A new comparison of the safety profiles of new targeted therapies for relapsed or refractory disease chronic lymphocytic leukemia (R/R CLL) suggests that they all have similar – and favorable – safety profiles.

the report, which was published in Therapeutic Advances in Medical Oncologyfound the selective B-cell lymphoma 2 inhibitor venetoclax (Venclexta) in combination with the anti-CD20 monoclonal antibody rituximab (Rituxan), the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence), and the BTK inhibitor zanukinsatinib (Brukinsatinib) to have acceptable safety profiles in patients with relapsed or refractory (R/R) CLL.¹

Acalabrutinib, zanubrutinib, and venetoclax plus rituximab all had similar rates of grade 3 or higher adverse events, serious adverse events, and discontinuation due to death. | Image credit: © fizkes – stock.adobe.com

The authors, from Poland’s Jagiellonian University, said the recent wave of new targeted therapies for CLL has been welcome news, but has also raised questions.

“While these advances have greatly improved patient outcomes, they have also brought new challenges in understanding the safety profiles of these therapies, particularly in often heavily pretreated patients,” they wrote.

Although all therapies have been the subject of studies evaluating safety, most of these studies have been limited in scope, the investigators said, and have not included a comprehensive evaluation of the range of available therapies. They therefore embarked on a network meta-analysis (NMA), which allowed them to take a broader look at comparisons across a range of studies.

“This approach is particularly valuable in the CLL setting, where multiple agents with different mechanisms of action have emerged,” they wrote.

The investigators conducted a systematic literature review of studies for patients with R/R CLL and found 14 randomized studies that met their inclusion criteria. Studies were included if at least 80% of participants had R/R CLL. Most of these studies were phase 2 or phase 3 multicenter open-label trials; 3 were double-blind trials; 1 was a single center trial.

When adverse events (AEs) were taken as a whole, the investigators said they found no significant differences in terms of overall AEs. However, when their analysis was segmented by severity, they found bendamustine (Treanda) plus rituximab outperformed the other treatments. Patients receiving bendamustine plus rituximab had a lower risk of grade 3 or higher adverse events compared with ibrutinib (Imbruvica; risk ratio (RR), 0.62; 95% credible interval (CI), 0.40-0.86), acalabrutinib (RR, 0.69; 95% CI, 0.45-0.94), zanubrutinib (RR, 0.64; 95% CI, 0.42-0.91) and venetoclax plus rituximab (RR, 0.87; 95% CI, 0.79-0.96).

“The results from the NMA highlighted the favorable safety profile of bendamustine + rituximab, which is reflected in clinical guidelines recommending this regimen, particularly for elderly patients and those with comorbidities,” they wrote.

Acalabrutinib, zanubrutinib, and venetoclax plus rituximab all had similar rates of grade 3 or higher adverse events, serious adverse events, and discontinuation due to death.

“There were no significant differences in the safety profiles for hematologic events, quality-of-life events, and infections for most comparisons of venetoclax + rituximab with BTK (inhibitors),” the researchers noted.

However, they found that among BTK inhibitors, use of zanubrutinib carried a higher risk of hypertension (RR, 2.96; 95% CI, 1.74-5.16) and bleeding (RR, 1.38; 95% CI, 1 .06-1.81) compared to acalabrutinib.

Nevertheless, previous research has suggested that second-generation BTK inhibitors, such as zanubrutinib and acalabrutinib, have superior cardiac safety profiles than first-generation BTK inhibitors, such as ibrutinib. A study published last year Comparing zanubrutinib and ibrutinib in patients with R/R CLL, it was found that the former resulted in fewer discontinuations due to adverse events and fewer cardiac events.²

The authors of the current study wrote that there were differences in the data collected and reported among the 14 studies in their analysis, and some studies used wide confidence intervals in their comparisons.¹ They said longer-term research is warranted to more comprehensively assess the safety profiles of the various therapies.

For now, however, these data suggest that acalabrutinib, zanubrutinib, and venetoclax plus rituximab all appear to have “relatively similar safety profiles.” This evidence suggests that the new therapies may be preferred in the setting of R/R CLL, according to the authors.

References

1. Monica M, Reczek M, Kawalec P. Comparative safety of new targeted therapies in relapsed/refractory chronic lymphocytic leukemia: a network meta-analysis. Ther Adv Med Oncol. 2024;16:17588359241285988. doi:10.1177/17588359241285988
2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582