Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation

Farhad Ravandi, Mona Lisa Alattar, Michael R. Grunwald, Michelle A. Rudek, Trivikram Rajkhowa, Mary Ann Richie, Sherry Pierce, Naval Daver, Guillermo Garcia-Manero, Stefan Faderl, Aziz Nazha, Marina Konopleva, Gautam Borthakur, Jan Burger, Tapan Kadia, Sara Dellasala, Michael Andreeff, Jorge Cortes, Hagop Kantarjian, Mark Levis

Research output: Contribution to journalArticle

Abstract

Patients received 5-azacytidine (AZA) 75 mg/m2 intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ∼1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsedAMLand FLT-3-ITD. This trial was registered at clinicaltrials.gov as#NCT01254890. (Blood. 2013;121(23): 4655-4662).

Original languageEnglish (US)
Pages (from-to)4655-4662
Number of pages8
JournalBlood
Volume121
Issue number23
DOIs
StatePublished - Jun 6 2013
Externally publishedYes

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Azacitidine
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Mutation
Chemotherapy
Blood
Phosphotransferases
sorafenib
Ligands
Plasmas
Therapeutics
Recovery
Drug Therapy

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Ravandi, F., Alattar, M. L., Grunwald, M. R., Rudek, M. A., Rajkhowa, T., Richie, M. A., ... Levis, M. (2013). Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood, 121(23), 4655-4662. https://doi.org/10.1182/blood-2013-01-480228

Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. / Ravandi, Farhad; Alattar, Mona Lisa; Grunwald, Michael R.; Rudek, Michelle A.; Rajkhowa, Trivikram; Richie, Mary Ann; Pierce, Sherry; Daver, Naval; Garcia-Manero, Guillermo; Faderl, Stefan; Nazha, Aziz; Konopleva, Marina; Borthakur, Gautam; Burger, Jan; Kadia, Tapan; Dellasala, Sara; Andreeff, Michael; Cortes, Jorge; Kantarjian, Hagop; Levis, Mark.

In: Blood, Vol. 121, No. 23, 06.06.2013, p. 4655-4662.

Research output: Contribution to journalArticle

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 2013, 'Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation', Blood, vol. 121, no. 23, pp. 4655-4662. https://doi.org/10.1182/blood-2013-01-480228
Ravandi, Farhad ; Alattar, Mona Lisa ; Grunwald, Michael R. ; Rudek, Michelle A. ; Rajkhowa, Trivikram ; Richie, Mary Ann ; Pierce, Sherry ; Daver, Naval ; Garcia-Manero, Guillermo ; Faderl, Stefan ; Nazha, Aziz ; Konopleva, Marina ; Borthakur, Gautam ; Burger, Jan ; Kadia, Tapan ; Dellasala, Sara ; Andreeff, Michael ; Cortes, Jorge ; Kantarjian, Hagop ; Levis, Mark. / Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. In: Blood. 2013 ; Vol. 121, No. 23. pp. 4655-4662.
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T1 - Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation

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AU - Rudek, Michelle A.

AU - Rajkhowa, Trivikram

AU - Richie, Mary Ann

AU - Pierce, Sherry

AU - Daver, Naval

AU - Garcia-Manero, Guillermo

AU - Faderl, Stefan

AU - Nazha, Aziz

AU - Konopleva, Marina

AU - Borthakur, Gautam

AU - Burger, Jan

AU - Kadia, Tapan

AU - Dellasala, Sara

AU - Andreeff, Michael

AU - Cortes, Jorge

AU - Kantarjian, Hagop

AU - Levis, Mark

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N2 - Patients received 5-azacytidine (AZA) 75 mg/m2 intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ∼1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsedAMLand FLT-3-ITD. This trial was registered at clinicaltrials.gov as#NCT01254890. (Blood. 2013;121(23): 4655-4662).

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