Photo by Bill Branson
A 2-drug combination has shown promise for treating patients with FLT3-ITD acute myeloid leukemia (AML), according to research published in Science Translational Medicine.
Researchers found that omacetaxine mepesuccinate (formerly known as homoharringtonine) exhibits preferential antileukemic activity against FLT3-ITD AML.
Subsequent preclinical experiments revealed that omacetaxine synergizes with sorafenib and other FLT3 inhibitors.
So researchers tested omacetaxine in combination with sorafenib in a phase 2 trial of patients with FLT3-ITD AML.
The combination produced complete responses (CRs) or CRs with incomplete hematologic recovery (CRis) in a majority of patients, and researchers said the treatment was well-tolerated.
Anskar Y. H. Leung, MD, PhD, of The University of Hong Kong, and his colleagues conducted this research.
The team first performed an in vitro screen on AML patient samples to determine their responses to various drugs.
One of the compounds tested, the protein translation inhibitor omacetaxine mepesuccinate, showed strong antileukemic effects against FLT3-ITD AML. In fact, omacetaxine preferentially inhibited the growth of FLT3-ITD cell lines.
The researchers then found that omacetaxine synergizes with sorafenib and other FLT3 inhibitors to suppress leukemia growth in FLT3-ITD AML cell lines.
Omacetaxine and sorafenib in combination also prolonged survival in mouse models of FLT3-ITD AML (mice transplanted with MV4-11 or MOLM-13 cells).
Phase 2 trial
The researchers went on to test omacetaxine and sorafenib in a phase 2 trial. The trial enrolled 24 patients with FLT3-ITD AML and a median age of 50 (range, 21-76).
Most of the patients had relapsed or refractory disease, but 2 were unsuitable for induction chemotherapy because of advanced age and comorbidities.
The patients received omacetaxine and sorafenib continuously until intolerance, disease progression, or allogeneic hematopoietic stem cell transplant (HSCT).
Twenty patients (83.3%) achieved a CR or CRi at a median of 22 days (range, 18-55). Three patients did not respond, and 1 patient experienced a near-CRi—a reduction of blasts without complete clearance.
Fifteen of the responders relapsed, but 3 of these patients received omacetaxine and sorafenib again and achieved a CRi. One patient received re-treatment and failed to achieve a response.
Seven patients proceeded to HSCT after receiving omacetaxine and sorafenib.
At a median follow-up of 7.1 months (range, 2.2 to 20.5), 4 patients were still in CR/CRi (3 patients after HSCT), and 1 patient who had relapsed was still alive.
The remaining 19 patients had died—14 due to relapse, 4 due to non-response (1 after re-treatment), and 1 due to HSCT.
The median leukemia-free survival was 88 days (range, 9-510), and the median overall survival was 228 days (range, 53 to 615).
Adverse events occurring after treatment with omacetaxine and sorafenib included fever (n=14), rash (n=8), hand-foot-skin reactions (n=6), pneumonia (n=2), neutropenic fever (n=1), and bacteremia (n=1).
The researchers said this study validated the principle and clinical relevance of in vitro drug testing and identified a drug combination that might improve the treatment of FLT3-ITD AML.
