Nilotinib vs dasatinib in achieving MR4.5 for de novo chronic myeloid leukemia: the randomized JALSG CML212 study

Abstract

Deep molecular response (DMR) is a prerequite for treatment-free remission (TFR) in chronic myeloid leukemia in chronic phase (CML-CP). The JALSG (Japan Adult Leukemia Study Group) conducted a prospective randomized phase 3 CML212 study for de novo CML-CP to compare the cumulative achievement of molecular response 4.5 (MR4.5; international scale BCR::ABL1 ≤0.0032%) by 18 months between nilotinib and dasatinib treatment as a primary end point. A total of 454 patients were randomly assigned to the 300 mg nilotinib twice daily arm or to the 100 mg dasatinib daily arm (both n = 227). BCR::ABL1 messenger RNA levels were monitored every 3 months. Study treatment was stopped if the patients were judged as failure according to the European LekemiaNet 2009 criteria or showed intolerance. The cumulative achievement rates of MR4.5 by 18 months were 32.6% (95% confidence interval [CI], 26.5-39.1) in the nilotinib arm and 30.8% (95% CI, 24.9-37.3) in the dasatinib arm with no significant difference (P = .66). The cumulative achievement rates of early molecular response, complete cytogenetic response, and major molecular response by 12, 18, 24, and 36 months were almost the same between the 2 arms. There was no significant difference in progression-free survival (PFS) or overall survival (OS) between the 2 arms by log-rank tests (PFS, P = .58; OS, P = .64). These results suggest that nilotinib and dasatinib would be equally effective for patients with de novo CML-CP. This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry as #UMIN000007909.

Graphical abstract

Figure 1.

Flow diagram of the patients and analyzed population. ITT population consisted of all patients who were randomized. Safety population consisted of individuals who received at least 1 dose of the protocol treatment. PP population consisted of subjects who received at least 1 dose of the protocol treatment and excluded those who were determined to be ineligible for the study.

Figure 2.

Comparison of MR4.5 and EMR between the nilotinib arm and the dasatinib arm. Cumulative achievement rates of MR^4.5 (A) and achievement rates of EMR (B). The results were calculated on the ITT population by means of the Cochran-Mantel-Haenszel (CMH) test.

Figure 3.

Comparison of cytogenetic and molecular responses between the nilotinib arm and the dasatinib arm. Cumulative achievement rates of CCyR (A), MMR (B), MR^4.0 (C), and MR^4.5 (D) by 12, 18, 24, and 36 months. The results were calculated on the ITT population by means of the CMH test. ∗Primary end point and same as Figure 2B.

Figure 4.

Comparison of times to cytogenetic and molecular responses between the nilotinib arm and the dasatinib arm. Times to the first CCyR (A), MMR (B), MR^4.0 (C), and MR^4.5 (D). Times to cytogenetic and molecular responses were defined as the intervals from the date of first dose to the response events and analyzed on the PP population by the cumulative incidence method with a Gray test. If the patients died or were lost to follow-up without achieving the events, these patients were treated as censored cases at the date of death or the last follow-up.

Figure 5.

Comparison of PFS, EFS, and OS between the nilotinib arm and the dasatinib arm. PFS (A), EFS (B), and OS (C). PFS, EFS, and OS were defined as the interval from the date of randomization until the date of progression or death from any causes, whichever came first (PFS); until the date of the earliest of defined events (EFS); and until the date of death from any causes (OS), respectively. PFS, EFS, and OS were analysis on the ITT population using the Kaplan-Meier method with a log-rank test.