ATLANTA—Within days of a presentation on the tyrosine kinase inhibitor (TKI) ponatinib at the American Society of Hematology Annual Meeting here, the drug was approved by the Food and Drug Administration for patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation (OT, 1/25/13 issue).
The data presented at the meeting were the 12-months' follow-up from the pivotal Phase II PACE (Ponatinib Ph+ ALL and CML Evaluation) trial, with ponatinib continuing to show substantial activity and a low toxicity profile in these heavily pretreated patients. Earlier, a Phase I trial had also shown ponatinib to be highly active (NEJM 2012;367:2075-2088).
For the ASH report (Abstract 163), first author Jorge E. Cortes, MD, Professor of Medicine and Deputy Chair of the Department of Leukemia and Chief of the CML and AML Sections at the University of Texas MD Anderson Cancer Center, said that despite progress in Ph+ leukemia therapy, patients who experience failure of TKIs and those with the T315I BCR-ABL mutation have had limited treatment options.
“This was a very, very heavily treated population—more than 90 percent [in the Phase II trial] had already received at least two tyrosine kinase inhibitors, and 60 percent in chronic phase had already received three or more,” he said. Patients were also very treatment-resistant, and only about one fourth had any response to the previous therapy.
Six Cohorts Tested
In the PACE trial, 449 patients were enrolled and assigned to one of six cohorts:
- Chronic-phase CML resistant or intolerant to dasatinib or nilotinib (203 patients);
- Chronic-phase CML with the T315I mutation (64 patients);
- Accelerated-phase CML resistant or intolerant to dasatinib or nilotinib (65 patients);
- Accelerated-phase CML with the T315I mutation (18 patients);
- Blast-phase CML or Ph+ ALL resistant or intolerant to dasatinib or nilotinib (48 patients); and
- Blast-phase CML or Ph+ ALL with the T315I mutation (46 patients).
The patients' median age was 59, 53 percent were male, and the median time from diagnosis to treatment with ponatinib was six years. A total of 96 percent had received prior treatment with imatinib; 84 percent, dasatinib; and 65 percent, nilotinib. The median number of prior TKIs was three, with 53 percent of patients exposed to all three approved TKIs.
In patients previously treated with dasatinib or nilotinib (427 patients), 88 percent had a history of resistance and 12 percent were purely intolerant to dasatinib or nilotinib. The median time to response (for responders) was 84 days in chronic-phase CML, 112 days in accelerated-phase CML, and 55 days in blast-crisis CML/Ph+ALL.
The most frequent reasons for discontinuation were disease progression (18% of patients) and adverse events (12%). The most common drug-related adverse events were thrombocytopenia (36%), rash (33%), and dry skin (31%).
High Cytogenetic Responses
Among the 267 patients with chronic-phase CML, 67 percent had a cytogenetic response (i.e., any kind), 56 percent had a major one, and 46 percent had a complete one. Response rates were higher in patients exposed to fewer prior TKIs and those whose disease had lasted for a shorter amount of time.
Similar response rates were observed in patients with and without BCR ABL mutations.
In the patients with chronic-phase CML, although the response rates were higher in those with T315I, a post hoc analysis found that the presence of T315I was not a predictor of response. Instead, the difference in response rate was explained by T315I patients' younger age, shorter duration of leukemia, and exposure to less prior therapy.
Cortes put these results in perspective, saying that studies with dasatinib and nilotinib in treatment-resistant patients who had not responded to only imatinib showed complete cytogenetic responses in approximately 40 percent of patients. “But here, in patients who have already failed three tyrosine kinase inhibitors, we get 46 percent complete cytogenetic response, and the responses continue to improve.”
The responses were very durable, he added, with 91 percent of patients predicted to maintain the response through 12 months.
The follow-up is still relatively short, he acknowledged, but said these very sustained responses are very encouraging.
The responses occur regardless of the mutations, he noted. Among patients with mutations other than T315I, 57 percent have achieved a major cytogenetic response, and even patients who have no mutations also have a very high response rate, 49 percent, he said.
He called ponatinib very well tolerated, with the most common side effects skin rash or dry skin, which is usually mild and very manageable, he said. “The one side effect that we saw that limited the dose in the Phase I trial was the development of pancreatitis, but fortunately this is not very common.” Grade 3 pancreatitis was seen only in six percent of the patients, and 11 percent had Grade 3 elevation of lipase.
The most frequent reasons for discontinuation were progression (18%) and adverse events (12%). The most common drug-related adverse events were thrombocytopenia (36%), rash (33%), and dry skin (31%). The pancreatitis is transient, he said, and only one of the total of 449 patients has come off study because of it.
“These results suggest that ponatinib has an outstanding clinical activity in patients with chronic myeloid leukemia or Philadelphia-positive AML, with responses regardless of the stage of the disease and regardless of the presence or absence of mutations,” he concluded.