, Garnache F, Berthou C, Kara-Slimane F, Harousseau JL; Groupe Ouest Est Leucémies Aiguës Myéloblastiques. Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia. Blood. 2003 Aug 15;102(4):1202-10. Epub 2003 Mar 27. link to original article contains dosing details in manuscript PubMed

Cytarabine, Daunorubicin, Vincristine

Regimen variant #1

Study Dates of enrollment Evidence
Rosenthal & Moloney 1972 NR Non-randomized

Chemotherapy


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Löwenberg et al. 1989 1983-1986 Phase 3 (E-esc) Best supportive care Seems to have superior OS

Note: this regimen uses both bolus and CI cytarabine.

Chemotherapy

1 to 2 cycles


Regimen variant #3

Study Dates of enrollment Evidence
Zittoun et al. 1989 (EORTC AML6) 1983-1986 Non-randomized part of RCT

Note: this regimen uses both bolus and CI cytarabine.

Chemotherapy

1 to 2 cycles

References

  1. Rosenthal DS, Moloney WC. The treatment of acute granulocytic leukemia in adults. N Engl J Med. 1972 Jun 1;286(22):1176-8. link to original article contains dosing details in manuscript PubMed
  2. EORTC AML6: Zittoun R, Jehn U, Fière D, Haanen C, Löwenberg B, Willemze R, Abels J, Bury J, Peetermans M, Hayat M, Suciu S, Solbu G, Stryckmans P; EORTC Leukemia Cooperative Group. Alternating v repeated postremission treatment in adult acute myelogenous leukemia: a randomized phase III study (AML6) of the EORTC Leukemia Cooperative Group. Blood. 1989 Mar;73(4):896-906. link to original article contains dosing details in manuscript PubMed
    1. Update: Jehn U, Zittoun R, Suciu S, Fiere D, Haanen C, Peetermans M, Löwenberg B, Willemze R, Solbu G, Stryckmans P; EORTC Leukemia Cooperative Group. A randomized comparison of intensive maintenance treatment for adult acute myelogenous leukemia using either cyclic alternating drugs or repeated courses of the induction-type chemotherapy: AML-6 trial of the EORTC Leukemia Cooperative Group. Haematol Blood Transfus. 1990;33:277-84. link to original article PubMed
  3. Löwenberg B, Zittoun R, Kerkhofs H, Jehn U, Abels J, Debusscher L, Cauchie C, Peetermans M, Solbu G, Suciu S, Stryckmans P; EORTC Leukemia Group. On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group. J Clin Oncol. 1989 Sep;7(9):1268-74. link to original article contains dosing details in manuscript PubMed

Cytarabine, Daunorubicin, Mercaptopurine, Prednisolone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kobayashi et al. 1996 (JALSG AML89) 1987-1991 Phase 3 (C) BHAC-DMP Seems to have superior EFS

Chemotherapy

Glucocorticoid therapy

One course

Subsequent treatment

  • Consolidation; see paper for details

References

  1. JALSG AML89: Kobayashi T, Miyawaki S, Tanimoto M, Kuriyama K, Murakami H, Yoshida M, Minami S, Minato K, Tsubaki K, Ohmoto E, Oh H, Jinnai I, Sakamaki H, Hiraoka A, Kanamaru A, Takahashi I, Saito K, Naoe T, Yamada O, Asou N, Kageyama S, Emi N, Matsuoka A, Tomonaga M, Saito H, Ueda R, Ohno R; Japan Acute Leukemia Study Group. Randomized trials between behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia. J Clin Oncol. 1996 Jan;14(1):204-13. link to original article contains dosing details in manuscript PubMed

Cytarabine, Doxorubicin, Vincristine, Prednisolone

Regimen

Study Dates of enrollment Evidence
Weinstein et al. 1980 1976-1979 Non-randomized

Chemotherapy

  • Cytarabine (Ara-C) as follows:
    • Course 1: 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
    • Course 2: 100 mg/m2/day IV continuous infusion over 5 days, started on day 1 (total dose: 500 mg/m2)
  • Doxorubicin (Adriamycin) as follows:
    • Course 1: 30 mg/m2 IV once per day on days 1 to 3
    • Course 2: 30 mg/m2 IV once per day on days 1 & 2
  • Vincristine (Oncovin) as follows:
    • Course 1: 1.5 mg/m2 IV once per day on days 1 & 5
    • Course 2: 1.5 mg/m2 IV once on day 1

