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In the Long Run, Ibrutinib Brings Disease Control, but Cardiac Risks, in Older Patients with Untreated CLL

February 20, 2024

March 2024

Thomas R. Collins

Thomas R. Collins is a medical journalist based in West Palm Beach, Florida.

Older patients with chronic lymphocytic leukemia (CLL) who were previously untreated continue to show durable responses with Bruton tyrosine kinase (BTK) inhibitor ibrutinib-based therapies. However, concerns about adverse events (AEs) persist, especially those relating to atrial fibrillation and hypertension, according to newly published phase III findings with long-term follow-up in Blood.

The results show the continued efficacy of ibrutinib-based therapies, often well after the drug is discontinued, while also highlighting the cardiac risk, suggesting the need for newer BTK inhibitor therapies for higher cardiac risk populations, said Jennifer Woyach, MD, lead study author and co-leader of the Leukemia Research Program at The Ohio State University Comprehensive Cancer Center in Columbus.

“Most patients now are being treated with acalabrutinib or zanubrutinib rather than ibrutinib — however, ibrutinib continues to be widely used,” she said. “These data do tell us that for the majority of patients, ibrutinib is a safe and very effective option. For those patients with a history of cardiac comorbidities or those who are very frail, we should be preferencing a second-generation inhibitor.”

The findings come from the Alliance for Clinical Trials in Oncology A041202 trial, a multicenter, randomized, phase III trial with patients who were at least 65 years old, an age parameter meant to maximize applicability to the real world. The median age of a patient with CLL is 70, and 75% of those patients are 65 or older when they are diagnosed. The median age on the study was 71 (range = 65-89).

“The study population of A041202 was designed to reflect the general population of patients with CLL, and thus these data are applicable to the majority of patients with CLL,” Dr. Woyach said.

Between 2013 and 2016, 183 patients were randomized to receive bendamustine plus rituximab (BR), 182 to receive ibrutinib alone, and 182 to receive ibrutinib plus rituximab.

At a median of 55 months, the median progression-free survival (PFS) for patients treated with the BR regimen was 44 months (95% CI 38-54), while the median PFS for the ibrutinib arms was not reached. The 48-month estimates for PFS are 47% for the BR arm, 76% for the ibrutinib arm, and 76% for the ibrutinib plus rituximab arm. There was no statistical difference in overall survival (OS) between the arms, with the 48-month OS estimates at 84%, 85%, and 86%, respectively.

Researchers found that 75 patients in the ibrutinib arm and 83 in the ibrutinib plus rituximab arm discontinued for reasons other than disease progression, including AEs (n=66; 18%), death on study (n=26; 7%), and other disease (n=21; 6%). Only 4% of patients in the ibrutinib arms had progressive disease while on treatment, and 10% had disease progression after discontinuing therapy, after a median of 24 months following the stoppage.

“This shows us that patients who continue on frontline treatment have an extremely small chance of having disease progression — within this time frame it is much more common to discontinue therapy and then see disease progression, than to experience disease progression while receiving ibrutinib,” researchers said.

Researchers found that while ibrutinib was protective across all subgroups, the treatment was more protective for those who were age 65 compared to those who were 80, for those with high-risk TP53 abnormalities, and those with Zap-70 unmethylated disease.

Over the first six months of treatment, the rate of discontinuation because of AEs was higher for the BR group than the ibrutinib arms, but by 12 months, the rate of discontinuation because of AEs was higher in the ibrutinib arms.

Researchers found that atrial fibrillation was seen in 3% (n=6) of the BR group and 18% (n=66) of the ibrutinib arms, and hypertension in 27% (n=47) of the BR arm and 55% (n=198) in the ibrutinib arms. Grade 3 hypertension or higher was seen in 12% (n=21) of the BR arm and 29% (n=103) of the ibrutinib arms. These findings indicate potential cardiac toxicities, warranting careful evaluation and consideration in an older patient population.

“From these data from A041202 and previous studies of ibrutinib, we have seen that rates of atrial fibrillation and hypertension continue to increase with time rather than plateau,” Dr. Woyach said. “These side effects are the main reason that the second-generation inhibitors have become more widely used in the U.S.”

Any conflicts of interest declared by the authors can be found in the original article.


Woyach, JA, Perez Burbano GE, Ruppert AS, et al. Long-term follow-up from A041202 shows continued efficacy of ibrutinib regimens for older adults with CLL [published online ahead of print, 2024 Jan 12]. Blood. doi: 10.1182/blood.2023021959.


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