Receptor kinase profiles identify a rationale for multitarget kinase inhibition in immature T-ALL.

International audienceConstitutively activated FLT3 signaling is common in acute myeloid leukemia, and is currently under evaluation for targeted therapy, whereas little data is available in T-cell acute lymphoblastic leukemia (T-ALL). We analyzed 357 T-ALL cases for FLT3 mutations and transcript expression. FLT3 mutations (3% overall) and overexpression (FLT3 high expresser (FLT3(High))) were restricted to imnnature/TCR gamma delta T-ALLs. In vitro FLT3 inhibition induced apoptosis in only 30% of FLT3(High) T-ALLs and did not correlate with mutational status. In order to investigate the mechanisms of primary resistance to FLT3 inhibition, a broad quantitative screen for receptor kinome transcript deregulation was performed by Taqman Low Density Array. FLT3 deregulation was associated with overexpression of a network of receptor kinases (RKs), potentially responsible for redundancies and sporadic response to specific FLT3 inhibition. In keeping with this resistance to FLT3 inhibition could be reversed by dual inhibition of FLT3 and KIT with a synergistic effect. We conclude that immature T-ALL may benefit from multitargeted RK inhibition and that exploration of the receptor kinome defines a rational strategy for testing multitarget kinase inhibition in malignant disease

Clinical impact of NOTCHI and/or FBXW7 mutations, FLASH deletion and TCR status in pediatric T-cell lymphoblastic lymphoma.

International audienc

Extensive molecular mapping of TCR / - and TCR -involved chromosomal translocations reveals distinct mechanisms of oncogene activation in T-ALL

International audienceno abstrac

A randomized phase II trial of azacitidine +/- epoetin- in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents

The efficacy of azacitidine in patients with anemia and with lower-risk myelodysplastic syndromes, if relapsing after or resistant to erythropoietic stimulating agents, and the benefit of combining these agents to azacitidine in this setting are not well known. We prospectively compared the outcomes of patients, all of them having the characteristics of this subset of lower-risk myelodysplastic syndrome, if randomly treated with azacitidine alone or azacitidine combined with epoetin-β. High-resolution cytogenetics and gene mutation analysis were performed at entry. The primary study endpoint was the achievement of red blood cell transfusion independence after six cycles. Ninety-eight patients were randomised (49 in each arm). Median age was 72 years. In an intention to treat analysis, transfusion independence was obtained after 6 cycles in 16.3% versus 14.3% of patients in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=1.00). Overall erythroid response rate (minor and major responses according to IWG 2000 criteria) was 34.7% vs. 24.5% in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one “epigenetic mutation” and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352)