Acute myeloid leukemia

Page editor
	Martin Schoen, MD, MPH St. Louis, MO

Note: biomarker-specific regimens have been moved to dedicated pages:

• AML, FLT3-positive
• AML, IDH-mutated

88 regimens on this page 144 variants on this page

Guidelines

ELN

Current

• 2017: Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel link to PMC article PubMed

Older

• 2010: Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet PubMed

ESMO

• 2013: Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

NCCN

• NCCN Guidelines - Acute Myeloid Leukemia

Upfront induction therapy, standard patients

7+3d & Gemtuzumab ozogamicin

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

Regimen

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

Chemotherapy

• Cytarabine (Cytosar) 200 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 1400 mg/m²)
• Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 1 to 3
• Gemtuzumab ozogamicin (Mylotarg) 3 mg/m² (maximum dose of 5 mg) IV over 2 hours once per day on days 1, 4, 7

7-day course

Subsequent treatment

• Patients in CR or CRp and platelet count at least 100 x 10⁹ by day 45 after the initiation of chemotherapy: Cytarabine, Daunorubicin, Gemtuzumab ozogamicin consolidation
• Patients in CR or CRp and platelet count less than 100 x 10⁹ by day 45 after the initiation of chemotherapy: Cytarabine & Daunorubicin consolidation

References

1. 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

ADE

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

Variant #1, high-dose Ara-C

Study	Evidence	Comparator	Efficacy
Willemze et al. 2013 (AML-12)	Phase III	Cytarabine (standard-dose), Daunorubicin, Etoposide	Might have superior OS

Chemotherapy

• Cytarabine (Cytosar) 3000 mg/m² IV over 3 hours q12h on days 1, 3, 5, 7
• Daunorubicin (Cerubidine) 50 mg/m² IV over 5 minutes once per day on days 1, 3, 5
• Etoposide (Vepesid) 50 mg/m² IV over 60 minutes once per day on days 1 to 5

7-day course

Variant #2, standard-dose Ara-C

Study	Evidence	Comparator	Efficacy
Willemze et al. 2013 (AML-12)	Phase III	Cytarabine (high-dose), Daunorubicin, Etoposide	Might have inferior OS

Chemotherapy

• Cytarabine (Cytosar) 100 mg/m²/day IV continuous infusion on days 1 to 10 (total dose: 1000 mg/m²)
• Daunorubicin (Cerubidine) 50 mg/m² IV over 5 minutes once per day on days 1, 3, 5
• Etoposide (Vepesid) 50 mg/m² IV over 60 minutes once per day on days 1 to 5

10-day course

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 PubMed
2. UK MRC AML15: 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
3. 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
4. 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 PubMed

CIA

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

Regimen

Study	Evidence
Nazha et al. 2013	Phase II

Chemotherapy

• Clofarabine (Clolar) 20 mg/m² IV over 60 minutes once per day on days 1 to 5
• Idarubicin (Idamycin) 10 mg/m² IV over 30 minutes once per day on days 1 to 3
• Cytarabine (Cytosar) 1000 mg/m² IV over 2 hours once per day on days 1 to 5

Supportive medications

• Levofloxacin (Levaquin)
• Itraconazole (Sporanox)
• Valacyclovir (Valtrex)
• Granulocyte colony-stimulating factor neither mandated nor forbidden and given per physician discretion

5-day course

Patients with only partial remission underwent a second course with the same drugs, doses, and schedule. Patients who achieved a CR or CRi (complete remission with incomplete platelet recovery) proceeded to 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 PubMed

Cytarabine & Daunorubicin

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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, 7+3d with standard-dose dauno (45 mg/m²), CI Ara-C (100 mg/m²)

Study	Evidence	Comparator	Efficacy
Rai et al. 1981 (CALGB 7421)	Phase III	7+3d (bolus Ara-C)	Seems to have superior CR rate
		5+2d	Superior CR rate
		5+2d (bolus Ara-C)	Superior CR rate
Yates et al. 1982 (CALGB 7721)	Phase III	7+3d, low-dose dauno (30 mg/m2)	Seems not superior
		7+3a (30 mg/m2)	Seems not superior
Preisler et al. 1987 (CALGB 7921)	Phase III	10+3d	Seems not superior
		TAD	Seems not superior
Wiernik et al. 1992	Phase III	7+3i	Seems to have inferior OS
Rowe et al. 2004	Phase III	7+3d + GM-CSF 7+3i 7+3i + GM-CSF 7+3m 7+3m + GM-CSF	Seems not superior
Fernandez et al. 2009 (ECOG E1900)	Phase III	7+3d (high-dose)	Inferior OS

Chemotherapy

• Cytarabine (Cytosar) 100 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 700 mg/m²)
• Daunorubicin (Cerubidine) 45 mg/m² IV once per day on days 1 to 3

7-day course

Patients in Rowe et al. 2004 with persistent disease at day 14 (greater than 5% blasts) underwent an identical second cycle of 7+3i.

Variant #2, 7+3d with standard-dose dauno (45 mg/m²), CI Ara-C (200 mg/m²)

Study	Evidence	Comparator	Efficacy
Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01)	Phase III	7+3d, high-dose dauno	Inferior CR rate
Stone et al. 2015 (ACCEDE)	Phase III	Amonafide & Cytarabine	Seems not superior

Chemotherapy

• Cytarabine (Cytosar) 200 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 1400 mg/m²)
• Daunorubicin (Cerubidine) 45 mg/m² IV once per day on days 1 to 3

7-day course

Treatment in Löwenberg et al. 2009 followed by MiDAC consolidation. In Stone et al. 2015, 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, 7+3d with intermediate-dose dauno (60 mg/m²), CI Ara-C (200 mg/m²)

Study	Evidence	Comparator	Efficacy
Holowiecki et al. 2004 (PALG AML1/1999)	Phase III	DAC	Inferior CR rate after first induction
Holowiecki et al. 2012 (PALG AML1/2004)	Phase III	DAC	Seems to have inferior OS
		DAF	Seems not superior
Castaigne et al. 2012 (ALFA-0701)	Phase III (C)	7+3d & Gemtuzumab ozogamicin	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

• Cytarabine (Cytosar) 200 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 1400 mg/m²)
• Daunorubicin (Cerubidine) 60 mg/m² IV over 5 minutes once per day on days 1 to 3

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

Patients with only partial remission in both PALG studies underwent a second course with the same drugs, doses, and schedule. Non-responders in PALG AML1/1999 proceeded to salvage therapy with CLAG. Patients in remission in both PALG studies underwent consolidation with HAM followed by HiDAC. ALFA-0701: Patients in CR or CRp proceeded to cytarabine & daunorubicin consolidation.

