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Genetic correlates in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with Hyper-CVAD plus dasatinib or ponatinib

ABSTRACT: Genetic correlates in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with Hyper-CVAD plus dasatinib or ponatinib

PROVIDER: PRJNA786932 | ENA |

REPOSITORIES: ENA

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Genetic correlates in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with Hyper-CVAD plus dasatinib or ponatinib

Project description:Recurring genetic abnormalities have been identified in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Among them, IKZF1 deletion was associated with poor prognosis in patients treated with imatinib-based or dasatinib-based regimens. However, the molecular determinants for clinical outcomes in ponatinib-treated patients remain unknown. We systematically analyzed genetic alterations in adults with Ph-positive ALL uniformly treated in clinical trials with dasatinib-based regimens or a ponatinib-based regimen and investigated the molecular determinants for treatment outcomes using pretreatment specimens collected from adults with Ph-positive ALL treated with Hyper-CVAD plus dasatinib or ponatinib. DNA sequencing and SNP microarray were performed and recurrent genetic abnormalities were found in 84% of the patients, among whom IKZF1 deletion was most frequently detected (60%). IKZF1 deletion frequently co-occurred with other copy-number abnormalities (IKZF1plus, 46%) and was significantly associated with unfavorable overall survival (OS) (false discovery rate < 0.1) and increased cumulative incidence of relapse (p = 0.01). In a multivariate analysis, dasatinib therapy, lack of achievement of 3-month complete molecular response, and the presence of IKZF1plus status were significantly associated with poor OS. The differential impact of IKZF1plus was largely restricted to patients given Hyper-CVAD plus ponatinib; dasatinib-based regimens had unfavorable outcomes regardless of the molecular abnormalities.

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Dasatinib Resistant K562 cell lines

Project description:A project to explore the acquisition of drug resistance mechanisms in a K562 erythroblastic leukemia cell line, with induced resistance to the tyrosine kinase inhibitor, dasatinib.

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