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New-generation TKIs for CML increase risk for cardiovascular events
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Certain new-generation tyrosine kinase inhibitors increased risk for vascular occlusive events without improving the rate of 1-year OS among patients with chronic myeloid leukemia, according to results of a meta-analysis.
“Dasatinib [Sprycel, Bristol-Myers Squibb], nilotinib [Tasigna, Novartis] and ponatinib [Iclusig, Ariad] are associated with a higher rate of vascular occlusive events than imatinib [Gleevec, Novartis],” Jonathan Douxfils, PharmD, PhD, research assistant at Universitè de Namur and an external pharmacovigilance expert for the Federal Agency for Medicines and Health Products in Belgium, told HemOnc Today. “We suggest that specific cardiovascular monitoring should be applied to all patients treated with these [agents].”
Jonathan Douxfils, PharmD, PhD
A previous phase 3 trial of ponatinib in patients with CML was interrupted due to an increase in vascular occlusive events. A similar risk was identified in other studies with the TKI nilotinib.
Thus, Douxfils and colleagues conducted this analysis to assess the risk for vascular occlusive events and clinical benefit associated with new-generation TKIs compared with imatinib among patients with CML.
The investigators analyzed data from 10 randomized clinical trials that included a total of 3,043 patients and had findings reported prior to Oct. 21, 2014.
Overall, TKIs dasatinib (OR = 3.86, 95% CI, 1.33-11.18), nilotinib (OR = 3.42; 95% CI, 2.07-5.63) and ponatinib (OR = 3.47; 95% CI, 1.23-9.78) appeared to increase risk for vascular occlusive events compared with imatinib.
A fourth TKI, bosutinib (Bosulif, Wyeth), showed an insignificant trend toward greater risk than imatinib (OR = 2.77; 95% CI, 0.39-19.77).
The researchers did not have access to individual data and, thus, they were not able to identify categories of patients for whom the risk for cardiovascular occlusive events may be predominant, Douxfils said.
“Importantly, our study does not discriminate between arterial or venous occlusive events and this needs to be addressed,” Douxfils added. “Also, the underlying mechanism behind the vascular occlusive potential of these drugs should be further investigated.”
For example, it is known that nilotinib-treated patients might develop increased fasting glucose levels as well as elevated cholesterol levels, which could be different for dasatinib and ponatinib, Douxfils said.
In addition, he said dose-ranging studies are needed to determine the optimal starting and maintenance doses for these treatments.
“These studies may provide helpful information to further propose additional risk minimization strategies and maybe identify new biomarkers of this risk,” he said.
TKIs increased the 1-year rate of major molecular response compared with imatinib (OR = 2.22; 95% CI, 1.87-2.63); however, there was no statistical difference in 1-year OS (OR = 1.2; 95% CI, 0.63-2.29).
“We suggest that regulatory agencies reassess the risk of vascular occlusive events with all BCR-ABL TKIs and discuss the need for class risk minimization strategies,” Douxfils said. “Finally, we are convinced that there is also a need to reinforce and harmonize the reporting of cardiovascular events in cancer trials, but also in specific registries, to prospectively collect data in a real-life setting.” – by Anthony SanFilippo
For more information:
Jonathan Douxfils, PharmD, PhD, can be reached at jonathan.douxfils@unamur.be.
Disclosure: Douxfils reports no relevant financial disclosures. Two researchers report receiving personal fees from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb-Pfizer, Celgene and Novartis.
Perspective
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Eunice S. Wang, MD
The development of BCR-ABL inhibitors for chronic myeloid leukemia radically altered the natural history of this disease, changing it from a life-threatening cancer into a chronic manageable condition for most patients.
Given the current availability of multiple tyrosine receptor inhibitors, the challenge in treating patients with CML now largely involves an issue perhaps more familiar to primary care physicians than medical oncologists: how to select the most appropriate tyrosine kinase to ensure patient compliance and minimize toxicities over years of therapy.
The researchers of the current article directly tackle this question of the risk–benefit ratio of TKI therapy.
They performed a meta-analysis of 10 randomized clinical trials involving 3,043 patients with CML receiving TKI therapy. The conclusions, bolstered by different statistical methods, are startling.
Out of the five available TKIs, three — dasatinib (Sprycel, Bristol-Myers Squibb), nilotinib (Tasigna, Novartis) and ponatinib (Iclusig, Ariad) — were associated with a significantly increased rate of vascular occlusive events compared with imatinib (Gleevec, Novartis) with a trend toward significance for the fourth TKI, bosutinib (Bosulif, Wyeth).
Although increased vascular events have prominently been reported with ponatinib, this analysis is the first to suggest that the second-generation TKIs (nilotinib and dasatinib) have similarly high cardiovascular risk profiles. Of note, the specific toxicities associated with each TKI are different: bleeding and pulmonary issues with dasatinib, and vascular occlusive events with nilotinib and ponatinib. The “safest” TKI appears to be the first, imatinib.
Are these newer TKIs worth the trouble? Yes and no.
Douxfils and colleagues demonstrate that newer-generation TKIs are dramatically better than imatinib in inducing major molecular response (MMR) after 1 year of therapy. However, OS at 1 year was not statistically different for imatinib vs. other TKIs.
This meta-analysis is limited by the lack of individual patient data, long-term survival data and inconsistent reporting of vascular events in these clinical trials. Nevertheless, the conclusions of this study are important.
With the exception of ponatinib, it is almost certain that prospective clinical trials addressing the most appropriate dose or duration of TKI therapy to minimize cardiovascular toxicities will never be performed. Therefore, this study is an important reminder that the choice of TKI therapy for individual patients is not benign.
Older individuals with a greater number of comorbidities and shorter overall life expectancies may benefit from imatinib as opposed to newer TKIs. Younger patients with CML and fewer cardiovascular risk factors could receive newer-generation TKIs with the goal of achieving earlier MMR and future discontinuation of TKI therapy.
Medical oncologists should work closely together with other medical providers to optimize the management of diabetes, hypertension, hyperlipidemia and coronary artery disease in our patients with CML on TKI therapy, as these conditions increasingly appear to result in mortality and morbidity in our patients.
Over the last decade-and-a-half, the prospect of dying of CML has dramatically diminished. To better serve our patients, however, we must also ensure that the years of life achieved for these patients are not cut short by adverse outcomes from other non-leukemia causes.
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