Meta-Analysis Confirms CML New-Generation TKI Vascular Occlusion Risk

Research indicates the magnitude of the risk of vascular occlusive events with new-generation tyrosine kinase inhibitors compared with imatinib

medwireNews: Dasatinib , nilotinib and ponatinib are all associated with a significantly greater risk of vascular occlusive events in patients with chronic myeloid leukaemia (CML) compared with imatinib treatment, suggests a meta-analysis of tyrosine kinase inhibitor (TKI) studies.

Writing in JAMA Oncology, the team therefore recommends: “Treatment with dasatinib, nilotinib, and ponatinib should be associated with frequent cardiovascular monitoring and an intensive support of comorbidities.”

Jonathan Douxfils, from the University of Namur in Belgium, and co-authorsidentified 10 clinical trial reports that compared second- and third-generation BCR–ABL TKIs with the standard of care imatinib, for a total of 3043 CML patients, and included reports of arterial or venous thrombosis.

Vascular occlusive events were identified in 5.88% of the 1582 patients treated with new-generation TKIs versus 1.04% of 1253 patients treated with imatinib, giving a Peto method odds ratio (OR) of 3.45 for this type of side effect.

When compared with imatinib, subgroup analysis indicated that the second-generation TKIs dasatinib and nilotinib, and the third-generation TKI ponatinib were all associated with a significantly increased risk of vascular occlusion, with ORs of 3.86, 3.42 and 3.47, respectively.

The OR for vascular occlusive events was 2.77 for the third-generation TKI bosutinib versus imatinib, and although this did not reach significance, the researchers caution that the meta-analysis included only one small study for this TKI and vascular adverse effects were reported for three bosutinib-treated patients versus one patient in the imatinib group.

“Most of these vascular adverse events involved arterial hypertension”, they note. “Nevertheless, 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.”

Efficacy analysis indicated that 44.18% of 1374 patients given a new-generation TKI achieved a major molecular response (MMR) compared with 27.35% of 1053 patients treated with imatinib, giving a significant OR of 2.22. The ORs for dasatinib, nilotinib and bosutinib were a comparable 2.17, 2.45 and 1.86, respectively, rising to 4.95 for ponatinib.

There was a “high rate of survival” for the CML patients, the researchers report, with 1-year mortality rates of 1.49% and 2.01% for the new-generation TKI and imatinib treatment groups, respectively. The OR for overall survival was 1.20 in favour of new-generation TKIs but this did not reach significance.

While there is a lack of long-term results for most of the new-generation TKIs, the authors note that a recent study suggested an improvement in 5-year overall survival for nilotinib versus imatinib. In the absence of such trial findings for dasatinib, they write that “further data are required before any conclusions can be drawn on its overall benefit in CML.”

Jonathan Douxfilset al emphasize that the choice of second- and third-line TKIs should be based on adverse events, individual patient health and mutational analysis.

“In cases of intolerance or resistance, it is recommended to switch to one of the other TKIs approved for first line therapy”, they write.

Acknowledging that phase I and II trials have reported higher rate of vascular occlusion with ponatinib than other TKIs, the researchers recommend: “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.”

They add: “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.”


Douxfils J, Haguet H, Mullier F, et al. Association between BCR–ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival. A systematic review and meta-analysis. JAMA Oncol 2016; Advance online publication 4 February.doi:10.1001/jamaoncol.2015.5932

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