With a 5-year overall survival of close to 90% in chronic lymphocytic leukemia (CLL), there have been large treatment shifts over the past decade in this disease, which now includes “more disciplines than it did before,” commented medical oncologist Danielle Shafer, DO, of Inova Schar Cancer Institute, Inova Fairfax Hospital, Falls Church, Virginia, at the recent 2024 American College of Cardiology (ACC) course on Advancing the Cardiovascular Care of the Oncology Patient.1
Danielle Shafer, DO
“Treatment of CLL has changed radically,” she added. The prior standard of care was immunochemotherapy, but based on numerous studies, Bruton’s tyrosine kinase (BTK) inhibitors have become a standard treatment.2 The first-generation BTK inhibitor ibrutinib became a “game-changer” in CLL, with newer-generation agents such as acalabrutinib, zanubrutinib, and now the noncovalent agent pirtobrutinib joining the therapeutic mix. Many experts believe that patients with CLL who are scheduled for therapy with BTK inhibitors and have at least two cardiovascular risk factors should be considered for referral to a cardio-oncologist. At this time, according to Dr. Shafer, patients receiving a BTK inhibitor for CLL will remain on that therapy indefinitely, until disease progression or intolerable toxicity.
“I cannot remember the last time I actually gave chemotherapy for this disease,” commented Dr. Shafer. “We use very little chemotherapy in the treatment of CLL.”
Other classes of treatment for CLL are represented by venetoclax, a BCL2 inhibitor, and anti-CD20 agents such as the older rituximab and newer obinutuzumab. Another newer strategy is time-limited therapy, which is the approach used with venetoclax and obinutuzumab; these agents are generally given over 48 weeks, she added.
“These drugs are great, but there are key toxicities,” explained Dr. Shafer. Among the common side effects associated with BTK inhibitors, such as diarrhea, headaches, fatigue, and infection, there are cardiovascular-related adverse events as well (bleeding, hypertension, and arrhythmia).
Case 1: Focus on Heart Rate and Blood Pressure
To explore the challenges clinicians face in managing patients with CLL, including whether to treat or not, Dr. Shafer presented an illustrative case study and explored the decision-making process with a panel of experts, representing medical oncology, cardiology, cardio-oncology, and pharmacy.
A 64-year-old man with newly diagnosed CLL requiring treatment had well-controlled hypertension, fatigue, and dyspnea. His left ventricular ejection fraction was 58%, and he was found to have severe anemia, nonbulky adenopathy, with a minimally enlarged spleen. He had normal cytogenetics and fluorescence in situ hybridization results as well as mutated heavy chain IGVH, which Dr. Shafer called “favorable” factors.
He was started on 420 mg of ibrutinib daily. At hospital discharge, his blood pressure was 126/78 mm Hg with carvedilol and lisinopril. He was seen frequently to start in clinic, as is routine according to Dr. Shafer. However, his hypertension was not well controlled, as he came into the clinic with blood pressure readings of 180/100 mm Hg.
Daniel Addison, MD
The discussion panel was asked to weigh in on how this patient should be monitored across various disciplines (primary care, medical oncology, and cardiology). “In that first year, what we often have to focus on is arrhythmia and hypertension,” commented practicing cardiologist Daniel Addison, MD, Director of the OSU Cardio-Oncology Program, Associate Professor of Medicine, The Ohio State University Wexner Medical Center, Columbus. This would include, he continued, a baseline ECG and routine blood pressure checks. Then, a symptom-triggered strategy, with a baseline echocardiography, may be considered. “This is our general practice for many of these patients initiated on treatment with a BTK inhibitor,” he said.
Nicolas Palaskas, MD, FACC, Associate Professor of Medicine, Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, also emphasized the importance of involving patients in a risk/benefit discussion regarding heart rate and blood pressure monitoring at home and symptoms to look for. Many patients are now using “biowearables,” he added, which can be very helpful in assessing cardiac effects.
Nicolas Palaskas, MD, FACC
“The whole reason why acalabrutinib and zanubrutinib were created was to be more specific to BTK, because ibrutinib has so many off-target effects,” explained Alana Ferrari, PharmD, BCOP, a hematology/oncology clinical pharmacist at UVA Health Emily Couric Clinical Cancer Center, The University of Virginia, Charlottesville. “The off-target effects of these agents cannot be overstated.”
“In this case, if we do not get good control of the blood pressure very soon, the risk of atrial fibrillation increases markedly,” noted Teresa López-Fernández, MD, who leads the Cardio-Oncology Unit at La Paz University Hospital in Madrid.
A member of the audience asked for guidance on selecting among the BTKs based on the risk of cardiovascular toxicities. “There has generally been a very recent shift away from ibrutinib in high-risk patients with CLL, given there is evidence of a lower risk of cardiac events with the newer-generation BTK inhibitors,” stated Dr. Shafer. However, she added, there are patients who tolerate ibrutinib well, and so no shift in therapy would be advisable for them.
