Genetic Correlates in Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated With Hyper-CVAD Plus Dasatinib or Ponatinib

Authors

Yuya Sasaki
Hagop M Kantarjian
Nicholas J Short
Feng Wang
Ken Furudate
Hidetaka Uryu
Rebecca Garris
Nitin Jain
Koji Sasaki
Farhad Ravandi
Marina Konopleva
Guillermo Garcia-Manero
Latasha Little
Curtis Gumbs
Li Zhao
P Andrew Futreal
Koichi Takahashi
Elias Jabbour

Publication Date

5-1-2022

Journal

Leukemia

Abstract

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.

Keywords

Acute Disease, Adult, Antineoplastic Combined Chemotherapy Protocols, Dasatinib, Dexamethasone, Humans, Imidazoles, Philadelphia Chromosome, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Pyridazines, Recurrence, Philadelphia-positive acute lymphoblastic leukemia, dasatinib, ponatinib, IKZF1

Comments

This article has been corrected. See Leukemia. 2022 Apr 11.

DOI

10.1038/s41375-021-01496-8

PMID

35132195

PMCID

PMC12001897

PubMedCentral® Posted Date

4-16-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes