PF407 TREATMENT‐FREE REMISSION IN PATIENTS WITH CHRONIC MYELOGENOUS LEUKEMIA FOLLOWING FIRST‐LINE DASATINIB, 1ST DADI/IMIDAS4
Authors: Murai K. , Kimura S. , Imagawa J. , Hino M. , Kitawaki T. , Okada M. , Tanaka H. , Shindo M. , Kumagai T. , Ikezoe T. , Uoshima N. , Sato T. , Watanabe R. , Kowata S. , Hayakawa M. , Hosoki T. , Ikeda K. , Kobayashi T. , Kakinoki Y. , Nishimoto T. , Takezako N. , Shibayama H. , Takaori A. , Nakamae H. , Kawaguchi A. , Ureshino H. , Sakamoto J. , Ishida Y. 
Published: June 2019

Background:The main treatment goal for patients with chronic phase chronic myelogenous leukemia (CML‐CP) is discontinuation of tyrosine kinase inhibitor (TKI) therapy. In the previous DAsatinib Discontinuation (DADI) trial, we showed that 44.4% of CML patients treated with second‐line or subsequent dasatinib could stop dasatinib safely if they sustained DMR (0.01% ≥ IS)for a minimum of 1 year. No study has examined treatment free remission (TFR) in a large cohort after discontinuation of first‐line dasatinib treatment.Aims:We report the the results of a phase II trial designed to investigate TFR after dasatinib discontinuation in CML patients who sustained DMR for at least 1 year after treatment with first‐line dasatinib (the 1st DADI / IMIDAS4 trial).Methods:In this trial, we enrolled patients with CML‐CP at 23 Japanese centers. Patients with CML‐CP with DMR and more than 24 months of first‐line dasatinib were enrolled. Patients with sustained DMR during the 1‐year dasatinib consolidation phase were eligible into the TFR phase. Molecular responses were assessed every 3 months during the consolidation phase and every month during the TFR phase by real‐time quantitative polymerase chain reaction.The primary end point was TFR at 6 months, and the secondary end point was TFR at 12 months. Molecular relapse was defined as loss of DMR at two consecutive times points or loss of major molecular response (MMR; 0.1% ≥ IS); in these cases, the patient was re‐administered dasatinib at the previously effective dose. Analysis of natural killer (NK) and T‐cell profiles was performed to identify the factors responsible for molecular relapse throughout the preregistration period of the study.Results:Patients (n = 68) diagnosed with CML‐CP and achieving DMR after receiving first‐line dasatinib treatment for at least 24 months, were eligible for the 1‐year consolidation phase. Nine patientswere excluded from the discontinuation phase.Fifty‐ nine patients were enrolled into the TFR phase of the study. The median age was 63 (31–94). Forty‐three patients had low Sokal risk scores and 16 patients had high or intermediate scores. The median duration of DMR and total time dasatinib treatment were 23.3 (11.1–56.2) months and 40.2 (35.1–111) months, respectively. The median dose of dasatinib during DMR and the total dose from initiation of treatment were 21,840 (3,600–38,700) mg and 67,100 (5,350–332,480) mg, respectively. Thirty‐three patients sustained TFR for a median follow‐up of 23.3 months (11.7 –31.0 months). Both overall probability of TFR at 6 and 12 months was 55.9% (95% CI, 44.6–70.1, Figure). The duration of first‐line dasatinib treatment (≥40 months or <40 months; P = 0.72) did not correlate with the TFR rate, which had been thought to correlate with duration of TKI treatment. Overall, 26 patients experienced loss of DMR within 6 months; all received dasatinib at the previously effective dose, resulting in rapid achievement of MMR (24 of the 26 patients achieved DMR). Univariate and multivariate analyses revealed that low CD4/CD8 ratio was a significant favorable prognostic factor [Hazard ratio, 0.33 (0.14–0.79; P = 0.012), meanwhile, NK cell counts did not affect TFR.Summary/Conclusion:The TFR rate of 55.9% (the present study used very stringent criteria for molecular relapse) is a clinically important outcome with the shortest treatment time among previous TKI discontinuation studies. T cell‐mediated immune responses have a greater impact on TFR in CML than NK cell‐mediated immune responses. This trial was registered as number UMIN000011099.image