Recap: Finding the Optimal Dose of Ponatinib for Chronic Phase CML


Experts discuss use of ponatinib in chronic myeloid leukemia and optimal dosing.

Decreasing the dose of ponatinib (Iclusig) among adults with chronic-phase chronic myeloid leukemia (CP-CML) may help reduce the risk of significant adverse events (AEs) while inducing good responses among patients resistant to or intolerant of tyrosine kinase inhibitors (TKIs) in earlier lines of therapy.

In December 2020, the FDA approved a supplemental new drug application for ponatinib, a third-generation TKI, to treat patients with CP-CML following at least 2 prior TKIs.1 The drug had received previous approval to treat adults with accelerated-phase or blast-phase CML or Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL) where no other TKI was indicated, T315I-positive CML, or T315I-positive/Ph-positive ALL.2

The pivotal phase 2 PACE trial (NCT01207440) showed impressive efficacy of ponatinib in patients with CML who had either resistance to or unacceptable toxicity with dasatinib (Sprycel) or nilotinib (Tasigna) or harbored BCR-ABL T315I mutations. In those with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response.3

However, serious AEs with ponatinib were concerning. The phase 2 OPTIC study (NCT02467270) study published in Blood in November 2021 explored a novel, response-based, dose-reduction strategy to reduce AEs while providing patients with optimal responses to therapy.4

Jorge E. Cortes, MD, director of the Georgia Cancer Center at Augusta University, and Hagop M. Kantarjian, MD, professor and chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, reviewed the use of ponatinib in patients with CP-CML who were ineligible for treatment with other TKIs in a recent CancerNetwork® Between the Lines program. Cortes was lead investigator of the OPTIC trial. “We now know that ponatinib is probably one of the most potent BCR-ABL tyrosine inhibitors, and it also is the one that has the most toxicities,” Kantarjian said.

Despite its impressive efficacy, Cortes pointed to the notable rate of arterial occlusive events (AOEs). In results presented in 2018 by Caocci et al, the most frequent AOEs seen in patients treated with ponatinib were myocardial infarction, ischemic cerebrovascular events, and peripheral vascular disease and occurred more frequently among patients 60 years or older.5

OPTIC Study Overview and Results

The OPTIC study included 283 patients with CP-CML who had previously received at least 2 TKIs or who harbored the T315I point mutation. “More than 90% [of the patients in the study] had received 2 TKIs or more, [and] more than 60% had received 3 TKIs or more,” Cortes said in the discussion.

This aim of the trial was to investigate the achievement of BCR-ABL transcript level of 1% or lower, with rates of molecular, cytogenetic, and hematologic responses and survival outcomes as secondary outcomes. Safety outcomes included evaluation of AEs in relation to discontinuation, dose reductions, and dose interruptions.

Participants were randomized into 1 of the 3 starting dose cohorts of either
45 mg, 30 mg, or 15 mg of ponatinib daily, with 94 patients in each group. Patients in the 45-mg and 30-mg cohorts would lower their dosage to 15 mg once they reached a response of 1% or lower BCR-ABL1 transcript levels at 12 months. Key takeaways from the findings were that patients with resistant CP-CML showed clinical benefits with the drug, regardless of the starting dose, but the optimal benefit was seen among the patients who started at 45 mg and reduced dosage to 15 mg once there was a response.

The results revealed promising responses across dosing strategies, although 18 patients (19.1%) in the 45-mg cohort, 15 (16.0%) in the 30-mg cohort, and 13 (13.8%) in the 15-mg cohort discontinued treatment. The most frequently cited reason for discontinuation was lack of efficacy, but most of these patients (77.4%) were in the 2 lower-dose cohorts.

“An important element of the design of the study was that once a patient achieved [optimal] response, they should lower the dose to 15 mg daily,” said Cortes. “This was a response-directed dose reduction, not a toxicity-driven dose reduction.” Seventy-three patients in the 45-mg cohort dropped to 15 mg after achieving the primary end point; of those, 55 (75%) maintained that response whereas 7 had to reescalate the dose.

