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

Jorge E Cortes,Huanling Zhu,Andreas Hochhaus,Giuseppe Saglio,Jerald Radich,Oumar Sy,Jianyu Weng,Qian Jiang,Dong-Wook Kim,Renuka Gurnani,Patricia Martin-Regueira,Michael Savona,Jianxiang Wang,Xiaoli Liu

doi:10.1038/s41375-020-0805-1

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.

Highlights

Achieving early molecular response (EMR), defined as a reduction in BCR-ABL1 transcripts to ≤10% (International Scale [IS]) at 3 or 6 months after initiating tyrosine kinase inhibitor (TKI) treatment, has been shown to improve the probability of achieving a subsequent deep molecular response (DMR; typically MR4.5 or BCR-ABL1 ≤ 0.0032% [IS]) and to be associated with superior progression-free and overall survival (OS) in chronic myeloid leukemia in chronic phase (CML-CP) [1, 2]
Achievement of EMR may increase the likelihood of attaining a subsequent DMR and having favorable longterm outcomes, but it is not known whether patients without an EMR at 3 months will benefit from an early switch to a potent second-generation TKI
Cumulative incidence of CCyR was similar in the dasatinib and imatinib arms; 29 (64%) patients initially randomized to the imatinib arm achieved a CCyR after having a suboptimal response and crossing over to dasatinib

Summary

Introduction

Achieving early molecular response (EMR), defined as a reduction in BCR-ABL1 transcripts to ≤10% (International Scale [IS]) at 3 or 6 months after initiating tyrosine kinase inhibitor (TKI) treatment, has been shown to improve the probability of achieving a subsequent deep molecular response (DMR; typically MR4.5 or BCR-ABL1 ≤ 0.0032% [IS]) and to be associated with superior progression-free and overall survival (OS) in chronic myeloid leukemia in chronic phase (CML-CP) [1, 2]. The prognostic significance of EMR has been established for both imatinib and second-generation TKIs in the first-line setting. Patients treated with dasatinib or imatinib with EMR at 3 months in DASISION

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Conclusion