A recent meta-analysis by Hwang et al. provided a comprehensive comparison of adverse event (AE) profiles of zanubrutinib with acalabrutinib in patients with B-cell malignancies. Specific AEs seen more commonly with acalabrutinib than zanubrutinib included infections, atrial fibrillation, diarrhea, nausea/vomiting, headaches, cough, fatigue and pyrexia. On the other hand, hematuria, neutropenia, and hypertension were observed more frequently with zanubrutinib than with acalabrutinib [1].

Chemoimmunotherapy (CIT), immunotherapy and chemotherapy regimens are commonly used for the treatment of patients with marginal zone lymphoma. Moreover, the BTK inhibitor zanubrutinib has shown activity in the relapsed/refractory setting based on the phase II, single-arm MAGNOLIA and BGB-3111-AU-003 trials [1, 2]. Walewska et al. conducted a matching-adjusted indirect comparison (MAIC) to estimate the comparative efficacy of these treatment strategies in relapsed/refractory marginal zone lymphoma [3].

In the setting of relapsed/refractory follicular lymphoma (FL), progression-free survival (PFS) deteriorates with successive relapses, which implies a high unmet need for therapies that can improve disease control and extend survival after relapse [1]. The Fc-silenced CD20 x CD3 bispecific antibody odronextamab is being investigated in patients with relapsed/refractory B-cell malignancies in the multicohort, multicenter, phase II ELM-2 study.

The combination of the first-generation BCL2 inhibitor venetoclax and the first-in-class BTK inhibitor ibrutinib has demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL) [1], although tolerability of this regimen is limited. Next-generation agents can be expected to provide optimized toxicity profiles. The second-generation BCL2 inhibitor sonrotoclax inhibits BCL2 in a more selective and pharmacologically potent manner than venetoclax, with a shorter half-life preventing drug accumulation that might contribute to toxicity [2].

The new class of BTK degraders is being developed in response to emerging patterns of resistance that limit the utility of BTK and BCL2 inhibitors. On one hand, BTK mutations decrease the efficacy of both covalent and non-covalent BTK inhibitors; on the other hand, some mutations lead to “kinase dead” or “kinase bypassing” BTK mutants with intact B-cell receptor signaling through a scaffolding function of BTK [1, 2].

In older or unfit patients with mantle cell lymphoma (MCL), bendamustine plus rituximab (BR) is the most common first-line therapy, while intensive regimens are usually unsuitable in this population even though they provide durable responses [1, 2]. The addition of the first-in-class BTK inhibitor ibrutinib to first-line BR has been shown to prolong progression-free survival (PFS) in the SHINE trial [3].

The second-generation BTK inhibitor zanubrutinib is being tested in the phase III SEQUOIA trial in the setting of untreated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with and without del(17p). Zanubrutinib monotherapy has shown high tolerability and efficacy in arm C of the study that included patients with del(17p) [1].

At the European Hematology Association (EHA) congress held in Madrid, Spain, and virtually from 13th–16th June 2024, world-leading experts from 150 countries presented cutting-edge research and clinical trials. This year, we witnessed significant advancements in the treatment of chronic lymphocytic leukemia (CLL).

In the setting of early-stage, asymptomatic chronic lymphocytic leukemia (CLL), the concept of watch & wait in the era of targeted agents was challenged by the placebo-controlled, double-blind, phase III CLL12 study. This trial assessed the use of ibrutinib 420 mg OD (n = 182) vs. placebo (n = 181) until symptomatic disease progression in treatment-naïve patients with asymptomatic CLL Binet stage A who had an increased risk due to factors such as del(17p), IGHV mutation status, or age.