FDA Greenlights Ponatinib for Patients With CML and Ph+ ALL

December 8, 2016

The US Food and Drug Administration is granting ponatinib (Iclusig) full approval for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia for whom no other tyrosine kinase inhibitor therapy is indicated.

The US Food and Drug Administration (FDA) is granting ponatinib (Iclusig) full approval for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated. It also is granting full approval for this kinase inhibitor for the treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Ph+ ALL.

The FDA full approval and label update for ponatinib is based on 48-month follow-up data from the phase II PACE trial in heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. Updated data on CP-CML patients showed 55% of patients achieved major cytogenetic response (MCyR) (primary endpoint) at any time, and 39% achieved a major molecular response (MMR). These data were presented at the 2016 meetings of the American Society for Clinical Oncology and the European Hematology Association (EHA).

“The four-year follow-up and updated safety profile demonstrate durability of responses in this heavily pre-treated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation,” said study investigator Jorge Cortes, MD, who is a professor and deputy chair in  the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston.

The efficacy and safety of ponatinib in CML and Ph+ ALL patients resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation, were evaluated in the PACE trial. A total of 449 patients were treated with ponatinib at a starting dose of 45 mg/day. An estimated 93% of patients previously received two or more approved tyrosine kinase inhibitors (TKIs). Updated data on 270 CP-CML patients from the ongoing trial indicate that with a minimum follow-up of 48 months, 110 patients continued to receive ponatinib.

This agent was associated with significant adverse side effects. With 4 years of follow-up, 33% (150/449) of all patients experienced arterial occlusive events (AOE). In addition, 21% of patients experienced cardiac vascular events, 12% experienced peripheral vascular events, and 9% experienced cerebrovascular arterial occlusive events. Some patients experienced more than one type of AOE. The study also showed that 22% experienced arterial occlusive serious adverse reactions (12% cardiac vascular, 8% peripheral vascular and 7% cerebrovascular) and 6% of all patients experienced a venous thromboembolic event.

The most common treatment-related adverse events of all grades (occurring in ≥ 20 percent of CP-CML patients) included hypertension (69%), rash (63%), abdominal pain (48%), fatigue (47%), headache (43%), arterial ischemia (42%), dry skin (42%), constipation (41%), arthralgia (32%), nausea (28%), pyrexia (26%), peripheral neuropathy (24%), myalgia (24%), pain in extremity (23%), back pain (21%), diarrhea (20%). Cases of reversible posterior leukoencephalopathy syndrome have also been reported.