ASH 2025: Emerging Clinical Evidence and Pivotal Trials in Lymphoma: Key Insights Shaping Modern Practice

This article summarizes recent pivotal hematology trials with direct implications for clinical practice, highlighting advances in targeted therapies, immunotherapy, and risk-adapted strategies in CLL, SLL, and high-risk MCL. By reviewing head-to-head comparisons of next-generation BTK inhibitors, early integration of CAR-T therapy, and chemotherapy-sparing approaches, clinicians gain an evidence-based overview of emerging strategies that may optimize efficacy while improving tolerability. The synthesis emphasizes translational relevance, supporting informed, patient-centered decision-making and guiding the evolving management of lymphoid malignancies.

ALPINE Trial (NCT03734016)¹

• Phase 3, randomized study comparing zanubrutinib to ibrutinib in patients with relapsed or refractory (R/R) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

• This head-to-head trial evaluates whether zanubrutinib, a second-generation, more selective BTK inhibitor, can match or exceed the efficacy of the established BTK inhibitor ibrutinib, while potentially improving tolerability and safety.

• If zanubrutinib shows equal or better response rates and a more favorable safety profile, the trial could support its use as a standard option for relapsed/refractory CLL/SLL, offering a potentially safer long-term therapy for many patients.

WINDOW-3 Pilot Study (NCT05495464)²

• Phase 1 study evaluating frontline therapy in previously untreated, high-risk Mantle Cell Lymphoma (MCL) that tests induction with Acalabrutinib + Rituximab followed by consolidation with Brexucabtagene autoleucel (CAR-T cell therapy).

• By combining a second-generation BTK inhibitor and anti-CD20 antibody with upfront CAR-T, the study aims to improve disease control in patients with high-risk features (e.g., aggressive histology, high Ki-67, TP53 or other high-risk mutations, bulky disease).

• If successful, this trial could support a paradigm shift: moving aggressive, high-risk MCL patients into CAR-T-based therapy earlier rather than after multiple relapses, potentially improving long-term outcomes and reducing reliance on conventional cytotoxic regimens.

BRUIN CLL-313 Trial (NCT05023980)³

• Phase 3, open-label, randomized study comparing the oral BTK inhibitor Pirtobrutinib (LOXO-305) with the standard chemo-immunotherapy regimen Bendamustine + Rituximab (BR) in previously untreated patients with CLL or SLL.

• This head-to-head comparison tests whether a non-chemotherapy, once-daily oral BTK inhibitor can replace chemo-immunotherapy as first-line treatment, potentially offering comparable efficacy with improved tolerability and convenience.

• If pirtobrutinib demonstrates similar or superior outcomes with a favorable safety profile, this trial could shift first-line CLL/SLL management toward a more targeted, less immunosuppressive strategy, thus reducing reliance on cytotoxic regimens.

Sources:

1. “A Study of Zanubrutinib (BGB-3111) versus Ibrutinib in Participants with Relapsed/​Refractory Chronic Lymphocytic Leukemia (ALPINE).” Clinicaltrials.gov, 30 Mar. 2025, www.clinicaltrials.gov/study/NCT03734016. Accessed 3 Dec. 2025.
2. “A Pilot “Window-3” Study of Acalabrutinib plus Rituximab Followed by Brexucabtagene Autoleucel Therapy in Patients with Previously Untreated High-Risk Mantle Cell Lymphoma.” Clinicaltrials.gov, 15 Aug. 2025, clinicaltrials.gov/study/NCT05495464. Accessed 3 Dec. 2025.
3. “A Study of Pirtobrutinib (LOXO-305) versus Bendamustine plus Rituximab (BR) in Untreated Patients with Chronic Lymphocytic Leukemia (CLL)/​Small Lymphocytic Lymphoma (SLL) (BRUIN CLL-313).” Clinicaltrials.gov, 23 July 2025, clinicaltrials.gov/study/NCT05023980. Accessed 3 Dec. 2025.