New dosing schedules of dasatinib for CML and adverse event management.

Siu-Fun Wong

doi:10.1186/1756-8722-2-10

Abstract

Resistance to imatinib in patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has emerged as a significant clinical issue. Dasatinib is a tyrosine kinase inhibitor that has 325-fold greater in vitro activity against native BCR-ABL (breakpoint cluster region-Abelson leukemia virus) compared with imatinib and can overcome primary (intrinsic) and secondary (acquired) imatinib resistance. Here, we review the clinical profile of dasatinib in imatinib-resistant and -intolerant patients and share clinical approaches for managing adverse events (AEs) to ensure maximum patient benefit. References were obtained through literature searches on PubMed as well as from the Proceedings of Annual Meetings of the American Society of Clinical Oncology, the American Society of Hematology, and European Hematology Association. Phase II and III studies of dasatinib in patients with imatinib-resistant or -intolerant CML in any phase or Ph+ ALL were selected for discussion. Dasatinib is currently indicated for the treatment of patients with imatinib-resistant or -intolerant CML or Ph+ ALL. AEs associated with dasatinib are typically mild to moderate, and are usually resolved with temporary treatment interruption and/or dose adjustments. A Phase III dose optimization study showed that in patients with chronic phase (CP) CML, 100 mg once-daily dasatinib improves the safety profile, particularly pleural effusion and thrombocytopenia, while maintaining efficacy compared with the previously recommended dose of 70 mg twice-daily. Dasatinib has a manageable safety profile. For patients with CP CML, a new recommended starting dose of 100 mg once daily has recently been approved. The recommended dose for patients with advanced CML or Ph+ ALL remains 70 mg twice daily.

Highlights

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder of blood stem cells [1]
This genetic aberration arises from an exchange of genetic material between chromosomes 9 and 22, which results in the fusion of the breakpoint cluster region (BCR) and the Abelson leukemia virus (ABL) genes
We review the clinical profile of dasatinib in imatinib-resistant and -intolerant patients, discuss the newly approved dose for patients with chronic phase (CP) CML, and share clinical approaches in managing adverse events (AEs) to ensure maximum patient benefit

Summary

Introduction

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder of blood stem cells [1]. Dasatinib is indicated for the treatment of patients with imatinib-resistant or -intolerant CML in any phase or Ph+ ALL. In the United States and Europe, dasatinib is the first and only dual SFK/BCR-ABL inhibitor indicated for the treatment of imatinib-resistant and imatinib-intolerant patients in all phases of CML or with Ph+ ALL. Clinical studies The phase II START program Dasatinib has shown efficacy in a series of multicenter, open-label Phase II clinical studies with patients in all phases of CML or with Ph+ ALL who are resistant to or intolerant of imatinib (the START [SRC/Abl Tyrosine kinase inhibition Activity: Research Trials of dasatinib] program). START-R was a randomized, comparative trial of dasatinib 70 mg twice daily versus high-dose imatinib (800 mg) in patients with imatinib-resistant CP CML [49]. Dasatinib treatment can be resumed, and lower doses should be considered [11]

Summary

Sawyers CL

Radich JP

Findings

Talpaz M