Glucocorticoid therapy

2 courses

References

  1. Weinstein HJ, Mayer RJ, Rosenthal DS, Camitta BM, Coral FS, Nathan DG, Frei E 3rd. Treatment of acute myelogenous leukemia in children and adults. N Engl J Med. 1980 Aug 28;303(9):473-8. link to original article contains dosing details in manuscript PubMed

Daunorubicin monotherapy

Regimen

Study Dates of enrollment Evidence
Bornstein et al. 1969 NR Non-randomized

Chemotherapy

Supportive therapy

  • Prednisone (Sterapred) 60 mg/day PO on days 1 to 5, in divided doses, then decreased to 40 mg/day PO once per day until platelet count rose to greater than 100 x 109/L.

One course

References

  1. Bornstein RS, Theologides A, Kennedy BJ. Daunorubicine in acute myelogenous leukemia in adults. JAMA. 1969 Feb 17;207(7):1301-6. link to original article contains dosing details in manuscript PubMed

DAT

DAT: Daunorubicin, Ara-C (Cytarabine), Thioguanine
TAD: Thioguanine, Ara-C (Cytarabine), Daunorubicin
TAD9: Thioguanine, Ara-C (Cytarabine), Daunorubicin over 9 days

Regimen variant #1, DAT (1 + 5)

Study Dates of enrollment Evidence
Rees et al. 1986 (UK MRC AML8) 1978-1983 Non-randomized part of RCT

Chemotherapy

14-day course

Subsequent treatment

  • UK MRC AML8, CR: DAT consolidation x 2 versus DAT consolidation x 6, then further maintenance treatment (see paper for details)


Regimen variant #2, DAT (3 + 7)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gale & Cline 1977 1975-1976 Non-randomized
Gale et al. 1981 1975-1978 Non-randomized
Büchner et al. 1982 1978-1981 Non-randomized
Champlin et al. 1984 NR Non-randomized
Büchner et al. 1999 1985-1992 Non-randomized part of RCT
Goldstone et al. 2001 (UK MRC AML11) 1990-1998 Phase 3 (C) 1. ADE Superior CR rate
2. MAC Seems to have superior CR rate
Büchner et al. 2003 1992-1999 Non-randomized part of RCT
Burnett et al. 2009 (LRF AML14) 1998-2007 Phase 3 (C) DAT; lower-dose Did not meet co-primary endpoints of CR/DFS/OS
Krug et al. 2016 (AMLCG 99) 2002-2008 Phase 3 (C) HAM Did not meet co-primary endpoints of EFS/RFS
Braess et al. 2018 (AML-CG 2008) 2009-2012 Phase 3 (C) S-HAM Did not meet primary endpoint of ORR

Note: LRF AML14 had multiple randomizations; see paper for details.

Chemotherapy

Subsequent treatment

  • LRF AML14: IDAC consolidation


Regimen variant #3, TAD9

Study Dates of enrollment Evidence
Büchner et al. 1985 1982-NR Non-randomized part of RCT

