Long-Term PACE Follow-Up Confirms Ponatinib’s Benefit in CP-CML

At five-year follow-up, treatment with the third-generation tyrosine kinase inhibitor (TKI) ponatinib led to deep and durable responses in patients with heavily pretreated chronic-phase chronic myeloid leukemia (CP-CML), according to results from the phase II PACE (Ponatinib Ph+ ALL and CML Evaluation) trial published in Blood.

Response to treatment occurred rapidly, noted Jorge E. Cortes, MD, of the University of Texas MD Anderson Cancer Center, and colleagues. “Response rates appeared to be higher than those reported in patients who had received second-generation TKIs … after resistance and/or intolerance to two prior TKIs,” they wrote. However, the incidence of arterial occlusive events (AOEs) increased over time, suggesting that clinicians should carefully weigh the risks and benefits of ponatinib before initiating therapy – particularly in patients who are already at an increased risk for vascular events.

“The long-term follow-up provides us with some reassurance that the responses achieved with ponatinib for patients with CP-CML who have received prior therapies can be quite durable and that is quite exciting,” Wendy Stock, MD, told ASH Clinical News, when asked for comment on the study’s findings. (Read more from Dr. Stock in “Perspectives” at the end of this article.)

The PACE trial enrolled 449 patients (median age = 59 years; range = 18-94 years) between September 2010 and October 2011, including patients with CML or Philadelphia chromosome–positive acute lymphocytic leukemia (ALL) who were resistant or intolerant to second-generation TKIs (dasatinib and nilotinib) or who had the BCR-ABL1 mutation.

Earlier results from the PACE trial supported the U.S. Food and Drug Administration’s approval of ponatinib for this patient population; this analysis focused on the 270 patients with CP-CML enrolled in PACE.

The participants with CP-CML were heavily pretreated: 93 percent had received at least two TKIs, and 56 percent had received at least three TKIs.

Patients received ponatinib 45 mg once-daily. However, following concerns related to AOEs, patients who achieved a major cytogenetic response (MCyR) at 12 months were permitted to reduce their dose to 15 mg once-daily; the recommended dose for patients whose disease did not achieve a MCyR was 30 mg once-daily. Treatment continued until disease progression, intolerance, or patient or investigator decision to discontinue.

As of February 6, 2017 (data cutoff), 267 patients with CP-CML were evaluable for efficacy, with a median follow-up of 56.8 months (range = 0.1-73.1 months). During long-term follow-up:

  • 60% achieved MCyR at any time (n=159)
  • 54% achieved a complete cytogenetic response (CCyR; n=144)
  • 40% achieved a major molecular response (MMR; n=108)
  • 24% achieved a molecular response (n=64)

In the initial published results, 56 percent of patients achieved the primary endpoint of MCyR by 12 months. The authors estimated that 82 percent of those who reached the primary endpoint maintained their response at five years. Also, 59 percent of those who achieved MMR at any time during the study maintained at least an MMR. At last follow-up, the median duration of MCyR and MMR had not been reached.

These responses occurred “rapidly” according to the authors: The median time to response was 2.8 months (range = 1.6-58.0 months) for MCyR, 2.9 months (range = 1.6-58.0 months) for CCyR, and 5.5 months (range = 1.8-55.4 months) for MMR.

The estimated five-year progression-free survival and overall survival rates were 53 percent and 73 percent, respectively.

Among those with CP-CML, nine patients (3%) experienced disease transformation to accelerated phase CML (n=5) or blast phase CML (n=4), with a median time to transformation of 6.4 months (range = 0.2-30.3 months). Six of these patients had not achieved MCyR.

Eighty-two percent of patients (n=221) required at least one dose reduction and 82 percent (n=221) had dose interruptions of at least three days at any point. Most dose reductions occurred prior to the October 2013 study protocol change, the authors noted.