Variant #4, 7+3d with standard-dose dauno (40 mg/m²), intermittent Ara-C

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

Chemotherapy

• Cytarabine (Cytosar) 80 mg/m² IV over 2 hours q12h on days 1 to 7
• Daunorubicin (Cerubidine) 40 mg/m² IV bolus once per day on days 1 to 3

7-day course

Variant #5, 7+3d with high-dose dauno (90 mg/m²), CI Ara-C (100 mg/m²)

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

Chemotherapy

• Cytarabine (Cytosar) 100 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 700 mg/m²)
• Daunorubicin (Cerubidine) 90 mg/m² IV once per day on days 1 to 3

7-day course

Patients with residual leukemia at day 14 in Zeidner et al. 2015 underwent 5+2d.

Variant #6, 7+3d with high-dose dauno (90 mg/m²), CI Ara-C (200 mg/m²)

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

Chemotherapy

• Cytarabine (Cytosar) 200 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 1400 mg/m²)
• Daunorubicin (Cerubidine) 90 mg/m² IV once per day on days 1 to 3

7-day course

Treatment in Löwenberg et al. 2009 followed by MiDAC consolidation. Patients achieving CR in COSAH C-022 proceeded to HiDAC consolidation if good- or intermediate-risk cytogenetics, or cytarabine & etoposide consolidation if high-risk cytogenetics.

Variant #7, 5+3d with standard-dose dauno (50 mg/m²)

Study	Evidence	Comparator	Efficacy
Berman et al. 1991 (L-19 Protocol)	Phase III	5+3i	Inferior CR rate

Chemotherapy

• Cytarabine (Cytosar) 25 mg/m² IV bolus, followed by 200 mg/m²/day IV continuous infusion on days 1 to 5
• Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1 to 3

5-day course

References

1. CALGB 7421: Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K, Obrecht JP, Preisler HD, Nawabi IW, Prager D, Carey RW, Cooper MR, Haurani F, Hutchison JL, Silver RT, Falkson G, Wiernik P, Hoagland HC, Bloomfield CD, James GW, Gottlieb A, Ramanan SV, Blom J, Nissen NI, Bank A, Ellison RR, Kung F, Henry P, McIntyre OR, Kaan SK. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood. 1981 Dec;58(6):1203-12. link to original article contains verified protocol PubMed
2. 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
3. CALGB 7921: Preisler H, Davis RB, Kirshner J, Dupre E, Richards F 3rd, Hoagland HC, Kopel S, Levy RN, Carey R, Schulman P et al. 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
4. L-19 Protocol: Berman E, Heller G, Santorsa J, McKenzie S, Gee T, Kempin S, Gulati S, Andreeff M, Kolitz J, Gabrilove J, Reich L, Mayer K, Keefe D, Trainor K, Schluger A, Penenberg D, Raymond V, O'Reilly R, Jhanwar S, Young C, Clarkson B. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood. 1991 Apr 15;77(8):1666-74. link to original article contains 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. 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
7. 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 PubMed
8. 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
9. 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, Dmoszynska 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
10. 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
11. ECOG 1900: 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
12. PALG AML1/2004: Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszynska 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. Journal of Clinical Oncology. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. link to original article contains verified protocol PubMed
13. 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
14. 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 PubMed
15. 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 PubMed
16. UK MRC AML15: 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
17. 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 link to PMC article PubMed
18. 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
19. 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 PubMed
20. 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
21. 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
22. 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
23. 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
24. 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

Cytarabine & Idarubicin

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

Variant #1, 7+3i with standard-dose ida (12 mg/m²), CI Ara-C (200 mg/m²)

Study	Evidence	Comparator	Efficacy
Pautas et al. 2010 (ALFA-9801)	Phase III	7+3d (high-dose) 7+4i	Seems not superior
Löwenberg et al. 2017 (HOVON-102)	Phase III	7+3i & Clofarabine	Seems not superior
Lee et al. 2017 (COSAH C-022)	Phase III	7+3d (high-dose)	Seems not superior

Chemotherapy

• Cytarabine (Cytosar) 200 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 1400 mg/m²)
• Idarubicin (Idamycin) 12 mg/m² IV over 3 hours once per day on days 1 to 3

7-day course

Patients achieiving CR in ALFA-9801 proceeded to cytarabine & idarubicin consolidation. Patients achieving CR in COSAH C-022 proceeded to HiDAC consolidation if good- or intermediate-risk cytogenetics, or cytarabine & etoposide consolidation if high-risk cytogenetics.

Variant #2, 7+3i with standard-dose ida (12 mg/m²), CI Ara-C (100 mg/m²)

Study	Evidence	Comparator	Efficacy
Haas et al. 1993	Non-randomized
Rowe et al. 2004	Phase III	7+3d 7+3d + GM-CSF 7+3i + GM-CSF 7+3m 7+3m + GM-CSF	Seems not superior

Chemotherapy

• Cytarabine (Cytosar) 100 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 700 mg/m²)
• Idarubicin (Idamycin) 12 mg/m² IV once per day on days 1 to 3

7-day course

Patients in Rowe et al. 2004 with persistent disease at day 14 (greater than 5% blasts) underwent an identical second cycle of 7+3i.