Chemotherapy

9-day course

Subsequent treatment

  • DAT consolidation, then maintenance versus no further treatment

References

  1. Gale RP, Cline MJ. High remission-induction rate in acute myeloid leukaemia. Lancet. 1977 Mar 5;1(8010):497-9. link to original article contains dosing details in manuscript PubMed
  2. Gale RP, Foon KA, Cline MJ, Zighelboim J. Intensive chemotherapy for acute myelogenous leukemia. Ann Intern Med. 1981 Jun;94(6):753-7. link to original article PubMed
  3. Büchner T, Urbanitz D, Emmerich B, Fischer JT, Fülle HH, Heinecke A, Hossfeld DK, Koeppen KM, Labedzki L, Löffler H, Nowrousian MR, Pfreundschuh M, Pralle H, Rühl H, Wendt FC. Multicentre study on intensified remission induction therapy for acute myeloid leukemia. Leuk Res. 1982;6(6):827-31. link to original article PubMed
  4. Champlin R, Jacobs A, Gale RP, Boccia R, Elashoff R, Foon K, Zighelboim J. Prolonged survival in acute myelogenous leukaemia without maintenance chemotherapy. Lancet. 1984 Apr 21;1(8382):894-6. link to original article PubMed
  5. Büchner T, Urbanitz D, Hiddemann W, Rühl H, Ludwig WD, Fischer J, Aul HC, Vaupel HA, Kuse R, Zeile G, Nowrousian MR, Konig HJ, Walter M, Wendt FC, Sodomann H, Hossfeld DK, von Paleske A, Loffler H, Gassmann W, Hellriegel KP, Fulle HH, Lunscken C, Emmerich B, Pralle H, Pees HW, Pfreundschuh M, Bartels H, Koeppen KM, Schwerdtfeger R, Donhuijsen-Ant R, Mainzer K, Bonfert B, Koppler H, Zurborn KH, Ranft K, Thiel E, Heinecke A; German AML Cooperative Group. Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group. J Clin Oncol. 1985 Dec;3(12):1583-9. link to original article contains dosing details in manuscript PubMed
  6. UK MRC AML8: Rees JK, Gray RG, Swirsky D, Hayhoe FG. Principal results of the Medical Research Council's 8th acute myeloid leukaemia trial. Lancet. 1986 Nov 29;2(8518):1236-41. link to original article contains dosing details in manuscript PubMed
  7. Büchner T, Hiddemann W, Wörmann B, Löffler H, Gassmann W, Haferlach T, Fonatsch C, Haase D, Schoch C, Hossfeld D, Lengfelder E, Aul C, Heyll A, Maschmeyer G, Ludwig WD, Sauerland MC, Heinecke A; German AML Cooperative Group. Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood. 1999 Jun 15;93(12):4116-24. link to original article PubMed
  8. UK MRC AML11: Goldstone AH, Burnett AK, Wheatley K, Smith AG, Hutchinson RM, Clark RE; Medical Research Council Adult Leukemia Working Party. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood. 2001 Sep 1;98(5):1302-11. link to original article PubMed
  9. Büchner T, Hiddemann W, Berdel WE, Wörmann B, Schoch C, Fonatsch C, Löffler H, Haferlach T, Ludwig WD, Maschmeyer G, Staib P, Aul C, Gruneisen A, Lengfelder E, Frickhofen N, Kern W, Serve HL, Mesters RM, Sauerland MC, Heinecke A; German AML Cooperative Group. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol. 2003 Dec 15;21(24):4496-504. link to original article PubMed
  10. LRF AML14: Burnett AK, Milligan D, Goldstone A, Prentice A, McMullin MF, Dennis M, Sellwood E, Pallis M, Russell N, Hills RK, Wheatley K; United Kingdom National Cancer Research Institute Haematological Oncology Study Group. The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. Br J Haematol. 2009 May;145(3):318-32. Epub 2009 Mar 8. link to original article PubMed NCT00005823
  11. AMLCG 99: Krug U, Berdel WE, Gale RP, Haferlach C, Schnittger S, Müller-Tidow C, Braess J, Spiekermann K, Staib P, Beelen D, Serve H, Schliemann C, Stelljes M, Balleisen L, Maschmeyer G, Grüneisen A, Eimermacher H, Giagounidis A, Rasche H, Hehlmann R, Lengfelder E, Thiel E, Reichle A, Aul C, Ludwig WD, Kern W, Haferlach T, Köpcke W, Görlich D, Sauerland MC, Heinecke A, Wörmann BJ, Hiddemann W, Büchner T. Increasing intensity of therapies assigned at diagnosis does not improve survival of adults with acute myeloid leukemia. Leukemia. 2016 Jun;30(6):1230-6. Epub 2016 Feb 9. link to original article PubMed NCT00266136
  12. AML-CG 2008: Braess J, Amler S, Kreuzer KA, Spiekermann K, Lindemann HW, Lengfelder E, Graeven U, Staib P, Ludwig WD, Biersack H, Ko YD, Uppenkamp MJ, De Wit M, Korsten S, Peceny R, Gaska T, Schiel X, Behringer DM, Kiehl MG, Zinngrebe B, Meckenstock G, Roemer E, Medgenberg D, Spaeth-Schwalbe E, Massenkeil G, Hindahl H, Schwerdtfeger R, Trenn G, Sauerland C, Koch R, Lablans M, Faldum A, Görlich D, Bohlander SK, Schneider S, Dufour A, Buske C, Fiegl M, Subklewe M, Braess B, Unterhalt M, Baumgartner A, Wörmann B, Beelen D, Hiddemann W; AML-CG. Sequential high-dose cytarabine and mitoxantrone (S-HAM) versus standard double induction in acute myeloid leukemia-a phase 3 study. Leukemia. 2018 Dec;32(12):2558-2571. Epub 2018 Oct 1. link to original article link to PMC article PubMed EudraCT 2007-003103-12

