Background Dasatinib, a potent Bcr‐Abl tyrosine kinase inhibitor, is approved for the treatment of chronic‐phase chronic myeloid leukemia (CML‐CP) in the frontline and salvage settings. Notable side effects include pleural effusions and myelosuppression. Dasatinib at 50 mg daily has previously been reported to be active and better tolerated than the approved 100‐mg daily dose. The aim of this study was to update the long‐term follow‐up results of dasatinib at 50 mg daily as frontline therapy for CML‐CP. Methods Eighty‐three patients with newly diagnosed CML‐CP received dasatinib at 50 mg daily. Eligibility and response criteria were standards used in previous protocols. Results After a minimum follow‐up of 12 months, 81 patients were evaluable. Two patients came off the study in less than 3 months. The rates of BCR‐ABL1 transcript levels (International Standard) at ≤10% and ≤1% at 3 months were 96% and 77%, respectively. The cumulative rates for a complete cytogenetic response by 6 and 12 months were 77% and 95%, respectively. The cumulative rates for a major molecular response, a molecular response with a 4.0‐log reduction, and a molecular response with a 4.5‐log reduction by 12 months were 81%, 55%, and 49%, respectively. Twenty‐one patients (25%) had treatment interruptions for a median of 13 days (range, 4‐64 days). Five patients (6%) developed pleural effusions; 4 of these patients (80%) required a dose reduction. Two patients (2%) failed to achieve any cytogenetic or molecular response and were taken off the study. At a median follow‐up of 24 months, none of the patients had disease transformation to an accelerated or blastic phase. The 2‐year event‐free and overall survival rates were 100%. Conclusions These updated results continue to support 50 mg of dasatinib daily as an effective and safe dose for early CML‐CP.
Dasatinib 50 mg daily is active and well tolerated in patients with newly diagnosed CML-CP. It should be further explored as a new potential standard-of-care option for chronic myeloid leukemia. Cancer 2018;124:2740-2747. © 2018 American Cancer Society.
Background Dasatinib is a second‐generation tyrosine kinase inhibitor that, when used as frontline therapy, produces more and faster cytogenetic and molecular responses compared with imatinib. The authors report the long‐term follow‐up from the first study using dasatinib as initial therapy for chronic‐phase chronic myeloid leukemia. Methods Between November 2005 and August 2014, patients were randomly assigned to receive 100 mg daily or 50 mg twice daily. After June 2009, all patients started with 100 mg daily. Results With a median follow‐up of 6.5 years, 94 of 149 treated patients (63%) were still receiving dasatinib on study. The median patient age was 48 years (interquartile range, 37‐55 years), and 9% of patients had a high risk Sokal risk score. The cumulative complete cytogenetic response rate at 11 years was 92.6%, the major molecular response (MR) rate was 88.2%, and the MR4.5 rate (indicating a ≥4.5‐log reduction in BCR‐ABL1 transcripts) was 79.5%. The median time to a major MR and MR4.5 was 6 and 23 months, respectively. A sustained MR4.5 (≥2 years) was achieved in 82 patients (55%). The 10‐year overall survival, transformation‐free survival, event‐free survival, and failure‐free survival rates were 89%, 95%, 86%, and 65%, respectively. Univariate analysis showed that the achievement of a complete MR was associated with improved overall survival. The most common reasons for treatment discontinuation were toxicity and elective discontinuation. The most common treatment‐emergent grade 3 and 4 adverse events were fatigue, thrombocytopenia, and infections. Conclusions After this long‐term follow‐up, dasatinib continues to show an excellent safety profile and produces rapid cytogenetic responses and MRs, durable deep MRs, and excellent long‐term survival outcomes in patients with chronic‐phase chronic myeloid leukemia.
Low‐dose dasatinib is safe and effective in patients with chronic myeloid leukemia in chronic phase (CML‐CP). No randomized trials have compared the outcome with standard‐dose dasatinib. This study aims to compare the outcome of patients with CML‐CP treated with frontline dasatinib 50 versus 100 mg/day. We analyzed 233 patients with newly diagnosed CML‐CP treated with low‐dose dasatinib (N = 83) or standard‐dose dasatinib (N = 150). Propensity score analysis with 1:1 matching was performed and identified 77 patients in each cohort without significant baseline differences. Response rates were reported as the cumulative incidences of complete cytogenetic response, major molecular response (MMR), molecular response (MR)4, and MR4.5. Failure‐free survival (FFS), event‐free survival (EFS), transformation‐free survival (TFS), and overall survival (OS) were also compared. Patients on low‐dose dasatinib with suboptimal response by European LeukemiaNet (ELN) 2013 criteria had the option to increase the dose to 100 mg/day. The overall median follow‐up time was 60 months. The 3‐year MMR rates were 92% and 84% for low‐dose and standard‐dose dasatinib, respectively (p = .23). Dasatinib 50 mg/day induced higher cumulative incidence of MR4 (77% vs. 66%; p = .04) and MR4.5 (77% vs. 62%; p = .02) at 3 years. The 4‐year FFS, EFS and OS rates were 89% versus 77% (p = .04), 95% versus 92% (p = .06), and 97% versus 96% (p = .78) with low‐dose and standard‐dose dasatinib, respectively. The rate of any grade pleural effusion was 5% with dasatinib 50 mg/day compared to 21% with 100 mg/day. Dasatinib 50 mg/day is at least as effective as 100 mg/day with a better safety profile and drug exposure.
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