Acute myeloid leukemia - historical

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only.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

33 regimens on this page
34 variants on this page

Contents


Upfront induction therapy

5+3d

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

Regimen

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

Chemotherapy

5-day course

References

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

5+3i

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

Regimen

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

Chemotherapy

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

5-day course

References

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

7+3d (low-dose)

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

Variant #1, 700/90

Study Evidence Comparator Efficacy
Nesbit et al. 1994 (CCG 251) Non-randomized portion of RCT
Löwenberg et al. 1998 (EORTC/HOVON AML-9) Phase III (C) 7+3m (low-dose) Might have inferior CR rate

Chemotherapy

Two courses

Variant #2, 1400/90

Study Evidence Comparator Efficacy
Löwenberg et al. 1997 (EORTC/HOVON AML-11) Phase III (C) 7+3d & GM-CSF Seems not superior

Chemotherapy

7-day course

References

  1. CCG 251: Nesbit ME Jr, Buckley JD, Feig SA, Anderson JR, Lampkin B, Bernstein ID, Kim TH, Piomelli S, Kersey JH, Coccia PF, O'Reilly RC, August C, Thomas ED, Hammond GD. Chemotherapy for induction of remission of childhood acute myeloid leukemia followed by marrow transplantation or multiagent chemotherapy: a report from the Childrens Cancer Group. J Clin Oncol. 1994 Jan;12(1):127-35. link to original article PubMed
    1. Pooled update: Smith FO, Alonzo TA, Gerbing RB, Woods WG, Arceci RJ; Children's Cancer Group. Long-term results of children with acute myeloid leukemia: a report of three consecutive phase III trials by the Children's Cancer Group: CCG 251, CCG 213 and CCG 2891. Leukemia. 2005 Dec;19(12):2054-62. link to original article PubMed
  2. EORTC/HOVON AML-11: Löwenberg B, Suciu S, Archimbaud E, Ossenkoppele G, Verhoef GE, Vellenga E, Wijermans P, Berneman Z, Dekker AW, Stryckmans P, Schouten H, Jehn U, Muus P, Sonneveld P, Dardenne M, Zittoun R. Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group. Blood. 1997 Oct 15;90(8):2952-61. link to original article contains protocol PubMed
  3. EORTC/HOVON AML-9: Löwenberg B, Suciu S, Archimbaud E, Haak H, Stryckmans P, de Cataldo R, Dekker AW, Berneman ZN, Thyss A, van der Lelie J, Sonneveld P, Visani G, Fillet G, Hayat M, Hagemeijer A, Solbu G, Zittoun R; European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. J Clin Oncol. 1998 Mar;16(3):872-81. link to original article PubMed

7+3i & Panobinostat

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

Regimen

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

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

Chemotherapy

19-day course

Subsequent treatment

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

References

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

7+3i & Vorinostat

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Regimen

Study Evidence
Garcia-Manero et al. 2012 Phase II

Chemotherapy

  • Cytarabine (Ara-C) 1500 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose: 6000 mg/m2)
    • Patients older than 60 received: 1500 mg/m2/day IV continuous infusion over 72 hours, started on day 4 (total dose: 4500 mg/m2)
  • Idarubicin (Idamycin) 12 mg/m2 IV once per day on days 4 to 6
  • Vorinostat (Zolinza) 500 mg PO three times per day on days 1 to 3

Supportive medications

7-day course for 1 to 2 cycles

Subsequent treatment

References

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

7+5i

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

Regimen

Study Evidence Comparator Efficacy
Solary et al. 2003 Phase III (C) 7+5i & Quinine Seems not superior

Chemotherapy

7-day course

References

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

Cytarabine, Daunorubicin, Vincristine

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Regimen

Study Evidence Comparator Efficacy
Rosenthal & Moloney 1972 Non-randomized
Zittoun et al. 1989 (EORTC AML6) Non-randomized portion of RCT
Löwenberg et al. 1989 Phase III (E) Best supportive care Seems to have superior OS

Chemotherapy

References

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

Cytarabine, Daunorubicin, Mercaptopurine, Prednisolone

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Regimen

Study Evidence Comparator Efficacy
Kobayashi et al. 1996 (JALSG AML89) Phase III (C) BHAC-DMP Seems to have superior EFS