Decitabine & Valproate

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Garcia-Manero et al. 2006 (MDACC 2003-0314) 2004-NR Phase 2
Issa et al. 2014 NR Randomized Phase 2 (E-esc) Decitabine Did not meet primary endpoint

Chemotherapy

28-day cycle for up to 24 cycles

References

  1. MDACC 2003-0314: Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, Rytting M, Wierda WG, Ravandi F, Koller C, Xiao L, Faderl S, Estrov Z, Cortes J, O'brien S, Estey E, Bueso-Ramos C, Fiorentino J, Jabbour E, Issa JP. Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006 Nov 15;108(10):3271-9. Epub 2006 Aug 1. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00075010
  2. Issa JP, Garcia-Manero G, Huang X, Cortes J, Ravandi F, Jabbour E, Borthakur G, Brandt M, Pierce S, Kantarjian HM. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015 Feb 15;121(4):556-61. Epub 2014 Oct 21. link to original article contains dosing details in manuscript link to PMC article PubMed

HAD

HAD: Homoharringtonine (Omacetaxine), Ara-C (Cytarabine), Daunorubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jin et al. 2013 2007-2011 Phase 3 (E-esc) 1. DA Might have superior EFS (co-primary endpoint)
2. HAA Not reported

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

Chemotherapy

7-day course

Subsequent treatment

  • IDAC consolidation x 2

References

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

VAMP (Amethopterin)

VAMP: Vincristine, Amethopterin (Methotrexate), Mercaptopurine, Prednisone

Regimen

Study Dates of enrollment Evidence
Thompson et al. 1965 1963-1965 Non-randomized

Note: this is to be distinguished from the VAMP protocols used in Hodgkin lymphoma and multiple myeloma.

Chemotherapy

Glucocorticoid therapy

42-day course

References

  1. Thompson I, Hall TC, Moloney WC. Combination therapy of adult acute myelogenous leukemia: experience with the simultaneous use of vincristine, amethopterin, 6-mercaptopurine and prednisone. N Engl J Med. 1965 Dec 9;273(24):1302-7. link to original article contains dosing details in manuscript PubMed

Consolidation after upfront therapy

Amsacrine & HiDAC

MA: M-AMSA (Amsacrine) & Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cassileth et al. 1992 (ECOG E3483) 1984-1988 Phase 3 (E-switch-ic) Cytarabine & Thioguanine maintenance Did not meet efficacy endpoints

Chemotherapy

One course

References

  1. ECOG E3483: Cassileth PA, Lynch E, Hines JD, Oken MM, Mazza JJ, Bennett JM, McGlave PB, Edelstein M, Harrington DP, O'Connell MJ. Varying intensity of postremission therapy in acute myeloid leukemia. Blood. 1992 Apr 15;79(8):1924-30. link to original article contains dosing details in manuscript PubMed

Cytarabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stone et al. 2001 1990-1993 Phase 3 (C) MC Did not meet co-primary endpoints of DFS/OS

Note: this is lower dose treatment than IDAC or HiDAC.

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 500 mg/m2)

1-month cycle for 4 cycles

References

  1. Stone RM, Berg DT, George SL, Dodge RK, Paciucci PA, Schulman PP, Lee EJ, Moore JO, Powell BL, Baer MR, Bloomfield CD, Schiffer CA. Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood. 2001 Aug 1;98(3):548-53. link to original article contains dosing details in manuscript PubMed

Cytarabine, Idarubicin, Vorinostat

Regimen

Study Dates of enrollment Evidence
Garcia-Manero et al. 2012 (MDACC 2007-0835) 2008-2010 Phase 2

Note: cycle length was not specified in the manuscript; 28-day cycles are fairly standard in this setting.

