Can Ponatinib Be Used to Treat Lymphocytic Leukemia?

Ponatinib is an oral targeted drug specifically indicated for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). In December 2012, the U.S. Food and Drug Administration (FDA) approved the drug as a candidate therapy. However, due to the risk of life-threatening blood clots and severe vascular stenosis, its marketing was suspended on October 31, 2013.

Ponatinib acts as an oral tyrosine kinase inhibitor, which can be administered to leukemia patients with either mutated or unmutated BCR-ABL genes. This includes patients harboring the BCR-ABL T315I mutation (threonine-to-isoleucine substitution at position 315) who have developed resistance to other tyrosine kinase inhibitors. To evaluate the efficacy of ponatinib in patients with CML or Ph-positive ALL, J.E. Cortes et al. from The University of Texas MD Anderson Cancer Center in Houston conducted a phase 2 clinical study.

The study enrolled 449 patients with CML or Ph-positive ALL who were either resistant or intolerant to dasatinib or nilotinib, or carried the BCR-ABL T315I mutation. All patients received ponatinib at an initial daily dose of 45 mg, with a median follow-up duration of 15 months.

Results

Among the 267 patients with chronic-phase CML:

56% achieved major cytogenetic response (51% in the dasatinib/nilotinib-resistant or intolerant subgroup, and 70% in the T315I-mutant subgroup).

46% achieved complete cytogenetic response (40% and 66% in the two subgroups, respectively).

34% achieved major molecular response (27% and 56% in the two subgroups, respectively).

The disease responses were independent of the baseline BCR-ABL kinase domain mutation status and highly durable, with approximately 91% of patients maintaining major cytogenetic response for more than 12 months. No single-site BCR-ABL mutation associated with ponatinib resistance was detected.

Among the 83 patients with accelerated-phase CML:

55% achieved major hematologic response and 39% achieved major cytogenetic response.

Among the 62 patients with blast-phase CML:

31% achieved major hematologic response and 23% achieved major cytogenetic response.

Among the 32 patients with Ph-positive ALL:

41% achieved major hematologic response and 47% achieved major cytogenetic response.

Adverse Reactions

The most common adverse events included thrombocytopenia (37%), rash (34%), xeroderma (32%), and abdominal pain (22%). Severe arterial thrombotic events occurred in 9% of patients, with 3% of these events considered treatment-related. A total of 12% of patients discontinued treatment due to adverse events.

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