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

• Published in: Leukemia Vol. 36; no. 5; pp. 1253 - 1260
• Main Authors: Sasaki, Yuya, Kantarjian, Hagop M., Short, Nicholas J., Wang, Feng, Furudate, Ken, Uryu, Hidetaka, Garris, Rebecca, Jain, Nitin, Sasaki, Koji, Ravandi, Farhad, Konopleva, Marina, Garcia-Manero, Guillermo, Little, Latasha, Gumbs, Curtis, Zhao, Li, Futreal, P. Andrew, Takahashi, Koichi, Jabbour, Elias
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2022; Nature Publishing Group
• Subjects: 45/23; 45/43; 631/208/2489/68; 631/67/69; 692/308/2056; Abnormalities; Acute Disease; Acute lymphoblastic leukemia; Adult; Adults; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Cancer Research; Chromosome deletion; Chromosomes; Clinical trials; Critical Care Medicine; Dasatinib - therapeutic use; Dexamethasone; DNA microarrays; DNA sequencing; Gene deletion; Genetic abnormalities; Hematology; Humans; Imatinib; Imidazoles; Inhibitor drugs; Intensive; Internal Medicine; Leukemia; Lymphatic leukemia; Medical prognosis; Medicine; Medicine & Public Health; Multivariate analysis; Oncology; Patients; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Pyridazines; Recurrence; Single-nucleotide polymorphism; Targeted cancer therapy
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-021-01496-8

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.