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.Advances in MZL Treatment
Chemo-Free Regimens Centered on Targeted Therapy as a New Trend
01. Classification and Characteristics of MZL
The latest WHO 5th classification adds two new subtypes, primary cutaneous MZL (PCMZL) and pediatric MZL (pNMZL), on top of the original three subtypes: MALT/EMZL, SMZL, and NMZL. MZL is highly heterogeneous, with different subtypes and onset sites exhibiting distinct biological characteristics and pathogenic mechanisms, resulting in varied treatment approaches.
02. Treatment Options for Patients with Localized Disease
The treatment principles for MZL are “subtype-specific treatment” for localized disease (stages I and II) and systemic treatment for widespread disease (stages III and IV), but there is no standard regimen yet. Local treatments include antibiotics, surgery, and radiotherapy, while systemic treatments include immunochemotherapy and chemo-free regimens based on targeted therapies, including BTK inhibitors. The guidelines do not yet offer an optimal systemic treatment regimen.
For gastric MALT lymphoma, treatment outcomes vary based on Helicobacter pylori (Hp) status. Zullo et al.’s analysis of 32 studies involving 1,408 patients with stage I-II¹ gastric MALT lymphoma treated with Hp eradication therapy showed a 90-98% Hp eradication rate, with a 77.5% tumor response rate and a 60-70% complete remission (CR) rate, with higher remission rates in Asian countries compared to Western countries (84.1% vs. 73.8%). In contrast, a meta-analysis by Jung et al. of 25 studies involving 2,485 Hp-negative gastric MALT lymphoma patients found that only 29.3% (95% CI: 22.2%-37.4%) achieved CR after Hp eradication therapy.
Regarding whether SMZL should replace splenectomy with drug therapy, early splenectomy achieved 5-year PFS and OS rates of 50-60% and 70-80%, respectively, but adding chemotherapy to splenectomy did not further improve clinical outcomes. In cases of severe bone marrow infiltration and associated cytopenias in SMZL, splenectomy may not effectively resolve cytopenias. Splenectomy is associated with short-term complications such as venous thrombosis, pulmonary dysfunction, and major bleeding, and long-term complications related to immunosuppression, primarily infections, with an infection-related mortality rate of 4-5%. In a study of 104 SMZL patients treated with rituximab monotherapy, the 10-year PFS and OS rates were 64% and 88%, respectively. Therefore, splenectomy should be avoided in patients with high surgical risk, such as the elderly or those with comorbidities, and in patients with severe bone marrow infiltration or lymphadenopathy. Young, healthy patients with hypersplenism-related cytopenias may benefit the most from splenectomy.
A prospective study from Spain showed that low-risk HPLLs/ABC-scored SMZL patients could be safely managed without treatment. The study included 181 SMZL patients from 2014 to 2020, divided into a rituximab-chemotherapy group (n=59), a rituximab group (n=40), and a splenectomy group (n=15). Using the HPLLs/ABC score, patients were stratified into three risk groups: Group A, Group B, and Group C, corresponding to no risk factors, 1-2 risk factors, and ≥3 risk factors, respectively. The study endpoints were lymphoma-specific survival (LSS), composite event-free survival (CEFS), and complete remission rate (CRR). Results showed that the rituximab-chemotherapy group and rituximab group had higher overall response rates compared to the splenectomy group (P<0.001); however, there was no statistically significant difference in 5-year LSS between the different first-line treatment approaches (P=0.68). The 5-year CEFS differed significantly between treatment strategies, with the W&W group having the longest 5-year CEFS (P=0.0046). The HPLLs/ABC score could identify Group A patients who do not require immediate treatment and could be followed with W&W, while rituximab appeared to be the first choice for Group B patients needing more aggressive treatment.
In addition, the prospective phase II study by MacManus et al. on radiotherapy for localized non-gastric MZL included 70 patients with stage I or II non-gastric MZL, with a median follow-up of 5 years (range 0.7-9.4 years). The 5-year PFS and OS rates were 79% and 95%, respectively. Among the 38 patients who received ocular irradiation, 27 (71%) developed cataracts, managed by lens extraction/replacement in 18 cases. The study suggested that radiotherapy was effective in treating localized non-gastric MZL, but complications need attention.
03. Strategies for Systemic Treatment
The updated NCCN guidelines (2024.v1) recommend the following first-line treatment options for MZL: bendamustine + rituximab (BR); CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab (R-CHOP); CVP (cyclophosphamide, vincristine, prednisone) + rituximab (R-CVP); and rituximab (375 mg/m², once weekly for four doses) for SMZL. The preferred first-line treatment for elderly or frail patients is rituximab (375 mg/m², once weekly for four doses).
The BRIGHT study compared the efficacy and safety of BR versus R-CHOP or R-CVP as first-line treatment for indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL), enrolling 447 previously untreated iNHL or MCL patients, including 46 MZL patients. Results showed that the 5-year PFS rate was significantly higher in the BR group than in the R-CHOP/R-CVP group (65.5% vs. 55.8%, P=0.0025). However, there was no difference in the 5-year PFS rates between the BR and R-CHOP/R-CVP groups in the MZL subgroup. Additionally, the incidence of secondary malignancies was significantly higher in the BR group than in the R-CHOP/R-CVP group.
The GALLIUM study explored the long-term benefits of different anti-CD20 monoclonal antibodies (G/R) in immunochemotherapy for MZL patients, enrolling 1,202 previously untreated follicular lymphoma (FL) or MZL patients, including 195 MZL patients. Patients were randomized to receive either obinutuzumab-based immunochemotherapy plus obinutuzumab maintenance therapy (G-Chemo, n=601, including 99 MZL patients) or rituximab-based immunochemotherapy plus rituximab maintenance therapy (R-Chemo, n=601, including 96 MZL patients). After a median follow-up of 59.3 months, no differences in PFS or OS were observed between the two groups, but grade 5 adverse events occurred in 15% of patients. Additionally, a real-world study retrospectively evaluated MALT lymphoma patients who received prior systemic treatment at Vienna Medical University between 1999 and 2019. Among 159 patients, 46% (74/159) received chemotherapy-based regimens, while 54% received chemotherapy-free regimens. The study found no difference in PFS between the two approaches, supporting further investigation into the concept of chemotherapy-free treatment for MALT lymphoma.
04. Considerations for the Application of Chemotherapy-Free Regimens
Given the indolent nature of MZL, the possibility of chemotherapy-free regimens has gained particular attention due to reduced toxicity and a lower risk of secondary malignancies. In the era of targeted and immunotherapy, new drugs are gradually being used, including Bruton tyrosine kinase (BTK) inhibitors, novel anti-CD20 monoclonal antibodies, phosphoinositide 3-kinase (PI3K) inhibitors, BCL2 inhibitors, chimeric antigen receptor T-cell therapy (CAR-T), and immune checkpoint inhibitors.
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.