Preceding treatment

Chemotherapy

Targeted therapy

Supportive therapy

  • Methylprednisolone (Solumedrol) (note: the paper spelled this as "salumedrol"--it's assumed this is what they meant) 50 mg IV on days of cytarabine to prevent fever and rash

28-day cycle for up to 5 cycles

Subsequent treatment

References

  1. MDACC 2007-0835: Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, Borthakur G, Kadia TM, Konopleva MY, Faderl S, Cortes JE, Brandt M, Hu Y, McCue D, Newsome WM, Pierce SR, de Lima M, Kantarjian HM. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol. 2012 Jun 20;30(18):2204-10. Epub 2012 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00656617

Maintenance after first-line therapy

BDMP-BMP-BAMP-BEVP

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ohno et al. 1993 (JALSG AML-87) 1987-06 to 1989-09 Phase 3 (C) BDMP-BMP-BAMP-BEVP x 3 Inferior DFS

Preceding treatment

Chemotherapy, BDMP portion

Glucocorticoid therapy, BDMP portion

Chemotherapy, BMP portion

Glucocorticoid therapy, BMP portion

Chemotherapy, BAMP portion

Glucocorticoid therapy, BAMP portion

Chemotherapy, BEVP portion

Glucocorticoid therapy, BEVP portion

References

  1. JALSG AML-87: Ohno R, Kobayashi T, Tanimoto M, Hiraoka A, Imai K, Asou N, Tomonaga M, Tsubaki K, Takahashi I, Kodera Y, Yoshida M, Murakami H, Naoe T, Shimoyama M, Tsukada T, Takeo T, Teshima H, Onozawa Y, Fujimoto K, Kuriyama K, Horiuchi A, Kimura I, Minami S, Miura Y, Kageyama S, Tahara T, Masaoka T, Shirakawa S, Saito H. Randomized study of individualized induction therapy with or without vincristine, and of maintenance-intensification therapy between 4 or 12 courses in adult acute myeloid leukemia: AML-87 Study of the Japan Adult Leukemia Study Group. Cancer. 1993 Jun 15;71(12):3888-95. link to original article PubMed

Cytarabine & Thioguanine

Regimen

Study Dates of enrollment Evidence
Peterson & Bloomfield 1977 1971-11 to 1975-10 Non-randomized

Chemotherapy

7-day cycles

References

  1. Peterson BA, Bloomfield CD. Prolonged maintained remissions of adult acute non-lymphocytic leukaemia. Lancet. 1977 Jul 23;2(8030):158-60. link to original article contains dosing details in manuscript PubMed

Panobinostat monotherapy

Regimen

Study Dates of enrollment Evidence
Ocio et al. 2015 (panobidara) NR Phase 1b/2

The panobinostat dose is the MTD in this phase Ib/2 study.

Preceding treatment

Targeted therapy

Continued indefinitely

References

  1. panobidara: Ocio EM, Herrera P, Olave MT, Castro N, Pérez-Simón JA, Brunet S, Oriol A, Mateo M, Sanz MÁ, López J, Montesinos P, Chillón MC, Prieto-Conde MI, Díez-Campelo M, González M, Vidriales MB, Mateos MV, San Miguel JF; PETHEMA. Panobinostat as part of induction and maintenance for elderly patients with newly diagnosed acute myeloid leukemia: phase Ib/II panobidara study. Haematologica. 2015 Oct;100(10):1294-300. Epub 2015 Jul 9. link to original article contains dosing details in manuscript link to PMC article PubMed

POMP

POMP: Purinethol (Mercaptopurine), Oncovin (Vincristine), Methotrexate, Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Morrison et al. 1992 1978-1982 Phase 3 (E-esc) OAP maintenance Seems to have superior OS

Chemotherapy

Glucocorticoid therapy

References

  1. Morrison FS, Kopecky KJ, Head DR, Athens JW, Balcerzak SP, Gumbart C, Dabich L, Costanzi JJ, Coltman CA, Saiki JH, Hussein KK, Fabian CJ, Appelbaum FR; SWOG. Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia--results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Leukemia. 1992 Jul;6(7):708-14. PubMed

