Abstract
OBJECTIVE: To evaluate the efficacy, safety, and predictive biomarker of a third-generation tyrosine kinase inhibitor (3G-TKI; ponatinib or olverembatinib) combined with azacitidine in chronic myeloid leukemia (CML) in myeloid blast phase. METHODS: We conducted a single-center, prospective study combining 3G-TKI with azacitidine in 28-day cycles. The primary end point was a major hematologic response (MaHR) by cycle 2. The trial is registered in Chinese Clinical Trial Registry (ChiCTR2200055887) RESULTS: In total, 37 patients were studied. The median follow-up was 30 months (interquartile range, 24-40 months). Twenty-five patients achieved a MaHR by cycle 2, 30 returned to chronic phase. Ten patients underwent transplantation. The patients who underwent transplantation had higher 3-year probability of survival compared with nontransplanted patients (50%; [95% confidence interval (CI), 9%-37%] versus 18% [95% CI, 3%-33%]; p = .01). The regimen was well tolerated. In adjusted logistic/Cox regression analyses, KRAS mutation was significantly associated with a lower MaHR rate (odds ratio, 0.1; 95% CI, 0-0.8; p = .03), worse progression-free survival (PFS; hazard ratio [HR], 3.1; 95% CI, 1.1-8.6; p = .04), and worse survival (HR, 8.2; 95% CI, 2.5-26.8; p < .001); PTPN11 mutation was associated with worse PFS (HR, 5.1; 95% CI, 1.2-22.2; p = 0.03) and worse survival (HR, 9.6; 95% CI, 2.2-41.5; p = .002); and increasing numbers of non-ABL1 mutations were associated with worse PFS (HR, 1.2; 95% CI, 1.0-1.3; p = .04). Transcriptomic analysis revealed that patients who did not achieve a MaHR experienced activation of cancer-, metabolism-, oxidative phosphorylation-related pathways. The KRAS signaling pathway was significantly activated in patients who lost MaHR during treatment. CONCLUSIONS: 3G-TKI with azacitidine is an effective and safe therapy providing more chance to receive a transplantation for CML in myeloid blast phase. Potential biomarkers associated with outcomes were identified.