Acute myeloid leukemia

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Martin Schoen, MD, MPH
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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. If you still can't find it, please let us know so we can add it!
Note: biomarker-specific regimens have been moved to dedicated pages:

77 regimens on this page
112 variants on this page

Contents


Guidelines

ELN

Current

Older

ESMO

NCCN

Upfront induction therapy, standard and older "fit" patients

These are aggressive remission induction regimens given with curative intent.

7+3d (standard-dose)

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

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

Study Evidence Comparator Efficacy
Yates et al. 1973 Non-randomized, <20 pts
Rai et al. 1981 (CALGB 7421) Phase III (E) 1. 7+3d (bolus Ara-C) Seems to have superior CR rate
2. 5+2d Superior CR rate
3. 5+2d (bolus Ara-C) Superior CR rate
Yates et al. 1982 (CALGB 7721) Phase III (C) 1. 7+3d, low-dose dauno (30 mg/m2) Seems not superior
2. 7+3a (30 mg/m2) Seems not superior
Preisler et al. 1987 (CALGB 7921) Phase III (C) 1. 10+3d Seems not superior
2. TAD Seems not superior
Wiernik et al. 1992 Phase III (C) 7+3i Seems to have inferior OS
Vogler et al. 1992 Phase III (C) 7+3i Seems to have inferior CR rate
Rowe et al. 2004 (ECOG E3993) Phase III (C) 1. 7+3d + GM-CSF
2. 7+3i
3. 7+3i + GM-CSF
4. 7+3m
5. 7+3m + GM-CSF
Seems not superior
Fernandez et al. 2009 (ECOG E1900) Phase III (C) 7+3d (high-dose) Inferior OS
Dombret et al. 2015 (AZA-AML-001) Phase III (C) Azacitidine Might have inferior OS

Note: this was the lower bound of the allowable daunorubicin dose in AZA-AML-001.

Chemotherapy

7-day course

Subsequent treatment

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

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

Study Evidence Comparator Efficacy
Weick et al. 1996 Phase III (C) HDAC+3d Seems not superior
Moore et al. 2004 (CALGB 9222) Non-randomized portion of RCT
Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01) Phase III (C) 7+3d (high-dose) Inferior CR rate
Stone et al. 2015 (ACCEDE) Phase III (C) Amonafide & Cytarabine Seems not superior

Chemotherapy

7-day course

Subsequent treatment

  • CALGB 9222: HiDAC versus multi-agent chemotherapy consolidation
  • HOVON 43 AML/SAKK 30/01: MiDAC consolidation
  • ACCEDE: patients received a second course of the same regimen if their day 14 bone marrow was positive. Patients with PR or better at time of count recovery received allogeneic stem cell transplant if eligible, otherwise HiDAC if younger than 60 or MiDAC if greater than or equal to 60.

Variant #3, intermittent Ara-C

Study Evidence Comparator Efficacy
Masaoka et al. 1996 Randomized Phase II (E) 7+3i Seems to have inferior CR rate

Chemotherapy

7-day course

References

  1. Yates JW, Wallace HJ Jr, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep. 1973 Nov-Dec;57(4):485-8. PubMed
  2. CALGB 7421: Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K, Obrecht JP, Preisler HD, Nawabi IW, Prager D, Carey RW, Cooper MR, Haurani F, Hutchison JL, Silver RT, Falkson G, Wiernik P, Hoagland HC, Bloomfield CD, James GW, Gottlieb A, Ramanan SV, Blom J, Nissen NI, Bank A, Ellison RR, Kung F, Henry P, McIntyre OR, Kaan SK. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood. 1981 Dec;58(6):1203-12. link to original article contains verified protocol PubMed
  3. CALGB 7721: Yates J, Glidewell O, Wiernik P, Cooper MR, Steinberg D, Dosik H, Levy R, Hoagland C, Henry P, Gottlieb A, Cornell C, Berenberg J, Hutchison JL, Raich P, Nissen N, Ellison RR, Frelick R, James GW, Falkson G, Silver RT, Haurani F, Green M, Henderson E, Leone L, Holland JF. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood. 1982 Aug;60(2):454-62. link to original article contains verified protocol PubMed
  4. CALGB 7921: Preisler H, Davis RB, Kirshner J, Dupre E, Richards F 3rd, Hoagland HC, Kopel S, Levy RN, Carey R, Schulman P, Gottlieb AJ, McIntyre OR. Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a Cancer and Leukemia Group B study. Blood. 1987 May;69(5):1441-9. link to original article contains verified protocol PubMed
  5. Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, Ritch PS, Enck RE, Weitberg AB. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992 Jan 15;79(2):313-9. link to original article contains verified protocol PubMed
  6. Vogler WR, Velez-Garcia E, Weiner RS, Flaum MA, Bartolucci AA, Omura GA, Gerber MC, Banks PL. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol. 1992 Jul;10(7):1103-11. link to original article contains protocol PubMed
  7. Masaoka T, Ogawa M, Yamada K, Kimura K, Ohashi Y. A phase II comparative study of idarubicin plus cytarabine versus daunorubicin plus cytarabine in adult acute myeloid leukemia. Semin Hematol. 1996 Oct;33(4 Suppl 3):12-7. contains protocol PubMed
  8. Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP, Bickers JN, Hynes HE, Welborn JL, Simon SR, Grever M. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 1996 Oct 15;88(8):2841-51. link to original article contains protocol PubMed
  9. ECOG E3993: Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. link to original article contains verified protocol PubMed
  10. CALGB 9222: Moore JO, George SL, Dodge RK, Amrein PC, Powell BL, Kolitz JE, Baer MR, Davey FR, Bloomfield CD, Larson RA, Schiffer CA. Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222. Blood. 2005 May 1;105(9):3420-7. Epub 2004 Nov 30. link to original article link to PMC article contains verified protocol PubMed
  11. 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 (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. link to original article contains verified protocol PubMed
  12. ECOG E1900: Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, Lazarus HM, Levine RL, Litzow MR, Paietta EM, Patel JP, Racevskis J, Rowe JM, Tallman MS, Sun Z, Luger SM. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016 Mar 24;127(12):1551-8. Epub 2016 Jan 11. link to original article link to PMC article PubMed
  13. ACCEDE: Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, Wetzler M, Rizzieri D, Erba HP, Damon L, Jang JH, Tallman MS, Warzocha K, Masszi T, Sekeres MA, Egyed M, Horst HA, Selleslag D, Solomon SR, Venugopal P, Lundberg AS, Powell B. Phase III open-label randomized study of cytarabine in combination with amonafide l-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10;33(11):1252-7. Epub 2015 Mar 2. link to original article contains verified protocol PubMed
  14. AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article link to PMC article contains verified protocol PubMed
    1. Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article PubMed

7+3d (intermediate-dose)

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

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

Study Evidence Comparator Efficacy
Schaich et al. 2013 (AML2003) Non-randomized portion of RCT
Serve et al. 2013 Randomized Phase II (C) 7+3d & Sorafenib Seems not superior
Petersdorf et al. 2013 (SWOG S0106) Phase III (C) 7+3d & GO Seems not superior
Dombret et al. 2015 (AZA-AML-001) Phase III (C) Azacitidine Might have inferior OS
Röllig et al. 2015 (SORAML) Randomized Phase II (C) 7+3d & Sorafenib Seems to have inferior EFS
Lancet et al. 2018 (CLTR0310-301) Phase III (C) CPX-351 Inferior OS

Note: this was the upper bound of the allowable daunorubicin dose in AZA-AML-001.

Chemotherapy

  • Cytarabine (Cytosar) 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
    • Note: Dombret et al. 2015 did not specify which days the daunorubicin is administered; some protocols give daunorubicin on days 3 to 5

7-day course

Subsequent treatment

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

Study Evidence Comparator Efficacy
Holowiecki et al. 2004 (PALG AML1/1999) Phase III (C) DAC Inferior CR rate after first induction
Holowiecki et al. 2012 (PALG AML1/2004) Phase III (C) 1. DAC Inferior OS
2. DAF Seems to have inferior OS
Castaigne et al. 2012 (ALFA-0701) Phase III (C) 7+3d & GO Seems to have inferior OS
Stone et al. 2017 (RATIFY) Phase III (C) 7+3d & Midostaurin Inferior OS

Note: patients in RATIFY had FLT3+ disease.

