Cytogenetic and Molecular Associations with Outcomes in Higher-Risk Myelodysplastic Syndromes Treated with Hypomethylating Agents plus Venetoclax

Authors

Alexandre Bazinet
Sai Prasad Desikan
Ziyi Li
Juan Jose Rodriguez-Sevilla
Sangeetha Venugopal
Samuel Urrutia
Guillermo Montalban-Bravo
Koji Sasaki
Kelly S Chien
Danielle Hammond
Rashmi Kanagal-Shamanna
Irene Ganan-Gomez
Tapan M Kadia
Gautam Borthakur
Courtney D DiNardo
Naval G Daver
Elias J Jabbour
Farhad Ravandi
Hagop Kantarjian
Guillermo Garcia-Manero

Publication Date

4-1-2024

Journal

Clinical Cancer Research

Abstract

Purpose: Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood.

Experimental design: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes.

Results: A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. In addition, 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes.

Conclusions: Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax.

Keywords

Humans, Myelodysplastic Syndromes, Prospective Studies, DNA Methylation, Cytogenetic Analysis, Retrospective Studies, Sulfonamides, Bridged Bicyclo Compounds, Heterocyclic

DOI

10.1158/1078-0432.CCR-23-2860

PMID

38300723

PMCID

PMC11815990

PubMedCentral® Posted Date

2-12-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes