A Call for More Research and Regulation

Moving forward, Dr Douxfils urged regulatory agencies to reassess the risk of vascular occlusive events with these agents. He also said that cardiovascular events in cancer trials must be consistently reported and that specific registries should be implemented to prospectively collect these data in a real-life setting.

For example, in this investigation, the researchers did not have access to individual data and time-to-event data. And they noted that differences in evaluation criteria among studies could have introduced bias.

Side effects of imatinib compared with the new-generation TKIs also must be studied further and weighed when choosing a therapy. For example, imatinib has been found to improve the fasting blood glucose level in patients with diabetes and CML.2

But dasatinib has been associated with bleeding-related events, fluid retention, cardiovascular events, pulmonary arterial hypertension, and QT prolongation.3 Investigators have found that nilotinib may be associated with arterial vascular occlusive events.4

“Clinical trials are good at proving the efficacy of a drug, but they are often significantly limited by their ability to determine potential side effects due to the limited number of patients and relatively shorter follow-up,” said Rizwan Romee, MD, assistant professor of medicine, Washington University School of Medicine in St. Louis, MO, in an interview with Cancer Therapy Advisor.

He said that based on the results from this study, clinicians must rethink how they choose TKIs for patients with CML and carefully monitor them for any major cardiovascular events. Dr Romee also stressed the importance of designing prospective studies aimed at reducing the cardiovascular complications from these agents.

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Michael Mauro, MD, professor at Weill Cornell Medicine and attending physician at Memorial Sloan Kettering Cancer Center in New York, NY, added that it is important to examine aggregate data from multiple trials with all the available TKIs to help better understand the vascular toxicity observations. He said clinicians should factor in the competing agendas of leukemia response, consequential side effects, and, ultimately, overall survival.

“We have a new era in the treatment of CML where the disease has become functionally curable, and this requires a change in perspective,” Dr Mauro told Cancer Therapy Advisor. “Success in the war against CML means minimizing collateral damage from side effects and viewing the race to remission as a marathon, not a sprint. We have highly effective therapies with relatively low risk; we need to be critical and use them with great precision.”

References

  1. 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 [published online ahead of print February 4, 2016]. JAMA Oncol. doi: 10.1001/jamaoncol.2015.5932.
  2. Breccia M, Muscaritoli M, Aversa Z, et al. Imatinib mesylate may improve fasting blood glucose in diabetic Ph+ chronic myelogenous leukemia patients responsive to treatment. J Clin Oncol. 2004;22(22):4653-4655.
  3. Highlights of Prescribing Information, Sprycel (dasatinib). U.S. Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021986s014lbl.pdf. Published 2014. Accessed February 12, 2016.
  4. Rea D, Mirault T, Cluzeau T, et al. Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia. Haematologica. 2014;99(7):1197-1203.