Chemotherapy

Supportive medications

  • "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

  • Patients with only partial remission in both PALG studies underwent a second course with the same drugs, doses, and schedule.
  • PALG AML1/1999, non-responders: CLAG salvage.
  • Patients in remission in both PALG studies: HAM, then HiDAC consolidation
  • ALFA-0701, CR or CRp: Cytarabine & daunorubicin consolidation

References

  1. PALG AML1/1999: Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, Skotnicki A, Jedrzejczak WW, Konopka L, Kuliczkowski K, Zdziarska B, Dmoszyńska A, Marianska B, Pluta A, Zawilska K, Komarnicki M, Kloczko J, Sulek K, Haus O, Stella-Holowiecka B, Baran W, Jakubas B, Paluszewska M, Wierzbowska A, Kielbinski M, Jagoda K; Polish Adult Leukemia Group (PALG). Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia: multicenter, phase III study. Leukemia. 2004 May;18(5):989-97. link to original article contains verified protocol PubMed
  2. PALG AML1/2004: Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszyńska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. link to original article contains verified protocol PubMed
  3. ALFA-0701: Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. Epub 2012 Apr 5. link to original article contains verified protocol PubMed
  4. AML2003: Schaich M, Parmentier S, Kramer M, Illmer T, Stölzel F, Röllig C, Thiede C, Hänel M, Schäfer-Eckart K, Aulitzky W, Einsele H, Ho AD, Serve H, Berdel WE, Mayer J, Schmitz N, Krause SW, Neubauer A, Baldus CD, Schetelig J, Bornhäuser M, Ehninger G. High-dose cytarabine consolidation with or without additional amsacrine and mitoxantrone in acute myeloid leukemia: results of the prospective randomized AML2003 trial. J Clin Oncol. 2013 Jun 10;31(17):2094-102. Epub 2013 Apr 29. link to original article contains verified protocol PubMed
  5. Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, Schaich M, Ottmann O, Duyster J, Wandt H, Fischer T, Giagounidis A, Neubauer A, Reichle A, Aulitzky W, Noppeney R, Blau I, Kunzmann V, Stuhlmann R, Krämer A, Kreuzer KA, Brandts C, Steffen B, Thiede C, Müller-Tidow C, Ehninger G, Berdel WE. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013 Sep 1;31(25):3110-8. Epub 2013 Jul 29. link to original article contains protocol PubMed
  6. 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 PubMed
  7. AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article link to PMC article contains verified protocol PubMed
    1. Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article PubMed
  8. SORAML: Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Schäfer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghanß C, Repp R, Heits F, Dürk H, Hase J, Klut IM, Illmer T, Bornhäuser M, Schaich M, Parmentier S, Görner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, Ehninger G; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015 Dec;16(16):1691-9. Epub 2015 Nov 6. link to original article PubMed
  9. RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains verified protocol PubMed
  10. CLTR0310-301: Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. Epub 2018 Jul 19. link to original article contains protocol PubMed

7+3d (high-dose)

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

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

Study Evidence Comparator Efficacy
Fernandez et al. 2009 (ECOG E1900) Phase III (E) 7+3d (standard-dose) Superior OS
Zeidner et al. 2015 (JHOC-J1101) Randomized Phase II (C) FLAM Inferior CR rate

Chemotherapy

7-day course

Subsequent treatment

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

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

Study Evidence Comparator Efficacy
Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01) Phase III (E) 7+3d (standard-dose) Superior CR rate
Lee et al. 2017 (COSAH C-022) Phase III (C) 7+3i Seems not superior

Chemotherapy

7-day course

Subsequent treatment

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

References

  1. HOVON 43 AML/SAKK 30/01: Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. link to original article contains verified protocol PubMed
  2. ECOG E1900: Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, Lazarus HM, Levine RL, Litzow MR, Paietta EM, Patel JP, Racevskis J, Rowe JM, Tallman MS, Sun Z, Luger SM. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016 Mar 24;127(12):1551-8. Epub 2016 Jan 11. link to original article link to PMC article PubMed
  3. JHOC-J1101: Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, Lancet JE, Bose P, Levy MY, Tibes R, Gojo I, Gocke CD, Rosner GL, Little RF, Wright JJ, Doyle LA, Smith BD, Karp JE. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015 Sep;100(9):1172-9. Epub 2015 May 28. link to original article contains verified protocol link to PMC article PubMed
  4. COSAH C-022: Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. link to original article contains verified protocol PubMed

7+3d & GO

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

Regimen

Study Evidence Comparator Efficacy
Castaigne et al. 2012 (ALFA-0701) Phase III (E) 7+3d (intermediate-dose) Seems to have superior OS

Chemotherapy

7-day course

Subsequent treatment

References

  1. ALFA-0701: Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. link to original article contains verified protocol PubMed

7+3i

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

Variant #1, 80/12, intermittent Ara-C

Study Evidence Comparator Efficacy
Masaoka et al. 1996 Randomized Phase II (E) 7+3d (standard-dose) Seems to have superior CR rate

Chemotherapy

7-day course

Variant #2, 100/12, CI Ara-C

Study Evidence Comparator Efficacy
Haas et al. 1993 Non-randomized
Rowe et al. 2004 (ECOG E3993) Phase III (E) 1. 7+3d (standard-dose)
2. 7+3d + GM-CSF
3. 7+3i + GM-CSF
4. 7+3m
5. 7+3m + GM-CSF
Seems not superior
Ohtake et al. 2010 (JALSG AML201) Phase III (C) 7+5d Seems not superior

Chemotherapy

7-day course

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

Variant #3, 100/13, CI Ara-C

Study Evidence Comparator Efficacy
Wiernik et al. 1992 Phase III (E) 7+3d (standard-dose) Seems to have superior OS

Chemotherapy

7-day course

Variant #4, 200/12, CI Ara-C

Study Evidence Comparator Efficacy
Löwenberg et al. 2003 (HOVON/SAKK AML 29) Phase III (C) 7+3i & G-CSF Seems to have inferior DFS
Pautas et al. 2010 (ALFA-9801) Phase III (C) 1. 7+3d (high-dose)
2. 7+4i
Seems not superior
Löwenberg et al. 2011 (HOVON/SAKK AML 42) Phase III (C) HDAC+3i Seems not superior
Löwenberg et al. 2017 (HOVON-102) Phase III (C) 7+3i & Clofarabine Seems not superior
Lee et al. 2017 (COSAH C-022) Phase III (C) 7+3d (high-dose) Seems not superior

Chemotherapy

  • Cytarabine (Cytosar) 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
    • Note: in HOVON/SAKK AML 29 & AML 42, idarubicin was given on days 5 to 7

7-day course

Subsequent treatment

Variant #5, with range

Study Evidence Comparator Efficacy
Dombret et al. 2015 (AZA-AML-001) Phase III (C) Azacitidine Might have inferior OS

Chemotherapy

7-day course

References

  1. Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, Ritch PS, Enck RE, Weitberg AB. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992 Jan 15;79(2):313-9. link to original article contains verified protocol PubMed
  2. Haas R, Ho AD, Del Valle F, Fischer JT, Ehrhardt R, Döhner H, Witt B, Huberts H, Kaplan E, Hunstein W. Idarubicin/cytosine arabinoside and mitoxantrone/etoposide for the treatment of de novo acute myelogenous leukemia. Semin Oncol. 1993 Dec;20(6 Suppl 8):20-6. PubMed
  3. Masaoka T, Ogawa M, Yamada K, Kimura K, Ohashi Y. A phase II comparative study of idarubicin plus cytarabine versus daunorubicin plus cytarabine in adult acute myeloid leukemia. Semin Hematol. 1996 Oct;33(4 Suppl 3):12-7. contains protocol PubMed
  4. HOVON/SAKK AML 29: Löwenberg B, van Putten W, Theobald M, Gmür J, Verdonck L, Sonneveld P, Fey M, Schouten H, de Greef G, Ferrant A, Kovacsovics T, Gratwohl A, Daenen S, Huijgens P, Boogaerts M; Dutch-Belgian Hemato-Oncology Cooperative Group; Swiss Group for Clinical Cancer Research. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med. 2003 Aug 21;349(8):743-52. link to original article contains verified protocol PubMed
  5. ECOG E3993: Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. link to original article contains verified protocol PubMed
  6. ALFA-9801: Pautas C, Merabet F, Thomas X, Raffoux E, Gardin C, Corm S, Bourhis JH, Reman O, Turlure P, Contentin N, de Revel T, Rousselot P, Preudhomme C, Bordessoule D, Fenaux P, Terré C, Michallet M, Dombret H, Chevret S, Castaigne S. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol. 2010 Feb 10;28(5):808-14. Epub 2010 Jan 4. link to original article contains verified protocol PubMed
  7. JALSG AML201: Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 2011 Feb 24;117(8):2358-65. Epub 2010 Aug 6. link to original article PubMed
  8. 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; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011 Mar 17;364(11):1027-36. link to original article contains verified protocol PubMed
  9. AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article contains protocol link to PMC article PubMed
    1. Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article PubMed
  10. 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; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK). Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML. Blood. 2017 Mar 23;129(12):1636-1645. Epub 2017 Jan 3. link to original article contains verified protocol PubMed
  11. COSAH C-022: Lee JH, Kim H, Joo YD, Lee WS, Bae SH, Zang DY, Kwon J, Kim MK, Lee J, Lee GW, Lee JH, Choi Y, Kim DY, Hur EH, Lim SN, Lee SM, Ryoo HM, Kim HJ, Hyun MS, Lee KH; Cooperative Study Group A for Hematology. Prospective randomized comparison of idarubicin and high-dose daunorubicin in induction chemotherapy for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2017 Aug 20;35(24):2754-2763. Epub 2017 Jun 20. link to original article contains verified protocol PubMed

7+3i & Sorafenib

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Regimen

Study Evidence
Ravandi et al. 2010 Phase I/II

Regimen details are from the phase II part of the published phase I/II trial.