Variant #3, 7+3i with higher-dose ida (13 mg/m²), CI Ara-C (100 mg/m²)

Study	Evidence	Comparator	Efficacy
Wiernik et al. 1992	Phase III	7+3d	Seems to have superior OS

Chemotherapy

• Cytarabine (Cytosar) 100 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 700 mg/m²)
• Idarubicin (Idamycin) 13 mg/m² IV once per day on days 1 to 3

7-day course

Variant #4, 7+3i with standard-dose ida (12 mg/m²), intermittent Ara-C

Study	Evidence	Comparator	Efficacy
Masaoka et al. 1996	Randomized Phase II	7+3d	Seems to have superior CR rate

Chemotherapy

• Cytarabine (Cytosar) 80 mg/m² IV over 2 hours q12h on days 1 to 7
• Idarubicin (Idamycin) 12 mg/m² IV bolus once per day on days 1 to 3

7-day course

Variant #5, 5+3i

Study	Evidence	Comparator	Efficacy
Berman et al. 1991 (L-19 Protocol)	Phase III	5+3d	Superior CR rate

Chemotherapy

• Cytarabine (Cytosar) 25 mg/m² IV bolus, followed by 200 mg/m²/day IV continuous infusion on days 1 to 5
• Idarubicin (Idamycin) 12 mg/m² IV bolus once per day on days 1 to 3

5-day course

References

1. Berman E, Heller G, Santorsa J, McKenzie S, Gee T, Kempin S, Gulati S, Andreeff M, Kolitz J, Gabrilove J, Reich L, Mayer K, Keefe D, Trainor K, Schluger A, Penenberg D, Raymond V, O'Reilly R, Jhanwar S, Young C, Clarkson B. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood. 1991 Apr 15;77(8):1666-74. link to original article contains verified protocol PubMed
2. Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, Ritch PS, Enck RE, Weitberg AB. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992 Jan 15;79(2):313-9. link to original article contains verified protocol PubMed
3. 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
4. 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
5. 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 PubMed
6. 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
7. 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
8. 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 PubMed
9. 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
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. 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, 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 on days 1 to 4 (total dose: 6000 mg/m²)
  • Patients older than 60 received: 1500 mg/m²/day IV continuous infusion on days 1 to 3 (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

Treatment followed by cytarabine, idarubicin, sorafenib consolidation.

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

Cytarabine, Idarubicin, Vorinostat

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Regimen

Study	Evidence
Garcia-Manero et al. 2012	Phase II

Chemotherapy

• Cytarabine (Cytosar) 1500 mg/m²/day IV continuous infusion on days 4 to 7 (total dose: 6000 mg/m²)
  • Patients older than 60 received: 1500 mg/m²/day IV continuous infusion on days 4 to 6 (total dose: 4500 mg/m²)
• Idarubicin (Idamycin) 12 mg/m² IV once per day on days 4 to 6
• Vorinostat (Zolinza) 500 mg PO TID on days 1 to 3

Supportive medications

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

7-day course for 1 to 2 cycles

To be followed by Cytarabine, Idarubicin, Vorinostat consolidation therapy.

References

1. Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, Borthakur G, Kadia TM, Konopleva MY, Faderl S, Cortes JE, Brandt M, Hu Y, McCue D, Newsome WM, Pierce SR, de Lima M, Kantarjian HM. Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome. J Clin Oncol. 2012 Jun 20;30(18):2204-10. Epub 2012 May 14. link to original article contains verified protocol link to PMC article PubMed

Cytarabine & Mitoxantrone

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

Regimen

Study	Evidence	Comparator	Efficacy
Rowe et al. 2004	Phase III	7+3d 7+3d + GM-CSF 7+3i 7+3i + GM-CSF 7+3m + GM-CSF	Seems not superior

Chemotherapy

• Cytarabine (Cytosar) 100 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 700 mg/m²)
• Mitoxantrone (Novantrone) 12 mg/m² IV once per day on days 1 to 3

7-day course

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

References

1. 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

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	DA	Superior CR rate after first induction
Holowiecki et al. 2012 (PALG AML1/2004)	Phase III	DA	Superior OS
		DAF	Seems to have superior OS

Chemotherapy

• Daunorubicin (Cerubidine) 60 mg/m² IV over 5 minutes once per day on days 1 to 3
• Cytarabine (Cytosar) 200 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 1400 mg/m²)
• Cladribine (Leustatin) 5 mg/m² IV over 3 hours once per day on days 1 to 5

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

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 proceeded to salvage therapy with CLAG. Patients in remission underwent consolidation with HAM followed by HiDAC.

References

1. Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, Skotnicki A, Jedrzejczak WW, Konopka L, Kuliczkowski K, Zdziarska B, Dmoszynska 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. Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszynska 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. Journal of Clinical Oncology. 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	Comparator	Efficacy
Burnett et al. 2013 (UK MRC AML15)	Phase III	FLAG-Ida & GO	Seems not superior

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days 2 to 6
• Cytarabine (Cytosar) 2000 mg/m² IV over 4 hours once per day on days 2 to 6, given 4 hours after Fludarabine (Fludara)
• Lenograstim (Granocyte) 263 mcg SC once per day on days 1 to 7
• Idarubicin (Idamycin) 8 mg/m² IV once per day on days 4 to 6

References

1. UK MRC AML15: 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 contains protocol PubMed

FLAM

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FLAM: FLavopiridol (Alvocidib), Ara-C (Cytarabine), Mitoxantrone

Regimen

Study	Evidence	Comparator	Efficacy
Zeidner et al. 2015	Randomized Phase II	7+3d, high-dose dauno	Superior CR rate

Chemotherapy

• Alvocidib (Flavopiridol) 50 mg/m² IV once per day on days 1 to 3
• Cytarabine (Cytosar) 667 mg/m²/day IV continuous infusion on days 6 to 8 (total dose: 2000 mg/m²)
• Mitoxantrone (Novantrone) 40 mg/m² IV once on day 9

One course

References

1. 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

HAA

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

Regimen

Study	Evidence	Comparator	Efficacy
Jin et al. 2013	Phase III	DA	Superior EFS
		HAD	Not reported

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

Chemotherapy

• Omacetaxine (Synribo)
• Cytarabine (Cytosar)
• Aclarubicin (Aclacinon)

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	DA	Might have superior EFS
		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

• Omacetaxine (Synribo)
• Cytarabine (Cytosar)
• Daunorubicin (Cerubidine)

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

MICE

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MICE: MItoxantrone, Cytarabine, Etoposide

Regimen

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

Chemotherapy

• Mitoxantrone (Novantrone) 7 mg/m² IV once per day on days 1, 3, 5
• Cytarabine (Cytosar) 100 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 700 mg/m²)
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

One course

References

1. 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 patients or "unfit" patients

Note: in distinction from upfront therapy for standard patients, these regimens are generally considered to be part of a non-curative line of treatment.

