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• W3096127669 abstract "Introduction Dasatinib, a second-generation tyrosine kinase inhibitor (TKI), has been administered at a fixed starting dose of 100 mg once daily for patients with chronic myeloid leukemia in chronic phase (CP-CML). However, the relationships between TKI exposure, and safety and efficacy responses suggest that such fixed dosing may not be optimal for many Asian patients. In this study, the relationships between the starting dose of dasatinib adjusted for BW (Dose/BW), and dose limiting toxicities (DLTs) and molecular responses (MRs) were evaluated to develop an initial dosing strategy of dasatinib. Methods The safety and efficacy responses of dasatinib therapy were explored from the clinical data obtained in patients newly diagnosed with CP-CML at seventeen hospitals in South Korea. The safety response was assessed as the occurrence of first DLTs by 36 months that required an interruption in dasatinib therapy. The efficacy responses were evaluated as the achievement of MR at 3 months (MR1), 6 months (MR2), 12 months (major molecular response, MMR) and 24 months (deep molecular response, MR4.5). The rates and patterns of DLT occurrence and MR achievement by 36 months were examined using a Kaplan-Meier method. A logistic regression method was used to determine the effect of the Dose/BW of dasatinib on the occurrence of first DLTs or the achievement of MRs. A chi-square test for trend was used to assess the trend of DLT occurrence and MR achievement in patient subgroups divided into quartiles (Q1 to Q4) based on Dose/BW. Results The clinical data were obtained from a total of 102 Asian patients with CP-CML whose median BW was 64.0 kg (range, 37.8 to 106.0 kg) and Dose/BW 1.60 mg/kg (1.00 to 2.80 mg/kg). Safety. The most frequent DLTs were thrombocytopenia (46%), pericardial or pleural effusion (31%) and anemia (7%); the median time of occurrence for the DLTs were 29 days (range, 7 to 417 days), 336 days (7 to 681 days) and 35 days (10 to 140 days), respectively. The rate of DLT occurred first increased rapidly by four months of starting dasatinib therapy and then steadily by 28 months until reaching approximately 56% in the Kaplan-Meier curve. Patients with higher Dose/BW had a greater risk of DLT occurrence by 36 months as determined using a logistic regression (logit [P] = 1.58 × [Dose/BW] - 2.27, p = 0.03). As Dose/BW increases from Q1 to Q4 (median Dose/BW; 1.23, 1.45, 1.65 and 2.00 mg/kg, respectively), the rate of DLTs rises from 43.5% (Q1) to 66.7% (Q4) with a statistically significant trend of increment (p = 0.03). The median dose that would produce the lowest rate of DLTs is 78.7 mg as calculated by multiplying the median Dose/BW of Q1 (1.23 mg/kg) by the median BW of patients (64.0 kg). Efficacy. The achievement rates of MMR and MR4.5 increased continuously and reached 82% and 43%, respectively, by 36 months of starting dasatinib therapy. The Dose/BW of dasatinib did not affect the rates of MR achievements based on a logistic regression analysis. Even though Dose/BW increased, the achievement rates of MR1, MR2 and MMR demonstrated neither an increasing nor a decreasing trend from Q1 to Q4. Conclusion The higher the starting Dose/BW of dasatinib, the greater is the risk of DLT occurrence without improving the potential for MR achievement. Therefore, in order to minimize the risk of DLTs without compromising MRs, a lower starting dose of dasatinib 80 mg once daily is suggested for Asian patients with CP-CML especially with lighter BW. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding." @default.
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• W3096127669 date "2020-11-05" @default.
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• W3096127669 title "Clinical Response Evaluation Toward Individualizing the Starting Dose of Dasatinib in Asian Patients with Chronic Myeloid Leukemia" @default.
• W3096127669 doi "https://doi.org/10.1182/blood-2020-140626" @default.
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