“The whole reason why acalabrutinib and zanubrutinib were created was to be more specific to BTK, because ibrutinib has so many off-target effects.”— Alana Ferrari, PharmD, BCOP
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Combination therapies (such as venetoclax and a BTK inhibitor or an anti-CD20 antibody) are often considered for high-risk patients. For instance, in the GAIA-CLL13 clinical trial, the combination of venetoclax and obinutuzumab (with or without ibrutinib) was superior to chemoimmunotherapy as first-line treatment of fit patients with CLL.3
Dr. Addison briefly reviewed the potential cardiovascular considerations of BTK inhibitors in CLL.4 The most common cardiac events were found to be atrial fibrillation, hypertension, and bleeding, with ventricular arrhythmia, heart failure, and stroke being potential events as well. “Venetoclax,” on the other hand, “does not appear to have similar major cardiovascular toxicities that we know of at this point,” noted Dr. Addison. “And although the risk of hypertension with the second-generation BTK inhibitors is significantly reduced, it is still not zero,” he added. Thus, at least during the first year of treatment, cardiac monitoring should be considered.4
Case 2: Focus on Atrial Fibrillation and Bleeding
A 76-year-old woman diagnosed with CLL with a long-standing history of atrial fibrillation, had progressive disease meriting treatment. She was on the antiarrhythmic agent dofetilide as well as the anticoagulant apixaban. She was started on ibrutinib and rituximab (standard at that time), after a discussion with the patient and her cardiologist.
Teresa López-Fernández, MD
Within the past decade, it has been observed that the link between atrial fibrillation and ibrutinib therapy was fairly common, noted Dr. Addison. The incidence of atrial fibrillation with this agent may reach between 20% and 30%, with a lower incidence (up to 1%–2%) of symptomatic ventricular arrhythmia and (less frequently) sudden death, according to several studies, he added.
After the patient was on therapy with ibrutinib for about 12 months, more persistent atrial fibrillation returned, with cardioversion being successful for only a limited time. She was switched to zanubrutinib and has since been mostly in normal sinus rhythm.
“Although we may be concerned about arrhythmia, atrial fibrillation, or hypertension, these patients need their cancer control,” stated Dr. Addison. “In our practice, in the absence of clear evidence of profound heart failure ... or sustained ventricular arrhythmia, we do not necessarily say the patient should come off the BTK inhibitor.” Other agents, such as beta-blockers and calcium channel blockers, are often used for cardiovascular control.
Dr. Palaskas agreed with Dr. Addison’s viewpoint here. He would continue with treatment, with close monitoring of atrial fibrillation. “From a cardiovascular perspective, we never want to deny cancer treatment,” Dr. Palaskas emphasized.
However, a “bigger clinical conundrum” with these patients, according to Dr. Palaskas, is the question of anticoagulation and whether to continue the use of apixaban with the start of BTK inhibitors (especially ibrutinib), where platelet aggregation will be inhibited. “We are really trying to balance that risk of stroke and bleed,” said Dr. Ferrari, noting the clinical challenge of such a decision. Although the bleeding risks reported with BTK inhibitors seem to be the highest with ibrutinib, bleeding may still be somewhat of an issue with the use of the other BTK inhibitors. As for the use of venetoclax, which is associated with many drug-drug interactions, noted Dr. Ferrari, very little bleeding has been reported with this agent.4
DISCLOSURE: Dr. Shafer reported no conflicts of interest. Dr. Addison has received research support from the National Institutes of Health and the American Heart Association–Robert Wood Johnson Foundation. Dr. Palaskas has served as a consultant to Kiniksa and Replimune and has received research grants from the Cancer Prevention Research Institute of Texas and the Andrew Sabin Family Foundation. Dr. Ferrari reported no conflicts of interest. Dr. López-Fernández has received consultant fees or honoraria from AstraZeneca, Bayer Healthcare Pharmaceuticals, and Philips; and has served on a speakers bureau for Beigene, Daiichi Sankyo, Janssen Pharmaceuticals, Myocardial Solutions, Pfizer, and Philips.
REFERENCES
1. Addison D, Shafer D: Harmony in hematology: Cardiovascular risk mitigation and monitoring in CLL cases. 2024 ACC Conference: Advancing the Cardiovascular Care of the Oncology Patient. Presented February 11, 2024.
2. Burger JA: Treatment of chronic lymphocytic leukemia. N Engl J Med 383:460-473, 2020.
3. Eichhorst B, Niemann CU, Kater AP, et al: First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med 388:1739-1754, 2023.
4. Quartermaine C, Ghazi SM, Yasin A, et al: Cardiovascular toxicities of BTK inhibitors in chronic lymphocytic leukemia: JACC: CardioOncology state-of-the-art review. JACC CardioOncol 5:570-590, 2023.