Chemotherapy

References

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

Cytarabine, Doxorubicin, Vincristine, Prednisolone

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Regimen

Study Evidence
Weinstein et al. 1980 Non-randomized

Chemotherapy

References

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

Daunorubicin monotherapy

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Regimen

Study Evidence
Bornstein et al. 1969 Non-randomized

Chemotherapy

References

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

DAT

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

Regimen

Study Evidence Comparator Efficacy
Gale & Cline 1977 Non-randomized
Gale et al. 1981 Non-randomized
Büchner et al. 1982 Non-randomized
Champlin et al. 1984 Non-randomized
Büchner et al. 1985 Non-randomized portion of RCT
Rees et al. 1986 (UK MRC AML8) Non-randomized portion of RCT
Steuber et al. 1991 (POG 8101) Phase III (C) VADx Seems to have superior CR rate
Büchner et al. 1999 Non-randomized portion of RCT
Goldstone et al. 2001 (UK MRC AML11) Phase III (C) ADE Superior CR rate
MAC Seems to have superior CR rate
Büchner et al. 2003 Non-randomized portion of RCT
Burnett et al. 2009 (LRF AML14) Phase III (C) Lower-dose DAT Seems not superior
Krug et al. 2016 (AMLCG 99) Phase III (C) HAM Seems not superior
Braess et al. 2018 (AML-CG 2008) Phase III (C) S-HAM Seems not superior

