Acute myeloid leukemia

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58 regimens on this page
82 variants on this page

Contents


Guidelines

ELN

Current

Older

ESMO

NCCN

Induction therapy, standard patients

ADE

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

Regimen #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

7-day course

Regimen #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

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. 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 medical research council AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed
  3. Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, Muus P, Mistrik M, Amadori S, Specchia G, Fabbiano F, Nobile F, Sborgia M, Camera A, Selleslag DL, Lefrère F Sr, Magro D, Sica S, Cantore N, Beksac M, Berneman Z, Thomas X, Melillo L, Guimaraes JE, Leoni P, Luppi M, Mitra ME, Bron D, Fillet G, Marijt EW, Venditti A, Hagemeijer A, Mancini M, Jansen J, Cilloni D, Meert L, Fazi P, Vignetti M, Trisolini SM, Mandelli F, de Witte T. High-Dose Cytarabine in Induction Treatment Improves the Outcome of Adult Patients Younger Than Age 46 Years With Acute Myeloid Leukemia: Results of the EORTC-GIMEMA AML-12 Trial. J Clin Oncol. 2014 Jan 20;32(3):219-28. Epub 2013 Dec 2. link to original article contains verified protocol PubMed

CIA

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

Regimen

Study Evidence
Nazha et al. 2013 Phase II

Chemotherapy

Supportive medications

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 Clofarabine, Idarubicin, and Cytarabine (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 PubMed Central article contains verified protocol PubMed

Cytarabine & Daunorubicin

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

Regimen #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) 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) 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) 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 dauno]] Inferior OS

Chemotherapy

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. 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.

Regimen #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/AMLSG/SAKK) Phase III 7+3d, high-dose dauno Inferior CR rate
Stone et al. 2015 (ACCEDE) Phase III Amonafide & Cytarabine Seems not superior

Chemotherapy

7-day course

Treatment followed by MiDAC consolidation.

Regimen #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

Chemotherapy

Supportive medications

  • "according to commonly accepted guidelines with no prophylactic IV antibiotics"
  • Granulocyte colony-stimulating factor recommended only for patients greater 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.

Regimen #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

7-day course

Regimen #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

7-day course

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

Regimen #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

Chemotherapy

7-day course

Treatment followed by MiDAC consolidation.

Regimen #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

5-day course

References

  1. 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. 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. 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. Berman E, Heller G, Santorsa J, McKenzie S, Gee T, Kempin S, Gulati S, Andreeff M, Kolitz J, Gabrilove J, et al. 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. 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
  8. 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
  9. 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
  10. 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 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 PubMed
  11. 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
  12. 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 PubMed
  13. 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
  14. 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 medical research council AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed
  15. 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
  16. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal Del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. Epub 2015 May 18. link to original article contains protocol PubMed
  17. 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 PubMed
  18. 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
  19. 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 PubMed

Cytarabine & Idarubicin

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7+3i: 7 days of cytarabine + 3 days of idarubicin

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

Study Evidence Comparator Efficacy
Löwenberg et al. 2017 (HOVON-102) Phase III 7+3i & Clofarabine Seems not superior

Chemotherapy

7-day course

Regimen #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

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.

Regimen #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

7-day course

Regimen #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

7-day course

Regimen #5, 5+3i

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

Chemotherapy

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, et al. 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. Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 15;103(2):479-85. Epub 2003 Sep 25. link to original article contains verified protocol PubMed
  6. 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 PubMed
  7. 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

Cytarabine & Idarubicin -> Amsacrine & Cytarabine

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Note: Amsacrine is not generally available; this reference is here for historic purposes, only.

