In this clinical presentation, the speaker reviews data on ponatinib for chronic-phase chronic myeloid leukemia (CML), emphasizing its high potency and associated toxicity. Two major studies are compared: the PACE trial, which used a continuous 45 mg daily dose of ponatinib, and the OPTIC trial, which employed a dose‑optimization strategy—starting at 45 mg (or 30 mg/15 mg) and reducing to 15 mg daily once patients achieved a PCR ≤1%. The speaker reports that ponatinib yields a 50% complete cytogenetic response (CCyR) within two years for patients resistant to second‑generation TKIs, with an estimated 2‑year survival of 85–93%. Efficacy between the continuous‑dose PACE regimen and the dose‑adjusted OPTIC regimen is comparable, with a trend toward better outcomes in OPTIC. Crucially, the toxicity profile improves markedly with dose adjustment: arterial‑occlusive events drop from 16% in PACE to 3% in OPTIC, and severe adverse events are similarly reduced. The conclusion is that a dose‑adjusted ponatinib schedule maintains high efficacy while substantially lowering toxicity, supporting its use in chronic‑phase CML after prior second‑generation TKI exposure.
Chapters
So I'm going to start by discussing first the data on ponatinib in chronic phase CML. So as you know, in chronic myeloid leukemia, we have 5 BCR-ABL tyrosine kinase inhibitors, which are highly effective. In the frontline and salvage setting, we often use either imatinib or a second generation tyrosine kinase inhibitors. But oftentimes we are using also the second generation kinase inhibitors frontline. Now ponatinib is probably the most potent, but also the more toxic BCR-ABL kinase inhibitor. And there has been a reluctance at using ponatinib, particularly at the FDA approved dose of 45 milligrams daily continuously. Since it is felt that ponatinib is very potent, the question is, can we alleviate the side effects which are worrisome? And these include vaso-occlusive disease, hypertension, skin rashes, pancreatitis, and others. So in this study, what we did is compare the results of ponatinib at 2 dose schedules. The first one is from an older study, which is called the PACE trial, where ponatinib was given to patients at the FDA-approved dose of 45 milligrams daily continuously. And the dose was not reduced unless there were side effects. And then we compared the results to one of the arms of what's called the OPTIC trial. So the OPTIC trial is a dose optimization study where patients with chronic phase CML who are resistant to previous tyrosine kinase inhibitors receive ponatinib at either 45, 30, or 15 milligrams at the starting dose. And then they were all reduced to 15 milligrams a day once they achieved PCR level of less than 1%. So what we found are 2 things. One is that ponatinib is probably the most highly active drug. So if you take patients who are resistant to second-generation kinase inhibitors, and you give them another second-generation kinase inhibitor, the results are not that good. The response rate is lower, and the survival is not that great. When they are resistant to second-generation kinase inhibitors, and we give them ponatinib, we found that 50% of them achieve a complete cytogenetic response by 2 years of therapy. But most importantly, the estimated 2-year survival rate was 85 to 93%. So a highly effective drug. Now, when we looked at the efficacy of patients on the PACE trial, which received ponatinib 45 milligrams daily continuously, versus the patient on the OPTIC arm who received 45 milligrams daily, and then they were reduced to 15 milligrams daily once they achieved the PCR level of 1% or less. We found that the results in terms of efficacy are equivalent. In fact, the patients on the latter trial, the OPTIC, had a trend for better results than on the PACE. Now, more importantly is the toxicity profile. So when we looked, for example, at the incidence of arterio-occlusive disease, that incidence was 16% on the PACE trial, And it was only 3% on the OPTIC trial. And the same applied to the other incidence of severe side effects. So what we concluded from this study is ponatinib is highly effective, but also equally importantly, that the dose-adjusted schedule of starting with ponatinib 45 milligrams daily, and reducing it to 15 milligrams daily once we had an optimal response was not only effective, but also quite safe. So that's the first study of ponatinib, the comparative analysis of the chronic phase CML data using ponatinib at the FDA-approved dose schedule with dose adjustments, or at the dose-adjusted dose schedule with the OPTIC trial that demonstrated a high efficacy, And less toxicity with the dose-adjusted schedule.
