Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to 3 months of imatinib therapy: final 5-year results from DASCERN

Abstract

Early molecular response at 3 months is predictive of improved overall survival and progression-free survival in patients with chronic myeloid leukemia in the chronic phase. Although about one-third of patients treated with first-line imatinib do not achieve an early molecular response, long-term overall survival and progression-free survival are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved an early molecular response after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib than those randomized to imatinib (77% vs. 44%, P<0.001). The median time to MMR was 13.9 months with dasatinib versus 19.7 months with imatinib. The safety profile was consistent with previous reports. These results demonstrate that switching to dasatinib after a suboptimal response to imatinib at 3 months leads to faster MMR, provides earlier deep molecular responses, and improves some outcomes in patients with chronic myeloid leukemia in the chronic phase.

Figure 1.

Cumulative incidence of major molecular response and major molecular response rates in the intent-to-treat population. ^aFour patients achieved then lost a major molecular response and subsequently crossed over to dasatinib. ^bThe cumulative incidence curve accounts for competing risk and censored patients. ITT: intent-to-treat; MMR: major molecular response; 95% CI: 95% confidence interval.

Figure 2.

Deep molecular response by cumulative incidence of MR (A) and MR⁴⁵ (B). Error bars indicate the 95% confidence interval. MR: 4-log reduction in BCR::ABL1 or ≤0.01% International Standard; MR.: 4.5-log reduction in BCR::ABL1 transcript levels or ≤0.0032% International Standard.

Figure 3.

Survival outcomes in the intent-to-treat population and by switch status. (A, B) Progression-free survival in the intent-to treat population (A) and by switch status (B). Progression-free survival is defined as the time from randomization to progression or death, whichever occurred first. (C, D) Overall survival in the intent-to treat population (C) and by switch status (D). PFS: progression-free survival; ITT: intent-to-treat; 95% CI: 95% confidence interval; NE: not estimable; OS: overall survival.