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Clinical Trial
. 2010 Apr 10;28(11):1856-62.
doi: 10.1200/JCO.2009.25.4888. Epub 2010 Mar 8.

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

Farhad Ravandi  1 , 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
Affiliations
Clinical Trial

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

Farhad Ravandi et al. J Clin Oncol. .

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/m(2) by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m(2) 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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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
(A) Survival for patients treated with idarubicin and cytarabine plus sorafenib (IA + S) and a historical IA alone, (B) progression-free survival for the patients treated with IA + S, (C) progression-free survival for FMS-like tyrosine kinase-3–mutated (FLT3+) patients treated with IA + S, and (D) duration of complete remission for FLT3+ patients treated with IA + S.
Fig 2.
Fig 2.
Plasma samples from patients were incubated with TF-ITD cells (upper blots) and SEMK2 FLT3 wild type (FLT3-WT) cells (lower blots). The cells were then lysed and FLT3 was immunoprecipitated and subject to sodium dodecyl sulfate polyacrylamide gel electrophoresis. After transfer, the membranes were probed with antiphosphotyrosine (upper rows of each blot). The membranes were stripped and reprobed with anti-FLT3 to confirm equal loading (lower rows). The percent baseline refers to the densitometric measurement of the day 7 (D7) sample compared with the D1 sample for each patient. P-FLT3, phospho-FLT3.
Fig 3.
Fig 3.
Effect of (A) sorafenib, (B) PKC412 (midostaurin), and (C) CEP-701 (lestaurtinib) on FMS-like tyrosine kinase-3 (FLT3) phosphorylation in TF-ITD cells (upper blots) and SEMK2 FLT3 wild type (FLT3-WT) cells (middle blots) in culture media (upper two blots) and plasma (lower blots).
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