Vascular Occlusion Risk Reviewed For CML New-Generation TKIs

By Lynda Williams, Senior medwireNews Reporter

A meta-analysis highlights the significantly increased risk of vascular occlusive events in patients with chronic myeloid leukaemia (CML) using some new-generation BCR-ABL tyrosine kinase inhibitors (TKIs) compared with use of imatinib.

The study collated data from 10 clinical trials comparing the second-generation TKIs dasatinib and nilotinib, or the third-generation TKIs ponatinib and bosutinib with the standard of care imatinib in 3043 CML patients.

Vascular occlusive events were reported in nine studies, affecting 5.88% of 1582 patients using a new-generation TKI and 1.04% of patients taking imatinib, with an odds ratio (OR) of 3.45, report Jonathan Douxfils (University of Namur, Belgium) and co-workers in JAMA Oncology.

Subgroup analysis of five dasatinib trials, two nilotinib trials and the single ponatinib trial indicated the agents were all associated with a significantly higher risk of vascular occlusion compared with imatinib, with ORs of 3.86, 3.42 and 3.47, respectively.

"Treatment with dasatinib, nilotinib, and ponatinib should be associated with frequent cardiovascular monitoring and an intensive support of comorbidities", the researchers therefore recommend.

A bosutinib study was also included in the meta-analysis and the third-generation TKI had a non-significant OR of 2.77 for vascular occlusion compared with imatinib, although the researchers note that the BELA study's small size could mask any harmful effects.

While arterial hypertension is the most common vascular adverse events reported for bosutinib, the team cautions that "pleural effusion and other vascular adverse events have been reported that call into question the vascular safety profile of bosutinib and suggest the need of further investigations."

In efficacy analysis, a major molecular response (MMR) was achieved by 44.18% of the 1374 patients given a new-generation TKI compared with 27.35% of the 1053 imatinib-treated participants, giving a significant OR of 2.22.

And subanalysis gave significant ORs for a MMR with dasatinib, nilotinib and bosutinib versus imatinib of 2.17, 2.45 and 1.86, respectively, rising to an OR of 4.95 for ponatinib.

Survival was high, the authors summarise, with 1-year mortality of just 1.49% for patients given new-generation TKIs and 2.01% for imatinib-treated patients, with a non-significant trend towards improved survival for the new-generation agents (OR=1.20).

The choice of second- or third-line TKI should be guided by patient health, mutational analysis and adverse events, say the researchers, adding that "[i]n cases of intolerance or resistance, it is recommended to switch to one of the other TKIs approved for first line therapy".

They continue: "If treatment failure occurs, a more potent TKI is preferred. In this setting, ponatinib, and to a lesser extent bosutinib, should be considered as potential treatment."

However, as ponatinib has been more strongly associated with vascular occlusion in phase I and II studies than other TKIs, the authors qualify their recommendation: "If the patient has the T315I mutation, ponatinib is clearly the rational choice because it is reserved for patients with serious conditions and must be avoided in patients with good prognosis, such as patients with CML in chronic phase without the T315I mutation."

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