Sixty-nine patients were in MCyR when they required a dose reduction, and all but three patients maintained MCyR afterward. MMR was also maintained in 90 percent of patients who had a dose reduction. “Maintenance of response, including deep response, was high among [patients with] CP-CML irrespective of dose reductions,” the authors wrote. In a post hoc analysis assessing the effect of prospective dose reductions on durability of response, they also found that, at 40 months post-reduction, there was “no detectable difference in the rates of MCyR or MMR” in patients with CP-CML who did or did not require dose reductions.

“Tolerability was acceptable in this heavily treated population,” the researchers reported. The most common treatment-related adverse events (AEs) included rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The most common grade 3/4 AEs included thrombocytopenia (35%), neutropenia (17%), hypertension (14%), increased lipase (13%), abdominal pain (10%), and anemia (10%).

During long-term follow-up of the patients with CP-CML enrolled in the PACE trial, the incidence of AOEs increased – from approximately 17 percent at two years to 31 percent at five years (26% of which were considered serious events).

While the higher cumulative incidence correlated with longer duration of treatment, the exposure-adjusted incidence of new events remained relatively constant, the authors noted (see TABLE).

These conditions should be managed as clinically indicated, and ponatinib dosing should be reduced, interrupted, or discontinued as needed.

“Further research on the mechanisms of vascular events with TKIs is ongoing, and may help determine more specific interventions to mitigate or eliminate risk,” the authors noted, adding that the risk of AOEs appeared to be related to preexisting cardiovascular disease and other factors (i.e., hypertension, hypercholesterolemia, diabetes, obesity, a history of ischemic disease, non-ischemic cardiac disease, or venous thromboembolism).

the extent of
prior exposure
to multiple TKIs
in this patient
[the final PACE]
results compare
favorably with
those of second-generation

—Jorge E. Cortes, MD

Patients with these risk factors were twice as likely to develop serious AOEs as patients without these risk factors (risk ratio = 2.2; 95% CI 1.5-3.3; p value not reported).

Twelve patients (4%) died during the study or within 30 days after the end of ponatinib treatment, including four deaths due to disease progression. One patient death (pneumonia and acute myocardial infarction) was deemed possibly or probably related to ponatinib.

“Considering the extent of prior exposure to multiple TKIs in this patient population, [the final PACE] results compare favorably with those of second-generation TKIs,” the researchers concluded, noting that the study was limited by a lack of a comparator arm.

However, “these final results of the PACE study support ponatinib as an effective treatment for patients with CML who have received prior therapies.”

ARIAD Pharmaceuticals supported the study.

The corresponding authors report financial support from ARIAD, Bristol-Myers Squibb, Novartis, Pfizer, and Teva. Peloton Advantage and ARIAD provided editorial support.


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. Blood. 2018. [Epub ahead of print]

“The durability of responses to ponatinib in patients with CP-CML is quite exciting. Unfortunately, the responses in patients with other disease subtypes (BP-CML, Ph-positive ALL, etc.) do not appear to be nearly as durable.

The information from the PACE trial also is valuable because it provides clinicians with a guideline for how and when to try potentially curative treatment, like allogeneic transplant for patients with advanced disease who achieve MMR or MR with ponatinib.

The safety profile is not exactly the same for ponatinib as it is for the TKIs. Because arterial vaso-occlusive events may occur more frequently and earlier in patients treated with ponatinib, this is something to which we should pay particular attention. As long-term follow-up data emerge with other TKIs, it may indeed be an effect of the drug class, yet I believe that the ponatinib-treated patients must be particularly closely monitored.

Initiation of ponatinib must be carefully considered on a case-by-case basis, especially for patients at higher risk of arterial occlusive disease (e.g. with a history of diabetes, cardiovascular disease, hypertension). Dose reductions are indicated, particularly as soon as the disease responds to treatment.

One of the important unanswered questions that is now being studied prospectively is whether similar efficacy can be achieved with lower risk of toxicity (particularly the vascular events) when ponatinib is initiated at lower doses. Another issue to be studied is the optimal timing of ponatinib dose reductions. I also wonder whether, in addition to aggressive blood pressure management, the routine use of daily aspirin (or other antiplatelet agent) would be useful.”

Wendy Stock, MD, Anjuli Seth Nayak Professor in Leukemia, The University of Chicago Medicine