Acute myeloid leukemia

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Induction therapy

Clofarabine, Idarubicin, and Cytarabine (CIA) Induction

Regimen, Nazha et al.2013

Phase II

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

Supportive medications:

• Prophylactic levofloxacin, itraconazole, and valacyclovir were administered to all patients
• Granulocyte colony-stimulating factor neither mandated nor forbidden and given per physician discretion

5-day course; patients with only partial remission underwent a second course with the same drugs, doses, and schedule

Patients who achieved a CR or CRi (complete remission with incomplete platelet recovery) proceeded to 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. long link to original article contains verified protocol PubMed

7+3 Cytarabine & Daunorubicin ("Standard" or "conventional" dose)

Regimen #1

Phase III

• Cytarabine (Cytosar) 100 to 200 mg/m2/day IV continuous infusion on days 1 to 7
• Daunorubicin (Cerubidine) 45 mg/m2 IV once per day on days 1 to 3

7-day course

Regimen #2, Holowiecki et al. 2012

Phase III

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

Supportive medications:

• "according to commonly accepted guidelines with no prophylactic IV antibiotics"
• Granulocyte colony-stimulating factor recommended only for patients >50 years old whose leukemic blasts were negative for CD114 expression

7-day course; patients with only partial remission underwent a second course with the same drugs, doses, and schedule

References

1. 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
2. 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
3. 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
4. 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
5. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD; European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010 Jan 21;115(3):453-74. Epub 2009 Oct 30. link to original article contains verified protocol PubMed
6. 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

7+3 Cytarabine & Daunorubicin ("High" or "escalated" dose)

Regimen #1, Fernandez et al. 2009

Phase III

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

7-day course

Regimen #2, Löwenberg et al. 2009 (HOVON/AMLSG/SAKK)

Phase III

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

7-day course

References

1. Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. link to original article contains verified protocol PubMed
2. 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

7+3 Cytarabine & Idarubicin

Regimen

Phase III

• Cytarabine (Cytosar) 100 to 200 mg/m2/day IV continuous infusion on days 1 to 7
• Idarubicin (Idamycin) 12 mg/m2 IV once per day on days 1 to 3

7-day course

References

1. Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, Ritch PS, Enck RE, Weitberg AB. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992 Jan 15;79(2):313-9. link to original article PubMed
2. Haas R, Ho AD, Del Valle F, Fischer JT, Ehrhardt R, Döhner H, Witt B, Huberts H, Kaplan E, Hunstein W. Idarubicin/cytosine arabinoside and mitoxantrone/etoposide for the treatment of de novo acute myelogenous leukemia. Semin Oncol. 1993 Dec;20(6 Suppl 8):20-6. PubMed
3. Masaoka T, Ogawa M, Yamada K, Kimura K, Ohashi Y. A phase II comparative study of idarubicin plus cytarabine versus daunorubicin plus cytarabine in adult acute myeloid leukemia. Semin Hematol. 1996 Oct;33(4 Suppl 3):12-7. PubMed
4. 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
5. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD; European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010 Jan 21;115(3):453-74. Epub 2009 Oct 30. link to original article contains verified protocol PubMed

Cytarabine, Idarubicin, Sorafenib

Regimen, Ravandi et al. 2010

Phase II

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

• Cytarabine (Cytosar) 1500 mg/m2/day IV continuous infusion on days 1 to 4
  • Patients older than 60 received: Cytarabine (Cytosar) 1500 mg/m2/day IV continuous infusion on days 1 to 3
• Idarubicin (Idamycin) 12 mg/m2 IV over 1 hour once per day on days 1 to 3
• Sorafenib (Nexavar) 400 mg PO BID on days 1 to 7

7-day course, followed by Cytarabine, Idarubicin, Sorafenib consolidation therapy

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

Cytarabine, Idarubicin, Vorinostat

Regimen, Garcia-Manero et al. 2012

Phase II

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

Supportive medications:

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

7-day course x 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

DAC

DAC: Daunorubicin, Ara-C, Cladribine

Regimen, Holowiecki et al. 2013

Phase III

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

Supportive medications:

• "according to commonly accepted guidelines with no prophylactic IV antibiotics"
• Granulocyte colony-stimulating factor recommended only for patients >50 years old whose leukemic blasts were negative for CD114 expression