7+3i & Panobinostat

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

Regimen

Study	Evidence	Efficacy
Ocio et al. 2015 (panobidara)	Phase II	CR rate: 64%

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

Chemotherapy

• Cytarabine (Cytosar) 100 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 700 mg/m²)
• Idarubicin (Idamycin) 8 mg/m² IV once per day on days 1 to 3
• Panobinostat (Farydak) 10 mg PO once per day on days 8, 10, 12, 15, 17, 19

One course

Non-responders could undergo an identical second cycle. Responders proceeded to receive the same regimen in consolidation (one course), followed by panobinostat maintenance.

References

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

Azacitidine monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Dombret et al. 2015	Phase III	7+3d 7+3i Best supportive care Cytarabine	Might have superior OS

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² SC once per day on days 1 to 7

28-day cycle for at least 6 cycles

References

1. 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

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

• Hydroxyurea (Hydrea) 1500 mg PO twice per day or "in higher doses if necessary"

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

Chemotherapy, induction

• Azacitidine (Vidaza) 75 mg/m² SC or IV once per day on days 1 to 7
• Gemtuzumab ozogamicin (Mylotarg) 3 mg/m² IV once on day 8

Supportive medications

• "Appropriate premedications" which were not specified, for Gemtuzumab ozogamicin (Mylotarg)

If D14 bone marrow with 5% or more blasts, a second induction cycle identical to the first was administered. Patients achieving CR or CRi were to receive azacitidine and gemtuzumab ozogamicin consolidation within 60 days.

References

1. Nand S, Godwin J, Smith S, Barton K, Michaelis L, Alkan S, Veerappan R, Rychlik K, Germano E, Stiff P. Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial. Leuk Lymphoma. 2008 Nov;49(11):2141-7. link to original article contains 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	Phase III	Decitabine	Might have inferior OS
Dombret et al. 2015	Phase III	Azacitidine	Might have inferior OS
Amadori et al. 2016 (EORTC/GIMEMA AML-19)	Phase III	Gemtuzumab ozogamicin (Mylotarg)	Inferior OS

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

References

1. Kantarjian HM, Thomas XG, Dmoszynska 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. 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
3. 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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Regimen

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

Chemotherapy

• Clofarabine (Clolar) 30 mg/m² IV over one hour once per day on days 1 to 5

One course

A second induction was permitted for SD or better. Responders in Faderl et al. 2008 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

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	Clofarabine	Seems to have superior EFS

Chemotherapy

• Clofarabine (Clolar) 30 mg/m² IV over one hour once per day on days 1 to 5, given first
• Cytarabine (Cytosar) 20 mg SC once per day on days 1 to 14, given 4 hours after clofarabine on days 1 to 5

One course

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

• Clofarabine (Clolar) 20 mg/m² IV once per day on days 1 to 5
• Cytarabine (Cytosar) 20 mg SC BID on days 1 to 10

One course

Patients not achieving CR could undergo an identical second induction after at least 28 days. Patients not achieving CR after the second induction were given salvage decitabine. Patients achieving CR proceeded to consolidation with clofarabine & low-dose cytarabine alternating with decitabine.

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. 2016 (CLTR0310-301)	Phase III (E)	7+3d	Superior OS

Chemotherapy

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

One or two courses

Subsequent treatment

• CPX-351 monotherapy consolidation

References

1. Abstract: 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, Chiarella M, Louie AC, Medeiros BC. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016 34:15_suppl, 7000-7000 link to abstract contains partial protocol ClinicalTrials.gov

Cytarabine monotherapy

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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	LDAC & Lintuzumab	Seems not superior
Burnett et al. 2013 (UK NCRI AML16)	Phase III	Clofarabine	Seems not superior
Dennis et al. 2015	Randomized	LDAC & Vosaroxin	Seems not superior
		Vosaroxin	Seems not superior
Burnett et al. 2015	Randomized	Sapacitabine	Might have inferior CR rate
Dombret et al. 2015	Phase III	Azacitidine	Might have inferior OS

Chemotherapy

• Cytarabine (Cytosar) 20 mg/m² SC BID on days 1 to 10

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

Variant #2, indefinite duration

Study	Evidence	Comparator	Efficacy
Kantarjian et al. 2012	Phase III	Decitabine	Might have inferior OS

Chemotherapy

• Cytarabine (Cytosar) 20 mg/m² SC once per day on days 1 to 10

28-day cycles until progression or intolerance

References

1. Kantarjian HM, Thomas XG, Dmoszynska 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. 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. 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

Decitabine monotherapy

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Variant #1

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

Chemotherapy

• Decitabine (Dacogen) 20 mg/m² IV over 60 minutes once per day on days 1 to 5

4- to 6-week cycles

Variant #2

Study	Evidence	Comparator	Efficacy
Kantarjian et al. 2012	Phase III	Cytarabine Best supportive care	Might have superior OS

Chemotherapy

• Decitabine (Dacogen) 20 mg/m² IV over 60 minutes once per day on days 1 to 5
• Hydroxyurea (Hydrea) could be used up until cycle 1 day 15

28-day cycles

Variant #3

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

Chemotherapy

• Decitabine (Dacogen) 20 mg/m² IV over 60 minutes once per day on days 1 to 10
• Hydroxyurea (Hydrea) allowed during and prior to cycle 1

28-day cycles

Additional therapy depending on response in Blum et al.:

• Patients with persistent AML (greater than or equal to 5% blasts) received repeated cycles with 10 days of decitabine as described above.
• Patients with 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. Kantarjian HM, Thomas XG, Dmoszynska 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;375:2023-36. link to original article contains verified protocol link to PMC article PubMed

Decitabine & Valproate

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Regimen

Study	Evidence	Comparator	Efficacy
Garcia-Manero et al. 2006	Phase II
Issa et al. 2014	Randomized Phase II	Decitabine & Valproate	Seems not superior

Chemotherapy

• Decitabine (Dacogen) 15 mg/m² IV over 60 minutes once per day on days 1 to 10
• Valproate (Depakote) 50 mg/kg/day (divided in 2 or 3 doses per day) PO on days 1 to 10

28-day cycle for up to 24 total cycles

References

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

• Idarubicin (Idamycin) 8 mg/m² IV once per day on days 1 to 5
• Cytarabine (Cytosar) 100 mg/m²/day IV continuous infusion on days 1 to 7
• Lomustine (Ceenu) 200 mg/m² PO once on day 1

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

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

Allogeneic hematopoietic stem cell transplant

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To be completed.

