Tips for Managing CV Toxicity With TKIs in Leukemia Patients

Veronica Hackethal, MD

September 17, 2015

Practical recommendations for managing cardiovascular risk in patients with chronic myeloid leukemia (CML) who are taking tyrosine kinase inhibitors (TKIs) are outlined in a review published online September 14 in the Journal of Clinical Oncology.

The review was prompted by recent advances in oncology, which have seen TKIs improve survival in many patients with CML. For the growing number of patients with CML who are treated with long-term TKI therapy, this has resulted in the need for long-term follow-up to monitor for toxicity.

"For most patients, TKIs have turned CML into a chronic disease. Since TKIs are generally not curative, most patients require long-term therapy," authors Michael Deininger, MD, PhD, from the University of Utah in Salt Lake City, and Javid Moslehi, MD, from the Vanderbilt University School of Medicine in Nashville, Tennessee, said in an email to Medscape Medical News.

Moreover, the age at which most people are diagnosed with CML coincides with the age when cardiovascular disease becomes more common — about 60 years. That makes TKI-related cardiovascular risk a particular concern in these patients, according to Drs Deininger and Moslehi.

"Given the high population frequency of cardiovascular disease and the fact that many CML patients are older, cardiovascular risk assessment and, if necessary, treatment need to be integrated into the management of patients with CML on TKIs," they emphasized. "This is particularly important given the increased frequency of vascular events with nilotinib and ponatinib."

Imatinib (Gleevec, Novartis) was the first TKI to improve survival in CML and the first to be granted approval by the US Food and Drug Administration (FDA). Although data from in vitro studies, mouse studies, and case series have linked imatinib to cardiac toxicity, long-term follow-up suggests a "low incidence of cardiomyopathy," according to the authors. Retrospective analyses of phase 3 clinical trials have even suggested that imatinib is protective. On the whole, the suggestion is that nonhematologic adverse events are "typically manageable" with imatinib.

The newer second- and third-generation TKIs improved responses and decreased disease progression rates in CML, although recent reports of cardiovascular toxicity with these drugs have raised concerns about their long-term effects.

Dasatinib (Sprycel, Bristol-Myers Squibb) is approved for first-line therapy in CML. After the first case of dasatinib-related pulmonary arterial hypertension was reported in 2009, the FDA issued a warning in 2011 about cardiopulmonary risks related to dasatinib, and recommended screening for cardiopulmonary disease before and during dasatinib therapy without indicating what specific types of screening to use. Drs Deininger and Moslehi recommend an echocardiogram with Doppler flow, and suggest referral to a cardiologist when indicated. The evidence is "not entirely clear" about whether dasatinib increases the risk for cardiovascular events, they point out.

Nilotinib (Tasigna, Novartis), also first-line in CML, may prolong the QT interval, according to results from phase 1 studies. Monitoring for QT prolongation and avoidance of medication that could increase the QT interval is recommended.

Studies have suggested increased risk for hyperglycemia and abnormal lipids with nilotinib therapy. Reports of ischemic heart disease, ischemic cerebrovascular disease, and peripheral artery disease have suggested that nilotinib could aggravate pre-existing atherosclerotic disease. The European Medicines Agency has recommended close cardiovascular monitoring for patients on nilotinib, including fasting blood lipids and blood glucose levels. The nilotinib drug label has been updated to include vascular events in the toxicity profile.

Bosutinib (Bosulif, Pfizer) is approved as salvage therapy in CML. Current evidence suggests a "relatively low" incidence of cardiovascular adverse events and "reassuring" cardiovascular safety with the drug, although longer follow-up is needed, according to the authors.

The third-generation ponatinib (Iclusig, Ariad) was specifically designed to target BCR-ABL1. It carries the highest cardiovascular risk among the FDA-approved TKIs, which has limited its use in patients with the BCR-ABL1 mutation, they note. Ponatinib also inhibits the VEGFR signaling pathway, which has been linked to hypertension and thrombosis. Clinical trial data have led to the suggestions that ponatinib-related cardiovascular toxicity is dose-dependent and that older patients with diabetes or previous ischemic events are most vulnerable. Dose-optimization studies are needed, the authors point out.

Although some patients will "undoubtedly" benefit from ponatinib, risk factor modification and dose reduction, once the desired response has been achieved, is important, they write. They provide a checklist for consideration.

Table. ABCDE Checklist for the Prevention of CVD in Patients With CML on TKIs

A Awareness about cardiovascular disease
  Aspirin (in select patients)
  Ankle-brachial index at baseline and follow-up to assess peripheral arterial disease
B Blood pressure control
C Cigarette, tobacco cessation
  Cholesterol monitoring and treatment as indicated
D Diabetes monitoring and treatment as indicated
  Diet and weight control
E Exercise

 

Drs Deininger and Moslehi also provide more detailed provisional recommendations for specific TKIs and cardiovascular follow-up. They emphasized the need for prospective studies that use terminology for classifying cardiovascular toxicity that is similar to terminology used in cardiology trials.

"We need better mechanistic understanding of the cardiovascular toxicities in newer TKIs to make more evidenced-based recommendations. More accurate reporting of cardiovascular events in clinical trials is critical to achieve this. In addition, we need better preclinical models to elucidate the mechanisms of toxicities," they conclude.

Dr. Deininger reports consulting/advising for, providing expert testimony, and/or receiving travel/accommodation expenses from Novartis, Bristol-Myers Squibb, Incyte, ARIAD, Pfizer, and Celgene (Inst). Dr. Moslehi reports consulting/advising for Novartis, ARIAD, Takeda/Millennium, Bristol-Myers Squibb, and Acceleron Pharma.

J Clin Oncol. Published online September 14, 2015. Abstract

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