7-day course; patients with only partial remission underwent a second course with the same drugs, doses, and schedule

References

1. 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

Decitabine (Dacogen)

Regimen, Blum et al. 2010

Phase II

• Decitabine (Dacogen) 20 mg/m2 IV over 1 hour once per day on days 1 to 10

Supportive medications:

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

28-day cycles, with additional therapy depending on response:

1. Patients with persistent AML (≥5% blasts) received repeated cycles with 10 days of decitabine as described above.
2. Patients with no morphologic evidence of AML (<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

Decitabine & Valproate

Regimen, Garcia-Manero et al. 2006

Phase II

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

28-day cycles x 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

IAP

IAP: Idarubicin, Ara-C, Pravastatin

Regimen, Advani et al. 2013 (SWOG S0919)

Phase II

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

Patients achieving a CR could receive 2 cycles of consolidation

References

1. Anjali S. Advani, Shannon McDonough, Edward Copelan, Cheryl L. Willman, Deborah A. Mulford, Alan F. List, Mikkael A. Sekeres, Megan Othus, Harry P. Erba, Frederick R. Appelbaum. SWOG S0919: A phase II study of idarubicin and cytarabine in combination with pravastatin for relapsed acute myeloid leukemia (AML). J Clin Oncol 31, 2013 (suppl; abstr 7028). link to original article contains verified protocol

Consolidation therapy

Clofarabine, Idarubicin, and Cytarabine (CIA) Consolidation

Regimen, Nazha et al.2013

Phase II

To be preceded by Clofarabine, Idarubicin, and Cytarabine (CIA) Induction

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

3-day cycle; 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

Cytarabine & Daunorubicin

Regimen, Gardin et al. 2007 (ALFA 9803)

Phase III

Ambulatory regimen

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

1-month cycles x 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

Regimen, Ravandi et al. 2010

Phase II

Preceded by Cytarabine, Idarubicin, Sorafenib induction therapy. Regimen details are from the phase II part of the published trial.

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

4 to 6-week cycles x up to 5 cycles, followed by Sorafenib maintenance therapy

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

Cytarabine, Idarubicin, Vorinostat

Regimen, Garcia-Manero et al. 2012

Phase II

Preceded by Cytarabine, Idarubicin, Vorinostat induction therapy.

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

Supportive medications:

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

6-day course x 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

HiDAC/HDAC

HiDAC: High Dose Ara-C

Regimen

Phase III

• Cytarabine (Cytosar) 2000 to 3000 mg/m2 IV over 3 hours Q12H on days 1, 3, 5 (6 total doses)

28-day (minimum) cycles or 1 week after marrow recovery, whichever comes later, x up to 4 cycles

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. 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

MiDAC/MDAC

MiDAC: Mid Dose Ara-C

Regimen

Phase III

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

subsequent cycles started after marrow recovery

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

Maintenance therapy

Azacitidine (Vidaza)

Regimen, Grövdal et al. 2010

Phase II

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

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

28-day cycles

References

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

Decitabine (Dacogen)

Preceded by decitabine monotherapy induction.

Regimen, Blum et al. 2010

Phase II

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

• 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 <500/uL) persisting ≥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

LoDAC: Low Dose Ara-C (cytarabine)

Regimen

Phase III

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

2-month cycles, continue until relapse

References

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

Sorafenib (Nexavar)

Regimen, Ravandi et al. 2010

Phase II

Preceded by Cytarabine, Idarubicin, Sorafenib consolidation therapy. Regimen details are from the phase II part of the published trial.

• Sorafenib (Nexavar) 400 mg PO BID

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

References

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

Vorinostat (Zolinza)

Regimen, Garcia-Manero et al. 2012

Phase II

Preceded by Cytarabine, Idarubicin, Vorinostat consolidation therapy.