Vorinostat monotherapy

Regimen

Study Dates of enrollment Evidence
Garcia-Manero et al. 2012 (MDACC 2007-0835) 2008-2010 Phase 2

Preceding treatment

Targeted therapy

28-day cycle for up to 12 cycles

References

  1. MDACC 2007-0835: Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, Borthakur G, Kadia TM, Konopleva MY, Faderl S, Cortes JE, Brandt M, Hu Y, McCue D, Newsome WM, Pierce SR, de Lima M, Kantarjian HM. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol. 2012 Jun 20;30(18):2204-10. Epub 2012 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00656617

Relapsed or refractory, salvage therapy

High-dose Cytarabine monotherapy (HiDAC)

HiDAC: High Dose Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Vogler et al. 1994 NR Phase 3 (C) HiDAC & Etoposide Did not meet efficacy endpoints of RR/DOR/OS

Chemotherapy

References

  1. Vogler WR, McCarley DL, Stagg M, Bartolucci AA, Moore J, Martelo O, Omura GA; Southeastern Cancer Study Group. A phase III trial of high-dose cytosine arabinoside with or without etoposide in relapsed and refractory acute myelogenous leukemia: a Southeastern Cancer Study Group trial. Leukemia. 1994 Nov;8(11):1847-53. PubMed

IAP

IAP: Idarubicin, Ara-C (cytarabine), Pravastatin

Regimen

Study Dates of enrollment Evidence
Advani et al. 2014 (SWOG S0919) 2009-2012 Phase 2

Chemotherapy

8-day course

Subsequent treatment

  • SWOG S0919, patients achieving CR: Optional IAP consolidation

References

  1. SWOG S0919: Advani AS, McDonough S, Copelan E, Willman C, Mulford DA, List AF, Sekeres MA, Othus M, Appelbaum FR. SWOG0919: a phase 2 study of idarubicin and cytarabine in combination with pravastatin for relapsed acute myeloid leukaemia. Br J Haematol. 2014 Oct;167(2):233-7. Epub 2014 Jul 18. link to original article link to PMC article PubMed NCT00840177

SHAI

SHAI: Sequential High-dose Ara-C (Cytarabine), Idarubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fiegl et al. 2013 NR Phase 3 (C) F-SHAI Seems to have inferior TTTF

Chemotherapy

  • Cytarabine (Ara-C) by the following criteria:
    • Standard patients: 1000 mg/m2 IV twice per day on days 1, 2, 8, 9 (total dose: 8000 mg/m2)
    • Patients 60 or younger with refractory AML or greater than or equal to 2nd relapse: 3000 mg/m2 IV twice per day on days 1, 2, 8, 9 (total dose: 24,000 mg/m2)
  • Idarubicin (Idamycin) 10 mg/m2 IV once per day on days 3, 4, 10, 11

11-day course

References

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

Cytarabine & Vosaroxin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ravandi et al. 2015 (VALOR) 2010-2013 Phase 3 (E-esc) IDAC Might have superior OS (co-primary endpoint)
Median OS: 7.5 vs 6.1 mo
(HR 0.87, 95% CI 0.73-1.02)

Note: cycle length was not specified in the manuscript; 28-day cycles are typical in this setting.

Chemotherapy

  • Cytarabine (Ara-C) as follows:
    • Cycles 1 to 3: 1000 mg/m2 IV over 2 hours once per day on days 1 to 5
  • Vosaroxin (SNS-595) as follows:
    • Cycle 1: 90 mg/m2 IV once per day on days 1 to 4
    • Cycle 2 onwards: 70 mg/m2 IV once per day on days 1 to 4

28-day cycles (see note)

References

  1. VALOR: Ravandi F, Ritchie EK, Sayar H, Lancet JE, Craig MD, Vey N, Strickland SA, Schiller GJ, Jabbour E, Erba HP, Pigneux A, Horst HA, Recher C, Klimek VM, Cortes J, Roboz GJ, Odenike O, Thomas X, Havelange V, Maertens J, Derigs HG, Heuser M, Damon L, Powell BL, Gaidano G, Carella AM, Wei A, Hogge D, Craig AR, Fox JA, Ward R, Smith JA, Acton G, Mehta C, Stuart RK, Kantarjian HM. Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2015 Sep;16(9):1025-1036. Epub 2015 Jul 30. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01191801 NCT01191801]

Relapsed or refractory, subsequent lines of therapy

Azacitidine, Vorinostat, Gemtuzumab ozogamicin

Regimen

Study Dates of enrollment Evidence
Walter et al. 2013 (NCI-2012-01147) 2009-2012 Phase 1/2

Note: This is the MTD used in the phase 2 portion, which was tested on 43 patients. Cycle length was not specified; 28-day cycles are typical in this setting.

