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Ponatinib Effective in Resistant CML

The novel agent ponatinib produced a high rate of anti-cancer responses among patients with chronic myeloid leukemia (CML) and Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) that had stopped responding to prior therapies. These results were recently published in the New England Journal of Medicine.

Leukemias are a type of cancer that originate in immune cells. There are several different types of leukemia, two of which are CML and ALL. CML has 3 distinct phases: the chronic-phase, the accelerated-phase and the blast-phase.

Among patients with CML and ALL, some have very specific genetic mutations. Agents have been developed to target these specific mutations and improve outcomes for patients with the disease. As such, each patient undergoes laboratory testing for identification of possible mutations to guide optimal therapeutic decisions.

Ponatinib is an agent that inhibits the actions of a type of protein in the cell, called a tyrosine kinase. Specifically, it is an oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor–refractory threonine-to-isoleucine mutation at position 315 (T315I). Its actions reduce the replication and growth of some types of cancer cells.

Researchers recently conducted a phase II clinical trial with ponatinib among patients with CML and Ph-Positive ALL. The trial included 449 patients who had received prior therapy and had either stopped responding to therapy, or were not able to tolerate side effects of other therapies. The median follow-up was 15 months.

Among patients with chronic-phase CML, 56% achieved a major cytogenetic (chromosomal) response, 46% had a complete cytogenetic response and 34% had a major molecular response.
At 12 months, 91% of patients were estimated to have retained the major cytogenetic response.
Among patients with accelerated-phase CML, 55% had a major hematologic (blood) response and 39% had a major cytogenetic response.
Among patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response.
Among patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response.
Common side effects were low levels of platelets, rash, dry skin and abdominal pain.
12% of patients discontinued therapy due to side effects.
No BCR-ABL mutations conferred lack of responses to ponatinib.
The researchers concluded that ponatinib provides significant and sustained anti-cancer activity among patients with CML and Ph-positive ALL who have stopped responding to prior therapies. Furthermore, “Ponatinib had significant antileukemic activity across categories of disease stage and mutation status.”

Reference: Cortes J, Kim D, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. New England Journal of Medicine. 2013; 369:1783-1796.