The 2025 Annual Meeting of the American Society of Hematology (ASH 2025) recently concluded successfully in Orlando, USA. As the most influential annual event in hematology, this year’s meeting showcased multiple breakthrough advances in lymphoma, offering new directions for optimizing clinical practice.To translate cutting-edge research into clinical insight, Oncology Frontier – Hematology Frontier, in collaboration with Professor Qinqing Cai from Sun Yat-sen University Cancer Center, launches the special series “Lymphoma Insights · ASH Edition.” Every Friday, this column highlights landmark lymphoma studies from ASH, providing authoritative interpretation, clinical context, and evidence-based guidance to support expert practice.
In this issue, Professor Qinqing Cai and Dr. Bijing Wu present and analyze key ASH 2025 studies on relapsed/refractory marginal zone lymphoma (R/R MZL).
Abstract 709: Patient-Reported Outcomes with Lisocabtagene Maraleucel (liso-cel) in 3L+ R/R MZL — TRANSCEND FL Phase 2 Study
Title: Patient-reported outcomes (PROs) with lisocabtagene maraleucel (liso-cel) in patients with third line or later (3L+) R/R MZL from the Phase 2 TRANSCEND FL study Authors: Reem Karmali, et al.
Background
Lisocabtagene maraleucel (liso-cel) is a CD19-targeted CAR-T therapy that has demonstrated efficacy and safety in heavily pretreated R/R MZL in the TRANSCEND FL trial. This analysis evaluates patient-reported outcomes (PROs) to assess changes in quality of life, symptom burden, and functional status following treatment.
Study Design
Adults with R/R MZL who had received ≥2 prior lines of therapy were enrolled. Following leukapheresis, patients underwent lymphodepleting chemotherapy (with optional bridging therapy) and received a single infusion of liso-cel.
PRO tools included EORTC QLQ-C30, FACT-LymS, and EQ-5D-5L, assessed at baseline, days 1/15/29 post-infusion, and at months 2, 3, 6, 9, 12, 18, 24, and end-of-study. Eight key domains were analyzed, including global quality of life, physical function, lymphoma-related symptoms, and overall health perception.
Results
Among 67 treated patients, 60 completed at least one post-baseline PRO assessment. Median age was 63 years, including extranodal, nodal, and splenic MZL subtypes. PRO completion exceeded 80% through 18 months.
A transient decline in quality-of-life scores occurred during the first 1–15 days post-infusion, followed by progressive and sustained improvement across most functional and symptom domains from day 15 onward.
By 18 months, clinically meaningful improvements were observed in:
- Global quality of life
- Physical and role functioning
- Fatigue
FACT-LymS scores showed symptom improvement beginning at day 15, reaching clinically meaningful benefit by month 2. EQ-5D-5L results demonstrated continuous improvement in patients’ perceived health status.
From day 29 onward, most patients experienced stable or improved PRO scores across all domains.
Conclusion
In the TRANSCEND FL trial, liso-cel not only achieved durable disease control in 3L+ R/R MZL but also significantly improved quality of life and symptom burden. This represents one of the largest PRO analyses in this population, reinforcing the holistic clinical value of CAR-T therapy.
Professor Qinqing Cai’s Commentary
Unlike traditional studies focused solely on response rates and survival, this research provides a patient-centered evaluation of CAR-T therapy. Despite early transient discomfort, most patients experienced sustained, clinically meaningful improvements in quality of life and lymphoma-related symptoms. These findings support incorporating PRO metrics as a core endpoint when evaluating high-intensity immunotherapies.
Abstract 7117: Orelabrutinib Plus Rituximab-Based Chemoimmunotherapy in R/R MZL — Phase II Study
Title: Orelabrutinib plus rituximab-based chemoimmunotherapy regimens in relapsed or refractory marginal zone lymphoma: A multicentric phase II trial Authors: Shaohua Wu, et al.
Background
Orelabrutinib, a highly selective BTK inhibitor, has shown promising efficacy in R/R MZL. This study evaluated combining orelabrutinib with rituximab-based chemoimmunotherapy, tailored according to relapse patterns.