Azacitidine monotherapy

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Regimen

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

Preceding treatment

• Azacitidine & Gemtuzumab ozogamicin consolidation

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² SC once on day 1

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

• Azacitidine & Gemtuzumab ozogamicin induction

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² SC or IV once per day on days 1 to 7
• Gemtuzumab ozogamicin (Mylotarg) 3 mg/m² IV once on day 8

Supportive medications

• "Appropriate premedications" which were not specified, for Gemtuzumab ozogamicin (Mylotarg)
• Growth factors per physician discretion

1 cycle

Patients were to start azacitidine maintenance within 42 days of completion of consolidation.

References

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

• CIA induction

Chemotherapy

• Clofarabine (Clolar) 15 mg/m² IV once per day on days 1 to 3
• Idarubicin (Idamycin) 8 mg/m² IV once per day on days 1 & 2
• Cytarabine (Cytosar) 750 mg/m² IV once per day on days 1 to 3

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	Randomized Phase II	HDAC & G-CSF	Seems to have superior RFS

Chemotherapy

• Clofarabine (Clolar) 30 mg/m² IV over 2 hours once per day on days 2 to 6, given first
• Cytarabine (Cytosar) 1000 mg/m² IV over 2 hours once per day on days 1 to 5, given second, 4 hours after clofarabine, on days 2 to 5
• Filgrastim (Neupogen) 5 mcg/kg IV once per day on days 1 to 6

35-day cycle for 3 cycles

References

1. 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

• Clofarabine (Clolar) 20 mg/m² IV once per day on days 1 to 3
• Cytarabine (Cytosar) 20 mg SC BID on days 1 to 7

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

Chemotherapy, decitabine portion

• Decitabine (Dacogen) 20 mg/m² IV once per day on days 1 to 5

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. 2016 (CLTR0310-301)	Non-randomized portion of RCT

Preceding treatment

• CPX-351 monotherapy induction

Chemotherapy

• CPX-351 (Vyxeos) 65 units/m² over 90 minutes IV once per day on days 1 & 3

Up to two courses

References

1. Abstract: 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, Chiarella M, Louie AC, Medeiros BC. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016 34:15_suppl, 7000-7000 link to abstract does not contain protocol ClinicalTrials.gov

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

• 7+3d or 7+3d & Gemtuzumab ozogamicin induction

Chemotherapy

• Cytarabine (Cytosar) 1000 mg/m² IV every 12 hours on days 1 to 4 (8 total doses)
• Daunorubicin (Cerubidine) as follows:
  • Course 1: 60 mg/m² IV once on day 1
  • Course 2: 60 mg/m² IV once per day on days 1 & 2

2 courses

Variant #2

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

Preceding treatment

• 4d + 7 induction

Chemotherapy

• Cytarabine (Cytosar) 60 mg/m² SC every 12 hours on days 1 to 5 (10 total doses)
• Daunorubicin (Cerubidine) 45 mg/m² IV once on day 1

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. 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

• 7+3d & Gemtuzumab ozogamicin induction

Chemotherapy

• Cytarabine (Cytosar) 1000 mg/m² IV every 12 hours on days 1 to 4 (8 total doses)
• Daunorubicin (Cerubidine) as follows:
  • Course 1: 60 mg/m² IV once on day 1
  • Course 2: 60 mg/m² IV once per day on days 1 & 2
• Gemtuzumab ozogamicin (Mylotarg) 3 mg/m² (maximum dose of 5 mg) IV once on day 1

2 courses

References

1. 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 consolidaton regimen was for patients with high-risk cytogenetics.

Preceding treatment

• AD versus AI

Chemotherapy

• Cytarabine (Cytosar) 1000 mg/m² IV once per day on days 1 to 6
• Etoposide (Vepesid) 150 mg/m² IV once per day on days 1 to 3

4 courses

Patients eligible for allogeneic HSCT with available donors usually proceeded to transplant after 2 courses.

References

1. 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	4 + 7 with idarubicin	Seems to have superior OS

Preceding treatment

• 4i + 7 induction

Chemotherapy

• Cytarabine (Cytosar) 60 mg/m² SC every 12 hours on days 1 to 5 (10 total doses)
• Idarubicin (Idamycin) 9 mg/m² IV once on day 1

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

• Cytarabine, Idarubicin, Sorafenib induction

Chemotherapy

• Cytarabine (Cytosar) 750 mg/m²/day IV continuous infusion on days 1 to 3 (total dose: 2250 mg/m²)
• Idarubicin (Idamycin) 8 mg/m² IV over 60 minutes once per day on days 1 & 2
• Sorafenib (Nexavar) 400 mg PO BID "for up to 28 days"

4 to 6-week cycle for up to 5 cycles

Treatment followed by sorafenib maintenance.

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

Cytarabine, Idarubicin, Vorinostat

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Regimen

Study	Evidence
Garcia-Manero et al. 2012	Phase II

Preceding treatment

• Cytarabine, Idarubicin, Vorinostat induction

Chemotherapy

• Cytarabine (Cytosar) 750 mg/m²/day IV continuous infusion on days 4 to 6 (total dose: 2250 mg/m²)
• Idarubicin (Idamycin) 8 mg/m² IV once per day on days 4 & 5
• Vorinostat (Zolinza) 500 mg PO TID on days 1 to 3

Supportive medications

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

6-day course for up to 5 cycles

To be followed by Vorinostat (Zolinza) maintenance therapy.

