Phase II 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 and Mark Levis

Key points

  • Azacytidine together with sorafenib are effective in patients with relapsed and refractory FLT3 mutated AML


We examined the efficacy of combining sorafenib and 5-azacytidine (AZA) in patients with AML and the FLT3-ITD mutation. Patients received AZA 75 mg/m2 IV daily for 7 days and sorafenib 400 mg PO twice daily continuously; cycles were repeated at approximately one month intervals. Forty-three AML patients with a median age of 64 years (range, 24-87) were enrolled; 37 were evaluable for response. The FLT-3-ITD mutation was detected in 40 (93%) patients with a median allelic ratio of 0.28 (range, 0 - 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%) CRi, 6 (16%) CR, and 1 (3%) PR. 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). 64% 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. FL 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 relapsed AML and the FLT-3-ITD mutation. (The study was registered on as NCT01254890.)

  • Submitted January 25, 2013.
  • Accepted April 8, 2013.