Dual targeting of BCR::ABL1 and DNA methylation in advanced CML: A 3-year survival analysis of TKI-Azacitidine combination therapy.

BACKGROUND: 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/m2/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.