Nilotinib Vs. Dasatinib in Achieving MR4.5 for Newly Diagnosed Chronic Myeloid Leukemia: Results of the Prospective Randomized Phase 3 Study, JALSG CML212

Background: Treatment-free remission (TFR) is a new therapeutic goal for chronic myeloid leukemia in chronic phase (CML-CP). Deep molecular response (DMR) is a prerequisite condition to discontinue a tyrosine kinase inhbitor (TKI). In ENESTnd and DASISION trials, both nilotinib and dasatinib achieved DMR more effectively than imatinib. However, there is no direct comparative study to determine which TKI is better to achieve DMR for de novo CML-CP. So, we conducted a randomized phase 3 JALSG CML212 study to compare the achievement of MR^4.5 (BCR-ABL IS≤0.0032%) between nilotinib and dasatinib.

Methods: The JALSG CML212 study is a multicentral open-labeled prospective randomized controlled phase 3 study for de novo CML-CP. This study was reviewed and approved by the institutional review board of each institute and registered in the UMIN Clinical Trials Registry (#UMIN000007909). All patients provided written informed consent before enrollment. Diagnosis of CML was done by a cytogenetic study (G-banding or FISH) and/or detection of BCR-ABL by RT-PCR. The primary endpoint is a rate of cumulative achievement of MR^4.5 by 18 mon. Major secondary endpoints were safety, continuity, progression-free survival (PFS), event-free survival (EFS), overall survival (OS), and cytogenetic and molecular responses. A total of 461 patients were registered from 82 institutes and 454 patients were randomly assigned to the nilotinib arm or dasatinib arm (both, n=227) with Sokal risk scores as a stratification factor. Treatment doses were 300 mg, bid for nilotinib and 100 mg, qd for dasatinib. Treatment responses were evaluated by ELN2009. Patients were allowed to stop study treatment if judged as failure by ELN2009 or showed intolerance (repetitive ≥Grade 3 or continuous Grade 2 side effects) to the allocated TKI. BCR-ABL mRNA levels were monitored every three months with international scales using a MolecularMD, ODK-1201, or M135R kit with ≥MR^4.5 sensitivities. Adverse events were evaluated by the CTCAE ver 4.0.

Results: The median age of the patients was 53 years old in both arms. The proportions of Sokal low, intermediate, and high risk groups were 44.1%, 37.0%, and 18.9% in the nilotinib arm and 44.5%, 37.0%, and 18.5% in the dasatinib arm, respectively, without a significant difference. Also, there was no significant difference in ECOG PS, EUTOS risk groups, complications, or frequencies of additional chromosomal abnormalities in both arms. In the ITT population, the cumulative achievement rates of MR^4.5 by 18 mon were 33.0% (75/227) (95% CI:27.0-39.6%) in the nilotinib arm and 30.8% (70/227) (95% CI: 24.9-37.3%) in the dasatinib arm with no significant difference with a CMH test (p=0.62). This finding was also confirmed in the per-protocol (PP) population (33.5% in the nilotinib arm and 31.8% in the dasatinib arm, p=0.72). At 18 mon, 75.9% and 79.6% of the patients continued the allocated TKI in the nilotinib and dasatinib arms, respectively (p=0.36) (in the PP population).There was no significant difference in PFS, EFS, or OS between two arms by log-rank tests (the estimated rates at 36 mon: 98.8%, 67.2%, and 98.8% in the nilotinib arm; 99.0%, 65.4%, and 99.0% in the dasatinib arm). In addition, PFS, EFS and OS didn’t differ between both arms regardless of Sokal and EUTOS risk groups. The cumulative CCyR rates by 12, 18, 24, and 36 mon were 77.1%, 78.0%, 78.4%, and 78.4% in the nilotinib arm and 78.4%, 78.9%, 78.9%, and 78.9% in the dasatinib arm, respectively without no significant difference. The MMR rates by 12, 18, 24, and 36 mon were 62.6%, 67.0%, 72.3%, and 73.1% in the nilotinib arm and 68.7%, 73.1%, 75.3%, and 77.1% in the dasatinib arm, respectively, without no significant difference. The MR^4.5 rates by 12, 24, and 36 mon were 25.6%, 37.4%, and 40.5% in the nilotinib arm and 23.4%, 36.6%, and 44.5% in the dasatinib arm, respectively, with no significant difference. In the safety population, Grade 3/4 adverse events observed with ≥10% frequencies were lipase elevation (11.5%) in the nilotinib arm and neutropenia (12.8%) and thrombocytopenia (16.8%) in the dasatinib arm. Any new safety issue was observed in neither of the arms.

Conclusions: Based on these results, we consider that nilotinib and dasatinib are equally effective for de novo CML-CP patients in achieving MR^4.5 as well as in achieving CCyR and MMR in terms of both frequencies and times to achievement with similar continuity.