Chemotherapy

  • Cytarabine (Cytosar) 1500 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose: 6000 mg/m2)
    • Patients older than 60 received: 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
  • Sorafenib (Nexavar) 400 mg PO BID on days 1 to 7

7-day course

Subsequent treatment

References

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

7+3m

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7+3m: 7 days of cytarabine + 3 days of mitoxantrone

Regimen

Study Evidence Comparator Efficacy
Rowe et al. 2004 (ECOG E3993) Phase III (E) 1. 7+3d (standard-dose)
2. 7+3d + GM-CSF
3. 7+3i
4. 7+3i + GM-CSF
5. 7+3m + GM-CSF
Seems not superior

Chemotherapy

7-day course

Patients with persistent disease at day 14 (greater than 5% blasts) underwent an identical second cycle of 7+3m.

References

  1. ECOG E3993: Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. link to original article contains verified protocol PubMed

ADE (standard-dose Ara-C)

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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

Variant #1, 7-3-7

Study Evidence Comparator Efficacy
Bishop et al. 1996 Phase III (C) ADE (high-dose Ara-C) Inferior DFS

Chemotherapy

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

Subsequent treatment

  • 5-2-5 consolidation x 2

Variant #2, 8-3-5, intermittent Ara-C

Study Evidence Comparator Efficacy
Hann et al. 1997 (UK MRC AML10) Phase III (E) DAT 3+8 Seems not superior
Burnett et al. 2010 (UK MRC AML15) Phase III (C) See note See note
Gamis et al. 2014 (COG AAML0531) Phase III (C) See note See note

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

Preceding treatment

Chemotherapy

8-day course

Subsequent treatment

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

Variant #3, 10-3-5, intermittent Ara-C

Study Evidence Comparator Efficacy
Hann et al. 1997 (UK MRC AML10) Phase III (E) DAT 3+10 Seems not superior
Burnett et al. 1999 (UK MRC AML12) Phase III (C) See note See note
Burnett et al. 2010 (UK MRC AML15) Phase III (C) See note See note
Gamis et al. 2014 (COG AAML0531) Phase III (C) See note See note

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

Chemotherapy

10-day course

Subsequent treatment

  • ADE 8-3-5

Variant #4, 10-3-5, 100/50/50, CI Ara-C

Study Evidence Comparator Efficacy
Willemze et al. 2013 (EORTC-GIMEMA AML-12) Phase III (C) ADE (high-dose Ara-C) Might have inferior OS

Chemotherapy

10-day course

Variant #5, 10-3-5, 100/50/100, CI Ara-C

Study Evidence Comparator Efficacy
Mandelli et al. 2009 (EORTC-GIMEMA AML-10) Phase III (C) 1. AIE
2. AME
Seems not superior

Chemotherapy

10-day course

References

  1. Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Herrmann R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja S. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996 Mar 1;87(5):1710-7. link to original article contains protocol PubMed
  2. UK MRC AML10: Hann IM, Stevens RF, Goldstone AH, Rees JK, Wheatley K, Gray RG, Burnett AK; Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia: results of the Medical Research Council's 10th AML trial (MRC AML10). Blood. 1997 Apr 1;89(7):2311-8. link to original article contains verified protocol PubMed
    1. Update: Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG, Wheatley K; UK Medical Research Council Adult and Children's Leukaemia Working Parties. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet. 1998 Mar 7;351(9104):700-8. link to original article PubMed
  3. UK MRC AML12: Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the randomized MRC trial. Blood. 1999 Jun 15;93(12):4131-43. link to original article PubMed
    1. Update: Burnett AK, Hills RK, Milligan DW, Goldstone AH, Prentice AG, McMullin MF, Duncombe A, Gibson B, Wheatley K. Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol. 2010 Feb 1;28(4):586-95. Epub 2009 Dec 28. link to original article PubMed
  4. 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. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol. 2009 Nov 10;27(32):5397-403. Epub 2009 Oct 13. Erratum in: J Clin Oncol. 2010 Mar 10;28(8):1438. link to original article link to PMC article PubMed
  5. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed
    1. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed
  6. EORTC-GIMEMA AML-12: Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, Muus P, Mistrik M, Amadori S, Specchia G, Fabbiano F, Nobile F, Sborgia M, Camera A, Selleslag DL, Lefrère F Sr, Magro D, Sica S, Cantore N, Beksac M, Berneman Z, Thomas X, Melillo L, Guimaraes JE, Leoni P, Luppi M, Mitra ME, Bron D, Fillet G, Marijt EW, Venditti A, Hagemeijer A, Mancini M, Jansen J, Cilloni D, Meert L, Fazi P, Vignetti M, Trisolini SM, Mandelli F, de Witte T. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: Results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2014 Jan 20;32(3):219-28. Epub 2013 Dec 2. link to original article contains verified protocol PubMed
  7. COG AAML0531: Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. link to original article link to PMC article contains verified protocol PubMed

ADE (high-dose Ara-C)

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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

Variant #1, HIDAC-3-5

Study Evidence Comparator Efficacy
Willemze et al. 2013 (EORTC-GIMEMA AML-12) Phase III (E) ADE (standard-dose Ara-C) Might have superior OS

Chemotherapy

7-day course

Variant #2, HIDAC-3-7

Study Evidence Comparator Efficacy
Bishop et al. 1996 Phase III (E) ADE (standard-dose Ara-C) Superior DFS

Chemotherapy

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

Subsequent treatment

  • 5-2-5 consolidation x 2

References

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

CIA

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

Variant #1, 15/10/1000

Study Evidence Comparator Efficacy
Jabbour et al. 2017 Randomized Phase II (E) FIA Seems not superior

Chemotherapy

One course

Subsequent treatment

  • Patients not achieving CR or CRp could undergo a second induction
  • Patients achieving CR or CRp: CIA consolidation

Variant #2, 20/10/1000

Study Evidence
Nazha et al. 2013 Phase II

Chemotherapy

Supportive medications

5-day course

Subsequent treatment

  • Patients with PR: a second course with the same drugs, doses, and schedule.
  • Patients achieving CR or CRi: CIA consolidation

References

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

DA 3 + 10, GO

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

Regimen

Study Evidence Comparator Efficacy
Burnett et al. 2010 (UK MRC AML15) Phase III (E) See note See note
Burnett et al. 2012 (UK NCRI AML16) Phase III (E) DA 3 + 10 Seems to have superior OS

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

Chemotherapy

One course

Subsequent treatment

  • See paper for details (to be completed).

References

  1. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article contains verified protocol PubMed
    1. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed
  2. UK NCRI AML16: Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. link to original article contains verified protocol PubMed
    1. Update: Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. link to original article link to PMC article PubMed

DA 3 + 10

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

Variant #1, 50 mg/m2 dauno

Study Evidence Comparator Efficacy
Burnett et al. 2010 (UK MRC AML15) Phase III (C) See note See note
Burnett et al. 2012 (UK NCRI AML16) Phase III (C) DA 3 + 10, GO Seems to have inferior OS

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

Chemotherapy

One course

Subsequent treatment

  • See papers for details (to be completed).

Variant #2, 60 mg/m2 dauno

Study Evidence Comparator Efficacy
Burnett et al. 2015 (UK NCRI AML17) Phase III (C) DA 3 + 10 (high-dose) Seems not superior

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

One course

Subsequent treatment

  • Complex randomization; see paper for details (to be completed).