References

  1. 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
  2. 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

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

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 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 PubMed

Cytarabine, Idarubicin, Vorinostat

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Regimen

Study Evidence
Garcia-Manero et al. 2012 Phase II

Chemotherapy

Supportive medications

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 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

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 Seems to have superior OS
DAF Seems not superior

Chemotherapy

Supportive medications

  • "according to commonly accepted guidelines with no prophylactic IV antibiotics"
  • Granulocyte colony-stimulating factor recommended only for patients greater 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 (MRC AML15) Phase III ADE Seems not superior

Chemotherapy

References

  1. 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 medical research council 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

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 PubMed

Induction therapy, older patients or "unfit" patients

7+3i & Panobinostat

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7+3i: 7 days of cytarabine + 3 days of idarubicin

Regimen

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

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

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. 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 PubMed

Azacitidine (Vidaza)

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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

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 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 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 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 & Cytarabine

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Regimen #1

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

Chemotherapy

One course

Regimen #2

Study Evidence
Faderl et al. 2010 Phase II

Chemotherapy

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 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 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 PubMed

Cytarabine (Cytosar)

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

Regimen #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

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

Regimen #2, indefinite duration

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

Chemotherapy

4-week 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 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 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 PubMed

Cytarabine, Daunorubicin, Sorafenib

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Regimen

Study Evidence
Uy et al. 2017 (CALGB 11001) Phase II

Chemotherapy

7-day course

Patients not achieving a hypoplastic marrow on day 14 received re-induction with 5+2 with sorafenib. Patients achieving a CR or CRi proceeded to IDAC & sorafenib consolidation.

References

  1. Uy, G. L., Mandrekar, S. J., Laumann, K., Marcucci, G., Zhao, W., Levis, M. J., Klepin, H. D., Baer, M. R., Powell, B. L., Westervelt, P., DeAngelo, D. J., Stock, W., Sanford, B., Blum, W. G., Bloomfield, C. D., Stone, R. M., & Larson, R. A. (2017). A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Advances, 1(5), 331-340. Accessed January 26, 2017. link to original article contains verified protocol

Decitabine (Dacogen)

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Regimen #1

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

Chemotherapy

4- to 6-week cycles

Regimen #2

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

Chemotherapy

Supportive medications

28-day cycles, given until progression of disease or unacceptable toxicity

Regimen #3

Study Evidence
Blum et al. 2010 Phase II

Chemotherapy

Supportive medications

  • Hydroxyurea (Hydrea) allowed during and prior to cycle 1 in order to maintain WBC less than 40,000/L

28-day cycles

Additional therapy depending on response:

  • 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 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 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 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

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 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 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

To be completed

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 PubMed

Temozolomide (Temodar)

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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 therapy

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

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, Idarubicin, and Cytarabine (CIA) Consolidation

Regimen

Study Evidence
Nazha et al. 2013 Phase II

Treatment preceded by Clofarabine, Idarubicin, and Cytarabine (CIA) Induction.

Chemotherapy

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

References

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

Clofarabine & low-dose Cytarabine alternating with Decitabine

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Regimen

Study Evidence
Faderl et al. 2010 Phase II

Treatment preceded by clofarabine & low-dose cytarabine, which is counted as "Cycle 1". Cycles are given every 4 to 7 weeks pending hematologic recovery and resolution of other toxicities.

Clofarabine & low-dose Cytarabine portion

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

Decitabine portion

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

References

  1. Faderl S, Ravandi F, Huang X, Wang X, Jabbour E, Garcia-Manero G, Kadia T, Ferrajoli A, Konopleva M, Borthakur G, Burger J, Feliu J, Kantarjian HM. Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients. Cancer. 2012 Sep 15;118(18):4471-7. Epub 2012 Jan 26. link to original article contains verified protocol 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 PubMed

Cytarabine & Daunorubicin

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Regimen

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

Ambulatory regimen; treatment preceded by 4 + 7 induction with daunorubicin.

Chemotherapy

1-month cycle for up to 6 cycles

References

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

Cytarabine & Idarubicin

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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

Ambulatory regimen; treatment preceded by 4 + 7 induction with idarubicin.

Chemotherapy

1-month cycle for up to 6 cycles

References

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

Cytarabine, Idarubicin, Sorafenib

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Regimen

Study Evidence
Ravandi et al. 2010 Phase I/II

Treatment preceded by cytarabine, idarubicin, sorafenib induction. Regimen details are from the phase II part of the published phase I/II trial.

Chemotherapy

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 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 PubMed

Cytarabine, Idarubicin, Vorinostat

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Regimen

Study Evidence
Garcia-Manero et al. 2012 Phase II

Treatment preceded by Cytarabine, Idarubicin, Vorinostat induction therapy.

