Phase I study of sorafenib in patients with refractory or relapsed acute leukemias

Abstract

BackgroundSorafenib is a multi-kinase inhibitor with activity against fms-like tyrosine kinase 3 with internal tandem duplication mutation and Raf kinase among others. A phase I dose escalation study of sorafenib was conducted in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. Design and MethodsFifty patients received one of two different schedules; Schedule "A": once or twice daily, five days per week, every week for a 21 day cycle, and Schedule "B": once or twice daily, for 14 days every 21 days. Dose limiting toxicities were grade 3/4 hypertension, hyperbilirubinemia, and amylase elevation. The recommended phase II dose in hematologic malignancies is 400 mg twice daily for both schedules. ResultsComplete remissions or complete remissions with incomplete recovery of platelets were achieved in 5 (10%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Significant reduction in bone marrow and/or peripheral blood blasts was seen in an additional 17 (34%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Eleven of these responses (including 3 complete remissions/complete remissions with incomplete recovery) lasted for 2 cycles or beyond. In conclusion, sorafenib is active and well tolerated in acute myelogenous leukemia with fms-like tyrosine kinase 3 internal tandem duplication mutation. ConclusionsAdditional studies of sorafenib in patients with acute myelogenous leukemia, particularly those with fms-like tyrosine kinase 3 internal tandem duplication, are warranted, including sorafenibbased combinations. (ClinicalTrials.

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

“…Although sorafenib responses in FLT3-ITD AML patients are usually transient, 11,13,14,16 we and others have previously published several cases with relapsed FLT3-ITD AML who showed extended remissions under sorafenib monotherapy. 17,[18][19][20][21][22][23] This stimulated us to gain a better understanding of the value of sorafenib monotherapy in FLT3-ITD AML-in particular with respect to the circumstances where complete and long-lasting remissions may be obtained.…”

“…11 Three subsequent phase I studies underscored this evidence by demonstrating consistent activity of sorafenib in relapsed and refractory FLT3-ITD AML, while primary resistance was frequently seen in AML expressing the wild-type form of FLT3. [12][13][14] Thus, although sorafenib simultaneously blocks FLT3 and multiple other kinases, such as the serine threonine kinase Raf-1, plateletderived growth factor receptor and vascular endothelial growth factor receptor, 15 its most relevant target in AML appears to be FLT3-ITD.…”

Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

“…33 On the other hand, phase I/II studies using sorafenib in AML and myelodysplastic syndrome patients, showed promising results and targeted inhibition of both ERK phosphorylation, as well as FLT3 signaling. [34][35][36] A combined inhibitory effect on both RAS and FLT3 signaling may well be highly effective in the treatment of MLL-rearranged infant ALL as the majority of these patients are also characterized by constitutive FLT3 activation. 15 In conclusion, we demonstrate that RAS mutations frequently occur in MLL-rearranged infant ALL cases and especially in t(4;11)-positive infant ALL patients, and their presence represents an independent poor prognostic factor.…”

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

“…All patients with FLT3-ITD positive AML also receive sorafenib during induction and consolidation. Based on the positive experiences of combining FLT3 inhibitors with chemotherapy from pilot studies [90][91][92][93] and from the emerging German and Intergroup randomized trials (discussed later), this approach may soon become a standard of care, certainly in FLT3-ITD AML, but also perhaps in all patients with AML regardless of FLT3 status.…”