The 2025 Annual Meeting of the American Society of Hematology (ASH 2025) has recently concluded successfully in Orlando, USA. As the “grand finale” of the hematology field each year, this meeting showcased a series of cutting-edge breakthroughs in lymphoma research, providing new directions for optimizing clinical practice.To better disseminate scientific advances and empower clinical decision-making, Oncology Frontier – Hematology Frontier, in collaboration with Professor Cai Qingqing from Sun Yat-sen University Cancer Center, has launched the “Lymphoma Roundtable · ASH Special” column. This series highlights landmark lymphoma studies presented at ASH every Friday, offering authoritative interpretation of frontier research through a clinically oriented lens. The goal is to distill truly practice-changing evidence from the vast body of data and provide high-quality academic reference for clinicians and researchers.
In this issue of Lymphoma Roundtable · ASH Special, Professor Cai Qingqing and Dr. Qiu Liyun present and interpret several major studies on relapsed/refractory follicular lymphoma (R/R FL) from ASH 2025.
**Abstract 468 | Tisagenlecleucel in Patients with Relapsed/Refractory Follicular Lymphoma:
Five-Year Follow-up of the Phase II ELARA Study**
Title: Clinical outcomes of tisagenlecleucel in patients with relapsed/refractory follicular lymphoma (r/r FL): Phase 2 ELARA 5-year update
Authors: Stephen Schuster, et al.
Background
Tisagenlecleucel (tisa-cel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. Based on results from the phase II ELARA study, tisa-cel was approved in the United States and Europe in 2022 for adult patients with relapsed/refractory (r/r) follicular lymphoma (FL) who had received at least two prior lines of therapy. Earlier ELARA data demonstrated favorable efficacy and manageable safety. The current report presents final results after a median follow-up exceeding five years.
Study Design
The study enrolled patients with grade 1–3A FL who had received ≥2 prior systemic therapies, including an anti-CD20 monoclonal antibody and an alkylating agent. Patients received a single infusion of tisa-cel (0.6–6 × 10⁸ CAR-T cells). Bridging therapy was permitted. The primary endpoint was the complete response (CR) rate as assessed by an independent review committee.
Results
As of May 28, 2025, all infused patients (N = 97) had a median follow-up of 61.0 months (range, 3.1–67.0). All patients were evaluable for safety, and 94 were evaluable for efficacy. At baseline, 60% had a FLIPI score ≥3; 62% experienced progression within 24 months after first-line therapy (POD24); 64% had bulky disease (>7 cm or ≥3 lesions >3 cm); 68% were double-refractory to prior anti-CD20 antibody and alkylating agents; and 21% had high tumor burden (total metabolic tumor volume >510 mL).
The objective response rate (ORR) and CR rate were consistent with previously reported data, at 86.2% and 68.1%, respectively. Median duration of response (DOR) was not reached (95% CI, 35.8–NE). Median progression-free survival (PFS) was 53.2 months (95% CI, 18.2–NE), with an estimated 5-year PFS rate of 46% (95% CI, 35.0–56.3). Median overall survival (OS) was not reached; the estimated 5-year OS rate was 74.1% (95% CI, 63.0–82.3).
CAR-T cells were detectable in vivo for up to 60.9 months, with a median persistence of 8.6 months (range, 0.6–60.9 months).
Long-term follow-up revealed a favorable safety profile with no new safety signals. More than one year after tisa-cel infusion, 11 patients (13.1%) experienced hematologic adverse events, and 34 patients (40.5%) developed infections. Seven patients (7.2%) developed second primary malignancies. A total of 22 deaths occurred during the study, due to disease progression (n = 8), adverse events (n = 13, mainly infections), and euthanasia.
Conclusion
After more than five years of follow-up, patients with r/r FL treated with tisa-cel continued to demonstrate durable responses. Approximately 75% of patients remained alive, and nearly half remained progression-free, with no newly identified safety concerns.
Commentary by Professor Cai Qingqing
The ELARA study’s extended follow-up beyond five years provides compelling evidence of the long-term efficacy and safety of tisa-cel in r/r FL. Both ORR and CR rates remained stable compared with earlier reports, and the median DOR has not yet been reached, with a 5-year PFS rate of approximately 46%, indicating sustained disease control. CAR-T cell persistence of up to 60.9 months suggests the potential for long-term antitumor immune surveillance.
From a safety perspective, no new safety signals were observed during long-term follow-up, although continued long-term monitoring and structured survivorship management remain essential for patients receiving CAR-T therapy. Overall, this study supports CAR-T therapy as a reliable later-line option for patients with r/r FL who have received at least two prior lines of therapy.
Despite these encouraging results, durability of response after CAR-T therapy remains a key concern in B-cell lymphomas, highlighting the role of the immune microenvironment as a limiting factor. Based on this, our team has designed a prospective phase II study exploring the combination of CAR-T therapy with immune checkpoint inhibition in patients with R/R B-cell lymphomas. This study aims to address CAR-T functional exhaustion associated with PD-1/PD-L1 upregulation by introducing maintenance therapy with sintilimab to enhance CAR-T persistence and prolong response depth and duration. The study is currently enrolling patients and may offer a novel strategy for preventing post–CAR-T relapse.