References

  1. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed
    1. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed
  2. UK NCRI AML16: Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, Hunter AE, Yin J, Craddock CF, Dufva IH, Wheatley K, Milligan D. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012 Nov 10;30(32):3924-31. Epub 2012 Jul 30. link to original article contains verified protocol PubMed
    1. Update: Burnett AK, Russell NH, Hills RK, Kell J, Nielsen OJ, Dennis M, Cahalin P, Pocock C, Ali S, Burns S, Freeman S, Milligan D, Clark RE. A comparison of clofarabine with ara-C, each in combination with daunorubicin as induction treatment in older patients with acute myeloid leukaemia. Leukemia. 2017 Feb;31(2):310-317. Epub 2016 Sep 2. link to original article link to PMC article PubMed
  3. UK NCRI AML17: Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 Jun 18;125(25):3878-85. Epub 2015 Apr 1. link to original article contains verified protocol link to PMC article PubMed

DAC

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

Regimen

Study Evidence Comparator Efficacy
Holowiecki et al. 2004 (PALG AML1/1999) Phase III (E) DA Superior CR rate after first induction
Holowiecki et al. 2012 (PALG AML1/2004) Phase III (E) 1. DA Superior OS
2. DAF Seems to have superior OS

Chemotherapy

Supportive medications

  • "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

  • Patients with only partial remission in both studies underwent a second course with the same drugs, doses, and schedule.
  • Non-responders in PALG AML1/1999: CLAG salvage
  • Patients in remission in both studies: HAM, then HiDAC consolidation

References

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

FLAG-Ida

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

Regimen

Study Evidence
Burnett et al. 2010 (UK MRC AML15) Phase III (*)

This trial has a complex randomization; to be completed.

Chemotherapy

One course

Subsequent treatment

  • See paper for details

References

  1. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed
    1. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed

HAA

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

Regimen

Study Evidence Comparator Efficacy
Jin et al. 2013 Phase III (E) 1. DA Superior EFS
2. HAD Not reported

Unlikely to be completed since there were significantly more deaths in this arm, despite a superior primary efficacy endpoint.

Chemotherapy

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 PubMed

HAD

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

Regimen

Study Evidence Comparator Efficacy
Jin et al. 2013 Phase III (E) 1. DA Might have superior EFS
2. HAA Not reported

Unlikely to be completed since there were significantly more deaths in this arm, despite a trend towards a superior primary efficacy endpoint.

Chemotherapy

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 PubMed

MEC

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MEC: Mitoxantrone, Etoposide, Cytarabine
MICE: MItoxantrone, Cytarabine, Etoposide

Regimen

Study Evidence Comparator Efficacy
Amadori et al. 2013 (EORTC/GIMEMA AML-17) Phase III (C) GO, then MICE Might have superior OS

Chemotherapy

One course

References

  1. EORTC/GIMEMA AML-17: Amadori S, Suciu S, Stasi R, Salih HR, Selleslag D, Muus P, De Fabritiis P, Venditti A, Ho AD, Lübbert M, Thomas X, Latagliata R, Halkes CJ, Falzetti F, Magro D, Guimaraes JE, Berneman Z, Specchia G, Karrasch M, Fazi P, Vignetti M, Willemze R, de Witte T, Marie JP. Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17). J Clin Oncol. 2013 Dec 10;31(35):4424-30. Epub 2013 Oct 14. link to original article contains verified protocol PubMed

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

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

Azacitidine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Dombret et al. 2015 (AZA-AML-001) Phase III (E) Investigator's choice of:
1. 7+3d (standard-dose)
2. 7+3d (intermediate-dose)
3. 7+3i
4. Best supportive care
5. LoDAC
Might have superior OS

Chemotherapy

28-day cycle for at least 6 cycles

References

  1. AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article contains verified protocol link to PMC article PubMed
    1. Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article PubMed

Azacitidine & Venetoclax

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Regimen

Study Evidence
DiNardo et al. 20018 (M14-358) Phase Ib

Patients with WBC greater than 25 x 109/L at presentation were pre-treated with hydroxyurea or leukapheresis.

Chemotherapy, induction

References

  1. 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. link to original article contains verified protocol PubMed NCT02203773

Azacitidine & Gemtuzumab ozogamicin

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Regimen

Study Evidence
Nand et al. 2008 Phase II
Nand et al. 2013 (SWOG S0703) Phase II

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

Chemotherapy, pre-treatment phase

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

Chemotherapy, induction

Supportive medications

Subsequent treatment

References

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

Best supportive care

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Regimen

Study Evidence Comparator Efficacy
Kantarjian et al. 2012 (DACO-016) Phase III (C) Decitabine Might have inferior OS
Dombret et al. 2015 (AZA-AML-001) Phase III (C) Azacitidine Might have inferior OS
Amadori et al. 2016 (EORTC/GIMEMA AML-19) Phase III (C) Gemtuzumab ozogamicin Inferior OS

No active antineoplastic treatment, although some trials consider Hydroxyurea (Hydrea) to be a component of best supportive care.

References

  1. DACO-016: Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. link to original article contains verified protocol link to PMC article PubMed
  2. AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article contains verified protocol link to PMC article PubMed
    1. Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article PubMed
  3. 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. 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 PubMed

Clofarabine monotherapy

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Variant #1, 20 mg/m2

Study Evidence Comparator Efficacy
Burnett et al. 2013 (UK NCRI AML16) Phase III (E) LoDAC Seems not superior

Chemotherapy

4- to 6-week cycle for 4 cycles

Variant #2, 30 mg/m2

Study Evidence Comparator Efficacy
Faderl et al. 2008 Randomized Phase II (E) Clofarabine & LoDAC Seems to have inferior EFS
Burnett et al. 2010 (UWCM-001 and BIOV-121) Phase II

Chemotherapy

One course

Subsequent treatment

  • A second induction was permitted for SD or better.
  • Faderl et al. 2008: Responders proceeded to clofarabine & cytarabine consolidation

References

  1. Faderl S, Ravandi F, Huang X, Garcia-Manero G, Ferrajoli A, Estrov Z, Borthakur G, Verstovsek S, Thomas DA, Kwari M, Kantarjian HM. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008 Sep 1;112(5):1638-45. Epub 2008 Jun 18. link to original article contains verified protocol link to PMC article PubMed
  2. Burnett AK, Russell NH, Kell J, Dennis M, Milligan D, Paolini S, Yin J, Culligan D, Johnston P, Murphy J, McMullin MF, Hunter A, Das-Gupta E, Clark R, Carr R, Hills RK. European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy. J Clin Oncol. 2010 May 10;28(14):2389-95. Epub 2010 Apr 12. link to original article PubMed
  3. UK NCRI AML16: Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. link to original article contains verified protocol PubMed

Clofarabine & LoDAC

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

Variant #1

Study Evidence Comparator Efficacy
Faderl et al. 2008 Randomized Phase II (E) Clofarabine Seems to have superior EFS

Chemotherapy

One course

Subsequent treatment

  • A second induction was permitted for SD or better
  • Responders proceeded to clofarabine & cytarabine consolidation

Variant #2

Study Evidence
Faderl et al. 2010 Phase II

Chemotherapy

One course

Subsequent treatment

References

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

CPX-351 monotherapy

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CPX-351: Liposomal Cytarabine and Daunorubicin

Regimen

Study Evidence Comparator Efficacy
Lancet et al. 2018 (CLTR0310-301) Phase III (E) 7+3d (intermediate-dose) Superior OS

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

References

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

Decitabine monotherapy

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Variant #1

Study Evidence Comparator Efficacy
Issa et al. 2014 Randomized Phase II (C) Decitabine & Valproate Seems not superior

Chemotherapy

4- to 6-week cycles

Variant #2

Study Evidence Comparator Efficacy
Kantarjian et al. 2012 (DACO-016) Phase III (E) 1. LoDAC
2. Best supportive care
Might have superior OS

Chemotherapy

28-day cycles

Variant #3

Study Evidence
Blum et al. 2010 Phase II
Welch et al. 2016 Phase II

Chemotherapy

28-day cycles

Subsequent treatment

  • Blum et al. 2010, persistent AML (greater than or equal to 5% blasts): repeated cycles with 10 days of decitabine as described above
  • Blum et al. 2010, no morphologic evidence of AML (less than 5% blasts): received 5 days of decitabine as described by decitabine monotherapy maintenance

References

  1. Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7473-8. Epub 2010 Apr 5. link to original article contains verified protocol link to PMC article PubMed
  2. DACO-016: Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. link to original article contains verified protocol link to PMC article PubMed
  3. Issa JP, Garcia-Manero G, Huang X, Cortes J, Ravandi F, Jabbour E, Borthakur G, Brandt M, Pierce S, Kantarjian HM. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015 Feb 15;121(4):556-61. Epub 2014 Oct 21. link to original article contains verified protocol link to PMC article PubMed
  4. Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, Wilson RK, Baty JD, Duncavage EJ, Tandon D, Lee Y, Wartman LD, Uy GL, Ghobadi A, Tomasson MH, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Cashen AF, Schroeder MA, Jacoby MA, Heath SE, Luber K, Janke MR, Hantel A, Khan N, Sukhanova MJ, Knoebel RW, Stock W, Graubert TA, Walter MJ, Westervelt P, Link DC, DiPersio JF, Ley TJ. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016 Nov 24;375(21):2023-2036. link to original article contains verified protocol link to PMC article PubMed

Decitabine & Venetoclax

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Regimen

Study Evidence
DiNardo et al. 20018 (M14-358) Phase Ib

Patients with WBC greater than 25 x 109/L at presentation were pre-treated with hydroxyurea or leukapheresis.

