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Combination Therapy Under Study in Resistant FLT3-ITD–Mutated AML

By: Cordi Craig
Posted: Wednesday, October 7, 2020

Previous studies have found that some patients with FLT3-ITD–mutated acute myeloid leukemia (AML) may develop resistance to therapy caused by stroma-leukemia interactions that are mediated by adhesion molecules such as CXCR4, CD44, and VLA4, and their respective ligands. A recent report, by Michael Andreeff, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues, suggested that treatment strategies combining the inhibition of FLT3 kinase and stromal adhesive interactions may benefit this patient population. The findings were published in the American Journal of Hematology.

The phase I study included 28 patients with relapsed or refractory FLT3-ITD–mutated AML. Between December 2010 and December 2013, patients received the tyrosine kinase inhibitor sorafenib, granulocyte colony-stimulating factor, and the immunostimulant plerixafor.

Among the intention-to-treat population, the response rate was 36%. Of those patients, four achieved complete responses, four achieved complete responses with incomplete platelet recovery, and a single patient achieved complete remission with incomplete hematologic recovery. A single patient also achieved a partial response. Although toxicities were not observed within the 4-week dose-limiting toxicity window, most patients did require dose reductions due to hand-foot syndrome and rashes that developed beyond the dose-limiting window.

The study authors observed a negative correlation between the expression of CXCR4, CD44, and VLA4 with the mobilization of “progenitor” cells (CD34+/38–, CD34+/38–/123+; P ≤ .002). In two patient samples, a mass cytometry analysis demonstrated an early emergence of resistance from subclones with persistent AKT and/or ERK pathway signaling.

“Our data provide a rationale for combined inhibition of FLT3-ITD and stroma-mediated signaling that can potentially be added to chemotherapeutic or epigenetic agents in the front-line setting,” the researchers concluded.

Disclosure: The study authors reported no conflicts of interest.



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