Cortes pointed out that the 12-month rate of BCR-ABL transcript level at or
below 1% in the 45-mg cohort was 44.1% compared with 29.0% in the
30-mg cohort and 23.1% in the 15-mg cohort. Additionally, the benefit among the highest-dose group was already evident at 6 months. Patients with T315I point mutations also showed improvement with the higher dose. “The response rate for these patients is 60% [on 45-mg starting dose], whereas for patients [who] received 30 mg, it’s only 25.0% and even lower at 10.5% for the 15-mg [cohort],” he said.

More Serious AEs Observed

More frequent and severe AEs were noted in the 45-mg cohort of the OPTIC trial. Forty-two patients (44.7%) in the 45-mg cohort, 32 (34.0%) in the 30-mg cohort, and 29 (30.9%) in the 15-mg cohort had to reduce the dose of ponatinib due to treatment-emergent AEs (TEAEs).

Overall, the most common hematologic TEAEs were thrombocytopenia (40%), neutropenia (26%), and anemia (19%). Among the nonhematologic TEAEs were arterial hypertension (28%), headache (18%), and increased lipase (17%).

Four patients—2 each in the 45-mg and 15-mg cohorts—died due to TEAEs. Of these, the patients who received the higher dose had cardiovascular risk factors at baseline.5

Future Implications and Closing Thoughts

During the discussion, Kantarjian questioned whether giving ponatinib in earlier lines of therapy for patients who have failed frontline, second-generation TKIs would be worthwhile. He pointed out that patients on second-generation treatments who fail because of resistance are then rotated through other second-generation TKIs.

“If the patients fail because of toxicity, then you cannot rotate the second-generation TKIs,” Kantarjian added. “If they failed because of resistance, I think the first salvage therapy that would be most effective will probably be with ponatinib.” He followed this by saying further data analysis or additional randomized studies would be needed. Cortes agreed, seeing this as a great unmet need.

Both physicians agreed that ponatinib remains a necessary part of the treatment armamentarium for certain patients with CML, but they disagreed on some specifics such as initial dosing. “I think [it’s] a useful drug in [CML] in the salvage setting and maybe needs to be moved to salvage 1,” Kantarjian said. Although both agreed that 45 mg is needed initially in patients with T315I point mutations as the induction dose, Kantarjian prefers to use 30 mg as a starting dose in all other situations whereas Cortes prefers 45 mg.

Kantarjian also rounded back to the toxicity related to ponatinib. “[It] is a drug [for which] we have to be very respectful of the toxicities,” he said. “We’re not just talking about arterial occlusive events, which can be really serious [and can lead to] mortality, loss of vision, mesenteric occlusion, and peripheral arterial occlusive disease. You’re talking about severe hypertension, severe skin rashes, and pancreatitis.”

As to when to start using ponatinib, Kantarjian does not feel it should be an early go-to treatment. “Now that the TKIs are generic, the issue of cost is not there. And we know very well the long-term [AEs] which are quite reasonable with imatinib [Gleevec] and second-generation TKIs,” he said. But for patients who are at high risk and for whom other therapies are no longer warranted, the risks of using ponatinib are reasonable. “We need to take this in the context of what’s at stake and then balance the risk-benefit ratio.”


  1. U.S. FDA approves supplemental new drug application for Takeda’s Iclusig (ponatinib) for adult patients with resistant or intolerant chronic-phase CML. Takeda Pharmaceutical Co Ltd. December 18, 2020. Accessed April 4, 2022.
  2. Iclusig. Prescribing information. Takeda; 2012. Accessed April 4, 2022.
  3. Cortes JE, Kim DW, Pinilla-Ibarz J, et al; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome–positive leukemias. N Engl J Med. 2013;369(19):1783-1796. doi:10.1056/NEJMoa1306494
  4. Cortes J, Apperley J, Lomaia E, et al. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial. Blood. 2021;138(21):2043-2050. doi:10.1182/blood.2021012082
  5. Caocci G, Mulas O, Abruzzese E, et al. Arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life practice: prophylaxis and identification of risk factors. Blood. 2018;132(suppl 1):3006. doi:10.1182/blood-2018-99-111502
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