References

1. Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, Borthakur G, Kadia TM, Konopleva MY, Faderl S, Cortes JE, Brandt M, Hu Y, McCue D, Newsome WM, Pierce SR, de Lima M, Kantarjian HM. Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome. J Clin Oncol. 2012 Jun 20;30(18):2204-10. Epub 2012 May 14. link to original article contains verified protocol 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	Bu/Cy, then auto HSCT	Might have inferior RFS

Preceding treatment

• 7+3i, then Amsacrine & Cytarabine

Chemotherapy

• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 5
• Mitoxantrone (Novantrone) 10 mg/m² IV once per day on days 1 to 5

References

1. 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

HAM

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

Regimen

Study	Evidence
Wierzbowksa et al. 2008 (PALG)	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

• Cytarabine (Cytosar) 1500 mg/m² IV once per day on days 1 to 3
• Mitoxantrone (Novantrone) 10 mg/m² IV once per day on days 3 to 5

Followed by HiDAC consolidation.

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, Wrzesien-Kus 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. Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszynska 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. Journal of Clinical Oncology. 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	Randomized Phase II	CLARA	Seems to have inferior RFS

Chemotherapy

• Cytarabine (Cytosar) 3000 mg/m² IV over 3 hours Q12H on days 1, 3, 5 (6 total doses)
• Filgrastim (Neupogen) 5 mcg/kg IV once per day on days 1 to 5

35-day cycle for 3 cycles

References

1. 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)

Variant #1

Study	Evidence	Comparator	Efficacy
Mayer et al. 1994	Phase III	Low-dose continuous infusion cytarabine	Seems to have superior OS
Röllig et al. 2015 (SORAML)	Randomized Phase II	HiDAC & Sorafenib	Seems to have inferior EFS

Chemotherapy

• Cytarabine (Cytosar) 3000 mg/m² IV over 3 hours Q12H on days 1, 3, 5 (6 total doses)

28-day (minimum) cycle or 1 week after marrow recovery, whichever comes later

Patients in Mayer et al. 1994 received up to 4 cycles. Patients in SORAML received 3 cycles.

Variant #2

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

Preceding treatment

• BHAC-MMV

Chemotherapy

• Cytarabine (Cytosar) 2000 mg/m² IV over 60 minutes Q12H on days 1 to 5 (10 total doses)

Two cycles

Treatment followed by A-VVV.

Variant #3

Study	Evidence
Holowiecki et al. 2012	Non-randomized

Details in the text are scant.

Preceding treatment

• Cytarabine & Mitoxantrone consolidation

Chemotherapy

• Cytarabine (Cytosar) 2000 mg/m² IV Q12H on days 1, 3, 5 (6 total doses)

References

1. Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei E 3rd. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 1994 Oct 6;331(14):896-903. link to original article contains verified protocol PubMed
2. 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 PubMed
3. 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 PubMed
4. 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 PubMed
5. 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
6. 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 PubMed
7. 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
8. Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszynska 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. Journal of Clinical Oncology. 2012 Jul 10;30(20):2441-8. Epub 2012 Apr 16. link to original article contains verified protocol PubMed
9. 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
10. 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

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

Preceding treatment

• BHAC-MMV

Chemotherapy

• Cytarabine (Cytosar) 1000 mg/m² IV over 60 minutes Q12H on days 1 to 5 (10 total doses)

Two cycles

Treatment followed by A-VVV.

Variant #2

Study	Evidence
Stone et al. 2015	Phase II

Preceding treatment

• 7+3d

Chemotherapy

• Cytarabine (Cytosar) 1000 mg/m² IV over 3 hours once per day on days 1, 3, 5 (3 total doses)

Variant #3

Study	Evidence
Löwenberg et al. 2009 (HOVON/AMLSG/SAKK)	Non-randomized portion of RCT

Preceding treatment

• 7+3d, standard-dose daunorubicin versus 7+3d, high-dose daunorubicin

Chemotherapy

• Cytarabine (Cytosar) 1000 mg/m² IV over 6 hours Q12H on days 1 to 6 (12 total doses)

One cycle

Eligible patients could proceed to allogeneic HSCT; others were randomized to gemtuzumab ozogamicin maintenance versus no further 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. 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

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.

Chemotherapy

• Azacitidine (Vidaza) 60 mg/m² SC once per day on days 1 to 5

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

• Decitabine induction

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, given until relapsed disease or unacceptable toxicity

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

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	Observation	Might have superior DFS

Chemotherapy

• Cytarabine (Cytosar) 10 mg/m² SC BID on days 1 to 21

2-month cycles, continue until relapse

References

1. 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. contains protocol PubMed

Observation

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Regimen

Study	Evidence	Comparator	Efficacy
Robles et al. 2000 (ECOG E5483)	Phase III	LoDAC	Might have inferior DFS

No further antineoplastic treatment; included here because it was used as a comparator arm in this setting.

References

1. 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. contains protocol PubMed

Panobinostat monotherapy

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Regimen

Study	Evidence
Ocio et al. 2015 (panobidara)	Phase Ib/II

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

Preceding treatment

• 7+3i & Panobinostat x 2 to 3 cycles

Chemotherapy

• Panobinostat (Farydak) as follows:
  • Odd weeks: 40 mg PO once per day three days of the week
  • Even weeks: no treatment

Continued until progression or intolerance

References

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

Sorafenib monotherapy

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Regimen

Study	Evidence
Ravandi et al. 2010	Phase I/II

Preceding treatment

• Cytarabine, Idarubicin, Sorafenib consolidation

Chemotherapy

• Sorafenib (Nexavar) 400 mg PO BID

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

Vorinostat monotherapy

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Regimen

Study	Evidence
Garcia-Manero et al. 2012	Phase II

Preceding treatment

• Cytarabine, Idarubicin, Vorinostat consolidation

Chemotherapy

• Vorinostat (Zolinza) 200 mg PO TID on days 1 to 14

28-day cycle for up to 12 cycles

References

1. Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, Borthakur G, Kadia TM, Konopleva MY, Faderl S, Cortes JE, Brandt M, Hu Y, McCue D, Newsome WM, Pierce SR, de Lima M, Kantarjian HM. Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome. J Clin Oncol. 2012 Jun 20;30(18):2204-10. Epub 2012 May 14. link to original article contains verified protocol 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	Non-randomized

Preceding treatment

• 7+3d (high-dose)

Chemotherapy

• Cytarabine (Cytosar) 100 mg/m²/day IV continuous infusion on days 1 to 5 (total dose: 500 mg/m²)
• Daunorubicin (Cerubidine) 45 mg/m² IV once per day on days 1 to 3

