Improved Reporting of Cardiovascular Events Needed in Chronic Myeloid Leukemia Clinical Trials

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Second- and third-generation tyrosine kinase inhibitors are associated with a variety of cardiovascular events.
Second- and third-generation tyrosine kinase inhibitors are associated with a variety of cardiovascular events.

The treatment landscape of chronic myeloid leukemia (CML) completely changed with the advent of tyrosine kinase inhibitors (TKIs), which first entered the marketplace in 2001 with the approval of imatinib. Since then, new agents have been developed to treat CML, including the second-generation TKIs nilotinib, dasatinib, and bosutinib and the third-generation TKI ponatinib. The introduction of next-generation TKIs has given patients a wider range of treatment options, and CML has shifted from a once-fatal disease to a chronic condition, with many patients enjoying an expected survival similar to that in the general population.

Despite the benefits, the use of TKIs has also been associated with cardiovascular events (CVE) and the burden of cardiotoxicity could interfere with the ability to administer optimal cancer treatment, which can ultimately compromise patient outcomes. The majority of cardiotoxicities have been associated with the second- and third-generation TKIs and include vascular events such as myocardial infarction, stroke, and peripheral arterial disease. QT prolongation, pleural effusions, and both systemic and pulmonary hypertension have also been reported.

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On one hand, this is a good problem to have, explained Javid J. Moslehi, MD, assistant professor of medicine and director of Cardio-Oncology at Vanderbilt University Medical Center in Nashville, Tennessee. “If you [were diagnosed with] CML 20 years ago, we did not have many effective treatments,” he said. “Now, in many cases, patients can have [a] normal life expectancy.”   

He explained that for many patients with CML, cancer has become a chronic disease. “In the past, only 50% of patients survived initial treatment, and now with chronic-phase CML, 99% are alive,” Dr Moslehi told Hematology Advisor. “Thus, cardiovascular events have become more relevant, and it's become a new problem for patients who are living for many years.”

Dr Moslehi emphasized that new oral drugs have become chronic therapies for the patient. “But each of the 5 therapies approved can have divergent effects on the cardiovascular system,” he said. “Vascular adverse events have been observed with nilotinib and ponatinib and pulmonary hypertension with dasatinib. Not all of them fall into one bucket, and it's important to identify the nature of [cardiovascular] problems so we can better prevent them and treat them.”

To date, collecting quality data on potential cardiovascular safety of TKIs along with other cancer therapies has been somewhat limited, according to a review paper published in Leukemia. CVEs in investigational drug trials are not systematically defined or collected, and therefore cannot be compared across different oncology trials as well as with the general population.

One issue is that adverse events in oncology trials are reported using the Common Terminology Criteria for Adverse Events (CTCAE), which differs from the way outcomes are measured in cardiology trials. ”In most oncology trials,” wrote the authors, “CVEs are often inconsistently defined and combined…compared with cardiovascular outcome studies.”

There is also the possibility of bias in measuring CVE rates in CML studies. It is estimated that about 1 in 3 Americans have 1 or more types of cardiovascular disease (CVD), and those with pre-existing CVD are at a higher risk of future CVEs. Given the incidence of CVD in the general population, it is important to differentiate drug-related from non-drug-related CVEs. Almost all trials evaluating new TKIs have enrolled CML patients who have a history of CVD, and when cardiac safety outcomes are reported, patients with pre-existing CVD have not been assessed in a separate subanalysis. The risk of future CVEs is greater in CML patients with CVD than in both patients without it and those with multiple cardiovascular risk factors.

Another problem is the inconsistency of terminology used to describe CVEs in CML trials compared with cardiology trials. The study authors point out that in order to provide unified care and conduct good quality research, there has to be consistent use of medical terminologies across clinical trials.

In CML trials, a composite endpoint of major adverse cardiovascular events (MACE) is often used to describe CVEs that include non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. In assessing safety of investigational agents in patients with cancer, it is imperative that the American College of Cardiology/American Heart Association (ACC/AHA) definitions of CVEs be used to report them in CML studies.

Finally, the authors recommend a number of strategies that may assist in standardizing reporting of CVEs:

  • Standardized definitions for CVEs should be used based on ACC/AHA recommendations for endpoint definitions in cardiovascular trials, and adding primary cardiovascular safety outcomes should be considered in investigational drug trials with the possibility of adjudication of the endpoints.
  • When conducting a new drug trial, quality data should be collected regarding baseline cardiovascular risk factors and pre-existing CVD.
  • CVEs should be evaluated and reported separately for patients with pre-existing CVD at baseline.
  • Patients who have experienced recent acute coronary syndrome or an acute myocardial infarction and those with stable CVD should not be merged together unless each cohort is sufficiently powered for subgroup analysis of safety and efficacy, as the CVE rates for the groups differ.

“Cardiologists and oncologists need to work together to understand this toxicity to improve outcomes for the patient,” concluded Dr Moslehi.

Reference

1. Aghel N, Delgado DH, Lipton JH. Cardiovascular events in chronic myeloid leukemia clinical trials. Is it time to reassess and report the events according to cardiology guidelines? [published online September 10, 2018] Leukemia. doi: 10.1038/s41375-018-0247-1

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