**Abstract 227 | Final Results of the Phase II ROSEWOOD Study:
Zanubrutinib Plus Obinutuzumab vs Obinutuzumab Monotherapy in R/R Follicular Lymphoma**
Title: Final analysis of the randomized phase 2 ROSEWOOD study of zanubrutinib + obinutuzumab vs obinutuzumab monotherapy in patients with relapsed/refractory follicular lymphoma
Authors: Pier Luigi Zinzani, et al.
Background
Zanubrutinib is a next-generation Bruton tyrosine kinase (BTK) inhibitor. The phase II ROSEWOOD study compared zanubrutinib plus obinutuzumab (ZO) with obinutuzumab monotherapy (O) in patients with relapsed/refractory follicular lymphoma. Earlier analyses demonstrated significantly improved ORR with the ZO regimen. The current report presents final results after a median follow-up of 34.6 months.
Study Design
Patients with grade 1–3A FL who had received ≥2 prior systemic therapies, including an anti-CD20 antibody and an alkylating agent, were randomized 2:1 to receive ZO or O. The primary endpoint was ORR assessed by an independent review committee (IRC). Secondary endpoints included DOR, PFS, OS, and safety.
Results
As of December 31, 2024, 217 patients with R/R FL were enrolled, and 214 received treatment. In the O arm, 36 patients (50.0%) crossed over to receive ZO. Baseline characteristics were well balanced. Median age was 64.0 years. High-risk FLIPI scores were observed in 53.5% of patients, 82.5% had Ann Arbor stage III/IV disease, and 37.3% experienced POD24. The median number of prior therapies was three (range, 2–11).
At a median follow-up of 34.6 months (range, 0.1–69.7), the ZO regimen significantly improved IRC-assessed ORR compared with O alone (70.3% vs 44.4%; P = 0.0003), with a higher CR rate (42.1% vs 19.4%). Superior ORR with ZO was consistently observed across high-risk subgroups. Median DOR was 32.9 months with ZO versus 14.0 months with O. Median PFS was 22.1 months versus 10.3 months (HR = 0.54; P = 0.0012). Median OS was not reached in the ZO arm and was 41.2 months in the O arm (HR = 0.66).
Treatment-emergent adverse events led to discontinuation in 21.7% of patients in the ZO group and 12.7% in the O group. The most common TEAEs in the ZO arm were thrombocytopenia (21.7%), COVID-19, diarrhea, and pneumonia (each 20.3%). No new safety signals were identified.
Conclusion
Zanubrutinib plus obinutuzumab demonstrated robust and durable efficacy in patients with R/R FL, with increasing ORR and CR rates over time and manageable safety. A phase III MAHOGANY study (NCT05100862) is ongoing to further evaluate this regimen in patients with ≥1 prior line of therapy.
Commentary by Professor Cai Qingqing
The final analysis of the ROSEWOOD study provides strong evidence supporting the combination of the BTK inhibitor zanubrutinib with the anti-CD20 antibody obinutuzumab in R/R FL. The study population included a high proportion of patients with adverse prognostic features, enhancing the clinical relevance of the results. With a median follow-up of 34.6 months, the ZO regimen demonstrated significant improvements in ORR, CR rate, DOR, and PFS compared with obinutuzumab monotherapy. Importantly, this combination not only increased response rates but also substantially deepened and prolonged responses, with manageable toxicity and no new safety signals. These findings further support chemotherapy-free strategies for R/R FL.
Building on ROSEWOOD, our team is also conducting a phase II study of orelabrutinib plus rituximab in BTK inhibitor–naïve patients with R/R FL, followed by orelabrutinib maintenance for up to two years. We anticipate that this study will further expand therapeutic options for patients with R/R FL.
Abstract 1006 | Golcadomide (GOLCA), a First-in-Class Oral CELMoD™, ± Rituximab, in R/R Follicular Lymphoma: Extended Follow-up of a Phase 1/2 Study
Title: Golcadomide (GOLCA), a potential, first-in-class, oral CELMoD™ agent, ± rituximab (R) in patients with relapsed/refractory follicular lymphoma (R/R FL): Phase 1/2 study extended follow-up results
Authors: Julio Chavez, et al.
Background
With the advent of T-cell–directed therapies such as CAR-T cells and T-cell engagers, outcomes for patients with R/R FL have improved. Nevertheless, the development of effective, safe, and convenient chemotherapy-free regimens remains a clinical priority. Golcadomide (GOLCA) is a first-in-class, oral cereblon E3 ligase modulator (CELMoD™) designed for lymphoma, with preferential distribution to lymphoid tissues, enhanced activity in lymphoma cell lines, direct tumoricidal effects, and immunomodulatory properties. In this multicenter first-in-human phase 1/2 study, GOLCA demonstrated favorable tolerability and efficacy. The current report presents extended follow-up data from Part B of the study.
