High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses

Abstract

Preliminary evidence suggests that the multikinase inhibitor sorafenib has clinical activity in FLT3-ITD-positive (FLT3-ITD) acute myeloid leukemia (AML). However, the quality and sustainability of achievable remissions and clinical variables that influence the outcome of sorafenib monotherapy are largely undefined. To address these questions, we evaluated sorafenib monotherapy in 65 FLT3-ITD AML patients treated at 23 centers. All but two patients had relapsed or were chemotherapy-refractory after a median of three prior chemotherapy cycles. Twenty-nine patients (45%) had undergone prior allogeneic stem cell transplantation (allo-SCT). The documented best responses were: hematological remission in 24 patients (37%), bone marrow remission in 5 patients (8%), complete remission (with and without normalization of peripheral blood counts) in 15 patients (23%) and molecular remission with undetectable FLT3-ITD mRNA in 10 patients (15%), respectively. Seventeen of the patients without prior allo-SCT (47%) developed sorafenib resistance after a median treatment duration of 136 days (range, 56-270 days). In contrast, allo-SCT patients developed sorafenib resistance less frequently (38%) and significantly later (197 days, range 38-225 days; P ¼ 0.03). Sustained remissions were seen exclusively in the allo-SCT cohort. Thus, sorafenib monotherapy has significant activity in FLT3-ITD AML and may synergize with allogeneic immune effects to induce durable remissions.

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

“…For this reasons, TKI with FLT3-inhibiting activity have also been tested after allo-SCT. 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.…”

Successful treatment of post-transplant relapsed acute myeloid leukemia with FLT3 internal tandem duplication using the combination of induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Report of three cases

“…(5,6,9) In the context of AML with FLT3-ITD, the use of sorafenib, a multi-kinase inhibitor with activity against mutant FLT3, has also been explored to treat post-transplantation relapse with conflicting results. (7,8) This case report describes the outcome of three patients who achieved disease control after treatment of AML with FLT3-ITD post-transplantation relapse with the combination of chemotherapy, DLI, azacitidine and sorafenib. All three patients developed GVHD during treatment.…”

“…This led to the hypothesis that the efficacy of sorafenib may depend on a synergism with allo-immune effects. (7) Finally, in some series, the use of sorafenib was associated with the development or worsening of GVHD, (11,12) suggesting the mechanism of action of sorafenib in inducing AML remissions may include direct effects in the leukemic blasts, as well as an immune-mediated effect.…”

“…Molecular studies confirmed the presence of NPM1 mutation and a newly acquired FLT3-ITD mutation. The patient was salvaged with high dose cytarabine followed by DLI (CD3: 4.2x10 7 /kg) and sorafenib at 200mg twice daily.…”

“…(5) In addition, the use of azacitidine alone or in combination with DLI is associated with only 14% 1-year overall survival. (6) Patients harboring FLT3-ITD mutations relapsing after HSCT can occasionally achieve sustained remissions with use of sorafenib, a tyrosine-kinase inhibitor, as monotherapy, (7) but other investigators have reported sorafenib is not effective in this setting. (8) We herein describe the outcomes of three patients with FLT3-ITD positive AML who relapsed after allogeneic HSCT, and were treated with the combination of re-induction chemotherapy, DLI, sorafenib and azacitidine.…”