Chemotherapy

Supportive medications

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 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 -> autoHCT Might have inferior RFS

Treatment preceded by 7+3i -> amsacrine & cytarabine.

Chemotherapy

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

Treatment in Wierzbowska et al. 2007 preceded by CLAG-M. Treatment in PALG AML1/2004 preceded by DA versus DAC versus DAF.

Chemotherapy

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: High Dose Ara-C (Cytarabine)

Regimen

Study Evidence Comparator Efficacy
Thomas et al. 2017 Randomized Phase II CLARA Seems to have inferior RFS

Chemotherapy

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/HDAC

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

Regimen #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

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.

Regimen #2

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

Treatment preceded by BHAC-MMV.

Chemotherapy

Two cycles

Treatment followed by A-VVV.

Regimen #3

Study Evidence
Holowiecki et al. 2012 Non-randomized

Treatment preceded by cytarabine & mitoxantrone consolidation. Details in the text are scant.

Chemotherapy

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 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

IDAC/mIDAC

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

Regimen #1

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

Treatment preceded by BHAC-MMV.

Chemotherapy

Two cycles

Treatment followed by A-VVV.

Regimen #2

Study Evidence
Stone et al. 2015 Phase II

Treatment preceded by 7+3d.

Chemotherapy

References

  1. 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
  2. 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

IDAC & Sorafenib

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IDAC: Intermediate Dose Ara-C (Cytarabine)

Regimen

Study Evidence
Uy et al. 2017 (CALGB 11001) Phase II

Treatment preceded by 7+3 with sorafenib induction.

Chemotherapy

Two cycles

Treatment followed by sorafenib maintenance.

References

  1. Uy, G. L., Mandrekar, S. J., Laumann, K., Marcucci, G., Zhao, W., Levis, M. J., Klepin, H. D., Baer, M. R., Powell, B. L., Westervelt, P., DeAngelo, D. J., Stock, W., Sanford, B., Blum, W. G., Bloomfield, C. D., Stone, R. M., & Larson, R. A. (2017). A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Advances, 1(5), 331-340. Accessed January 26, 2017. link to original article contains verified protocol

Maintenance therapy

Azacitidine (Vidaza)

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Regimen #1

Study Evidence
Nand et al. 2013 Phase II

Treatment preceded by azacitidine and gemtuzumab ozogamicin consolidation.

Chemotherapy

28-day cycle for 4 cycles

Regimen #2

Study Evidence
Grövdal et al. 2010 Phase II

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

Chemotherapy

28-day cycles

References

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

Decitabine (Dacogen)

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Regimen

Study Evidence
Blum et al. 2010 Phase II

Treatment preceded by decitabine monotherapy induction.

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.

Chemotherapy

  • Decitabine (Dacogen) 20 mg/m2 IV over 1 hour 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/μL) persisting greater than or equal to 14 days received 4 days instead of 5 days of decitabine starting with the following cycle. If neutropenia occurred again as above with 4 days of decitabine, patients received 3 days instead of 4 days of decitabine starting with the following cycle.

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 PubMed

LoDAC/LDAC

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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

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 (Farydak)

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7+3i: 7 days of cytarabine + 3 days of idarubicin

Regimen

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

Treatment preceded by 7+3i & panobinostat x 2 to 3 cycles. The panobinostat dose is the MTD in this phase Ib/II study.

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 PubMed

Sorafenib (Nexavar)

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Regimen

Study Evidence
Ravandi et al. 2010 Phase I/II
Uy et al. 2017 (CALGB 11001) Phase II

Treatment in Ravandi et al. 2010 preceded by cytarabine, idarubicin, and sorafenib consolidation; regimen details are from the phase II part of the published phase I/II trial. Treatment in CALGB 11001 preceded by IDAC & sorafenib consolidation.

