Ponatinib Given Early May Suppress New Mutations in Patients with CML

VBCC - September 2013, Volume 4, No 7 - Personalized Medicine
Alice Goodman

Chicago, IL—A new analysis of mutations at baseline and at the end of treatment provides information about the response to ponatinib (Iclusig) in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphocytic leukemia (ALL) enrolled in the phase 2 PACE study. The results were presented at the 2013 annual meeting of the American Society of Clinical Oncology.

Ponatinib is an oral pan-BCR-ABL1 Bruton’s tyrosine kinase (BTK) inhibitor with potent activity against native and mutated BCR-ABL1 and other kinases. The drug has demonstrated activity against all clinically relevant mutations associated with resistance to tyrosine kinase inhibitor (TKI) therapy in vitro, including the T315I mutation. Ponatinib is the first BTK that has shown activity against the T315I mutation in phase 2 studies.

The PACE study included 203 patients with disease that is resistant to or intolerant of the TKIs dasatinib (Sprycel) and/or nilotinib (Tasigna) and 64 patients with a confirmed T315I mutation at baseline. All patients were heavily pretreated—93% had previously received ≥2 TKIs and 58% had received ≥3 TKIs.

“We observed that the overall rate of mutations increases with [disease] stage, and so does the number of mutations for each individual,” noted lead investigator Michael W. N. Deininger, MD, PhD, Chief, Division of Hematology, Huntsman Cancer Institute, University of Utah, Salt Lake City.

When ponatinib was given at therapeutic doses during this study, no single mutation that confers resistance to ponatinib was found. In previous studies of TKIs used in patients with CML, the T315I mutation has typically been associated with resistance.

Patients with chronic-phase ALL and T315I mutations tend to respond very well to ponatinib, but patients with no single mutation do slightly worse, with only 25% showing major cytogenetic response in the chronic phase, Dr Deininger noted.

Overall results were reported separately, according to disease stage. In chronic-phase CML, few patients who discontinued treatment with ponatinib gained single mutations at the end of treatment, and many of the patients who did gain mutations had been receiving low-dose ponatinib. A few of these patients developed compound mutations, and there was no change in mutation status for the majority of the patients at the end of treatment.
Of patients with accelerated-phase CML, approximately 80% had no change in mutation status at the end of treatment.

The situation in patients with blast-crisis CML was different. Slightly more than 50% of patients who discontinued treatment with ponatinib developed multiple or compound mutations, but others did not.

“These findings suggest that mechanisms other than compound mutations are responsible for resistance to ponatinib in patients in blast crisis,” Dr Deininger said.

“If we introduce ponatinib early in the course of therapy, this drug may be able to suppress the emergence of single BCR-ABL1 mutations, and as a result, the development of compound mutations,” he stated.

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