CML-081: Effect of Comorbidities on Response Outcomes with First-Line Tyrosine Kinase Inhibitors (TKIs), Dasatinib Versus Imatinib, in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Exploratory Post Hoc Analysis of DASISION

Abstract

Background: Five-year follow-up of the open-label, phase 3 DASISION study (NCT00481247) demonstrated faster and deeper molecular responses with dasatinib versus imatinib as first-line therapy for CML-CP. NCCN guidelines recommend considering comorbidities when selecting first-line TKI therapy. This exploratory post hoc analysis of DASISION investigates the effect of comorbidities on responses with dasatinib versus imatinib. Design: Patients with newly diagnosed CML-CP were randomized to 100mg dasatinib (n=259) or 400mg imatinib (n=260) QD. Charlson Comorbidity Index (CCI) was retrospectively calculated for each patient at diagnosis; data were retrospectively stratified by CCI categories (2-4, 5-6, and ≥7 [high burden]). Major molecular response (MMR) and MR4.5 were compared between treatments using unstratified Cochran-Mantel-Haenszel tests. Time to response was evaluated using Kaplan-Meier methodology with HRs based on Cox proportional hazards models and P-values from unstratified log-rank tests. Results: Baseline characteristics were mostly balanced between treatments. Fourteen (3%) patients had CCI 2-4, 260 (50%) had 5-6, and 245 (47%) had ≥7. Responses were numerically greater with dasatinib versus imatinib for CCI 2-4 (MMR: 85.7% versus 57.1%, P=0.2542; MR4.5: 71.4% versus 14.3%, P=0.0374) and ≥7 (MMR: 70.8% versus 64.0%, P=0.2552; MR4.5: 45.0% versus 39.2%, P=0.3589), and significantly higher for CCI 5-6 (MMR: 81.1% versus 64.8%, P=0.0033; MR4.5: 42.4% versus 29.7%, P=0.0329). Median time to MMR (months) was significantly shorter with dasatinib than imatinib for CCI 5-6 (15.0 versus 24.0; HR, 1.64; P=0.0006) and ≥7 (12.0 versus 21.4; HR, 1.41; P=0.0279). Grade 3/4 treatment-related adverse events (TRAEs; dasatinib versus imatinib): 0% versus 14% (CCI 2-4), 8% versus 9% (CCI 5-6), 24% versus 13% (CCI ≥7). Frequency of grade 3/4 TRAEs leading to discontinuation was similar: 0% versus 0%, 1% versus 1%, 8% versus 7%. No deaths occurred for CCI 2-4; similar percentage of patients died between treatments for CCI 5-6 and ≥7. Conclusions: Dasatinib was effective across all CCI groups, consistent with previous findings, suggesting that comorbidities do not negatively affect TKI activity. These findings highlight the benefits of first-line dasatinib in patients with CML-CP and elevated comorbidity burden. Funding: Bristol Myers Squibb. Previous presentation: 62nd ASH Annual Meeting, December 5-8, 2020; republished with permission of Elsevier Inc.