Ponatinib Maintains Benefit in Chronic-Phase CML at 5 Years

Ponatinib maintained deep, durable responses in heavily pretreated patients with chronic-phase chronic myeloid leukemia (CP-CML).

Jorge Cortes, MD

Ponatinib (Iclusig) maintained deep, durable responses in heavily pretreated patients with chronic-phase chronic myeloid leukemia (CP-CML), according to 5-year results from the pivotal PACE trial published in the journal Blood.

At a median follow-up of 56.8 months, 60% (n = 159) of 267 evaluable patients achieved major cytogenic response (MCyR). Fifty-four percent (n = 144) of patients had complete cytogenic response. Forty percent (n = 108) of patients achieved major molecular response (MMR) and 24% (n = 64) achieved molecular response.1

At the median follow-up, an estimated 82% of patients who achieved MCyR by 12 months and an estimated 59% of those who achieved MMR at any time maintained those responses at 5 years.

“The PACE trial is among the longest and largest studies of patients with CP-CML who have received 2 or 3 prior TKIs, and the findings provide treating physicians with important updated information about the clinical benefits and safety profile of Iclusig,” lead author Jorge Eduardo Cortes, MD, deputy chair and professor of medicine, department of leukemia, MD Anderson Cancer Center, said in a statement. “These final PACE results demonstrate that Iclusig provides lasting, clinically meaningful responses, irrespective of dose reductions, in this population.”

In the overall 270-patient cohort, more than 90% of patients had received previously treatment with at least 2 TKIs. Investigators found that response was correlated with long-term outcomes. Estimated 5-year progression-free survival (PFS) was 53% and overall survival (OS) was 73%. PFS and OS rates were comparable in resistant/intolerant and T315I subgroups.

The pivotal phase II PACE trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily. However, a posthoc analysis of PACE data suggested that arterial occlusive events (AOEs) may be dose-related, with each 15-mg reduction in average daily dose intensity predicted to lead to an approximately 33% reduction in the risk of AOEs. Investigators implemented dose reductions in October 2013 to reduce the risk of vascular occlusive events, including AOEs.

Of patients who were in MCyR or MMR as of October 2013 and had their dose reduced, ≥90% maintained response 40 months after pre-emptive dose reductions, including those who had their dose reduced to just 15 mg per day.

Frank Neumann, MD, PhD, senior medical director for Takeda, the company that developed ponatinib, said in a statement that this analysis did not evaluate how initiating therapy with a lower dose might affect adverse events and response rates. The ongoing prospective dose-ranging OPTIC trial is expected to address that question.

“The publication of these data is an important milestone as it shows that Iclusig continues to be an effective treatment option for appropriate patients whose prior TKIs have failed, including patients with the T315I mutation, for whom no other TKI is indicated,” he said.

The most common (≥40%) all-grade treatment-emergent adverse events (TEAEs) were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43 %), dry skin (42%) and constipation (41%). The most common (≥10%) grade 3/4 TEAEs were thrombocytopenia (35%), neutropenia (17%), hypertension (14%), increased lipase (13%), abdominal pain (10%) and anemia (10%).

Researchers found that the cumulative incidences of treatment-emergent AOEs, including cardiovascular, cerebrovascular and peripheral vascular events, increased to 31% over time. However, the exposure-adjusted incidence of newly occurring AOEs—15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively—remained relatively constant throughout the study.

In November 2016, the FDA granted a full approval and label update to ponatinib for patients with CP, accelerated phase, or blast phase CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other TKI therapy is indicated, as well as for patients with T315I-positive CML or T315I-positive Ph+ ALL.

Overall, the PACE trial included 449 patients who received ponatinib at a starting dose of 45 mg daily. Patients were heavily pretreated, with an estimated 93% and 56% of patients having previously received ≥2 TKIs and ≥3 TKIs, respectively.

At a minimum of 48 months’ follow-up (data cutoff: August 3, 2015), 110 of 270 CP-CML patients continued to receive ponatinib. The median durations of MCyR (range 2.7 to >50 months) and MMR (range 1.7 to >50 months) had not yet been reached.

In the overall 449-patient population, 150 patients had experienced AOEs at 4 years. Some patients had more than 1 type of AOE, with cardiac vascular, peripheral vascular, and cerebrovascular arterial occlusive events occurring in 21%, 12%, and 9% of patients, respectively. Arterial occlusive serious adverse reactions were reported for 22% of patients, including 12% cardiac vascular, 8% peripheral vascular, and 7% cerebrovascular. Venous thromboembolic events were reported in 6% of patients.

Ponatinib initially received an accelerated approval from the FDA in 2012 based on earlier findings from the PACE trial.


  1. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial [published online March 22, 2018]. Blood. doi: https://doi.org/10.1182/blood-2016-09-739086.
  2. Cortes JE, Pinilla-Ibarz J, Le Coutre PD, et al. 4-year results of the ponatinib phase II PACE trial in patients (pts) with heavily pretreated leukemia. J Clin Oncol 34, 2016 (suppl; abstr 7013)..


The full approval was based on 4-year follow-up data from the phase II PACE trial, which, overall, evaluated ponatinib in patients with CML or Ph+ ALL who were refractory to dasatinib (Sprycel) or nilotinib (Tasigna), or who harbored a T315I mutation.2 At 4 years, among patients with CP-CML in the study, the MCyR rate was 55% and the MMR rate was 39% among the cohort of patients with CP-CML.