Chemotherapy

Varied duration, as follows:

  • Ravandi et al 2010: Up to one year of sorafenib therapy, including consolidation course(s)
  • CALGB 11001: 28-day cycle for up to 12 cycles

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 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 PubMed
  2. Uy, G. L., Mandrekar, S. J., Laumann, K., Marcucci, G., Zhao, W., Levis, M. J., Klepin, H. D., Baer, M. R., Powell, B. L., Westervelt, P., DeAngelo, D. J., Stock, W., Sanford, B., Blum, W. G., Bloomfield, C. D., Stone, R. M., & Larson, R. A. (2017). A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Advances, 1(5), 331-340. Accessed January 26, 2017. link to original article contains verified protocol

Vorinostat (Zolinza)

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Regimen

Study Evidence
Garcia-Manero et al. 2012 Phase II

Treatment preceded by cytarabine, idarubicin, and vorinostat consolidation.

Chemotherapy

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 PubMed

Relapsed/refractory

5+2d

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Regimen

Study Evidence
Zeidner et al. 2015 Non-randomized

Treatment preceded by 7+3d (high-dose).

Chemotherapy

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 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

Course 2

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

Azacitidine (Vidaza)

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Regimen

Study Evidence
Thepot et al. 2010 Phase II

Chemotherapy

28-day cycle for at least 4 to 6 cycles

References

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

Azacitidine & Sorafenib

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Regimen

Study Evidence
Ravandi et al. 2013 Phase II

Majority of patients in the phase II trial were FLT-3 ITD positive

Chemotherapy

Supportive medications

  • "All patients received antimicrobials, supportive care, and transfusions of blood products according to the institutional guidelines."

4 to 8 week cycles at treating physician's discretion

References

  1. Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA, Pierce S, Daver N, Garcia-Manero G, Faderl S, Nazha A, Konopleva M, Borthakur G, Burger J, Kadia T, Dellasala S, Andreeff M, Cortes J, Kantarjian H, Levis M. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013 Jun 6;121(23):4655-62. Epub 2013 Apr 23. link to original article contains verified protocol PubMed

Cladribine (Leustatin)

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Regimen

Study Evidence
Santana et al. 1992 Phase II

Chemotherapy

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

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, CLAM

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

Regimen

Study Evidence
Wierzbowksa et al. 2008 (PALG) Phase II

All patients enrolled in this study had received first-line DA, 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 less than or equal to 20k: 300 μg SC once per day on days 0 to 5; first dose is given 24 hours prior to chemotherapy
    • WBC greater than 20k: 300 μg 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

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 (Clolar)

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Regimen

Study Evidence
Kantarjian et al. 2003 Phase II

Chemotherapy

3- to 6-week cycles

References

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

Clofarabine & Cytarabine

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Regimen #1

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

Chemotherapy

  • Clofarabine (Clolar) 40 mg/m2 IV over 1 hour 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."

Regimen #2

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

Chemotherapy

At least one cycle

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

Regimen #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

Cycle duration not explicitly defined; presumably 28 days

Regimen #4

Study Evidence
Agura et al. 2011 Phase II

Chemotherapy

  • Clofarabine (Clolar) 40 mg/m2 IV over 1 hour 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

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 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 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 (Cytosar)

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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

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 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 PubMed

Cytarabine & Mitoxantrone

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Regimen

Study Evidence
Sternberg et al. 2000 Phase II

Chemotherapy

References

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

Etoposide & Mitoxantrone

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Regimen

Study Evidence
Ho et al. 1988 Phase II

Chemotherapy

References

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

FLAG

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

Regimen

Study Evidence
Montillo et al. 1998 Phase II

Chemotherapy

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

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

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

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

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 PubMed

IAP

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

Regimen

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

Chemotherapy

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 PubMed

MEC

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MEC: Mitoxantrone, Etoposide, Cytarabine

Regimen #1

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

Chemotherapy

Regimen #2

Study Evidence
Amadori et al. 1991 Phase II

Chemotherapy

Regimen #3

Study Evidence
Kohrt et al. 2010 Retrospective

Chemotherapy

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

Ruxolitinib (Jakafi)

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Regimen

Study Evidence
Eghtedar et al. 2012 Phase II

Chemotherapy

28-day cycles

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

References

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

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

Response criteria

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

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

Revised International Working Group recommendations (2003)

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

Prognosis

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

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

Risk stratification:

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

References

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

Prognosis in cytogenetically normal AML

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

Investigational agents

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

Additional information

Antifungal prophylaxis

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