Chemotherapy, induction

References

  1. 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. link to original article contains verified protocol PubMed NCT02203773

Gemtuzumab ozogamicin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Amadori et al. 2016 (EORTC-GIMEMA AML-19) Phase III (E) Best supportive care Superior OS

Chemotherapy

One course

Subsequent treatment

References

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

ICL

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ICL: Idarubicin, Cytarabine, Lomustine

Regimen

Study Evidence
Pigneux et al. 2016 (GOELAMS LAM-SA2002) Non-randomized portion of RCT

Chemotherapy

One course

See paper for further details about post-induction therapy

References

  1. Pigneux A, Béné MC, Guardiola P, Recher C, Hamel JF, Sauvezie M, Harousseau JL, Tournilhac O, Witz F, Berthou C, Escoffre-Barbe M, Guyotat D, Fegueux N, Himberlin C, Hunault M, Delain M, Lioure B, Jourdan E, Bauduer F, Dreyfus F, Cahn JY, Sotto JJ, Ifrah N. Addition of Androgens Improves Survival in Elderly Patients With Acute Myeloid Leukemia: A GOELAMS Study. J Clin Oncol. 2017 Feb;35(4):387-393. Epub 2016 Oct 24. link to original article contains verified protocol PubMed

LoDAC

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

Variant #1, limited duration

Study Evidence Comparator Efficacy
Sekeres et al. 2012 Randomized Phase II (C) LDAC & Lintuzumab Seems not superior
Burnett et al. 2013 (UK NCRI AML16) Phase III (C) Clofarabine Seems not superior
Dennis et al. 2015 Randomized (C) 1. LDAC & Vosaroxin Seems not superior
2. Vosaroxin Seems not superior
Burnett et al. 2015 Randomized (C) Sapacitabine Might have inferior CR rate
Dombret et al. 2015 (AZA-AML-001) Phase III (C) Azacitidine Might have inferior OS

Chemotherapy

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

Variant #2, indefinite duration

Study Evidence Comparator Efficacy
Kantarjian et al. 2012 (DACO-016) Phase III (C) Decitabine Might have inferior OS

Chemotherapy

28-day cycles until progression or intolerance

References

  1. DACO-016: Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. link to original article contains verified protocol link to PMC article PubMed
  2. Sekeres MA, Lancet JE, Wood BL, Grove LE, Sandalic L, Sievers EL, Jurcic JG. Randomized phase IIb study of low-dose cytarabine and lintuzumab versus low-dose cytarabine and placebo in older adults with untreated acute myeloid leukemia. Haematologica. 2013 Jan;98(1):119-28. Epub 2012 Jul 16. link to original article link to PMC article PubMed
  3. UK NCRI AML16: Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, Yin J, McMullin MF, Ali S, Bowen D, Hills RK; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94. Epub 2013 Jul 9. link to original article contains verified protocol PubMed
  4. Dennis M, Russell N, Hills RK, Hemmaway C, Panoskaltsis N, McMullin MF, Kjeldsen L, Dignum H, Thomas IF, Clark RE, Milligan D, Burnett AK. Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia. Blood. 2015 May 7;125(19):2923-32. Epub 2015 Mar 24. link to original article contains verified protocol link to PMC article PubMed
  5. Burnett AK, Russell N, Hills RK, Panoskaltsis N, Khwaja A, Hemmaway C, Cahalin P, Clark RE, Milligan D. A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia. Leukemia. 2015 Jun;29(6):1312-9. Epub 2015 Feb 13. link to original article contains verified protocol PubMed
  6. AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article contains verified protocol link to PMC article PubMed
    1. Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article PubMed

LoDAC & Venetoclax

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

Regimen

Study Evidence
Wei et. al. 2017 (M14-387) Phase II

Note: this trial has not been published other than in abstract form, to our knowledge.

Chemotherapy

28-day cycles

References

  1. Abstract: Wei A, Strickland SA, Roboz GJ, Hou J, Fiedler W, Lin TL, Walter RB, Enjeti A, Chyla B, Popovic R, Fakouhi K, Shah P, Dunbar M, Xu, T, Mabry M, Hayslip J. Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes. Blood, 130(Suppl 1), 890. link to abstract contains protocol
  2. NCT02287233 contains protocol

Temozolomide monotherapy

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Regimen

Study Evidence
Brandwein et al. 2014 Phase II

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

Chemotherapy

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

28-day cycle for up to 12 cycles

References

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

Consolidation after upfront therapy

5+2d

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Regimen

Study Evidence
Lancet et al. 2018 (CLTR0310-301) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

5-day course

References

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

Azacitidine monotherapy

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Regimen

Study Evidence
Nand et al. 2013 (SWOG S0703) Phase II

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

References

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

Azacitidine & Gemtuzumab ozogamicin

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Regimen

Study Evidence
Nand et al. 2013 (SWOG S0703) Phase II

Preceding treatment

Chemotherapy

Supportive medications

1 cycle

Subsequent treatment

References

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

BuCy, then auto HSCT

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BuCy: Busulfan & Cyclophosphamide

Variant #1, 16/120

Study Evidence Comparator Efficacy
Vellenga et al. 2011 (HOVON-SAKK AML-29/AML-42) Phase III (E) Etoposide & Mitoxantrone Might have superior RFS

Preceding treatment

  • 7+3i, then amsacrine & cytarabine

Chemotherapy

Variant #2, 16/200

Study Evidence Comparator Efficacy
Ravindranath et al. 1996 Phase III (E) Intensive chemotherapy Seems not superior

Preceding treatment

Chemotherapy

References

  1. Ravindranath Y, Yeager AM, Chang MN, Steuber CP, Krischer J, Graham-Pole J, Carroll A, Inoue S, Camitta B, Weinstein HJ; Pediatric Oncology Group. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med. 1996 May 30;334(22):1428-34. link to original article contains verified protocol PubMed
  2. 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; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON); Swiss Group for Clinical Cancer Research Collaborative Group (SAKK). Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood. 2011 Dec 1;118(23):6037-42. Epub 2011 Sep 27. link to original article contains verified protocol PubMed

BuFlu, then allo HSCT

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BuFlu: Busulfan & Fludarabine

Regimen

Study Evidence
Devine et al. 2015 (CALGB 100103) Phase II, <20 pts in subgroup

Chemotherapy

GVHD prophylaxis

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

Stem cells transfused on day 0

References

  1. Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. Epub 2015 Nov 2. link to original article contains verified protocol link to PMC article PubMed

CIA

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

Regimen

Study Evidence
Nazha et al. 2013 Phase II

Preceding treatment

Chemotherapy

3-day course; repeated every 3 to 4 weeks depending on disease response and recovery from regimen toxicity for up to six cycles

References

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

CLARA

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CLARA: CLofarabine and ARA-C (Cytarabine)

Regimen

Study Evidence Comparator Efficacy
Thomas et al. 2017 (ALFA-0702) Randomized Phase II (E) HDAC & G-CSF Seems to have superior RFS

Preceding treatment

  • Cytarabine, Daunorubicin, G-CSF induction

Chemotherapy

35-day cycle for 3 cycles

References

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

Clofarabine & LoDAC/Decitabine

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

Regimen

Study Evidence
Faderl et al. 2010 Phase II

Preceding treatment

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

Chemotherapy, clofarabine & LoDAC portion

Cycles 2, 3, 7 to 9, 13 to 15

Chemotherapy, decitabine portion

Cycles 4 to 6, 10 to 12, 16 to 18

References

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

CPX-351 monotherapy

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CPX-351: Liposomal Cytarabine and Daunorubicin

Regimen

Study Evidence
Lancet et al. 2018 (CLTR0310-301) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

Up to two courses

References

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

Cytarabine & Daunorubicin

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Variant #1

Study Evidence
Castaigne et al. 2012 (ALFA-0701) Non-randomized portion of 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. Length of courses is not specified.

Preceding treatment

Chemotherapy

2 courses

Variant #2

Study Evidence Comparator Efficacy
Gardin et al. 2007 (ALFA 9803) Phase III (E) 4 + 7 with daunorubicin Seems to have superior OS

Preceding treatment

  • 4d + 7 induction

Chemotherapy

1-month cycle for up to 6 cycles

References

  1. Gardin C, Turlure P, Fagot T, Thomas X, Terre C, Contentin N, Raffoux E, de Botton S, Pautas C, Reman O, Bourhis JH, Fenaux P, Castaigne S, Michallet M, Preudhomme C, de Revel T, Bordessoule D, Dombret H. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007 Jun 15;109(12):5129-35. Epub 2007 Mar 6. link to original article contains verified protocol PubMed
  2. ALFA-0701: Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. link to original article contains verified protocol PubMed

Cytarabine, Daunorubicin, Gemtuzumab ozogamicin

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Regimen

Study Evidence
Castaigne et al. 2012 (ALFA-0701) Non-randomized portion of RCT

Note: length of courses is not specified.