Study Design
R/R MZL patients were stratified by response to first-line therapy and time to relapse:
- Patients without PR after 4 cycles or relapsing within 2 years received Orelabrutinib + Bendamustine + Rituximab (BR)
- Patients achieving PR or relapsing ≥2 years received Orelabrutinib + R-CHOP or Orelabrutinib + R-CVP
Primary endpoint: ORR Secondary endpoints: CR, PFS, OS, safety
Results
10 patients enrolled (median age 68 years); 90% extranodal MZL, 100% intermediate- to high-risk (MZL-IPI).
At cycle 3:
- CR: 20%
- PR: 80%
At data cutoff:
- CR: 50%
- PR: 50%
- ORR: 100%
Median PFS and OS not reached.
Safety:
- AEs in 60%, all grade 1–2
- Most common: rash (30%), bleeding (20%)
- No grade ≥3 toxicities
Conclusion
Orelabrutinib combined with rituximab-based chemoimmunotherapy demonstrated high activity and manageable safety, supporting BTK inhibitor–based combination strategies in R/R MZL.
Professor Qinqing Cai’s Commentary
This study reflects a precision-oriented treatment paradigm, tailoring therapy based on relapse kinetics and treatment history. Even in higher-risk populations, response rates were strong. Importantly, BTK inhibitors are no longer merely salvage agents, but integrated into structured relapse-stage treatment frameworks.
Abstract 1801: Nemtabrutinib in R/R MZL — BELLWAVE-003 Phase II Study
Title: Phase 2 bellwave-003 cohort F: Updated clinical outcomes of nemtabrutinib in participants with relapsed or refractory marginal zone lymphoma Authors: Alessandra Tucci, et al.
Background
Nemtabrutinib is a non-covalent, reversible BTK inhibitor, active in BTK-mutant and pirtobrutinib-exposed disease. This update reports extended follow-up results.
Study Design
Single-arm Phase II trial enrolling R/R MZL patients previously treated with chemoimmunotherapy and covalent BTK inhibitors. Dose: 65 mg daily until progression or intolerance
Results
23 patients treated (median age 68 years, median 3 prior lines). Median follow-up: 10.3 months Median treatment duration: 4.7 months 55% remained on therapy
Efficacy:
- ORR (independent review): 52%
- ORR (investigator): 48%
- Median DOR: 7.4 months
Safety:
- Any-grade AEs: 87%
- Grade 3–4 AEs: 52%
- Common AEs: pneumonia (21%), anemia (13%)
- No treatment-related deaths
Conclusion
Nemtabrutinib represents a promising post-covalent BTKi option, offering a mechanism-driven therapeutic pathway for heavily pretreated R/R MZL.
Professor Qinqing Cai’s Commentary
This study addresses a critical unmet need in BTKi-resistant R/R MZL. Non-covalent BTK inhibitors demonstrate sustained activity despite resistance, supporting future BTKi sequencing strategies and mutation-guided therapy personalization.
Nemtabrutinib’s activity in BTK/PLCG2-mutant disease provides a strong foundation for next-generation resistance-adapted treatment approaches.
References
- Karmali R, et al. ASH 2025 Abstract 709
- Wu S, et al. ASH 2025 Abstract 7117
- Tucci A, et al. ASH 2025 Abstract 1801
Authors
Professor Qinqing Cai
Expert Profile — Professor Qinqing Cai
Chief Physician, PhD Supervisor Deputy Director, Department of Internal Medicine Lead PI in Lymphoma Changjiang Scholar (Ministry of Education) Chair, Lymphoma Committee, China Anti-Cancer Association Senior Author in The Lancet Haematology, Blood, Leukemia, Clinical Cancer Research, and others Recipient of 2023 Guangdong Science and Technology Progress Award (First Prize) Principal Investigator of multiple national research grants
Dr. Bijing Wu Sun Yat-sen University Cancer Center
