San Diego, CA—Targeting a second-generation tyrosine kinase inhibitor (TKI) in mutation-specific chronic myeloid leukemia (CML) led to deep and durable responses that were maintained beyond 3 years in some cases, reported Neil Shah, MD, PhD, Department of Medicine/Hematology-Oncology, University of California San Francisco, during a poster presentation at the 2016 American Society of Hematology meeting.
Of the 76 evaluable patients with chronic phase CML and the BCR-ABL T315I mutation, more than 70% achieved complete cytogenetic response with ponatinib (Iclusig). Nearly 40% of patients achieved deep molecular response, defined as no BCR-ABL transcripts in the bone marrow.
Ponatinib Overcomes Resistance to Traditional TKIs
The majority of the patients had disease progression or were intolerant to at least 2 previous TKI regimens.
“Ponatinib gives us a salvage regimen for people who progress on imatinib [Gleevec] or dasatinib [Sprycel] or other agents that may develop resistance because of emergence of the T315I mutation,” said Dr Shah.
Historically, the development of ponatinib focused on overcoming the BCR-ABL T315I mutation, which emerges in 5% to 10% of patients with chronic phase CML. In the absence of effective treatment, the BCR-ABL T315I mutation is associated with resistance to conventional TKIs—an aggressive disease phenotype—and worse outcomes, including survival.
Dr Shah and colleagues reported findings from their analysis of pooled data from a phase 1 clinical trial and a pivotal phase 2 clinical trial that involved a subgroup of patients with chronic phase CML and with the T315I mutation, or patients who were resistant or intolerant to dasatinib or nilotinib (Tasigna).
The median age of the 76 patients who were included in the study was 50 years, and the median interval from diagnosis to the start of ponatinib therapy was 4.6 years.
Overall, 50% of patients had disease progression, and 20 patients received 3 previous TKI regimens during or after treatment with dasatinib or nilotinib. The study population had a median follow-up of 40 months.
In this study, 75% of the patients achieved major cytogenetic response with ponatinib, including 72% of patients who had complete cytogenetic response. More than 80% of patients who attained complete cytogenetic response maintained the status throughout the 4 years of follow-up. In addition, 61% of the patients achieved major molecular response, and 37% had molecular response at 4.5 years.
Phase 2 Study Results
Progression-free survival (PFS) and overall survival were the end points in the phase 2 clinical trial, which involved 64 of the 76 patients from the pooled analysis. These patients had an estimated 3-year PFS of 60% and an overall survival of 78%. The median values had yet to be reached for PFS or overall survival. The results suggested that the continuation of ponatinib beyond the 2-year landmark of the phase 2 clinical trial led to improved survival compared with historical data.
Ponatinib is associated with an increased risk for arterial thrombosis, which led to an FDA-mandated partial shutdown of its clinical development in 2013. Historically, approximately 33% of patients who receive ponatinib have arterial thrombi. Consistent with that statistic, 32% of patients in the pooled data analysis had arterial occlusive events, including a 20% incidence of grade 3 or 4 arterial occlusive events.
“Survival outcomes with ponatinib treatment in these highly refractory patients were high overall and compare favorably with those observed in T315I-positive chronic phase CML patient populations prior to the availability of ponatinib,” Dr Shah and colleagues concluded.