“The arterial events were not well appreciated when EPIC was conceived,” Dr Lipton said. “It was not because arterial results were initially appreciated in EPIC, although on analysis, they were noted there as well.”

Although inconclusive due to small numbers, 8 out of 10 patients (80%) in the ponatinib arm and 5 out of 13 (38%) patients in the imatinib arm achieved the primary endpoint of MMR at 12 months (P = .074).

The rate of MMR was significantly greater at 3, 6, and 9 months for patients who received ponatinib. At 3 months, the rate was 31% with ponatinib compared with 3% with imatinib (P < .0001). These rates increased to 62% with ponatinib compared with 22% with imatinib at 6 months (P < .0001), and 86% vs 33%, respectively, at 9 months (P = .00031).

Patients who received ponatinib were more likely to achieve any MR (41% vs 18%; P < .0001), MR 4.0 (21% vs 1%; P < .0001), and MR 4.5 (15% vs 0%; P < .0001) compared with imatinib, regardless of Sokal risk. Median time to MMR was 3.3 months in the ponatinib arm compared with 5.6 months in the imatinib arm. In addition, median time to MR 4.0 was 5.6 months with ponatinib compared with 7.1 months with imatinib.

BCR-ABL1 transcript levels fell lower than 10% in 94% of patients who received ponatinib, compared with 68% of patients who received imatinib, regardless of Sokal risk. Patients who received ponatinib were more likely to achieve CCR at any time (74%) compared with imatinib (53%; P = .019), as well as at 6 months (86% vs 60%; P = .012); however, there was no significant difference at 12 months.

Arterial occlusion occurred more frequently in the ponatinib arm (7% of patients) compared with the imatinib arm (2% of patients; P = .052) and was serious in 6% who received ponatinib vs 1% given imatinib (P = .010). Dr Lipton noted, “There appears to be a dose effect that reduces these side effects. And it is being examined in 2 other studies: OPTIC and OPTIC-2L.”

In addition, 68% of patients who received ponatinib and 51% of patients who received imatinib experienced a minimum 1-grade increase from baseline in systolic or diastolic blood pressure.

Serious adverse events occurred more frequently in the ponatinib arm, although overall numbers were small, and included pancreatitis (5 patients), atrial fibrillation (3 patients), and thrombocytopenia (3 patients). There were no serious adverse events reported in the imatinib arm.

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Common grade 1 to 2 adverse events that occurred more frequently in the ponatinib arm included rash (31% vs 15%), abdominal pain (33% vs 10%), headache (32% vs 13%), constipation (27% vs 2%), increased lipase (12% vs 5%), and hypertension (13% vs 2%). In contrast, imatinib caused greater rates of grade 1 to 2 nausea (34% vs 21%), diarrhea (26% vs 12%), vomiting (18% vs 11%), peripheral edema (14% vs 9%), and periorbital edema (22% vs 1%).

“Ponatinib is not an option for first-line therapy at this time,” said Dr Lipton. “But successful completion of the OPTIC studies with a demonstration of reduced toxicity and sustained efficacy may open up the possibility of revisiting another study in newly diagnosed patients.”

References

  1. Lipton JH, Chuah C, Guerci-Bresler A, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial [published online ahead of print April 12, 2016]. Lancet Oncol. doi: 10.1016/S1470-2045(16)00080-2.
  2. Deininger MW, Shah NP, Cortes JE, et al. Impact of baseline (BL) mutations, including low-level and compound mutations, on ponatinib response and end of treatment (EOT) mutation analysis in patients (pts) with chronic phase myeloid leukemia (CP-CML). Blood. 2013;122(21):652.
  3. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Long-term follow-up of ponatinib efficacy and safety in the phase 2 PACE trial. Blood. 2014;124(21):3135.
  4. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783-1796.