Comparative safety of novel targeted therapies in relapsed/refractory chronic lymphocytic leukemia: a network meta-analysis

Abstract

Background: The emergence of new antileukemic drugs, including Bruton tyrosine kinase inhibitors (BTKis), phosphoinositide 3-kinase inhibitors (PI3Kis), and B-cell lymphoma 2 antagonists (BCL-2a), has significantly improved the outcomes for patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Despite advances in treatment efficacy, the comprehensive safety profile of these novel agents versus traditional chemotherapy and immunotherapy has not been adequately explored, and there have been few direct comparisons.

Objectives: This study aimed to compare the safety profiles of novel therapeutic agents, chemotherapy, and immunotherapy in patients with relapsed/refractory CLL using a Bayesian network meta-analysis (NMA).

Methods: A systematic literature review was conducted to identify randomized clinical trials on relapsed/refractory CLL. The search encompassed major medical databases (MEDLINE, Embase, and CENTRAL) and gray literature, with the aim to integrate the findings into a Bayesian NMA framework for safety outcome assessment.

Design: Systematic literature review with Bayesian NMA.

Results: The systematic search identified 14 randomized trials that formed networks for the comparison of safety outcomes. No differences were shown between therapies in terms of overall adverse events (AEs). However, bendamustine + rituximab had a more favorable safety profile for grade ⩾3 AEs when compared with ibrutinib (risk ratio 0.62 (95% credible interval 0.40-0.86)), acalabrutinib (0.69 (0.45-0.94)), zanubrutinib (0.64 (0.42-0.91)), and venetoclax + rituximab (0.87 (0.79-0.96)). The frequency of grade ⩾3 AEs, serious AEs, and treatment discontinuations and deaths due to AEs was comparable between acalabrutinib, zanubrutinib, and venetoclax + rituximab. There were no significant differences in the safety profiles regarding hematological events, events affecting the quality of life, and infections for most comparisons of venetoclax + rituximab with BTKis. Among BTKi-specific events, zanubrutinib was associated with a higher risk of hypertension (2.96 (1.74-5.16)) and bleeding (1.38 (1.06-1.81)) than acalabrutinib. No differences in the risk of atrial fibrillation were found between acalabrutinib and zanubrutinib (1.56 (0.74-3.34)).

Conclusion: Our findings showed that venetoclax + rituximab, acalabrutinib, and zanubrutinib have acceptable safety profiles, which indicates that they may be the preferred therapeutic options in the setting of relapsed/refractory CLL.

Trial registration: PROSPERO CRD42022304330.

Keywords: Bayesian statistics; chronic lymphocytic leukemia; meta-analysis; systematic reviews; systemic treatment; toxicity mitigation/prediction.

Figure 1.

PRISMA 2020 flow diagram.

Figure 2.

Network plot of the included studies. Blue color represents therapy based on BTKis, green—therapy based on PI3K inhibitors, purple—therapy based on BCL2 antagonists, and red—chemotherapy and/or immunotherapy. The size of nodes represents the number of patients for each treatment, edge width—number of studies. ACA, acalabrutinib; BEND, bendamustine; DUV, duvelisib; IBR, ibrutinib; IDE, idelalisib; OFA, ofatumumab; PC, physician’s choice; RTX, rituximab; UBL, ublituximab; VEN, venetoclax; ZAN, zanubrutinib.

Figure 3.

SUCRA values for each analyzed safety outcome. ACA, acalabrutinib; BEND, bendamustine; DUV, duvelisib; IBR, ibrutinib; IDE, idelalisib; OFA, ofatumumab; PC, physician’s choice; RTX, rituximab; SUCRA, surface under the cumulative ranking probabilities; UBL, ublituximab; VEN, venetoclax; ZAN, zanubrutinib.