Dasatinib vs. imatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) who have not achieved an optimal response to 3 months of imatinib therapy: the DASCERN randomized study

Abstract

Early molecular response is associated with improved probability of deep molecular response and superior survival in patients with CML-CP. However, ~1 in 3 patients on first-line imatinib do not achieve this threshold. The phase 2b DASCERN trial (NCT01593254) assessed the outcome of early switch to dasatinib in patients with suboptimal response to first-line imatinib. Adult patients with CML-CP were randomized (2:1) to receive 100 mg dasatinib (n = 174) or continue imatinib at ≥400 mg (n = 86). The primary endpoint was the rate of major molecular response (MMR) at 12 months, which was 29% (dasatinib) and 13% (imatinib; P = 0.005). After ≥2 years of follow-up, 45 patients (52%) randomized to continue imatinib had crossed over to dasatinib. Considering treatment crossover, the 2-year cumulative MMR rate was 64% with dasatinib and 41% with imatinib (66% and 67%, respectively by intent-to-treat). Adverse events were consistent with the established safety profiles of both drugs. The results of this first prospective study support early monitoring of patients treated with first-line imatinib, and suggest that switching to dasatinib in cases of suboptimal response may offer clinical benefit. Further follow-up is needed to assess the long-term clinical benefit of early switching.

Conflict of interest statement

JEC has served as a consultant to and received research funding from Bristol Myers Squibb, Novartis, Pfizer, and Takeda. QJ, JyW, HZ, and XL declare no conflicts to disclose. AH has received research funding from Bristol Myers Squibb, Incyte, Novartis, Pfizer, and Takeda. DWK has received research funding from Bristol Myers Squibb, IIyang, Novartis, and Pfizer. JR has served as a consultant to Bristol Myers Squibb, Novartis, Pfizer, and Takeda, and has received research funding from Novartis. JxW has received research funding from Celgene. MS has served as a consultant to, or served on the board of directors/advisors of Abbvie, Celgene, Incyte, Karyopharm, and Takeda, and received funding from Takeda and holds equity ownership in Karyopharm. PMR is an employee and holds equity ownership with Bristol Myers Squibb. OS and RG are employees of Bristol Myers Squibb. GS has served as a consultant to Ariad, Bristol Myers Squibb, Incyte, Novartis, and Pfizer.

Figures

Fig. 1. Study design.

*Patients initially randomized to imatinib, meeting ELN 2013 failure criteria, and without dasatinib-resistant mutations, were crossed over to the dasatinib arm. BID twice daily, CHR complete hematologic response, ELN European LeukemiaNet, IS International Scale, LPFV last patient first visit, QD once daily.

Fig. 2. MMR at 12 months in the ITT population (primary endpoint).

Error bars represent 95% CI. CI confidence interval, ITT intent-to-treat, MMR major molecular response.

Fig. 3. MMR after a minimum follow-up of 24 months.

a MMR according to study population and crossover. b Cumulative incidence of MMR accounting for competing risk. CI confidence interval, ITT intent-to-treat, MMR major molecular response.

Fig. 4. PFS.

Kaplan–Meier estimate of PFS in ITT population (a) and by switch status (b). PFS was defined as the time from randomization to transformation to CML-AP/BC or death, whichever occurred first. All patients who discontinued study treatment were followed for progression and survival unless consent was withdrawn. CI confidence interval, ITT intent-to-treat, NE not evaluable, PFS progression-free survival.

Fig. 5. OS.

Kaplan–Meier estimate of OS in ITT population (a) and by switch status (b). CI confidence interval, ITT intent-to-treat, NE not evaluable, OS overall survival.