Lymphoma
Innovative BCL2 inhibition: indications fanning out across B-cell malignancies
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].
BTK degraders: emerging activity in various B-cell malignancies
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].
Meeting unmet needs in mantle cell lymphoma
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].
Reducing risks further in chronic lymphocytic leukemia
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].
Preface – EHA 2024
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).
Current insights into BTK inhibition and other targeted approaches in chronic lymphocytic leukemia
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.
Innovative agents in marginal zone lymphoma and other B-cell malignancies
Relapses are common in patients with marginal zone lymphoma (MZL), and sequential therapy is often necessary. At ASH 2023, Tedeschi et al. reported findings for 22 patients with relapsed/refractory MZL who received the oral second-generation Bcl-2 inhibitor sonrotoclax at different dose levels (i.e., 40 mg, 160 mg, 320 mg, 640 mg OD) in the first-in-human, phase I, multicenter BGB-11417-101 study.
Exploring chemotherapy-free approaches in the treatment of DLBCL
For decades, the CHOP regimen has been the first-line standard of care for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Significant improvement was achieved through the addition of rituximab (R-CHOP). Ever since, however, multiple clinical trials investigating expanded or alternative treatment regimens have not succeeded in further improving patient outcomes.
