Novel Therapies for T315I-Mutant Chronic Myeloid Leukemia
Published Online: Friday, January 10, 2014
AbstractThe 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.
Omar Al Ustwani, MD
IntroductionAbelson 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
Development of second-generation TKIs (dasatinib, nilotinib) helped overcome most mutations except T315I.5 Dasatinib was able to overcome 14 of the initially identified 15 imatinib-resistant mutations.6 Subsequently, dasatinib was found to be less effective against additional mutations such as F317L and T315A due to the important role of phenylalanine 317 and threonine 315 serving as contact residues to imatinib and dasatinib.7 Nilotinib is not affected by the phenylalanine 317 position. Thus, F317L is not considered resistant to nilotinib. However, other mutations, such as E459K and Y253H, were found to be resistant to nilotinib.8 In T315I, a threonine to isoleucine gatekeeper mutation results in alteration of the structure of the ATP-binding pocket by eliminating a hydrogen-bonding interaction involved in binding first- and second-generation TKIs.9 Several third-generation TKIs (including bosutinib) were designed to target T315I, but only a few agents have shown clinical activity.
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
Based on these results, a phase I trial enrolled 48 patients (31 with refractory chronic-phase [CP] CML, six with accelerated-phase [AP] CML, five with blast-phase [BP] CML, and two with Philadelphia-positive acute lymphoblastic leukemia [ALL]), 18 of whom had the T315I mutation.12 Interim results showed that pancreatitis was the dose-limiting toxicity at 60 mg orally daily, and 45 mg became the recommended dosage for future studies. CCyR was noted in 33%, and major molecular response (MMR) in 48% of all patients. CCyR was achieved in 57% of patients with the T315I mutation. Significant adverse events (AEs) included nausea (20%) and fatigue (15%). Additional data on 11 patients with the T315I mutation from the same trial showed that 82% achieved major cytogenetic response (MCyR) and 40% achieved MMR.13 The final results of the dose-escalation trial (n = 81) were recently published.14 Among 12 patients who had T3151-mutant CP CML, 100% had a complete hematologic response (CHR) and 92% had a MCyR. AEs were similar to previously published results.
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