Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia

Farhad Ravandi, Jorge E. Cortes, Daniel Jones, Stefan Faderl, Guillermo Garcia-Manero, Marina Y. Konopleva, Susan O'Brien, Zeev Estrov, Gautam Borthakur, Deborah Thomas, Sherry R. Pierce, Mark Brandt, Anna Byrd, B. Nebiyou Bekele, Keith Pratz, Rajyalakshmi Luthra, Mark Levis, Michael Andreeff, Hagop M. Kantarjian

Research output: Contribution to journalArticle

Abstract

Purpose: To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. Patients and Methods; In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m2 IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. Results: Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. Conclusion: Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.

Original languageEnglish (US)
Pages (from-to)1856-1862
Number of pages7
JournalJournal of Clinical Oncology
Volume28
Issue number11
DOIs
StatePublished - Apr 10 2010
Externally publishedYes

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Idarubicin
Cytarabine
Acute Myeloid Leukemia
Therapeutics
sorafenib
Drug Therapy
Intravenous Infusions
Protein-Tyrosine Kinases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. / Ravandi, Farhad; Cortes, Jorge E.; Jones, Daniel; Faderl, Stefan; Garcia-Manero, Guillermo; Konopleva, Marina Y.; O'Brien, Susan; Estrov, Zeev; Borthakur, Gautam; Thomas, Deborah; Pierce, Sherry R.; Brandt, Mark; Byrd, Anna; Bekele, B. Nebiyou; Pratz, Keith; Luthra, Rajyalakshmi; Levis, Mark; Andreeff, Michael; Kantarjian, Hagop M.

In: Journal of Clinical Oncology, Vol. 28, No. 11, 10.04.2010, p. 1856-1862.

Research output: Contribution to journalArticle

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 2010, 'Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia', Journal of Clinical Oncology, vol. 28, no. 11, pp. 1856-1862. https://doi.org/10.1200/JCO.2009.25.4888
Ravandi, Farhad ; Cortes, Jorge E. ; Jones, Daniel ; Faderl, Stefan ; Garcia-Manero, Guillermo ; Konopleva, Marina Y. ; O'Brien, Susan ; Estrov, Zeev ; Borthakur, Gautam ; Thomas, Deborah ; Pierce, Sherry R. ; Brandt, Mark ; Byrd, Anna ; Bekele, B. Nebiyou ; Pratz, Keith ; Luthra, Rajyalakshmi ; Levis, Mark ; Andreeff, Michael ; Kantarjian, Hagop M. / Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 11. pp. 1856-1862.
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abstract = "Purpose: To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. Patients and Methods; In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m2 IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. Results: Overall, 38 (75{\%}) patients have achieved a complete remission (CR), including 14 (93{\%}) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66{\%}) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74{\%}. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. Conclusion: Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.",
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T1 - Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia

AU - Ravandi, Farhad

AU - Cortes, Jorge E.

AU - Jones, Daniel

AU - Faderl, Stefan

AU - Garcia-Manero, Guillermo

AU - Konopleva, Marina Y.

AU - O'Brien, Susan

AU - Estrov, Zeev

AU - Borthakur, Gautam

AU - Thomas, Deborah

AU - Pierce, Sherry R.

AU - Brandt, Mark

AU - Byrd, Anna

AU - Bekele, B. Nebiyou

AU - Pratz, Keith

AU - Luthra, Rajyalakshmi

AU - Levis, Mark

AU - Andreeff, Michael

AU - Kantarjian, Hagop M.

PY - 2010/4/10

Y1 - 2010/4/10

N2 - Purpose: To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. Patients and Methods; In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m2 IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. Results: Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. Conclusion: Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.

AB - Purpose: To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. Patients and Methods; In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m2 IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. Results: Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. Conclusion: Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.

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