Novel Therapies for T315I-Mutant Chronic Myeloid Leukemia

Omar Al Ustwani, MD, and Meir Wetzler, MD
Published: Friday, Jan 10, 2014

Abstract

The use of tyrosine kinase inhibitors (TKIs) to inhibit BCR-ABL protein in chronic myeloid leukemia (CML) is one of the major milestones in modern oncology. After the FDA approval of imatinib (a first-generation TKI), dasatinib, nilotinib, and later bosutinib, recurrence of disease due to multiple mechanisms of resistance became the new challenge in CML treatment. The T315I mutation is of special interest as it continues to be an obstacle to the use of TKIs. In this review, we cover the clinical efficacy data of the approved agents for this indication, ponatinib and omacetaxine, in addition to discussing the role of stem cell transplantation and other novel agents in the treatment of CML.


Dr. Omar Al Ustwani

Omar Al Ustwani, MD

Introduction

Abelson tyrosine kinase (ABL1) is a nonreceptor tyrosine kinase involved in cell growth and proliferation. Chronic myeloid leukemia (CML) arises from the fusion of the ABL1 gene (chromosome 9q34) with the breakpoint cluster region (BCR) gene (chromosome 22q11.2), generating the Philadelphia chromosome expressing BCR-ABL1. BCR-ABL1 is a constitutively activated tyrosine kinase that activates many signaling pathways, thus providing a proliferative advantage.1 Imatinib, the first tyrosine kinase inhibitor (TKI), competitively inhibiting the BCR-ABL1 kinase, was approved based on the results of the International Randomized Study of Interferon versus STI571 (IRIS) trial showing that at 18 months, 76.2% of the patients achieved complete cytogenetic response (CCyR) and 96.7% were free from disease progression.2 Longer follow-up revealed significant relapses3; of these patients, 40% to 50% were identified as having point mutations at the ATP-binding site of the ABL1 kinase domain.4

Ponatinib (AP24534) Ponatinib was designed to accommodate the T315I side chain via a carbon-carbon triple bond and was confirmed to bind to the inactive mode of the kinase domain in the murine ABL1T315I. Preclinical data suggested that it prevents the autophosphorylation of both native and T315I-mutant kinase and inhibits growth and signaling in the cells expressing native or mutant BCR-ABL1. Dose-dependent antitumor activity was shown in a BCR-ABL1T315I mouse xenograft model, with significant response at daily doses of 10 mg/kg and 30 mg/kg.10 It was also shown to inhibit compound mutations, in addition to multiple other kinase pathways such as the SRC family kinases, platelet-derived growth factor receptor-, vascular endothelial growth factor receptor pathways, and c-KIT.10,11

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