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Chronic myeloid leukemia (CML) has evolved into a chronic disease that is managed with tyrosine kinase inhibitor therapy. Now that long‐term survival has been achieved in patients with CML, the focus of treatment has shifted to dose optimization, with the goal of maintaining response while improving quality of life. In this review, the authors discuss optimizing the dose of the second‐generation tyrosine kinase inhibitor dasatinib. Once‐daily dosing regimens for dasatinib in the first and later lines of treatment were established through long‐term (5‐year and 7‐year) trials. Recently published data have indicated that further dose optimization may maintain efficacy while minimizing adverse events. Results obtained from dose optimization and discontinuation trials currently in progress will help practitioners determine the best dose and duration of dasatinib for patients with CML, because treatment decisions will be made through continued discussions between physicians and patients. Cancer 2018;124:1660‐72. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., The focus of the treatment of chronic myeloid leukemia is shifting to dose management, with the goal of maintaining response while improving quality of life. Results obtained from dasatinib dose optimization and discontinuation trials will help practitioners determine the best dose and duration of dasatinib for patients with chronic myeloid leukemia.

Figure S1. Scatter plots depicting the distribution of WBC levels (A), spleen size changes (B), and haemoglobin levels (C) in individual patients at each treatment cycle based on BMF status.

Table S1. Changes in BMF according to baseline characteristics and clinical response.

BackgroundResistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.MethodsIn this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140).ResultsDose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.ConclusionsPonatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).