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

28-day cycles x 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

ADE

ADE: Ara-C, Daunorubicin, Etoposide

Regimen, Milligan et al. 2006 (MRC AML-HR)

Phase III

Course 1

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

Course 2

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

References

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

Azacitidine (Vidaza)

Regimen, Thepot et al. 2010

Phase II

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

28-day cycles x 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

Regimen

Phase II

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

• Azacitidine (Vidaza) 75 mg/m2 SC or IV once per day on days 1 to 7
• Sorafenib (Nexavar) 400 mg PO BID

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)

Regimen, Santana et al. 1992

Phase II

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

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

CLAG: CLadribine, Ara-C, G-CSF

Regimen

Phase II

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

References

1. Robak T, Wrzesien'-Kus' A, Lech-Maran'da E, Kowal M, Dmoszyn'ska A. Combination regimen of cladribine (2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma. 2000 Sep;39(1-2):121-9. link to original article contains verified protocol PubMed
2. Retrospective: Martin MG, Welch JS, Augustin K, Hladnik L, DiPersio JF, Abboud CN. Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma. 2009 Aug;9(4):298-301. PubMed

CLAG-M, CLAM

CLAG-M: CLadribine, Ara-C, G-CSF, Mitoxantrone

Regimen

Phase II

• Cladribine (Leustatin) 5 mg/m2 IV over 2 hours once per day on days 1 to 5, given first
• Cytarabine (Cytosar) 2000 mg/m2 IV over 4 hours once per day on days 1 to 5, given second, 2 hours after Cladribine (Leustatin)
• Filgrastim (Neupogen) 300 mcg SC once per day on days -1 to 5; first dose is given 24 hours before first dose of Cladribine (Leustatin)
• Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 to 3

References

1. Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Hołowiecki J, Kyrcz-Krzemień S, Grosicki S, Giebel S, Skotnicki AB, Piatkowska-Jakubas B, Kuliczkowski K, Kiełbiński M, Zawilska K, Kłoczko J, Wrzesień-Kuś A; Polish Adult Leukemia Group. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008 Feb;80(2):115-26. Epub 2007 Dec 11. link to original article 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 & Cytarabine

Regimen #1, Agura, et al., 2011

Phase II

• 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:

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

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

Regimen #2, Faderl, et al., 2012 (CLASSIC I)

Phase III

• 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."

References

1. 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
2. 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

Cytarabine (Cytosar)

Regimen, Faderl, et al., 2012 (CLASSIC I)

Phase III

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

Supportive medications:

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

1 to 3 cycles; 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."

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

Cytarabine & Mitoxantrone

Regimen, Sternberg et al. 2000

Phase II

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

References

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

Decitabine (Dacogen)

Regimen, Kantarjian et al. 2012

Phase III

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

Supportive medications:

• Hydroxyurea (Hydrea) could be used up until cycle 1 day 15.

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

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

Etoposide & Mitoxantrone

Regimen, Ho et al. 1988

Phase II

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

References

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

FLAG

FLAG: FLudarabine, Ara-C, G-CSF

Regimen, Montillo et al. 1998

Phase II

• Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days 1 to 5, given first
• Cytarabine (Cytosar) 2000 mg/m2 IV over 4 hours once per day on days 1 to 5, given second, 4 hours after the start of Fludarabine (Fludara)
• Filgrastim (Neupogen) or Lenograstim (Granocyte) 5 mcg/kg SC once per day starting on day -1 (the paper described this as "day 0"), first dose given 24 hours before first dose of chemotherapy, to continue until neutrophil recovery

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

FLAG-IDA: FLudarabine, Ara-C, G-CSF, IDArubicin

Regimen

Phase II

• Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days 1 to 5, given first
• Cytarabine (Cytosar) 2000 mg/m2 IV over 4 hours once per day on days 1 to 5, given second, 4 hours after Fludarabine (Fludara)
• Filgrastim (Neupogen) 5 mcg/kg SC once per day starting on day 6, to continue until neutrophil recovery
• Idarubicin (Idamycin) 10 mg/m2 IV once per day on days 1 to 3

References

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

MEC

MEC: Mitoxantrone, Etoposide, Cytarabine

Regimen #1, Amadori et al. 1991

Phase II

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

Regimen #2, Kohrt et al. 2010

Retrospective

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

References

1. Amadori S, Arcese W, Isacchi G, Meloni G, Petti MC, Monarca B, Testi AM, Mandelli F. Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol. 1991 Jul;9(7):1210-4. link to original article PubMed
2. 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