VIENNA—Administering ponatinib at lower doses can reduce the risk of arterial occlusive events (AOE) without hindering responses in patients with chronic-phase chronic myeloid leukemia (CP-CML), data from the PACE trial suggest.
When earlier results of this phase 2 study showed that ponatinib can cause AOEs, trials of the drug were put on partial clinical hold. Enrollment was stalled temporarily, and investigators began reducing ponatinib doses.
Now, updated data from the PACE trial suggest ponatinib can be administered safely and effectively in certain patients with CP-CML.
At a median follow-up of about 3.5 years, 95% of CP-CML patients who underwent dose reductions maintained a major cytogenetic response (MCyR). And AOEs occurred in 7% of patients who underwent dose reductions, compared to 13% of patients who did not.
“These continued responses . . . in such a heavily pretreated patient population are very encouraging,” said study investigator Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“Careful assessment of the benefit and risk of initiating ponatinib therapy, particularly in patients who may be at increased risk for arterial occlusive events, can help identify patients with refractory, Ph+ leukemias who can benefit most from this treatment.”
Dr Cortes and his colleagues presented data from the PACE trial at the 20th Congress of the European Hematology Association as abstract P234*. The study was sponsored by Ariad Pharmaceuticals, the company developing ponatinib.
Updated results
The trial included patients with resistant or intolerant CML or Philadelphia chromosome-positive acute lymphoblastic leukemia. A total of 449 patients received ponatinib at a starting dose of 45 mg/day.
Ninety-three percent of patients had previously received 2 or more approved tyrosine kinase inhibitors (TKI), and 55% had previously received 3 or more approved TKIs.
Dr Cortes and his colleagues presented data on 270 CP-CML patients. At a median follow-up of 42.3 months (data as of February 2, 2015), 114 patients (42%) continue to receive ponatinib.
Eighteen percent of patients discontinued treatment due to adverse events (AEs), 10% due to disease progression, 3% due to death, and 27% for other reasons.
Fifty-nine percent of CP-CML patients achieved an MCyR at any time during the study, and 83% of responders are estimated to remain in MCyR at 3 years. Thirty-nine percent of patients achieved a major molecular response (MMR).
The estimated progression-free survival at 3 years is 60%, and the estimated overall survival is 81%.
Twenty-three percent of CP-CML patients experienced an AOE designated a serious AE, and 28% experienced any AOE. The median time to onset for AOEs was 14.1 months (range, 0.3–44.0).
Four percent of CP-CML patients experienced a venous thromboembolism (VTE) that was considered an serious AE, and 5% experienced any VTE.
The most common all-grade, treatment-emergent AEs occurring in at least 40% of CP-CML patients were abdominal pain (46%), rash (46%), thrombocytopenia (45%), headache (43%), constipation (41%), and dry skin (41%).
Outcomes after dose reductions
On October 10, 2013, Ariad provided dose-reduction recommendations to investigators for patients remaining on the PACE trial. The following dose reductions were recommended, unless the benefit-risk analysis warranted treatment with a higher dose:
- CP-CML patients who already achieved an MCyR should have their ponatinib dose reduced to 15 mg/day
- CP-CML patients who had not already achieved an MCyR should have their dose reduced to 30 mg/day
- Advanced-phase patients should have their dose reduced to 30 mg/day.
As of February 2015, with 1.3 years (16 months) of follow-up after these recommendations, 95% of CP-CML patients maintained their response, whether or not they underwent prospective dose reductions.
Of the patients who were in MCyR as of October 10, 2013, and had a prospective dose reduction, 95% (61/64) maintained their response at 1.3 years. Of the patients who were in MMR as of October 10, 2013, and had a prospective dose reduction, 94% (44/47) maintained their response at 1.3 years.
Forty-two patients in MCyR did not undergo prospective dose reductions (the majority of which were already at a reduced dose of 30 mg or 15 mg as of October 10, 2013). Of these patients, 93% (n=39) maintained an MCyR after 1.3 more years of ponatinib treatment.
Twenty-four patients in MMR did not undergo prospective dose reductions, and 96% of these patients (n=22) maintained their response at 1.3 years.
Seven percent (5/71) of patients without prior AOEs who underwent dose reductions had a new AOE during the 1.3-year interval after dose reduction.
Thirteen percent (9/67) of patients without prior AOEs who did not undergo dose reductions had a new AOE in the same time interval.
*Information in the abstract differs from that presented at the meeting.