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Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib.

Stein, Eytan M; DiNardo, Courtney D; Fathi, Amir T; Pollyea, Daniel A; Stone, Richard M; Altman, Jessica K; Roboz, Gail J; Patel, Manish R; Collins, Robert; Flinn, Ian W; Sekeres, Mikkael A; Stein, Anthony S; Kantarjian, Hagop M; Levine, Ross L; Vyas, Paresh; MacBeth, Kyle J; Tosolini, Alessandra; VanOostendorp, Jason; Xu, Qiang; Gupta, Ira; Lila, Thomas; Risueno, Alberto; Yen, Katharine E; Wu, Bin; Attar, Eyal C; Tallman, Martin S; de Botton, Stéphane.
Blood; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510081
Approximately 8-19% of patients with acute myeloid leukemia (AML) have isocitrate dehydrogenase-2 (IDH2) mutations, which occur at active site arginine residues, R140 and R172. IDH2 mutations produce an oncometabolite, 2-hydroxyglutarate (2-HG), that leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase I/II study evaluated enasidenib doses of 50-650 mg/day, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies (, NCT01915498). Overall, 214/345 patients (62%) with relapsed/refractory AML received enasidenib 100 mg/day. Median age was 68 years. Forty-two patients (19.6%) attained complete remission (CR), 19 patients (10.3%) proceeded to an allogeneic bone marrow transplant, and overall response rate was 38.8% (95%CI 32.2-45.7). Median overall survival was 8.8 months (95%CI 7.7-9.6). Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Response rates were similar among patients who, at study entry, were in relapse (37.7%), or were refractory to intensive (37.5%) or non-intensive (43.2%) therapies. Sixty-six RBC transfusion-dependent (43.1%) and 53 platelet transfusion-dependent (40.2%) patients achieved transfusion independence. The magnitude of 2-HG reduction on-study was associated with CR in IDH2-R172 patients. Clearance of mutant-IDH2 clones was also associated with achievement of CR. Among all 345 patients, the most common grade 3-4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation syndrome (6%). Enasidenib was well-tolerated and induced molecular remissions and hematologic responses in patients with AML for whom prior treatments had failed. The study is registered to as NCT01915498.
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