Editor’s Note: Marginal zone lymphoma (MZL), a group of indolent mature B-cell lymphomas, presents a significant challenge in treatment selection due to its high heterogeneity. Despite improvements in survival rates for MZL patients with the advent of new drugs and advancements in clinical diagnostic and therapeutic techniques, developing a balanced management plan that addresses both efficacy and safety across a long disease course and lifetime management remains an urgent issue. At the recent "8th Academic Conference on Hematologic Oncology" organized by the Chinese Society of Clinical Oncology (CSCO), Dr. Huilai Zhang from Tianjin Medical University Cancer Institute & Hospital delivered a compelling presentation titled "Current Status and Treatment Progress for Chinese Patients with Marginal Zone Lymphoma." This report offers valuable insights and forward-looking guidance for comprehensively understanding the current state of MZL diagnosis and treatment in China and mastering the latest developments in the field. This article summarizes the key points of Professor Zhang's presentation for our readers.

Considerations for the Application of Chemotherapy-Free Regimens

1. BTK Inhibitors

BTK inhibitors as monotherapy have shown good efficacy and safety in R/R MZL. A multicenter, open-label phase II study explored the efficacy of ibrutinib monotherapy as second-line treatment for MZL, enrolling 63 R/R MZL patients who had undergone at least one prior CD20 monoclonal antibody-containing regimen, including 51% EMZL, 22% SMZL, and 27% NMZL patients. After a median follow-up of 19.4 months, the objective response rate (ORR) was 48%, with a median PFS of 14.2 months. The incidence of grade ≥3 treatment-related adverse events (TEAEs) was 67%, with a 17% discontinuation rate due to ibrutinib-related adverse events (AEs). A matching-adjusted indirect comparison (MAIC) study presented at the 2024 EHA reported data on the use of zanubrutinib in R/R MZL based on two phase II single-arm trials (MAGNOLIA, n=66; BGB-3111-AU-003, n=20). Results showed that zanubrutinib significantly reduced the risk of progression (P=0.001) and death (P<0.001) compared to chemotherapy-immunotherapy (CIT) or chemotherapy. The study demonstrated that zanubrutinib had a significant advantage over CIT or chemotherapy in PFS and OS in R/R MZL.

Orelabrutinib, the first BTK inhibitor approved for MZL in China, is recommended as a first-line treatment for MZL in the 2024 CSCO Lymphoma Treatment Guidelines. The key 104 study is a single-arm, open-label, multicenter phase II clinical trial enrolling 90 R/R MZL patients. Results showed a robust response in R/R MZL patients, with an investigator-assessed ORR of 58.9%, an independent review committee (IRC)-assessed 2-year duration of response (DOR) of 88.5%, and an IRC-assessed 2-year PFS rate of 75.8%. Additionally, consistent high response rates were observed across different MZL subtypes and in patients with poor prognostic factors, with good patient tolerance, mainly grade 1-2 treatment-related adverse events.

Chemotherapy-free combinations based on BTK inhibitors also showed good efficacy and safety in previously untreated MZL. A phase II study by Gordon et al. used a BTK inhibitor + lenalidomide + rituximab regimen for first-line treatment of MZL, enrolling 48 patients, including 38 FL and 10 MZL patients. Results showed that the best ORR for MZL patients was 90%, with a best CR rate of 80%. The estimated 24-month PFS rate was 78.8%, and the 60-month PFS rate was 59.7%. The most common grade ≥3 AEs were rash (50%), neutropenia (14.6%), and diarrhea (12.5%). The IELSG47/MALIBU study enrolled 45 CD20+ MZL patients (including 30 SMZL and 15 NMZL patients), who received R + ibrutinib induction therapy and ibrutinib monotherapy maintenance. After a median follow-up of 23 months, the ORR of BTK inhibitor + rituximab treatment in first-line MZL was 97%, with a CR rate of 53% and a 2-year OS rate of 92%, with a low incidence of grade 3-4 adverse events.

A study presented at ASH 2023 explored the efficacy and safety of BTK inhibitors combined with obinutuzumab in first-line MZL patients, enrolling 28 patients, including 15 FL and 13 MZL patients, who received obinutuzumab + ibrutinib during both induction and maintenance phases. Results showed that the ORR in the MZL subgroup was 100%, with a 2-year PFS rate also of 100%. The most common grade 3-4 AEs were infections (n=10), including COVID-19 (n=5), pneumonia (n=2), febrile neutropenia (n=1), influenza (n=1), and diverticulitis (n=1). A retrospective study evaluated 10 MZL patients treated with orelabrutinib (150 mg QD) combined with rituximab (375 mg/m², IV, every 28 days for one cycle) as first-line therapy. After six cycles of treatment, patients continued with orelabrutinib monotherapy for one year. Results showed that 3 patients (30%) achieved CR, with a best ORR of 90%. After a median follow-up of 13.0 months, the median PFS was not reached, with a 6-month PFS rate of 100%. No serious adverse events were observed, and there were no reports of off-target AEs such as atrial fibrillation, diarrhea, or major bleeding.

Additionally, non-covalent BTK inhibitors have shown preliminary efficacy in R/R MZL patients. In the dose-escalation or expansion phase of the multicenter phase 1/2 BRUIN study, previously treated B-cell malignancy patients (including MZL) received pirtobrutinib monotherapy. Among 36 MZL patients, 34 (94%) received the recommended phase II dose of pirtobrutinib (200 mg QD). The median age was 68 years, and the ORR in the MZL cohort was 50%, including 1 CR (2.8%) and 17 PRs (47.2%). The median DOR was 12.7 months, with a median PFS of 16.5 months and a 24-month OS rate of 77.5%. In summary, BTK inhibitor-based chemo-free regimens show comparable efficacy to immunochemotherapy with better safety profiles.

