Efficacy, safety and predictive biomarker of third‐generation tyrosine kinase inhibitors with azacitidine in myeloid blast phase of chronic myeloid leukemia

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.