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

Chemotherapy

Subsequent treatment

  • LRF AML14: MIDAC

References

  1. Gale RP, Cline MJ. High remission-induction rate in acute myeloid leukaemia. Lancet. 1977 Mar 5;1(8010):497-9. link to SD article PubMed
  2. Gale RP, Foon KA, Cline MJ, Zighelboim J. Intensive chemotherapy for acute myelogenous leukemia. Ann Intern Med. 1981 Jun;94(6):753-7. link to original article PubMed
  3. Büchner T, Urbanitz D, Emmerich B, Fischer JT, Fülle HH, Heinecke A, Hossfeld DK, Koeppen KM, Labedzki L, Löffler H, Nowrousian MR, Pfreundschuh M, Pralle H, Rühl H, Wendt FC. Multicentre study on intensified remission induction therapy for acute myeloid leukemia. Leuk Res. 1982;6(6):827-31. PubMed
  4. Champlin R, Jacobs A, Gale RP, Boccia R, Elashoff R, Foon K, Zighelboim J. Prolonged survival in acute myelogenous leukaemia without maintenance chemotherapy. Lancet. 1984 Apr 21;1(8382):894-6. link to original article PubMed
  5. Büchner T, Urbanitz D, Hiddemann W, Rühl H, Ludwig WD, Fischer J, Aul HC, Vaupel HA, Kuse R, Zeile G, Nowrousian MR, Konig HJ, Walter M, Wendt FC, Sodomann H, Hossfeld DK, von Paleske A, Loffler H, Gassmann W, Hellriegel KP, Fulle HH, Lunscken C, Emmerich B, Pralle H, Pees HW, Pfreundschuh M, Bartels H, Koeppen KM, Schwerdtfeger R, Donhuijsen-Ant R, Mainzer K, Bonfert B, Koppler H, Zurborn KH, Ranft K, Thiel E, Heinecke A. Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group. J Clin Oncol. 1985 Dec;3(12):1583-9. link to original article PubMed
  6. UK MRC AML8: Rees JK, Gray RG, Swirsky D, Hayhoe FG. Principal results of the Medical Research Council's 8th acute myeloid leukaemia trial. Lancet. 1986 Nov 29;2(8518):1236-41. link to SD article PubMed
  7. POG 8101: Steuber CP, Civin C, Krischer J, Culbert S, Ragab A, Ruymann FB, Ravindranath Y, Leventhal B, Wilkinson R, Vietti TJ. A comparison of induction and maintenance therapy for acute nonlymphocytic leukemia in childhood: results of a Pediatric Oncology Group study. J Clin Oncol. 1991 Feb;9(2):247-58. link to original article PubMed
  8. Büchner T, Hiddemann W, Wörmann B, Löffler H, Gassmann W, Haferlach T, Fonatsch C, Haase D, Schoch C, Hossfeld D, Lengfelder E, Aul C, Heyll A, Maschmeyer G, Ludwig WD, Sauerland MC, Heinecke A. Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood. 1999 Jun 15;93(12):4116-24. link to original article PubMed
  9. UK MRC AML11: Goldstone AH, Burnett AK, Wheatley K, Smith AG, Hutchinson RM, Clark RE; Medical Research Council Adult Leukemia Working Party. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood. 2001 Sep 1;98(5):1302-11. link to original article PubMed
  10. Büchner T, Hiddemann W, Berdel WE, Wörmann B, Schoch C, Fonatsch C, Löffler H, Haferlach T, Ludwig WD, Maschmeyer G, Staib P, Aul C, Gruneisen A, Lengfelder E, Frickhofen N, Kern W, Serve HL, Mesters RM, Sauerland MC, Heinecke A; German AML Cooperative Group. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol. 2003 Dec 15;21(24):4496-504. link to original article PubMed
  11. LRF AML14: Burnett AK, Milligan D, Goldstone A, Prentice A, McMullin MF, Dennis M, Sellwood E, Pallis M, Russell N, Hills RK, Wheatley K; United Kingdom National Cancer Research Institute Haematological Oncology Study Group. The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. Br J Haematol. 2009 May;145(3):318-32. Epub 2009 Mar 8. link to original article PubMed
  12. AMLCG 99: Krug U, Berdel WE, Gale RP, Haferlach C, Schnittger S, Müller-Tidow C, Braess J, Spiekermann K, Staib P, Beelen D, Serve H, Schliemann C, Stelljes M, Balleisen L, Maschmeyer G, Grüneisen A, Eimermacher H, Giagounidis A, Rasche H, Hehlmann R, Lengfelder E, Thiel E, Reichle A, Aul C, Ludwig WD, Kern W, Haferlach T, Köpcke W, Görlich D, Sauerland MC, Heinecke A, Wörmann BJ, Hiddemann W, Büchner T. Increasing intensity of therapies assigned at diagnosis does not improve survival of adults with acute myeloid leukemia. Leukemia. 2016 Jun;30(6):1230-6. Epub 2016 Feb 9. link to original article PubMed
  13. AML-CG 2008: Braess J, Amler S, Kreuzer KA, Spiekermann K, Lindemann HW, Lengfelder E, Graeven U, Staib P, Ludwig WD, Biersack H, Ko YD, Uppenkamp MJ, De Wit M, Korsten S, Peceny R, Gaska T, Schiel X, Behringer DM, Kiehl MG, Zinngrebe B, Meckenstock G, Roemer E, Medgenberg D, Spaeth-Schwalbe E, Massenkeil G, Hindahl H, Schwerdtfeger R, Trenn G, Sauerland C, Koch R, Lablans M, Faldum A, Görlich D, Bohlander SK, Schneider S, Dufour A, Buske C, Fiegl M, Subklewe M, Braess B, Unterhalt M, Baumgartner A, Wörmann B, Beelen D, Hiddemann W; AML-CG. Sequential high-dose cytarabine and mitoxantrone (S-HAM) versus standard double induction in acute myeloid leukemia-a phase 3 study. Leukemia. 2018 Dec;32(12):2558-2571. Epub 2018 Oct 1. link to original article link to PMC article PubMed

DCTER

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DCTER: Dexamethasone, Cytarabine, Thioguanine, Etoposide, Rubidomycin (Daunomycin)

Regimen

Study Evidence Comparator Efficacy
Wells et al. 1994 (CCG 213) Phase III (E) 7+3d (standard-dose) Seems not superior
Woods et al. 1996 (CCG 2891) Phase III (E) Standard-timed DCTER Superior DFS
Lange et al. 2007 (CCG 2961) Phase III (C) IdaDCTER/DCTER Seems not superior