Preceding treatment

Chemotherapy

2 courses

References

  1. ALFA-0701: Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. link to original article contains verified protocol PubMed

CYVE

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CYVE: CYtarabine & VEpesid (Etoposide)

Regimen

Study Evidence
Lee et al. 2017 (COSAH C-022) Non-randomized portion of RCT

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

Preceding treatment

Chemotherapy

4 courses

Subsequent treatment

  • Transplant eligible patients with available donors usually proceeded to allogeneic HSCT after 2 courses (details not specified)

References

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

Cytarabine & Idarubicin

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Regimen

Study Evidence Comparator Efficacy
Gardin et al. 2007 (ALFA 9803) Phase III (E) 4 + 7 with idarubicin Seems to have superior OS

Preceding treatment

  • 4i + 7 induction

Chemotherapy

1-month cycle for up to 6 cycles

References

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

Cytarabine, Idarubicin, Sorafenib

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Regimen

Study Evidence
Ravandi et al. 2010 Phase I/II

Regimen details are from the phase II part of the published phase I/II trial.

Preceding treatment

Chemotherapy

4 to 6-week cycle for up to 5 cycles

Subsequent treatment

References

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

Cyclophosphamide & TBI, then allo HSCT

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Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study Evidence Comparator Efficacy Non-relapse mortality
Zittoun et al. 1995 Phase III (E) Intensive chemotherapy Superior DFS
Bornhäuser et al. 2012 Phase III (C) Fludarabine & TBI, then allo HSCT Seems not superior Seems not superior

Preceding treatment

  • Zittoun et al. 1995: 7+3d with CR, then amsacrine & IDAC

Details in the manuscripts are limited.

Chemoradiotherapy

Stem cells transfused on day 0

References

  1. 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; European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 1995 Jan 26;332(4):217-23. link to original article contains protocol PubMed
  2. Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, Baurmann H, Schäfer-Eckart K, Holler E, Kröger N, Schmid C, Einsele H, Kiehl MG, Hiddemann W, Schwerdtfeger R, Buchholz S, Dreger P, Neubauer A, Berdel WE, Ehninger G, Beelen DW, Schetelig J, Stelljes M. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012 Oct;13(10):1035-44. Epub 2012 Sep 7. link to original article contains protocol PubMed
  3. Retrospective: Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, Aljurf M, van Besien K, Bredeson C, Cahn JY, Costa LJ, de Lima M, Gale RP, Hale GA, Halter J, Hamadani M, Inamoto Y, Kamble RT, Litzow MR, Loren AW, Marks DI, Olavarria E, Roy V, Sabloff M, Savani BN, Seftel M, Schouten HC, Ustun C, Waller EK, Weisdorf DJ, Wirk B, Horowitz MM, Arora M, Szer J, Cortes J, Kalaycio ME, Maziarz RT, Saber W. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013 Dec 5;122(24):3863-70. Epub 2013 Sep 24. link to original article link to PMC article PubMed

Etoposide & Mitoxantrone

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Regimen

Study Evidence Comparator Efficacy
Vellenga et al. 2011 (HOVON-SAKK AML-29/AML-42) Phase III (C) Bu/Cy, then auto HSCT Might have inferior RFS

Preceding treatment

  • 7+3i, then Amsacrine & Cytarabine

Chemotherapy

References

  1. HOVON-SAKK AML-29/AML-42: Vellenga E, van Putten W, Ossenkoppele GJ, Verdonck LF, Theobald M, Cornelissen JJ, Huijgens PC, Maertens J, Gratwohl A, Schaafsma R, Schanz U, Graux C, Schouten HC, Ferrant A, Bargetzi M, Fey MF, Löwenberg B; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON).; Swiss Group for Clinical Cancer Research Collaborative Group (SAKK). Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood. 2011 Dec 1;118(23):6037-42. Epub 2011 Sep 27. link to original article contains verified protocol PubMed

Fludarabine & TBI, then allo HSCT

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Variant #1

Study Evidence Comparator Efficacy Non-relapse mortality
Bornhäuser et al. 2012 Phase III (E) Cyclophosphamide & TBI, then allo HSCT Seems not superior Seems not superior

Details in the abstract are limited.

Chemoradiotherapy

Variant #2, low-dose TBI

Study Evidence
Gyukocza et al. 2010 Non-randomized

Details are best described in Maris et al. 2003.

Chemoradiotherapy

GVHD prophylaxis

  • Cyclosporine A (type not specified) 6.25 mg/kg PO BID starting 4 to 6 hours after transplant, tapered at day 100 over 80 days (if no GVHD)
  • Mycophenolate mofetil (CellCept) 15 mg/kg PO BID starting 4 to 6 hours after transplant, tapered at day 40 over 56 days (if no GVHD)

References

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

Fludarabine, Busulfan, ATG, then allo HSCT

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Regimen

Study Evidence
Devine et al. 2015 (CALGB 100103) Phase II

Chemotherapy

GVHD prophylaxis

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

Stem cells transfused on day 0

References

  1. CALGB 100103: Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. Epub 2015 Nov 2. link to original article contains verified protocol link to PMC article PubMed

HAM

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

Regimen

Study Evidence
Wierzbowksa et al. 2007 Phase II
Holowiecki et al. 2012 (PALG AML1/2004) Non-randomized portion of RCT

Preceding treatment

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

Chemotherapy

Subsequent treatment

References

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

HDAC & G-CSF

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

Regimen

Study Evidence Comparator Efficacy
Thomas et al. 2017 (ALFA-0702) Randomized Phase II (C) CLARA Seems to have inferior RFS

Preceding treatment

  • Cytarabine, Daunorubicin, G-CSF induction

Chemotherapy

35-day cycle for 3 cycles

References

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

HiDAC

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

Variant #1, 2000 mg/m2 q12h x 6

Study Evidence
Holowiecki et al. 2012 (PALG AML1/2004) Non-randomized portion of RCT

Details in the text are scant.

Preceding treatment

Chemotherapy

Variant #2, 2 cycles of 2000 mg/m2 q12h x 10

Study Evidence Comparator Efficacy
Fukushima et al. 2012 Randomized, <20 pts in this arm (C) mIDAC Seems not superior

Preceding treatment

  • BHAC-MMV

Chemotherapy

2 cycles

Subsequent treatment

  • A-VVV

Variant #3, 1 cycle of 3000 mg/m2 q12h x 12

Study Evidence Comparator Efficacy
Cassileth et al. 1998 Phase III (C) BuCy, then auto HSCT Seems to have superior OS

Preceding treatment

  • 5+2i

Chemotherapy

One course

Variant #4, 3 cycles of 3000 mg/m2 q12h x 6

Study Evidence Comparator Efficacy
Moore et al. 2004 (CALGB 9222) Phase III (C) HiDAC, then CYVE, then AZQ & Mitoxantrone Seems not superior
Petersdorf et al. 2013 (SWOG S0106) Non-randomized portion of RCT
Schaich et al. 2013 (AML2003) Phase III (C) MAC/MAMAC/MAC Seems not superior
Stone et al. 2015 (ACCEDE) Non-randomized portion of RCT
Röllig et al. 2015 (SORAML) Randomized Phase II (C) HiDAC & Sorafenib Seems to have inferior EFS
Stone et al. 2015 (COSAH C-022) Non-randomized portion of RCT

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.

Preceding treatment

Chemotherapy

3 cycles of varying durations

Subsequent treatment

Variant #5, 3 cycles of 2000 mg/m2 q12h x 10

Study Evidence Comparator Efficacy
Miyawaki et al. 2010 (JALSG AML201) Phase III (E) Multiagent chemotherapy Seems not superior

Note: this was considered an experimental arm in Japan, given the timing of HiDAC approval.