2. PI3K Inhibitors

The CHRONOS-1 study is an open-label, single-arm phase II study exploring the efficacy and safety of the PI3K inhibitor copanlisib as monotherapy in R/R indolent B-cell lymphoma patients. This study enrolled 23 R/R MZL patients, with 47.8% refractory to their last treatment and 82.6% refractory to all previous treatments. The primary endpoint was ORR, with secondary endpoints including DOR, PFS, OS, and safety. The longest median follow-up was 28.4 months. Results showed that copanlisib monotherapy achieved an ORR of 78.3% in R/R MZL, with grade 3/4 TEAEs occurring in 82.6% of patients.

3. BCL-2 Inhibitors

A phase I study presented at ASH 2023 explored the efficacy and safety of the second-generation BCL-2 inhibitor sonrotoclax as monotherapy in MZL patients. As of April 24, 2023, 22 R/R MZL patients received sonrotoclax dose-escalation therapy (1 patient at 40 mg, 2 at 160 mg, 9 at 320 mg, and 10 at 640 mg) with a median follow-up of 6.5 months. The median age was 73 years, and the median number of prior treatments was 1. The overall ORR for the 22 patients was 62% (8/13), with a CR rate of 31% (4/13). In the 10 patients treated with 640 mg, the ORR was 70% (7/10) and the CR rate was 40% (4/10). One patient who died had baseline low lymphocyte and immunoglobulin levels and developed progressive multifocal leukoencephalopathy (PML), starting treatment 8 months later (and dying). The death was assessed as unrelated to the drug.

A study presented at EHA 2024 evaluated the mid-term results of adaptive therapy with mosunetuzumab combined with or without obinutuzumab and polatuzumab vedotin in previously untreated FL and MZL patients. Twenty-seven patients completed all mosunetuzumab treatment, with an ORR and CR rate of 100% and 77%, respectively. Twenty-one patients had baseline and on-treatment samples available for MRD analysis. Seventeen patients (81%) achieved PET CR after eight cycles of mosunetuzumab, with the other four patients in partial remission (PR). Regarding safety, four patients experienced serious adverse events (one patient with grade 3 lung infection followed by grade 3 shingles, one patient with grade 1 cytokine release syndrome, one patient with grade 2 upper respiratory infection, and one patient with grade 3 abdominal pain/malabsorption).

4. CAR-T Therapy

Axi-cel is a CD19-targeted CAR-T cell therapy approved by the FDA for the treatment of R/R FL. The ZUMA-5 study is a multicenter single-arm phase II study evaluating the efficacy and safety of axi-cel in treating R/R FL/MZL. As of March 31, 2023, 159 patients had been evaluated for efficacy (127 FL and 31 MZL), with a median follow-up of 53.7 months for FL and 43.8 months for MZL. The overall ORR for all patients was 90%, with a CR rate of 75%. The median PFS was 57.3 months for FL and 46.9 months for MZL, with OS not reached for both. The safety profile was similar to previous reports, with no new safety events observed.

In summary, MZL treatment is transitioning from chemotherapy and chemotherapeutic immunotherapy to a targeted “chemo-free” model with high efficacy, low toxicity, organ function preservation, and avoidance of excessive toxicity. While MZL has a generally good overall survival rate, patients are prone to multiple relapses, making it crucial to preserve sufficient organ function and avoid excessive toxicity. Future alternative endpoints for MZL treatment should include the definition of treatment success and the investigation of patient-reported outcomes and preferences.

Dr. Huilai Zhang

• Ph.D. in Oncology, Chief Physician, Doctoral Supervisor
• Director, Lymphoma Department, Tianjin Medical University Cancer Institute & Hospital
• Deputy Chairman, Lymphoma Committee, Chinese Anti-Cancer Association
• Standing Committee Member, Lymphoma Expert Committee, Chinese Society of Clinical Oncology (CSCO)
• Member, Lymphoma Group, Chinese Medical Association Oncology Branch
• Deputy Chairman, Oncology Branch, Chinese Medical Promotion Association
• Deputy Chairman, Lymphatic Diseases Committee, Chinese Medical Education Association
• Deputy Chairman, Lymphoma Committee, Chinese Geriatrics Association
• Chairman, Clinical Oncology Chemotherapy Committee, Tianjin Anti-Cancer Association
• Deputy Chairman, Hematology Disease Control Center, Tianjin
• Vice President, Hematology Physicians Branch, Tianjin Medical Association

Professor Zhang’s research focuses on the molecular diagnosis and personalized treatment of malignant lymphomas. He is a recipient of the Tianjin Medical Talent Cultivation Plan and the Tianjin Medical University Clinical Talent Cultivation Plan. He has published over 80 papers as the first or corresponding author in international and domestic journals, including Blood, J Exp Med, JITC, Leukemia, CTM, AJH, Clin Immunol, BJH, Blood Adv, Hematol Oncol, and Int J Cancer. He has received several awards, including the 2023 Science and Technology Progress Award from the Chinese Anti-Cancer Association. Professor Zhang is an editorial board member for several prestigious journals, including Tumor Pharmacology, Chinese Journal of Hematology, Leukemia & Lymphoma, Chinese Journal of Clinical Oncology, Hematological Oncology, Blood Research, and Discover Oncology. He was also awarded the “National Famous Doctor” title in the 4th edition of the award.