By Marilynn Larkin
NEW YORK (Reuters Health) - 26/9/2019
Ibrutinib, a BTK inhibitor, is associated with severe and occasionally fatal cardiac events that should be discussed with patients and considered in clinical trial designs, a retrospective observational study reveals.
"Ibrutinib has been a revolutionary drug and has been very effective for a number of cancer types," Dr. Javid Moslehi of Vanderbilt University in Nashville, told Reuters Health by email. "However, when used in front-line setting, we have seen an increased number of sudden deaths."
Indications for ibrutinib include chronic lymphocytic leukemia, mantle cell lymphoma, Waldenstrom's macroglobulinemia, and refractory chronic graft-versus-host disease. "Using a public database, we (found) more than 300 deaths related to ibrutinib that are probably cardiovascular in nature," Dr. Moslehi said.
"By no means does this mean that the drug should not be used, but in my opinion, the public should be aware of these toxicities," he noted. "Physicians need to be aware of this and I think the scientific and medical community needs to better delineate the nature of the deaths and cardiovascular events."
Dr. Moslehi and colleagues studied cardiovascular adverse drug reactions associated with ibrutinib using VigiBase, an international pharmacovigilance database.
As reported online September 23 in the Journal of the American College of Cardiology, 303 ibrutinib-associated cardiovascular deaths were identified. Overall, ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs; reporting odds ratio, 23.1), central nervous system hemorrhagic events (ROR, 3.7), heart failure (ROR: 3.5), ventricular arrhythmias (ROR, 4.7), conduction disorders (ROR: 3.5), CNS ischemic events (ROR, 2.2), and hypertension (ROR, 1.7).
Cardiovascular adverse drug reactions often occurred early after ibrutinib administration. These were associated with fatalities that ranged from about 10% (SVAs and ventricular arrhythmias) to about 20% (CNS events, heart failure, and conduction disorders).
Further, the authors note, "ibrutinib-associated SVA portends poor prognosis when CNS events occur concomitantly, with 28.8% deaths (15 of 52 cases)."
Dr. Moslehi said, "We hope we get funding to do a prospective study where we closely follow patients on ibrutinib in terms of cardiovascular events. We are also doing studies better delineating the mechanisms of this toxicity."
Dr. Nicole Lamanna, a medical oncologist at NewYork-Presbyterian Hospital and Columbia University Medical Center, commented in an email to Reuters Health, "The BTK inhibitors have truly transformed the care of patients with CLL. Ibrutinib was the first-to-market (and) is known to cause cardiac toxicities in approx. 5%-15% of patients."
"Knowing this is important, as one needs to educate patients about signs/symptoms associated with these issues. Depending upon comorbidities, some patients may benefit from alternative therapies," she said. "Given emerging resistance and the off-target side effects of ibrutinib, there is active development of second-generation and more specific BTK inhibitors, such as ACP-196 (acalabrutinib), BGB-3111 (zanabrutinib), and others."
"A head-to-head trial of ibrutinib versus acalabrutinib in high-risk relapsed/refractory CLL patients was performed and data are forthcoming," she added.
Dr. Neil Nagovski, a medical oncologist at 21st Century Oncology in Florida, commented by email, "Predisposing risk factors, such as advanced age, history of hypertension, strokes, pre-existing cardiac disorders, and some anatomic variations such as atrial dilatation identified by an echocardiogram have been reported in some studies."
"While I do not routinely screen patients with echocardiogram or ECG (or) request a cardiology workup prior to initiation of ibrutinib, I do review cardiac history and discuss the associated cardiac risks," he told Reuters Health.
"I discontinue ibrutinib once the patient develops any arrhythmia and refer to a cardiologist, preferably one who has experience in managing patients on antineoplastic therapy," he said. "Most patients are able to recover their cardiac rhythm once ibrutinib is stopped."
Further, he added, "I discuss with cardiologist the indications for anticoagulation with respect to thromboembolic risk, and permanently discontinue ibrutinib in patients who are at high risk for stroke and require anticoagulation. Patients who are able to maintain a cardiac rate / rhythm and have low estimated thrombotic risk are able to resume ibrutinib."
Janssen spokesperson Satu Kaarina Glawe commented by email to Reuters Health, "Cardiac arrythmias and hypertension are known adverse drug reactions in patients treated with (ibrutinib). As indicated in the U.S. prescribing information, careful monitoring and management should be conducted during treatment."
She added, "It is also important to note that many patients with these types of complex blood cancers are older, and older patients commonly have multiple co-morbidities which can make it difficult to discern whether the cardiovascular events or deaths were treatment-related or due to concurrent illnesses."
J Am Coll Cardiol 2019.
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