Preceding treatment

Chemotherapy

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

Variant #6, 4 cycles of 3000 mg/m2 q12h x 6

Study Evidence Comparator Efficacy
Mayer et al. 1994 Phase III (E) Low-dose continuous infusion cytarabine Seems to have superior OS
Thomas et al. 2011 (ALFA-9802) Phase III (C) Timed sequential chemotherapy (TSC) Seems not superior
Lee et al. 2017 (COSAH C-022) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

Up to 4 cycles

Subsequent treatment

  • ALFA-9802: Cytarabine & Daunorubicin maintenance

References

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

IDAC

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

Variant #1, 1000 mg/m2 x 3

Study Evidence
Stone et al. 2015 (ACCEDE) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

Variant #2, 1000 mg/m2 x 10

Study Evidence Comparator Efficacy
Fukushima et al. 2012 Randomized, <20 pts in this arm (E) HDAC Seems not superior

Preceding treatment

  • BHAC-MMV

Chemotherapy

Two cycles

Subsequent treatment

  • A-VVV

Variant #3, 1000 mg/m2 x 12

Study Evidence
Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

One cycle

Subsequent treatment

References

  1. 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 (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. link to original article contains verified protocol PubMed
  2. Fukushima T, Urasaki Y, Yamaguchi M, Ueda M, Morinaga K, Haba T, Sugiyama T, Nakao S, Origasa H, Umehara H, Ueda T. A randomized comparison of modified intermediate-dose Ara-C versus high-dose ara-c in post-remission therapy for acute myeloid leukemia. Anticancer Res. 2012 Feb;32(2):643-7. link to original article contains verified protocol PubMed
  3. ACCEDE: Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, Wetzler M, Rizzieri D, Erba HP, Damon L, Jang JH, Tallman MS, Warzocha K, Masszi T, Sekeres MA, Egyed M, Horst HA, Selleslag D, Solomon SR, Venugopal P, Lundberg AS, Powell B. Phase III open-label randomized study of cytarabine in combination with amonafide l-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015 Apr 10;33(11):1252-7. Epub 2015 Mar 2. link to original article contains verified protocol PubMed

Low-dose TBI, then allo HSCT

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TBI: Total Body Irradiation

Regimen

Study Evidence
Gyukocza et al. 2010 Non-randomized

Radiotherapy

GVHD prophylaxis

Stem cells transfused on day 0

References

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

Maintenance after first-line therapy

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

Azacitidine monotherapy

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Regimen

Study Evidence
Grövdal et al. 2010 Phase II

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

Preceding treatment

  • 7+2d

Chemotherapy

28-day cycles

References

  1. Grövdal M, Karimi M, Khan R, Aggerholm A, Antunovic P, Astermark J, Bernell P, Engström LM, Kjeldsen L, Linder O, Nilsson L, Olsson A, Holm MS, Tangen JM, Wallvik J, Oberg G, Hokland P, Jacobsen SE, Porwit A, Hellström-Lindberg E. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol. 2010 Aug;150(3):293-302. Epub 2010 May 20. link to original article contains verified protocol PubMed

Decitabine monotherapy

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Regimen

Study Evidence
Blum et al. 2010 Phase II

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

Preceding treatment

Chemotherapy

  • Decitabine (Dacogen) 20 mg/m2 IV over 60 minutes once per day on days 1 to 5
    • Patients with no evidence of residual disease by flow cytometry or cytogenetics who had grade 4 neutropenia (ANC less than 500/uL) 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.

28-day cycles

References

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

Gemtuzumab ozogamicin monotherapy

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Regimen

Study Evidence
Amadori et al. 2016 (EORTC-GIMEMA AML-19) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

Monthly cycle for up to 8 cycles

References

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

LoDAC

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

Regimen

Study Evidence Comparator Efficacy
Robles et al. 2000 (ECOG E5483) Phase III (E) Observation Might have superior DFS

Preceding treatment

  • HiDAC, then amsacrine induction

Chemotherapy

8-week cycles

References

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

Observation

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Regimen

Study Evidence Comparator Efficacy
Robles et al. 2000 (ECOG E5483) Phase III (C) LoDAC Might have inferior DFS
Löwenberg et al. 2010 (HOVON 43 AML/SAKK 30/01) Phase III (C) Gemtuzumab ozogamicin Seems not superior
Petersdorf et al. 2013 (SWOG S0106) Phase III (C) Gemtuzumab ozogamicin Seems not superior

No further antineoplastic treatment.

Preceding treatment

References

  1. ECOG E5483: Robles C, Kim KM, Oken MM, Bennett JM, Letendre L, Wiernik PH, O'Connell MJ, Cassileth PA. Low-dose cytarabine maintenance therapy vs observation after remission induction in advanced acute myeloid leukemia: an Eastern Cooperative Oncology Group Trial (E5483). Leukemia. 2000 Aug;14(8):1349-53. link to original article contains protocol PubMed
  2. HOVON 43 AML/SAKK 30/01: Löwenberg B, Beck J, Graux C, van Putten W, Schouten HC, Verdonck LF, Ferrant A, Sonneveld P, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, Breems D, de Muijnck H, Schaafsma R, Verhoef G, Döhner H, Gratwohl A, Pabst T, Ossenkoppele GJ, Maertens J; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON); German Austrian AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research Collaborative Group (SAKK). Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood. 2010 Apr 1;115(13):2586-91. Epub 2010 Jan 26. link to original article PubMed
  3. 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 PubMed

Sorafenib monotherapy

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Regimen

Study Evidence
Ravandi et al. 2010 Phase I/II

Preceding treatment

Chemotherapy

Up to one year of sorafenib therapy, including consolidation course(s)

References

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

Relapsed or refractory, salvage therapy

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

5+2d

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Regimen

Study Evidence
Zeidner et al. 2015 (JHOC-J1101) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

5-day course

References

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

ADE (standard-dose Ara-C)

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

Regimen

Study Evidence Comparator Efficacy
Milligan et al. 2006 (MRC AML-HR) Phase III (C) FLA Seems to have superior OS

Chemotherapy, Course 1

Chemotherapy, Course 2

References

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

CLAG

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

Regimen

Study Evidence
Robak et al. 2000 Phase II

Chemotherapy

  • Cladribine (Leustatin) 5 mg/m2 IV over 2 hours once per day on days 1 to 5, given first
  • Cytarabine (Cytosar) 2000 mg/m2 IV over 4 hours once per day on days 1 to 5, given second, 2 hours after cladribine
  • Filgrastim (Neupogen) 300 mcg SC once per day on days -1 to 5; first dose is given 24 hours before first dose of cladribine

References

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

CLAG-M

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

Regimen

Study Evidence
Wierzbowksa et al. 2007 Phase II

Chemotherapy

  • Cladribine (Leustatin) 5 mg/m2 IV over 2 hours once per day on days 1 to 5, given first
  • Cytarabine (Cytosar) 2000 mg/m2 IV over 4 hours once per day on days 1 to 5, given second, 2 hours after cladribine
  • Filgrastim (Neupogen) based on WBC count:
    • WBC count less than or equal to 20 x 109/L: 300 mcg SC once per day on days 0 to 5, started 24 hours prior to chemotherapy
    • WBC count greater than 20 x 109/L: 300 mcg SC once per day on days 1 to 5, started simultaneously to cladribine
  • Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 to 3

One course

Subsequent treatment

  • Patients with PR were recommended to undergo a second course of CLAG-M.
  • Others could receive another course of CLAG-M or HAM consolidation per investigator discretion

References

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

CLARA

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

Regimen

Study Evidence
Becker et al. 2011 Phase II

Chemotherapy

  • Clofarabine (Clolar) 25 mg/m2 IV over 60 minutes once per day on days 1 to 5, given first
  • Cytarabine (Cytosar) 2000 mg/m2 IV over 4 hours once per day on days 1 to 5, given second, 4 hours after start of clofarabine infusion
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day starting day -1, continuing until ANC at least 2000/uL for 2 consecutive days

One course with one re-induction allowed for patients with greater than 5% blasts at day 21

Subsequent treatment

  • Patients achieving CR could receive consolidation with clofarabine reduced to 20 mg/m2, and cytarabine reduced to 1000 mg/m2, up to 2 cycles

References

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

Clofarabine & Cytarabine

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Variant #1, 20/20

Study Evidence
Buckley et al. 2015 Phase I/II

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

Chemotherapy

Cycle duration not explicitly defined; presumably 28 days

Variant #2, 30/1000

Study Evidence
Middeke et al. 2015 (BRIDGE) Phase II

Chemotherapy

At least one cycle

Subsequent treatment

Variant #3, 40/1000

Study Evidence Comparator Efficacy
Faderl et al. 2004 Phase I/II
Agura et al. 2011 Phase II
Faderl et al. 2012 (CLASSIC I) Phase III (E) Cytarabine Superior EFS

Chemotherapy

  • Clofarabine (Clolar) 40 mg/m2 IV over 60 minutes once per day on days 1 to 5, given first
    • Note: in Faderl et al. 2004, clofarabine was given on days 2 to 6
  • Cytarabine (Cytosar) 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 medications

1 to 4 cycles

Subsequent treatment

  • See individual papers for details

References

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

Cytarabine & Mitoxantrone

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

Regimen

Study Evidence
Sternberg et al. 2000 Phase II

Chemotherapy

References

  1. Sternberg DW, Aird W, Neuberg D, Thompson L, MacNeill K, Amrein P, Shulman LN. Treatment of patients with recurrent and primary refractory acute myelogenous leukemia using mitoxantrone and intermediate-dose cytarabine: a pharmacologically based regimen. Cancer. 2000 May 1;88(9):2037-41. link to original article contains verified protocol PubMed

Etoposide & Mitoxantrone

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Regimen

Study Evidence ORR
Ho et al. 1988 Phase II 54%

Chemotherapy

References

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

FLAG

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

Variant #1, weight-based G-CSF

Study Evidence
Montillo et al. 1998 Phase II

Chemotherapy

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

One course

Variant #2, BSA-based G-CSF

Study Evidence Comparator Efficacy
Kaspers et al. 2013 (I-BFM-SG 2001/01) Phase III (C) FLAG-DNX Seems to have inferior CR rate

Note: this regimen was studied in patients up to 21 years of age.

