Genetic correlates in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with Hyper-CVAD plus dasatinib or ponatinib.
Kumiko ChinoHagop M KantarjianNicholas James ShortFeng WangKen FurudateHidetaka UryuRebecca GarrisNitin JainKoiji SasakiFarhad RavandiMarina Y KonoplevaGuillermo Garcia ManeroLatasha LittleCurtis GumbsLi ZhaoP Andrew FutrealKoichi TakahashiElias J JabbourPublished in: Leukemia (2022)
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 (IKZF1 plus , 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 IKZF1 plus status were significantly associated with poor OS. The differential impact of IKZF1 plus was largely restricted to patients given Hyper-CVAD plus ponatinib; dasatinib-based regimens had unfavorable outcomes regardless of the molecular abnormalities.
Keyphrases
- acute lymphoblastic leukemia
- chronic myeloid leukemia
- copy number
- newly diagnosed
- end stage renal disease
- poor prognosis
- genome wide
- allogeneic hematopoietic stem cell transplantation
- ejection fraction
- clinical trial
- peritoneal dialysis
- mitochondrial dna
- long non coding rna
- small molecule
- gene expression
- bone marrow
- type diabetes
- mesenchymal stem cells
- patient reported outcomes
- metabolic syndrome
- single cell
- phase iii
- open label
- high speed
- free survival