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

Abstract

• Azacytidine and sorafenib are effective in patients with relapsed and refractory FLT3-mutated AML.Patients received 5-azacytidine (AZA) 75 mg/m 2 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 relapsed AML and FLT-3-ITD. This trial was registered at clinicaltrials.gov as #NCT01254890. (Blood. 2013;121(23): 4655-4662)

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…For example, therapy with Sorafenib, a multikinase inhibitor with activity against FLT3 kinase, has demonstrated antileukemic activity with or without DLI in this situation and can induce complete molecular remissions in some patients [72,73]. Given the promising results of a recent phase-II trial combining Sorafenib and Aza in relapsed or refractory FLT3-ITD-mutated AML [74], we tested this combination based on an individual decision in 8 patients with relapsed FLT3+ AML after transplant. Following this combination, 4 patients achieved a complete remission (50%) with two of them remaining in remission > 1 year now without any antileukemic treatment [75].…”

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

“…In contrast to the study among younger patients, the addition of sorafenib was associated with a trend for lower CR (48% versus 60%; p 5 0.12) and higher early mortality rates (17% versus 7%; p 5 0.052) [143]. The combination of sorafenib 400 mg daily plus azacitidine 75 mg/ m 2 IV daily for 5 days in 37 patients with refractory-relapsed FLT3-ITD AML resulted in a response rate of 46% [144].…”

The Impact of Molecular Genetic in Acute Myeloid Leukemias

“…Better results have been reported in a recent paper from the MD Andreson Cancer Center with the association of sorafenib and azacytidine in elderly relapsed or refractory patients [72]. The treatment resulted in 46% overall response rate (ORR) with 27% complete response (CR) with a median remission duration of 2.3 months (range,1-12.2 months), without increasing toxicities [72]. Notwithstanding, FLT3 inhibition remains an important therapeutic target that is the subject of ongoing studies.…”

“…Actually the levels of Flt3 ligand increases shortly after an intensive chemotherapy, leading to a competitive displacement of the inhibitor. Better results have been reported in a recent paper from the MD Andreson Cancer Center with the association of sorafenib and azacytidine in elderly relapsed or refractory patients [72]. The treatment resulted in 46% overall response rate (ORR) with 27% complete response (CR) with a median remission duration of 2.3 months (range,1-12.2 months), without increasing toxicities [72].…”