Chemotherapy

Two cycles

Subsequent treatment

References

  1. Montillo M, Mirto S, Petti MC, Latagliata R, Magrin S, Pinto A, Zagonel V, Mele G, Tedeschi A, Ferrara F. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol. 1998 Jun;58(2):105-9. link to original article contains verified protocol PubMed
  2. I-BFM-SG 2001/01: Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. link to original article contains verified protocol PubMed

FLAG-Ida

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

Regimen

Study Evidence
Parker et al. 1997 Phase II, <20 patients
Pastore et al. 2003 Phase II

Chemotherapy

References

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

F-SHAI

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

Regimen

Study Evidence Comparator Efficacy
Fiegl et al. 2013 Phase III (E) SHAI Seems to have superior TTTF

Chemotherapy

  • Fludarabine (Fludara) 15 mg/m2 IV BID on days 1, 2, 8, 9, given 4 hours prior to each cytarabine dose
  • Cytarabine (Cytosar) 1000 mg/m2 IV BID on days 1, 2, 8, 9
    • Dose increased to 3000 mg/m2 for patients 60 or younger with refractory AML or greater than or equal to 2nd relapse
  • Idarubicin (Idamycin) 10 mg/m2 IV once per day on days 3, 4, 10, 11

Supportive medications

  • G-CSF 5 mcg/kg SC once per day from day 14 until ANC greater than 1500/uL
    • Discontinued if the post-treatment bmbx had greater than 5% bone marrow blasts

One 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 verified protocol PubMed

MEC

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MEC: Mitoxantrone, Etoposide, Cytarabine

Variant #1, 6/80/1000

Study Evidence
Amadori et al. 1991 Phase II

Chemotherapy

One course

Variant #2, 8/80/1000

Study Evidence Comparator Efficacy
Feldman et al. 2005 Phase III (C) MEC & Lintuzumab Seems not superior

Chemotherapy

One course

Variant #3, 8/100/1000

Study Evidence Comparator Efficacy
Greenberg et al. 2004 (ECOG E2995) Phase III (C) MEC & Valspodar Seems not superior

Chemotherapy

One course

References

  1. Amadori S, Arcese W, Isacchi G, Meloni G, Petti MC, Monarca B, Testi AM, Mandelli F. Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol. 1991 Jul;9(7):1210-4. link to original article PubMed
  2. ECOG E2995: Greenberg PL, Lee SJ, Advani R, Tallman MS, Sikic BI, Letendre L, Dugan K, Lum B, Chin DL, Dewald G, Paietta E, Bennett JM, Rowe JM. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol. 2004 Mar 15;22(6):1078-86. Erratum in: J Clin Oncol. 2004 Jul 1;22(13):2747. link to original article link to PMC article contains verified protocol PubMed
  3. Feldman EJ, Brandwein J, Stone R, Kalaycio M, Moore J, O'Connor J, Wedel N, Roboz GJ, Miller C, Chopra R, Jurcic JC, Brown R, Ehmann WC, Schulman P, Frankel SR, De Angelo D, Scheinberg D. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J Clin Oncol. 2005 Jun 20;23(18):4110-6. link to original article contains verified protocol PubMed

Consolidation after salvage therapy

BuCy, then allo HSCT

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BuCy: Busulfan & Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Rambaldi et al. 2015 Phase III (C) BuFlu, then allo HSCT Seems to have inferior 1-year non-relapse mortality

Chemotherapy

Supportive medications

Stem cells transfused on day 0

References

  1. Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. link to original article PubMed

BuFlu, then allo HSCT

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

Variant #1

Study Evidence Comparator Efficacy
Rambaldi et al. 2015 Phase III (E) BuCy, then allo HSCT Seems to improve 1 & 2 year NRM, similar OS

Chemotherapy

GVHD prophylaxis and key supportive medications

Stem cells transfused on day 0

Variant #2

Study Evidence Comparator Efficacy
Andersson et al. 2008 Non-randomized Suggested improved outcomes, but shorter follow up

Chemotherapy

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

GVHD prophylaxis and key supportive medications

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

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

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

Stem cells transfused on day 0

Variant #3

Study Evidence Comparator Efficacy
Lee et al. 2013 Phase III (E) BuCy, then allo HSCT Seems to have inferior OS

Chemotherapy

GVHD prophylaxis and key supportive medications

Stem cells transfused on day 0

References

  1. Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M, Roberson S, Giralt S, Pierre B, Russell JA, Shpall EJ, Jones RB, Champlin RE. Once daily IV busulfan and fludarabine (IV Bu-Flu) compares favorably with IV busulfan and cyclophosphamide (IV BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant. 2008;14(6):672-84. link to original article link to PMC article contains verified protocol Pubmed
  2. Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, Lee JH, Lee WS, Park JH, Bae SH, Hyun MS, Kim DY, Kim SD, Min YJ, Lee KH. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013 Feb 20;31(6):701-9. Epub 2012 Nov 5. link to original article contains verified protocol PubMed
  3. Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. Epub 2015 Sep 28. link to original article PubMed

Clofarabine & Melphalan, then allo HSCT

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Regimen

Study Evidence
Middeke et al. 2015 (BRIDGE) Phase II

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

Preceding treatment

Chemotherapy

Stem cells transfused on day 0

References

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

Cytarabine & Thioguanine

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Regimen

Study Evidence
Kaspers et al. 2013 (I-BFM-SG 2001/01) Non-randomized portion of RCT

Note: this regimen was studied in patients up to 21 years of age, and was intended for use when the time to transplant would be relatively short or for patients in "poor condition".

Preceding treatment

Chemotherapy

Subsequent treatment

  • Allogeneic HSCT

References

  1. I-BFM-SG 2001/01: Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. link to original article contains verified protocol PubMed

CYVE

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CYVE: CYtarabine & VEpesid (Etoposide)

Regimen

Study Evidence
Kaspers et al. 2013 (I-BFM-SG 2001/01) Non-randomized portion of RCT

Note: this regimen was studied in patients up to 21 years of age. It is unclear if the course is repeated more than once.

Preceding treatment

Chemotherapy

Subsequent treatment

References

  1. I-BFM-SG 2001/01: Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. link to original article contains verified protocol PubMed

Relapsed or refractory, subsequent lines of therapy

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

Azacitidine monotherapy

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Regimen

Study Evidence
Thepot et al. 2010 Phase II

Chemotherapy

28-day cycle for at least 4 to 6 cycles

References

  1. Thepot S, Itzykson R, Seegers V, Raffoux E, Quesnel B, Chait Y, Sorin L, Dreyfus F, Cluzeau T, Delaunay J, Sanhes L, Eclache V, Dartigeas C, Turlure P, Harel S, Salanoubat C, Kiladjian JJ, Fenaux P, Adès L; Groupe Francophone des Myelodysplasies (GFM). Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood. 2010 Nov 11;116(19):3735-42. Epub 2010 Jul 27. link to original article PubMed

Ruxolitinib monotherapy

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Regimen

Study Evidence
Eghtedar et al. 2012 Phase II

Chemotherapy

28-day cycles

Patients with progression were allowed to increase the dose to 50 mg PO BID

References

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

Response criteria

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

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

Revised International Working Group recommendations (2003)

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

Prognosis

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

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  • Relapse-free interval from first complete remission
    • Greater 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
    • Less than or equal to 35 years (0 points)
    • 36 to 45 years (1 point)
    • Greater than 45 years (2 points)
  • Stem cell transplantation performed before first relapse
    • No (0 points)
    • Yes, autologous or allogeneic (2 points)

Risk stratification:

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

References

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

Prognosis in cytogenetically normal AML

  1. Seminal paper comparing the mutational status of NPM1, FLT3, CEBPA, MLL, and NRAS with clinical outcome: Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008 May 1;358(18):1909-18. link to original article PubMed

Investigational agents

These are drugs under study with at least some promising results for this disease.

Additional information

Antifungal prophylaxis

  1. Halpern AB, Lyman GH, Walsh TJ, Kontoyiannis DP, Walter RB. Primary antifungal prophylaxis during curative-intent therapy for acute myeloid leukemia. Blood. 2015 Dec 24;126(26):2790-7. Epub 2015 Oct 26. Review. link to original article link to PMC article PubMed