Dual targeting of BCR::ABL1 and DNA methylation in advanced CML: A 3-year survival analysis of TKI-Azacitidine combination therapy
Zhuming Yang, Danlei Han, Renying Ge, Zhenhao Wang, Hanlin Du, Yigang Guo, Zhe Zhao, Li Liu, Jun Qin, Bangwei Yu, Jie Hu, Xiya Gui, Meifang Su, Shiming Chen, Daozi Jiang, Jing Zheng, Hongxiang Wang, Li Meng, Weiming Li, Zhenya HongBackground
Advanced-phase chronic myeloid leukemia (CML) remains associated with poor outcomes despite advances in tyrosine kinase inhibitor (TKI) therapy, underscoring the need for more effective treatment approaches.
Objectives
This multicenter study evaluated the efficacy and safety of tyrosine kinase inhibitor (TKI) plus azacitidine (with optional low-dose chemotherapy) in advanced-phase CML.
Design
Prospective multicenter single-arm study.
Methods
41 patients with accelerated- (AP) or blast-phase (BP) CML received azacitidine 75 mg/m 2 /day for 7 days per 28-day cycle (6 cycles) plus TKIs selected by ABL1 mutation status; chemotherapy was added based on early response. Major hematologic response (MaHR) was the primary endpoint. The secondary endpoints included cytogenetic/molecular responses—major cytogenetic response (MCyR), major molecular response (MMR), and undetectable minimal disease (UMD) — along with progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were documented.
Results
Among 36 evaluable patients (median age 51 years; range: 24-77; AP: 13, BP: 23) after excluding 5 noncompliant patients, 63.9% achieved MaHR, with a median response time of 1.33 months. The cumulative 3-year response rates were as follows: MCyR, 48.5%; MR2.0 (BCR::ABL1 IS ≤1%), 16.3%; MMR, 21.8%; and UMD, 14.2%. Patients maintained sustainable responses during follow-up. Four hematopoietic stem cell transplantation (HSCT) recipients maintained durable remission with TKI consolidation. At 28.1-month median follow-up, median OS was not reached and median PFS was 8.17 months; estimated 3-year OS and PFS rates were 50.3% and 41.1%, respectively. Elevated baseline WBC count and BCR::ABL1 transcript levels predicted poor survival. Hematologic toxicities of grade 3 or higher occurred in 55.6% of patients, including neutropenia (36.1%), thrombocytopenia (33.3%).
Conclusion
TKI–azacitidine therapy demonstrated promising efficacy and acceptable tolerability in patients with advanced-phase CML and may represent a feasible treatment option for this high-risk population.