Study Design
Patients with R/R FL who had received ≥2 prior lines of therapy (≥1 prior line in Part B if previously treated with anti-CD20 antibodies) were enrolled. In Part A, patients received GOLCA monotherapy once daily. In Part B, GOLCA was administered at 0.2 mg or 0.4 mg on a 14-days-on/14-days-off schedule, with or without rituximab. Treatment continued for up to two years or until disease progression or unacceptable toxicity. Primary endpoints included safety and determination of the recommended phase II dose.
Results
As of April 3, 2025, 72 patients with R/R FL were enrolled: 12 in Part A and 60 in Part B cohort D (all receiving GOLCA plus rituximab). The median number of prior therapies was 4.5 in Part A and 3 in Part B. Approximately one-third of patients had prior T-cell–directed therapy, one-third had prior lenalidomide exposure, and one-third were refractory to their last line of therapy.
Neutropenia was the most common adverse event and the most frequent grade 3/4 TEAE. GOLCA-related serious adverse events occurred in 22% of patients, most commonly infections and febrile neutropenia; one patient receiving 0.2 mg GOLCA developed pulmonary embolism. The most common reasons for dose interruption or reduction were infection and neutropenia. No treatment discontinuations or deaths were attributed to GOLCA-related TEAEs. Non-hematologic TEAEs were infrequent and mostly low grade.
At a median follow-up of 10.8 months, the ORR among evaluable patients was 89%, with a CR rate of 61%. ORR and CR rates were 81% and 43% in the 0.2 mg group, and 94% and 71% in the 0.4 mg group, respectively. In the 0.4 mg cohort, consistent efficacy was observed across high-risk subgroups, including patients previously treated with lenalidomide or T-cell–directed therapies. Ten patients receiving GOLCA 0.4 mg plus rituximab achieved responses lasting longer than 12 months.
Conclusion
GOLCA plus rituximab demonstrated durable responses with extended follow-up and no new safety signals. Compared with the 0.2 mg regimen, GOLCA 0.4 mg plus rituximab achieved higher ORR and CR rates with similar tolerability. A phase III GOLSEEK-4 study is ongoing to further evaluate this regimen in patients with FL who have received at least two prior lines of therapy.
Commentary by Professor Cai Qingqing
This study provides a systematic evaluation of the efficacy and safety of the novel oral CELMoD agent golcadomide, with or without rituximab, in R/R FL. The extended follow-up data demonstrate strong clinical relevance. Notably, the 0.4 mg GOLCA plus rituximab regimen achieved an ORR of 94% and a CR rate of 71%, with consistent efficacy in patients previously exposed to lenalidomide or T-cell–directed therapies, suggesting the potential to overcome certain resistance mechanisms. The safety profile was manageable, with no treatment discontinuations or deaths attributed to the drug. Overall, these findings support further development of chemotherapy-free combination strategies in R/R FL and warrant continued long-term follow-up and randomized phase III comparisons with existing modalities such as bispecific antibodies and CAR-T therapy.
References
- Schuster S, et al. Clinical outcomes of tisagenlecleucel in patients with relapsed/refractory follicular lymphoma (r/r FL): Phase 2 ELARA 5-year update. ASH Abstract 468, 2025.
- Zinzani PL, et al. Final analysis of the randomized phase 2 ROSEWOOD study of zanubrutinib + obinutuzumab vs obinutuzumab monotherapy in patients with relapsed/refractory follicular lymphoma. ASH Abstract 227, 2025.
- Chavez J, et al. Golcadomide (GOLCA), a potential, first-in-class, oral CELMoD™ agent, ± rituximab (R) in patients with relapsed/refractory follicular lymphoma: Phase 1/2 study extended follow-up results. ASH Abstract 1006, 2025.
Authors: Professor Cai Qingqing, Dr. Qiu Liyun
Affiliation: Sun Yat-sen University Cancer Center
Expert Profiles
Professor Cai Qingqing, MD, PhD Sun Yat-sen University Cancer Center
Chief Physician; Doctoral Supervisor Deputy Director, Department of Medical Oncology; Lead PI for Lymphoma Distinguished Professor, Changjiang Scholars Program, Ministry of Education Chair, Integrative Lymphoma Committee, Chinese Anti-Cancer Association Chair, Lymphoma Committee, Guangdong Anti-Cancer Association Chair, Lymphoma Committee, Guangdong Precision Medicine Association Vice Chair, CSCO Lymphoma Committee Vice Chair, Lymphoma Committee, China Association of Geriatric Health Care
Professor Cai has served as national or site PI in multiple registration clinical trials. Over the past five years, she has published more than 20 SCI papers as corresponding author in leading journals including The Lancet Haematology, Blood, Signal Transduction and Targeted Therapy, Clinical Cancer Research, and Leukemia. She has led five National Natural Science Foundation projects, including one Key Project, and was awarded the First Prize of the Guangdong Provincial Science and Technology Progress Award in 2023.
Dr. Qiu Liyun Sun Yat-sen University Cancer Center
Department of Medical Oncology PhD Candidate (Class of 2024) Supervisor: Professor Cai Qingqing