Chemotherapy

Targeted therapy

Antibody-drug conjugate therapy

28-day cycle for up to 6 cycles (see note)

References

  1. NCI-2012-01147: Walter RB, Medeiros BC, Gardner KM, Orlowski KF, Gallegos L, Scott BL, Hendrie PC, Estey EH. Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase 1/2 study. Haematologica. 2014 Jan;99(1):54-9. Epub 2013 Oct 18. link to original article link to PMC article contains dosing details in manuscript PubMed

Cladribine monotherapy

Regimen

Study Dates of enrollment Evidence
Santana et al. 1992 1990-1991 Phase 2

Chemotherapy

  • Cladribine (Leustatin) 8.9 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose: 44.5 mg/m2)

5-day course

References

  1. Santana VM, Mirro J Jr, Kearns C, Schell MJ, Crom W, Blakley RL. 2-Chlorodeoxyadenosine produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia. J Clin Oncol. 1992 Mar;10(3):364-70. link to original article PubMed

Clofarabine monotherapy

Regimen

Study Dates of enrollment Evidence
Kantarjian et al. 2003 NR Phase 2

Chemotherapy

3- to 6-week cycles

References

  1. Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, Giles F, Faderl S, O'Brien S, Jeha S, Davis J, Shaked Z, Craig A, Keating M, Plunkett W, Freireich EJ. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003 Oct 1;102(7):2379-86. Epub 2003 Jun 5. link to original article contains dosing details in manuscript PubMed

Intermediate-dose Cytarabine monotherapy (IDAC)

IDAC: Intermediate Dose Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Faderl et al. 2012 (CLASSIC I) 2006-2009 Phase 3 (C) Clofarabine & Cytarabine Did not meet primary endpoint of OS
Ravandi et al. 2015 (VALOR) 2010-2013 Phase 3 (C) Cytarabine & Vosaroxin Might have inferior OS

Note: In CLASSIC I, it was not clear if the consolidation cycle mentioned here would also be cytarabine or something else: "Patients who achieved remission after their induction cycle could receive a single (optional) consolidation cycle; patients who did not achieve remission after induction but who demonstrated hematologic improvement could receive a reinduction cycle followed by a single (optional) consolidation cycle." In VALOR, the total duration of treatment is not specified; 28-day cycles are typical in this setting.

Chemotherapy

Supportive therapy

  • "The use of prophylactic antibacterial, antifungal, and antiviral agents was recommended according to institutional guidelines."

28-day cycle for 1 to 3 cycles (see note)

References

  1. CLASSIC I: Faderl S, Wetzler M, Rizzieri D, Schiller G, Jagasia M, Stuart R, Ganguly S, Avigan D, Craig M, Collins R, Maris M, Kovacsovics T, Goldberg S, Seiter K, Hari P, Greiner J, Vey N, Recher C, Ravandi F, Wang ES, Vasconcelles M, Huebner D, Kantarjian HM. Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial. J Clin Oncol. 2012 Jul 10;30(20):2492-9. Epub 2012 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00317642
  2. VALOR: Ravandi F, Ritchie EK, Sayar H, Lancet JE, Craig MD, Vey N, Strickland SA, Schiller GJ, Jabbour E, Erba HP, Pigneux A, Horst HA, Recher C, Klimek VM, Cortes J, Roboz GJ, Odenike O, Thomas X, Havelange V, Maertens J, Derigs HG, Heuser M, Damon L, Powell BL, Gaidano G, Carella AM, Wei A, Hogge D, Craig AR, Fox JA, Ward R, Smith JA, Acton G, Mehta C, Stuart RK, Kantarjian HM. Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2015 Sep;16(9):1025-36. Epub 2015 Jul 30. link to original article contains dosing details in abstract link to PMC article PubMed NCT01191801
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