Chemotherapy

References

  1. CCG 213: Wells RJ, Woods WG, Buckley JD, Odom LF, Benjamin D, Bernstein I, Betcher D, Feig S, Kim T, Ruymann F, Smithson W, Srivastava A, Tannous R, Buckley CM, Whitt JK, Wolff L, Lampkin BC. Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group study. J Clin Oncol. 1994 Nov;12(11):2367-77. link to original article PubMed
    1. Pooled update: Smith FO, Alonzo TA, Gerbing RB, Woods WG, Arceci RJ; Children's Cancer Group. Long-term results of children with acute myeloid leukemia: a report of three consecutive phase III trials by the Children's Cancer Group: CCG 251, CCG 213 and CCG 2891. Leukemia. 2005 Dec;19(12):2054-62. link to original article PubMed
  2. CCG 2961: Lange BJ, Smith FO, Feusner J, Barnard DR, Dinndorf P, Feig S, Heerema NA, Arndt C, Arceci RJ, Seibel N, Weiman M, Dusenbery K, Shannon K, Luna-Fineman S, Gerbing RB, Alonzo TA. Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group. Blood. 2008 Feb 1;111(3):1044-53. Epub 2007 Nov 13. link to original article link to PMC article PubMed
  3. CCG 2891: Woods WG, Kobrinsky N, Buckley JD, Lee JW, Sanders J, Neudorf S, Gold S, Barnard DR, DeSwarte J, Dusenbery K, Kalousek D, Arthur DC, Lange BJ. Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group. Blood. 1996 Jun 15;87(12):4979-89. link to original article PubMed
    1. Pooled update: Smith FO, Alonzo TA, Gerbing RB, Woods WG, Arceci RJ; Children's Cancer Group. Long-term results of children with acute myeloid leukemia: a report of three consecutive phase III trials by the Children's Cancer Group: CCG 251, CCG 213 and CCG 2891. Leukemia. 2005 Dec;19(12):2054-62. link to original article PubMed

D-ZAPO

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D-ZAPO: Daunomycin, 5-Azacytidine, Ara-C (Cytarabine), Prednisone, Oncovin (Vincristine)

Regimen

Study Evidence
Baehner et al. 1979 (CCG 241) Non-randomized portion of RCT

Chemotherapy

References

  1. CCG 241: Baehner RL, Bernstein ID, Sather H, Higgins G, McCreadie S, Chard RL, Hammond D. Improved remission induction rate with D-ZAPO but unimproved remission duration with addition of immunotherapy to chemotherapy in previously untreated children with ANLL. Med Pediatr Oncol. 1979;7(2):127-39. link to original article PubMed

Decitabine & Valproate

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Regimen

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

Chemotherapy

28-day cycle for up to 24 cycles

References

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

Mercaptopurine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Heyn et al. 1960 Phase III (C) 6-MP & Azaserine Seems not superior

This was the first RCT of the Acute Leukemia Chemotherapy Cooperative Study Group A (ALCCSGA), subsequently renamed the Children's Cancer Group (CCG).

Chemotherapy

References

  1. Heyn RM, Brubaker CA, Burchenal JH, Cramblett HG, Wolff JA. The comparison of 6-mercaptopurine with the combination of 6-mercaptopurine and azaserine in the treatment of acute leukemia in children: results of a cooperative study. Blood. 1960 Mar;15:350-9. link to original article PubMed

PATCO

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PATCO: Prednisone, Ara-C (Cytarabine), Thioguanine, Cyclophosphamide, Oncovin (Vincristine)

Regimen

Study Evidence
Chard et al. 1978 (CCG 102) Non-randomized

Chemotherapy

References

  1. CCG 102: Chard RL Jr, Finklestein JZ, Sonley MJ, Nesbit M, McCreadie S, Weiner J, Sather H, Hammond GD. Increased survival in childhood acute nonlymphocytic leukemia after treatment with prednisone, cytosine arabinoside, 6-thioguanine, cyclophosphamide, and oncovin (PATCO) combination chemotherapy. Med Pediatr Oncol. 1978;4(3):263-73. link to original article PubMed

VAMP (Amethopterin)

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

Regimen

Study Evidence
Thompson et al. 1965 Non-randomized

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

Chemotherapy

References

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

Consolidation after upfront therapy

Amsacrine & Cytarabine

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

Regimen

Study Evidence Comparator Efficacy
Cassileth et al. 1992 (ECOG E3483) Phase III (E) Cytarabine & Thioguanine maintenance Seems not superior

Chemotherapy

References

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

Cytarabine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Stone et al. 2001 Phase III (C) Cytarabine & Mitoxantrone Seems not superior

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

Preceding treatment

Chemotherapy

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

1-month cycle for 4 cycles

References

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

Cytarabine, Idarubicin, Vorinostat

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Regimen

Study Evidence
Garcia-Manero et al. 2012 Phase II

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

Preceding treatment

Chemotherapy

Supportive medications

28-day cycle for up to 5 cycles

Subsequent treatment

References

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

Maintenance after first-line therapy

BDMP/BMP/BAMP/BEVP

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Regimen

Study Evidence Comparator Efficacy
Ohno et al. 1993 (JALSG AML-87) Phase III (C) BDMP/BMP/BAMP/BEVP x 3 Inferior DFS

To be completed?

