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Toxicity may limit use of ponatinib for first-line treatment of CML
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Most patients with newly diagnosed chronic myeloid leukemia in chronic phase achieved a complete cytogenetic response to first-line ponatinib; however, the risk for vascular thrombotic events may limit its use in this setting, according to results of a phase 2 study.
Ponatinib (Iclusig, ARIAD) — a third generation tyrosine kinase inhibitor — is highly active in patients with CML who have a resistance to other TKIs or who harbor a Thr315Ile gene mutation.
Jorge E. Cortes
Jorge E. Cortes MD, deputy department chair, professor of medicine and internist, chair of the acute myeloid leukemia section and D.B. Lane Cancer Research Distinguished Professor for Leukemia Research in the department of leukemia at The University of Texas MD Anderson Cancer Center in Houston, and colleagues conducted a single-arm, phase 2 study to assess whether ponatinib was safe and effective as an initial therapy for patients with CML in chronic phase.
The investigators enrolled 51 patients between May 3, 2012 and Sept. 24, 2013. All patients had early chronic-phase CML and were treated with ponatinib orally once daily. Patients enrolled prior to July 25, 2013 (n = 43) received a starting daily dose of 45 mg. Researchers lowered this dose to tolerability issues to 30 mg per day — which was the starting dose for anyone enrolled after July 25, 2013 (n = 8). Following an FDA warning on Oct. 6, 2013 concerning vascular complication with ponatinib, the researchers assigned all patients 81 mg of aspirin per day and reduced the ponatinib dose to 30 mg or 15 mg per day.
Median follow-up was 20.9 months (range, 14.9-25.2). A total of 94% of evaluable patients (n = 46) achieved a complete response at 6 months.
The most frequent toxicities experienced were skin-related (69%) and elevated lipase (63%). Cardiovascular events — mostly hypertension — occurred in 49% of the patients. Additionally, 29% of the population experienced grade 3 to grade 4 myelosuppression and 10% of the patients developed cerebrovascular or vaso-occlusive disease.
Eighty-five percent of the patients had their treatment interrupted at some point and 88% required dose reductions.
The study was ultimately terminated on June 18, 2014 after an FDA recommendation due to a concern about the increased risk for thromboembolism with ponatinib.
“Our study shows that ponatinib is a very potent TKI with high clinical activity in the first-line treatment of patients with chronic-phase CML,” Cortes and colleagues wrote. “However at the doses currently used in other settings, the safety profile might not be appropriate for treatment of this patient population who have other treatment options with high efficacy. … For now, ponatinib should be used only for patients who have failed other therapies.”
A lower dose of the TKI — such as 30 mg or 15 mg per day — may be enough to maintain an active profile yet reduce the risk for adverse effects, suggesting a possible use of ponatinib in a first-line setting, Massimo Breccia, MD, and Giuliana Alimena, MD, from the department of cellular biotechnologies and hematology at Sapienza University in Rome, wrote in an accompanying editorial.
Also, they suggested most of the patients who developed cardiovascular events may have been predisposed to them because of age or other comorbidities.
“It is of importance to assess cardiovascular risk profiles at baseline, excluding patients with previous myocardial infraction, stroke and severe peripheral arterial disease, and to strictly monitor and manage during follow-up hypertension and metabolic disorders,” they wrote. – by Anthony SanFilippo
Disclosure: The study was funded by MD Anderson Cancer Center, NCI and ARIAD Pharmaceutical. Cortes reports research funding from and consultant/advisory roles with ARIAD, Bristol-Myers Squibb, Novartis, Pfizer and Teva. Breccia and Alimena report no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Eunice S. Wang, MD
Imatinib (Gleevec, Novartis) has served as the standard of care for upfront therapy of chronic myeloid leukemia since its approval in 2001. However, with the recent development of newer, second- and third-generation tyrosine kinase inhibitors (TKIs) and the expected availability of generic imatinib in 2016, treatment decisions for patients with newly diagnosed chronic phase CML have become increasingly complicated.
Ponatinib (Iclusig, ARIAD) is a much heralded and highly potent third-generation TKI with demonstrated preclinical efficacy against both native and mutant CML cells with known resistance to prior TKIs. Although approved for the treatment of CML refractory to at least 2 prior TKIs, this drug has not previously been evaluated as frontline CML therapy.
Jain and colleagues from The University of Texas MD Anderson Cancer Center recently reported the results of a phase 2 trial of ponatinib in de novo CML patients. Despite the small number of patients enrolled (only 51), their results clearly show that ponatinib leads to the highest and deepest response rates ever reported with any TKI in this setting.
Ninety percent of evaluable patients achieved a complete cytogenetic response rate after 3 months, with 94% achieving a BCR/ABL ratio of 10% or less. This compares favorably with rates of 65% seen in imatinib-treated patients and 85% to 90% in dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) or nilotinib (Tasigna, Novartis)-treated patients. Based on these results, ponatinib is undeniably the most effective TKI ever reported for CML therapy.
Despite these impressive results, however, I agree wholeheartedly with the authors that ponatinib should never be used for upfront CML treatment pending further studies.
Why you ask?
First of all, there is no guarantee that these improved responses following ponatinib actually translate into improved clinical outcomes. In the past, although first-line therapy with dasatinib and nilotinib similarly improved the rate, depth and time to response in patients as compared with imatinib, neither of these TKIs resulted in improved OS or EFS.
Secondly, ponatinib therapy resulted in what I would consider unacceptably high toxicity in CML patients.
Almost 90% of patients required dose interruption and dose reduction, 49% developed at least one cardiovascular event (mostly hypertension) and a 10% experienced cerebrovascular or vaso-occlusive disease. Although many patients had known cardiovascular risk factors (ie, hypertension, obesity, etc), in this study and the prior PACE trial, some individuals with no risk factors had events.
It also remains unclear, given the small number of patients treated here, whether reducing the dose of drug from 45 mg to 30 mg or even 15 mg or requiring concomitant aspirin use had any effect at all in mitigating these toxicities.
Studies addressing these questions and the most appropriate effective dose of ponatinib for CML therapy are ongoing. Until these are resulted, given the abundance of other options, I would reserve ponatinib therapy for those CML patients failing all other options. For the rest, I would argue that imatinib still remains a valid treatment option, even 14 years later. In this case, newer is not always better.
References:
Cortes JE, et al. J Clin Oncol. 2012;30:3486-3492.
Hughes TP, et al. Blood. 2014;doi:10.1182/blood-2013-06-510396.
Jabbour E, et al. Blood. 2014;doi:10.1182/blood-2013-06-511592.
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