Rabbit Anti-Human FLT3 Polyclonal antibody

Midostaurin is an FMS-like tyrosine kinase 3 receptor (FLT3) inhibitor that provides renewed hope for treating acute myeloid leukaemia (AML). The limited efficacy of this compound as a monotherapy contrasts with that of its synergistic combination with standard cytarabine and daunorubicin (Dau), suggesting a therapeutic benefit that is not driven only by FLT3 inhibition. In an AML context, the activity of the enzyme aldo-keto reductase 1C3 (AKR1C3) is a crucial factor in chemotherapy resistance, as it mediates the intracellular transformation of anthracyclines to less active hydroxy metabolites. Here, we report that midostaurin is a potent inhibitor of Dau inactivation mediated by AKR1C3 in both its recombinant form as well as during its overexpression in a transfected cell model. Likewise, in the FLT3(-)AML cell line KG1a, midostaurin was able to increase the cellular accumulation of Dau and significantly decrease its metabolism by AKR1C3 simultaneously. The combination of those mechanisms increased the nuclear localization of Dau, thus synergizing its cytotoxic effects on KG1a cells. Our results provide new in vitro evidence of how the therapeutic activity of midostaurin could operate beyond targeting the FLT3 receptor.

Venetoclax and hypomethylating agent (HMA) combination therapy is FDA-approved for elderly or unfit acute myeloid leukemia (AML) patients unable to withstand intensive chemotherapy. The primary objective of the current study was to impart our institutional experience with the above regimen, outlining response, survival outcomes, and its determinants amongst 86 treatment- naive and relapsed/refractory AML patients. A total of 44 treatment-naive AML patients, median age 73.5 years, enriched with secondary, therapy related and ELN adverse risk disease (n = 27) were studied. The CR/CRi rates of 50% (22 of 44 patients) were superior to 23% in a matched AML cohort treated with HMA alone (P= .005). Response rates were similar withTP53,FLT3,NPM1andIDHmutations (P= .31). Moreover,CEPBAmutations (P= .03) and neutropenia (P= .05) emerged as predictors of complete response. Survivalwas prolonged in patients achieving CR/CRi (17 vs 3 months without CR/CRi,P < .001; conversely adverse ELN risk portended inferior survival. Amongst 42 relapsed/refractory AML patients, half received >= 2 prior therapies excluding transplant, and 15 (35.7%) had received HMA. A group of 14 patients (33.3%) attained CR/CRi; age > 65 years, AML with myelodysplasia,JAK2,DNMT3A, andBCORmutations predicted complete response. Survival distinctions were based on CR/CRi (median survival 15 vs 3 months with/without CR/CRi;P < .001), andTP53mutation status (P= .04). In summary, we corroborate existing reports demonstrating superior response and prolonged survival with venetoclax and HMA in treatment -naive and relapsed/refractory AML patients regardless of genotype. Additionally, we identify unique predictors of response to therapy which require validation.