Combination Treatment of TKIs Plus Azacitidine Yields Efficacy, Safety in CML

Findings from a prospective clinical study show that the combination treatment of a third-generation tyrosine kinase inhibitor (3G-TKI; ponatinib [Iclusig] or olverembatinib) with azacitidine is efficacious and well-tolerated in patients with chronic myeloid leukemia (CML). The trial is registered in the Chinese Clinical Trial Registry (ChiCTR2200055887).¹

In terms of efficacy, the combination therapy demonstrated significant clinical activity, effectively reducing disease burden and enabling a return to a more manageable disease state for most patients. After 1 cycle of treatment, 62% (n = 37) of patients achieved a major hematologic response (MaHR). By 2 cycles, 68% of patients (n = 25/37) achieved MaHR. After 1 cycle, 81% of patients returned to chronic phase (CP), and after 2 cycles 81% of patients (n = 30/37) returned to CP. During treatment, 35% of patients achieved a major cytogenetic response, and 16% achieved a major molecular response.

The median progression-free survival (PFS) of the total patient population was 5 months. Of the patients who achieved MaHR, the median PFS was 7 months. Of patients who did not achieve MaHR, median PFS was 2 months.

Ten patients who responded to therapy proceeded to transplantation. This group had significantly better PFS (P = .04) and overall survival (OS) (P =.01) compared to those who did not undergo transplantation. At the last follow-up, 5 transplant recipients were alive with undetectable disease. Of these patients (n = 10), median PFS was 11 months vs 4 months in patients who did not proceed to transplantation. The 3-year PFS of the total patients was 19%. Across the 4 groups of patients, the 3-year PFS was 29% vs 0% vs 40% vs 11%.

The median survival of the total patient population was 9 months. Across the 4 patient groups, the median survival was 13 months vs 7 months vs 16 months vs 8 months. The 3-year survival of the total patient population was 23%. Across the patient groups, the 3-year survival was 39% vs 0% vs 50% vs 18%.

Among the 10 patients who had previously failed 3G-TKI monotherapy, 80% responded to the combination therapy with azacitidine.

Safety Findings

The most common any-grade hematologic adverse events (AEs) were thrombocytopenia (86%), neutropenia (76%), and anemia (70%). The most common any-grade nonhematologic AEs were febrile neutropenia (57%), pulmonary infection (35%), hypocalcemia (32%), and fatigue (22%).

In terms of serious AEs, 1 patient died on day 31 of treatment from heart failure. Five patients (14%) died due to grade 5 AEs, including pulmonary infection (n = 3), abdominal infection (n = 1), and heart failure (n = 1).

Patient Characteristics

The study enrolled 37 heavily pretreated patients between July 2021 and July 2023. The median follow-up period for surviving patients was 30 months.

The median age of patients was 50 years (range, 33–54). Over half of patients were male (54%). Of the total patients, 78% transformed from CP and 54% received ≥ 3 prior TKIs. As for prior 3G-TKI exposure, 27% of patients had failed monotherapy with ponatinib, olverembatinib, and/or TGRX-678. In the study, 43% (n = 16) of patients received ponatinib and 57% (n = 21) received olverembatinib.

ABL1 mutations were detected in 49% of patients (n = 18/37), with T315I (27%) and E255K (22%) being the most frequent.

Non-ABL1 somatic mutations were detected in 89% of patients (n = 33/37). The most common were ASXL1 (30%), GATA2 (27%), RUNX1 (24%), and KRAS (16%). Of the total patients, additional cytogenetic abnormalities (ACAs) were present in 78% of patients (n = 29/37), with the majority classified as high-risk. The most frequent high-risk ACAs included complex aberrant karyotype (32%), trisomy 8 (30%), and a second Philadelphia chromosome (30%).

The presence of KRAS or PTPN11 mutations at baseline was significantly associated with lower response rates, worse PFS, and worse OS.

Transcriptomic analysis revealed that activation of the KRAS signaling pathway was significantly correlated with the eventual loss of MaHR in responding patients, providing a molecular rationale for treatment failure.

The results highlight the need for larger, prospective studies to validate these biomarkers and to explore novel therapeutic strategies that target the KRAS signaling pathway in CML blast phase.

“In conclusion, we observed that 3G-TKI with azacitidine is an effective and safe therapy for patients who have CML in myeloid blast phase,” concluded Bao et al, authors of the study. “Moreover, both RAS pathway mutations and the marked activation are associated with worse outcomes, which may serve as potential biomarkers for risk stratification and the development of future targeted therapies. Prospective validation in larger cohorts with integrated genomic and transcriptomic profiling is warranted.”

REFERENCE

1.Bao M, Zhang XS, Li ZR, et al. Efficacy, safety and predictive biomarker of third‐generation tyrosine kinase inhibitors with azacitidine in myeloid blast phase of chronic myeloid leukemia. Cancer. 2025;131(22):e70166-e70166. doi:10.1002/cncr.70166