5-day course

References

1. 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

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

Regimen

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

Course 1

• Cytarabine (Cytosar) 100 mg/m² IV push Q12H on days 1 to 10 (20 total doses)
• Daunorubicin (Cerubidine) 50 mg/m² IV slow push once per day on days 1, 3, 5
• Etoposide (Vepesid) 100 mg/m² IV over 60 minutes once per day on days 1 to 5

Course 2

• Cytarabine (Cytosar) 100 mg/m² IV push Q12H on days 1 to 8 (16 total doses)
• Daunorubicin (Cerubidine) 50 mg/m² IV slow push once per day on days 1, 3, 5
• Etoposide (Vepesid) 100 mg/m² IV over 60 minutes once per day on days 1 to 5

References

1. 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

Cladribine monotherapy

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Regimen

Study	Evidence
Santana et al. 1992	Phase II

Chemotherapy

• Cladribine (Leustatin) 8.9 mg/m²/day IV continuous infusion on days 1 to 5 (total dose: 44.5 mg/m²)

References

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

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

References

1. Robak T, Wrzesien'-Kus' A, Lech-Maran'da E, Kowal M, Dmoszyn'ska 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. 2008 (PALG)	Phase II

Preceding treatment

• DA or DAC or DAF

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; first dose is given 24 hours prior to chemotherapy
  • WBC count greater than 20 x 10⁹/L: 300 mcg SC once per day on days 1 to 5, commenced simultaneously to cladribine
• Mitoxantrone (Novantrone) 10 mg/m² IV once per day on days 1 to 3

One course

Patients with PR were recommended to undergo a second course of CLAG-M. Primary refractory patients achieving CR after 2nd CLAG-M proceeded to HAM consolidation. 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, Wrzesien-Kus 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

Clofarabine monotherapy

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Regimen

Study	Evidence
Kantarjian et al. 2003	Phase II

Chemotherapy

• Clofarabine (Clolar) 40 mg/m² IV over 60 minutes once per day on days 1 to 5

3- to 6-week cycles

References

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

Clofarabine & Cytarabine

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Variant #1

Study	Evidence	Comparator	Efficacy
Faderl et al. 2012 (CLASSIC I)	Phase III	Cytarabine	Superior EFS

Chemotherapy

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

Supportive medications

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

1 to 3 cycles

It was not clear if the consolidation cycle mentioned here would also be clofarabine and cytarabine or something else: "Patients who achieved remission after their induction cycle could receive a single (optional) consolidation cycle; patients who did not achieve remission after induction but who demonstrated hematologic improvement could receive a reinduction cycle followed by a single (optional) consolidation cycle."

Variant #2

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

Chemotherapy

• Clofarabine (Clolar) 30 mg/m² IV once per day on days 1 to 5
• Cytarabine (Cytosar) 1000 mg/m² IV once per day on days 1 to 5

At least one cycle

Chemo-responsive patients proceeded to clofarabine & melphalan, then allogeneic SCT.

Variant #3, Clofarabine & LDAC

Study	Evidence
Buckley et al. 2015	Phase I/II

LDAC: Low-Dose Ara-C (Cytarabine)

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

Chemotherapy

• Clofarabine (Clolar) 20 mg PO once per day on days 1 to 5
• Cytarabine (Cytosar) as follows (per physician choice):
  • 20 mg/m² SC BID on days 1 to 10
  • 20 mg/m² SC once per day on days 1 to 14

Cycle duration not explicitly defined; presumably 28 days

Variant #4

Study	Evidence
Agura et al. 2011	Phase II

Chemotherapy

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

Supportive medications

• Dexamethasone (Decadron) 10 mg IV once per day
• 5-HT3 antagonists on each day of chemotherapy
• Hydration at 150 mL/m²/H "to prevent tumor lysis syndrome" during chemotherapy
• Bumetanide (Bumex) 2 to 4 mg IV push once to twice per day as needed to keep weight within 1 kg of patient's initial weight
• Levofloxacin (Levaquin) 500 mg PO/IV once per day
• Acyclovir (Zovirax) 500 mg IV Q12H
• One of the following antifungals:
  • Caspofungin (Cancidas) 50 mg IV once per day
  • Voriconazole (Vfend) 200 mg (route not specified) BID
• Parenteral nutrition allowed
• No routine use of growth factors

Up to 4 total cycles; subsequent cycles start after hematologic recovery from the previous cycle and were recommended for patients who had hematologic response, but not complete response (CR)

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 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. 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. 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 monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Faderl, et al. 2012 (CLASSIC I)	Phase III	Clofarabine & Cytarabine	Inferior EFS
Ravandi et al. 2015 (VALOR)	Phase III	Cytarabine & Vosaroxin	Might have inferior OS

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

Chemotherapy

• Cytarabine (Cytosar) 1000 mg/m² IV over 2 hours once per day on days 1 to 5

Supportive medications

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

1 to 3 cycles (see note)

References

1. 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
2. Ravandi F, Ritchie EK, Sayar H, Lancet JE, Craig MD, Vey N, Strickland SA, Schiller GJ, Jabbour E, Erba HP, Pigneux A, Horst HA, Recher C, Klimek VM, Cortes J, Roboz GJ, Odenike O, Thomas X, Havelange V, Maertens J, Derigs HG, Heuser M, Damon L, Powell BL, Gaidano G, Carella AM, Wei A, Hogge D, Craig AR, Fox JA, Ward R, Smith JA, Acton G, Mehta C, Stuart RK, Kantarjian HM. Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2015 Sep;16(9):1025-36. Epub 2015 Jul 30.link to original article contains protocol link to PMC article PubMed

Cytarabine & Mitoxantrone

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Regimen

Study	Evidence
Sternberg et al. 2000	Phase II

Chemotherapy

• Cytarabine (Cytosar) 500 mg/m² IV over 90 minutes every 12 hours on days 1 to 6 (12 total doses)
• Mitoxantrone (Novantrone) 5 mg/m² IV bolus once per day on days 1 to 5

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

• Etoposide (Vepesid) 100 mg/m² IV over 30 minutes once per day on days 1 to 5
• Mitoxantrone (Novantrone) 10 mg/m² IV over 15 minutes once per day on days 1 to 5

