BCR-ABL Tyrosine Kinase Inhibitors May Increase Cardiovascular Events in Chronic Myeloid Leukemia

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Dasatinib, nilotinib, and ponatinib may improve major molecular response, but they may increase cardiovascular occlusive events in chronic myelogenous leukemia.
Dasatinib, nilotinib, and ponatinib may improve major molecular response, but they may increase cardiovascular occlusive events in chronic myelogenous leukemia.

New-generation BCR-ABL tyrosine kinase inhibitors (TKIs) dasatinib, nilotinib, and ponatinib may help improve major molecular response (MMR), but they do not improve overall survival at 1 year and may increase cardiovascular occlusive events in patients with chronic myelogenous leukemia (CML), an analysis has found.1

When choosing a TKI for treatment, the team of investigators suggested that the decision be based on the treatment goals and the patient's medical background and condition. And until further research uncovers specific risk factors for cardiovascular occlusive events, all patients being treated with these new-generation TKIs should be frequently monitored during treatment, with continued long-term follow-up.

Comparing Imatinib With New-generation TKIs

After a phase 3 trial with ponatinib in patients with CML was halted due to increases in vascular occlusive events, Belgium researchers decided to investigate whether a similar risk may be occurring in other new-generation TKIs[LB1] . In an effort to assess the global benefit-risk, the team included MMR and overall survival in its meta-analysis.

Using data collected from PubMed, Scopus, the Cochrane Library database, international congress abstracts, and trial registries, the researchers analyzed 10 randomized clinical trials (3043 patients) and found that the risk of vascular occlusive events increased with dasatinib (overall response [OR], 3.86), nilotinib (OR, 3.42), and ponatinib (OR, 3.47) compared with imatinib in patients with CML. No significant differences were found with bosutinib (OR, 2.77).

“We suggest that patients treated with these molecules should be more frequently monitored,” study author Jonathan Douxfils, PharmD, PhD, of the University of Namur in Brussels, Belgium, told Cancer Therapy Advisor.  “As we did not have access to individual data, it was impossible to clearly identify categories of patients for whom the risk of cardiovascular occlusive events is predominant. Therefore, the intensive monitoring proposed should be applied to all patients treated with these molecules.”

The analysis showed that new-generation TKIs increased the rate of MMR at 1 year compared with imatinib (OR, 2.22). But the researchers found that there were no statistical differences in overall survival at 1 year.

Choosing the Right TKI Therapy

Based on these data, Douxfils said that physicians should consider treatment goals when choosing the best TKI therapy.

For older patients, he said improving survival is the main objective, which means imatinib is still an excellent choice. For patients with a life expectancy of more than 10 years who are being treated to achieve a deep molecular response so they can potentially end treatment, dasatinib and nilotinib should be preferred.

However, he cautioned that before using dasatinib or nilotinib as first-line treatments, doctors should screen patients for potential risk factors such as diabetes and prior vascular occlusive events. For second- and third-line treatment, Dr Douxfils said that the treatment choice should be based on mutational analysis, previous adverse events, and the patient's medical condition.

RELATED: CML: Study Evaluates Long-term Outcomes After Imatinib Discontinuation

“In case of intolerance or resistance, patients can be switched to one of the other TKIs approved for first-line therapy,” he said in an interview with Cancer Therapy Advisor. “If treatment failure still occurs, a more potent TKI, such as bosutinib or ponatinib, is preferred.”

He further warned that ponatinib is reserved for patients with the T315I mutation and should be avoided in those with good prognosis.

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