Chemotherapy

References

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

Cytarabine & Thioguanine

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Regimen

Study Evidence
Peterson & Bloomfield 1977 Non-randomized

Chemotherapy

References

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

Panobinostat monotherapy

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Regimen

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

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

Preceding treatment

Chemotherapy

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

Continued indefinitely

References

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

POMP

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

Regimen

Study Evidence Comparator Efficacy
Morrison et al. 1992 Phase III (E) OAP maintenance Seems to have superior OS

Chemotherapy

References

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

Vorinostat monotherapy

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Regimen

Study Evidence
Garcia-Manero et al. 2012 Phase II

Preceding treatment

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 link to PMC article PubMed

Relapsed or refractory, salvage therapy

FLAG-DNX

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

Regimen

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

Note: this regimen was studied in patients up to 21 years of age. Liposomal daunorubicin (DaunoXome) is discontinued.

Chemotherapy

Growth factor therapy

2 cycles

Subsequent treatment

References

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

HiDAC

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HiDAC: High Dose Ara-C (Cytarabine)

Regimen

Study Evidence Comparator Efficacy
Vogler et al. 1994 Phase III (C) HiDAC & Etoposide Seems not superior

Chemotherapy

References

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

IAP

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

Regimen

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

Chemotherapy

8-day course

Subsequent treatment

  • Patients achieving a CR could receive 2 cycles of consolidation

References

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

SHAI

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

Regimen

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

Chemotherapy

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

11-day course

References

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

Vosaroxin & Cytarabine

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Regimen

Study Evidence Comparator Efficacy
Ravandi et al. 2015 (VALOR) Phase III (E) IDAC Seems not superior

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

Chemotherapy

  • Vosaroxin (SNS 595) 90 mg/m2 IV once per day on days 1 to 4 on cycle 1
    • 70 mg/m2 IV once per day on days 1 to 4 on subsequent cycles
  • Cytarabine (Ara-C) 1000 mg/m2 IV over 2 hours once per day on days 1 to 5

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

References

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

Relapsed or refractory, subsequent lines of therapy

Azacitidine, Vorinostat, Gemtuzumab ozogamicin

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Regimen

Study Evidence
Walter et al. 2013 (NCI-2012-01147) Phase I/II

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

Chemotherapy

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

References

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

Cladribine monotherapy

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Regimen

Study Evidence
Santana et al. 1992 Phase II

Chemotherapy

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

5-day course

References

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

Clofarabine monotherapy

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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

Gemtuzumab ozogamicin monotherapy

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Regimen

Study Evidence
Sievers et al. 2001 Phase II

Chemotherapy

14-day cycle for 2 cycles

References

  1. Sievers EL, Larson RA, Stadtmauer EA, Estey E, Löwenberg B, Dombret H, Karanes C, Theobald M, Bennett JM, Sherman ML, Berger MS, Eten CB, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR; Mylotarg Study Group. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001 Jul 1;19(13):3244-54. link to original article contains protocol PubMed
    1. Update: Larson RA, Boogaerts M, Estey E, Karanes C, Stadtmauer EA, Sievers EL, Mineur P, Bennett JM, Berger MS, Eten CB, Munteanu M, Loken MR, Van Dongen JJ, Bernstein ID, Appelbaum FR; Mylotarg Study Group. Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia. 2002 Sep;16(9):1627-36. link to original article PubMed
    2. Update: Larson RA, Sievers EL, Stadtmauer EA, Löwenberg B, Estey EH, Dombret H, Theobald M, Voliotis D, Bennett JM, Richie M, Leopold LH, Berger MS, Sherman ML, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer. 2005 Oct 1;104(7):1442-52. link to original article PubMed

IDAC

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IDAC: Intermediate Dose Ara-C (Cytarabine)

Regimen

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

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

Chemotherapy

Supportive medications

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

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

References

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