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 last, 4 hours after the start of Fludarabine (Fludara)
• Filgrastim (Neupogen) or 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	FLAG-DNX	Seems to have inferior CR rate

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

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days 1 to 5, given second
• Cytarabine (Cytosar) 2000 mg/m² IV once per day on days 1 to 5, given last, 4 hours after the start of Fludarabine (Fludara)
• Filgrastim (Neupogen) 200 mcg/m² (route not specified) once per day on days 0 to 5, given first

Two cycles

Subsequent treatment

• CYVE or Cytarabine & Thioguanine consolidation, as a bridge to allogeneic HSCT

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. 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-DNX

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FLAG-DNX: FLudarabine, Ara-C (Cytarabine), G-CSF, DauNoXome (Daunorubicin liposomal)

Regimen

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

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

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days 1 to 5, given second
• Cytarabine (Cytosar) 2000 mg/m² IV once per day on days 1 to 5, given last, 4 hours after the start of Fludarabine (Fludara)
• Filgrastim (Neupogen) 200 mcg/m² (route not specified) once per day on days 0 to 5, given first
• Daunorubicin liposomal (DaunoXome) as follows:
  • Cycle 1: 60 mg/m² IV once per day on days 1, 3, 5, given third
  • Cycle 2: none

2 cycles

Subsequent treatment

• CYVE or Cytarabine & Thioguanine consolidation, as a bridge to allogeneic HSCT

References

1. 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

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 Fludarabine (Fludara)
• Filgrastim (Neupogen) 5 mcg/kg SC once per day starting on day 6, to continue until neutrophil recovery
• Idarubicin (Idamycin) 10 mg/m² IV once per day on days 1 to 3

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 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	SHAI	Seems to have superior TTTF

Unclear from the abstract how many doses of fludarabine to be given.

Chemotherapy

• Fludarabine (Fludara) 15 mg/m² IV 4 hours prior to Cytarabine (Cytosar)
• 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

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 protocol PubMed

GCLAC

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GCLAC: G-csf, Clofarabine, Ara-C

Regimen

Study	Evidence
Becker et al. 2011	Phase II

Chemotherapy

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

One course with one re-induction allowed for patients with greater than 5% blasts at day 21 Patients achieving CR could receive induction 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

IAP

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

Regimen

Study	Evidence
Advani et al. 2014 (SWOG S0919)	Phase II

Chemotherapy

• Idarubicin (Idamycin) 12 mg/m² IV once per day on days 4 to 6
• Cytarabine (Cytosar) 1500 mg/m² IV once per day on days 4 to 7
• Pravastatin (Pravachol) 1280 mg PO once per day on days 1 to 8

Patients achieving a CR could receive 2 cycles of consolidation

References

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

MEC

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MEC: Mitoxantrone, Etoposide, Cytarabine

Variant #1

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

Chemotherapy

• Mitoxantrone (Novantrone) 8 mg/m² IV once per day on days 1 to 6
• Etoposide (Vepesid) 80 mg/m² IV once per day on days 1 to 6
• Cytarabine (Cytosar) 1000 mg/m² IV once per day on days 1 to 6

Variant #2

Study	Evidence
Amadori et al. 1991	Phase II

Chemotherapy

• Mitoxantrone (Novantrone) 6 mg/m² IV bolus once per day on days 1 to 6
• Etoposide (Vepesid) 80 mg/m² IV over 60 minutes once per day on days 1 to 6
• Cytarabine (Cytosar) 1000 mg/m² IV over 6 hours once per day on days 1 to 6

Variant #3

Study	Evidence
Kohrt et al. 2010	Retrospective

Chemotherapy

• Mitoxantrone (Novantrone) 8 mg/m² IV push once per day on days 1 to 5, given third
• Etoposide (Vepesid) 100 mg/m² IV over 2 hours once per day on days 1 to 5, given first
• Cytarabine (Cytosar) 1000 mg/m² IV once per day on days 1 to 5, given second

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. Retrospective: Kohrt HE, Patel S, Ho M, Owen T, Pollyea DA, Majeti R, Gotlib J, Coutre S, Liedtke M, Berube C, Alizadeh AA, Medeiros BC. Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: a single-center experience. Am J Hematol. 2010 Nov;85(11):877-81. link to original 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

SHAI

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

Regimen

Study	Evidence	Comparator	Efficacy
Fiegl et al. 2013	Phase III	F-SHAI	Seems to have inferior TTTF

Chemotherapy

• 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

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 protocol PubMed

Consolidation after salvage therapy

Allogeneic hematopoietic stem cell transplant

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To be completed.

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

• FLAG versus FLAG-DNX

Chemotherapy

• Cytarabine (Cytosar) 75 mg/m² SC once per day on days 1 to 4, every other week
• Thioguanine (Tabloid) 100 mg/m² PO once per day for up to 4 weeks maximum

Subsequent treatment

• allogeneic HSCT

References

1. 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

• FLAG versus FLAG-DNX

Chemotherapy

• Cytarabine (Cytosar) 500 mg/m²/day IV continuous infusion on days 1 to 4 (total dose: 2000 mg/m²)
• Etoposide (Vepesid) 100 mg/m² IV BID on days 1 to 4

Subsequent treatment

• allogeneic HSCT

References

1. 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

• Azacitidine (Vidaza) 75 mg/m² SC once per day on days 1 to 7

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

Azacitidine, Vorinostat, Gemtuzumab ozogamicin

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Regimen

Study	Evidence
Walter et al. 2013	Phase I/II

This is the MTD used in the phase II portion, which was tested on 43 patients.

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² SC or IV once per day on days 1 to 7
• Vorinostat (Zolinza) 400 mg PO once per day on days 1 to 9
• Gemtuzumab ozogamicin (Mylotarg) 3 mg/m² IV once on days 4 & 8

Up to 6 cycles based on response; cycle length not specified beyond 2nd cycle

References

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

Ruxolitinib monotherapy

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Regimen

Study	Evidence
Eghtedar et al. 2012	Phase II

Chemotherapy

• Ruxolitinib (Jakafi) 25 mg PO BID

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.

• Vadastuximab talirine (SGN-CD33A)
• Gilteritinib (ASP2215)
• Vosaroxin (SNS 595)

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