From September 13th to 17th, the 2024 European Society for Medical Oncology (ESMO) Annual Meeting was held in Barcelona, Spain. As one of the top international conferences in the oncology field, it brought together experts and scholars from around the world to share cutting-edge research findings and discuss future development directions. At this year's conference, a study led by Dr. Peng Liu's team from Zhongshan Hospital, Fudan University, was selected for a Mini Oral presentation, which was delivered on-site by Dr. Jiadai Xu. The study explored a chemotherapy-free first-line treatment approach for marginal zone lymphoma (MZL), with preliminary results proving promising. Hematology Frontier invited Dr. Xu for an in-depth discussion on the study and her expectations for the future of this treatment approach and research plans.

Hematology Frontier: At the ESMO conference, you reported preliminary results on the Orelabrutinib plus Obinutuzumab (O2) first-line treatment for MZL. Could you start by sharing the background and rationale for this study?

Dr. Jiadai Xu: At this conference, we presented an observational, prospective clinical study aimed at exploring a chemotherapy-free first-line treatment approach for newly diagnosed MZL patients. Currently, the first-line systemic treatment for MZL is based on immunochemotherapy with anti-CD20 monoclonal antibodies, but no universally accepted standard regimen exists. Furthermore, patients undergoing these immunochemotherapy regimens often experience treatment-related side effects that can impact overall survival. In this study, we chose a chemo-free combination of two drugs: Orelabrutinib, a BTK inhibitor independently developed in China and approved for second-line treatment of MZL, and Obinutuzumab, a second-generation anti-CD20 monoclonal antibody. Although the GALLIUM study found no statistically significant differences in overall survival (OS) and progression-free survival (PFS) compared to the control drug, the survival curves indicated that Obinutuzumab could significantly improve MZL outcomes, possibly due to the adverse events (AEs) caused by the immunochemotherapy regimen used in the study. Therefore, we aimed to combine these two targeted drugs to explore a chemotherapy-free regimen for MZL that would be both safe and effective.

Hematology Frontier: The study showed a 100% objective response rate (ORR) with the O2 regimen as a first-line treatment. What does this mean for clinical practice, and could it indicate a major shift in the first-line treatment strategy for MZL in the future?

Dr. Jiadai Xu: MZL patients generally have a long overall survival time, with most patients living more than 10 years and a median OS of approximately 5 years for those with high-risk factors. While the preliminary results of this study are encouraging, the median follow-up time is still short, not yet reaching one year, so further follow-up is needed to confirm whether this regimen can achieve deep remission and allow patients to reach long-term survival. The study is ongoing, with patients still in the maintenance phase, and we will continue to monitor the final outcomes. Based on these initial findings, we are optimistic about the future. Previous clinical studies have also suggested that MZL patients may be less suited for immunochemotherapy and may benefit more from chemo-free targeted regimens. If subsequent data continue to support these findings, I believe this could lead to changes in the current guidelines for first-line MZL treatment.

Hematology Frontier: The safety analysis showed some patients experienced adverse events such as neutropenia and thrombocytopenia. How do you evaluate the impact of these adverse events, and how would you manage these potential risks in clinical practice?

Dr. Jiadai Xu: Among all the patients enrolled in the study, seven experienced AEs. Five patients had grade 1–2 neutropenia, and two experienced grade 3–4 neutropenia, all of which were resolved with medication to boost white blood cells. In other words, the treatment regimen had relatively good safety, and no treatment discontinuations occurred due to AEs. Additionally, compared to previous chemotherapy regimens, we did not observe common severe side effects such as pneumonia, major bleeding, or cardiovascular events, making the overall safety profile of this chemo-free regimen favorable.

Hematology Frontier: Since the study is still recruiting patients, what are your expectations for future data collection and analysis? Are you and your team planning to explore the efficacy of the O2 regimen in different MZL subtypes, such as EMZL or SMZL?

Dr. Jiadai Xu: The study is ongoing, with patients continuously being enrolled and observed. The longest-enrolled patient is still in the maintenance phase, so future study updates will be provided as more data become available. We hope that these patients will continue to be followed for at least two years after maintenance therapy ends, allowing us to observe their responses to treatment discontinuation, including any signs of disease relapse or progression. One of the innovative aspects of this study, aside from its chemo-free approach, is the exploration of a defined treatment period. Patients undergo maintenance therapy for one year rather than indefinite treatment, but whether this one-year duration is appropriate will require longer follow-up to determine.

Among the three MZL subtypes, over 80% are mucosa-associated lymphoid tissue (MALT) or extranodal MZL (EMZL), while splenic MZL (SMZL) and nodal MZL are less common. Previous research data suggest that the clinical characteristics of nodal MZL are clearer. Additionally, we are currently focused on whether high-risk MZL patients (International Prognostic Index [IPI] scores 3–5) are more prone to disease progression, and these data will need further updates in future studies.

References:

1. Herold M, et al. Hemasphere. 2022 Feb 24;6(3)

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1. A prospective study of orelabrutinib plus obinutuzumab (O2) in treatment-naïve marginal zone lymphoma (MZL): preliminary analysis on efficacy and safety. ESMO 2024: 815MO.

Dr. Peng Liu

• Professor, Chief Physician, Ph.D. Supervisor
• Director of the Department of Hematology, Zhongshan Hospital, Fudan University
• Director of the Department of Hematology, Zhongshan Hospital Xiamen Branch
• Shanghai Talent Introduction Program at Fudan University, Outstanding Discipline Leader in Shanghai’s Healthcare System
• Chairman, Lymphoma Committee, Shanghai Anti-Cancer Association
• Vice Chairman, Hematology Branch, Shanghai Medical Association
• Vice Chairman, Hematologic Oncology Committee, Shanghai Anti-Cancer Association
• National Committee Member, Hematology Branch, Chinese Medical Association
• Committee Member, Hematology Physician Branch, Chinese Medical Doctor Association
• Committee Member, Hematologic Oncology Committee, Chinese Anti-Cancer Association
• Vice Chairman, Stem Cell Engineering Technology Committee, Chinese Society of Biomedical Engineering
• Vice Chairman, Myeloma Branch, Chinese Medical Education Association

Dr. Jiadai Xu

• Attending Physician, Zhongshan Hospital, Fudan University
• Ph.D. in Internal Medicine, Fudan University
• Youth Committee Member, Hematology Branch, Shanghai Medical Association
• Committee Member, Integrative Oncology Multiple Myeloma Committee, Chinese Anti-Cancer Association
• Principal Investigator of one National Natural Science Foundation project and one Fujian Provincial Natural Science Foundation project
• First author of several SCI papers
• Holder of multiple national utility model patents and one national invention patent
• “March 8th Red Flag Bearer,” Zhongshan Hospital, Fudan University
• Recipient of Fudan University’s First-Class Ph.D. Scholarship
• Awardee of Excellent Paper at Shanghai Hematology Annual Conference
• Third Prize for Jiangsu Science and Technology Progress Award
• Recipient of Jiangsu Province’s Excellent Master’s Thesis Award, National Scholarship, and Outstanding Instructor for the 7th Clinical Skills Training Program at Nanjing Medical University