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Investigational Drug Ponatinib Curbs Chronic Leukemia

Treatment achieves 56% major cytogenetic response (Dec. 9)

Twelve-month follow-up data have been reported from the pivotal PACE trial of ponatinib (Ariad Pharmaceuticals), an investigational BCR-ABL inhibitor, in heavily pretreated patients with resistant or refractory chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The new data show that 56% of chronic-phase CML patients in the trial — including 70% of patients with a T315I mutation — achieved a major cytogenetic response (MCyR), the primary endpoint for patients with chronic-phase CML.

The findings were presented at the 54th Annual Meeting of the American Society of Hematology (ASH), being held in Atlanta, Georgia. Ponatinib was submitted for FDA approval in the third quarter of 2012.

In the new study, efficacy data were reported from 444 patients treated with ponatinib 45 mg once daily, including 267 patients with chronic-phase CML. The findings were based on a minimum follow-up of 12 months in patients remaining in the study. Ninety-three percent of the patients had received at least two tyrosine kinase inhibitors (TKIs) before enrollment, and 58% had received three or more TKIs. Chronic-phase patients underwent bone-marrow assessments approximately every 3 months to determine the cytogenetic response.

Fifty-six percent (149/267) of chronic-phase CML patients achieved an MCyR, with 46% achieving a complete cytogenetic response (CCyR). The median follow-up period was 15.3 months.

Of the 64 evaluable chronic-phase CML patients with the T315I mutation, 70% (45/64) achieved an MCyR, with 66% achieving a CCyR. The MCyR rate in evaluable chronic-phase patients without the T315I mutation was 51% (104/203).

Thirty-four percent (91/267) of chronic-phase CML patients achieved a major molecular response (MMR), and 15% (39/267) achieved a 4.5-log reduction of BCR-ABL transcripts (MR4.5).

Nineteen chronic-phase patients treated with ponatinib had received only one TKI. Thirteen of these patients had been treated with imatinib only, and six had received either dasatinib or nilotinib. Of these 19 patients, 16 (84%) achieved an MCyR.

The most common non-hematologic treatment-emergent adverse events included rash (in 38% of patients), abdominal pain (38%), headache (35%), dry skin (35%), and constipation (34%). Most of these events were grade 1 or 2 in severity.

The most common hematologic treatment-emergent adverse events were thrombocytopenia (42%), neutropenia (24%), and anemia (20%), which were primarily grade 3 or 4 in severity.

The primary target for ponatinib is native BCR-ABL, an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL. Ponatinib also targets BCR-AL isoforms, which carry mutations that confer resistance to treatment with existing TKIs, including the T315I mutation, for which no effective therapy currently exists.

Source: Ariad Pharmaceuticals; December 9, 2012.

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