Diffuse large B-cell lymphoma (DLBCL) is a common and aggressive form of lymphoma, but its management is particularly challenging in elderly patients. Standard R-CHOP chemotherapy is often poorly tolerated in very old individuals or in those with significant comorbidities, leaving a substantial proportion of patients with unmet treatment needs. As a result, identifying effective and safe alternatives has become a major focus of clinical research.
In recent years, the emergence of CD20×CD3 bispecific antibodies—most notably mosunetuzumab—has brought new hope to this population. At the recent ASH Annual Meeting, a team led by Professor Jeff Sharman from the Willamette Valley Cancer Institute presented key data on the use of mosunetuzumab in treatment-naïve elderly patients with DLBCL, attracting widespread attention. Hematology Frontier invited Professor Sharman to summarize the core findings of this study and to share his perspectives on other important advances presented at the meeting.
Interview With Professor Jeff Sharman
Hematology Frontier
Jeff Sharman: Hello, my name is Jeff Sharman. I am the Medical Director of Hematology Research at the Sarah Cannon Research Institute. I had the honor and privilege of presenting, on behalf of my colleagues, data on the safety and efficacy of mosunetuzumab in treatment-naïve elderly patients with diffuse large B-cell lymphoma.
These patients were either 80 years of age or older, or between 65 and 80 years old with medical comorbidities that made them unsuitable for R-CHOP chemotherapy. R-CHOP is a very challenging regimen to administer in older populations, and our hope was that mosunetuzumab could represent a safer and effective alternative.
What we observed was encouraging. Approximately 70% of treated patients responded to therapy, and about half achieved a complete response. In many of these cases, patients achieved minimal residual disease (MRD) negativity. Importantly, this was accomplished with a favorable safety profile. Only 12% of patients developed cytokine release syndrome, and nearly all events were grade 1, with just a single episode of grade 2 CRS.
Among patients who achieved a complete response, the treatment effect appeared to be durable, with responses remaining ongoing at follow-up. We are very pleased with these findings and eager to explore the next steps. Our goal is to design future studies that could potentially replace R-CHOP chemotherapy as a treatment option for elderly patients with DLBCL, and planning for such trials is already underway.
This year’s ASH meeting has been exceptionally exciting overall. We have seen important studies in acute myeloid leukemia comparing traditional 3+7 chemotherapy with azacitidine plus venetoclax, showing impressive benefits with novel therapy. We have also seen provocative data in multiple myeloma, where salvage therapy using bispecific antibodies and daratumumab has been highly effective. In chronic lymphocytic leukemia, fixed-duration regimens are being compared with indefinite BTK inhibitor therapy, with very compelling results. Altogether, it has been a truly exciting conference.
Research Abstract
Abstract 62 Fixed-Duration Subcutaneous Mosunetuzumab Monotherapy for Treatment-Naïve Elderly or Chemotherapy-Ineligible Patients With Diffuse Large B-Cell Lymphoma: Interim Results From the Phase II MorningSun Study
Mosunetuzumab is an off-the-shelf CD20×CD3 T-cell–engaging bispecific antibody that redirects T cells to eliminate B cells, including malignant B cells. It has been approved by both the U.S. FDA and the European Medicines Agency for use as fixed-duration intravenous therapy in patients with relapsed or refractory follicular lymphoma after at least two prior lines of treatment and can be administered in the outpatient setting without mandatory hospitalization.
Early phase I/II data previously demonstrated promising efficacy and manageable safety of mosunetuzumab monotherapy in treatment-naïve DLBCL patients. The Phase II MorningSun study is the first to evaluate subcutaneous mosunetuzumab monotherapy in elderly patients with newly diagnosed DLBCL or in patients considered unfit for standard chemoimmunotherapy. The current report presents interim results from this study.
MorningSun (NCT05207670) is an open-label, multicenter, Phase II basket study designed to assess the safety, efficacy, and pharmacokinetics of subcutaneous mosunetuzumab in patients with B-cell non-Hodgkin lymphomas. In the DLBCL cohort, eligible patients were aged 80 years or older, or 65–79 years and deemed unfit for chemoimmunotherapy. The study was conducted primarily in community oncology centers in the United States, and hospitalization was not mandatory.
Mosunetuzumab was administered subcutaneously using a step-up dosing schedule: 5 mg on day 1 of cycle 1, 45 mg on days 8 and 15, followed by 45 mg on day 1 of each subsequent 21-day cycle, for up to 17 cycles or until unacceptable toxicity. The primary endpoint was progression-free survival at 24 months after first treatment. Secondary endpoints included objective response rate, complete response rate, time to response, duration of response, duration of complete response, overall survival, and safety. Exploratory circulating tumor DNA analyses were performed using the AOA-NHL assay.
A total of 49 patients were enrolled, most treated in community centers. The median age was 82.5 years (range 71–101). Many patients had advanced disease, extranodal involvement, or high International Prognostic Index scores. As of the data cutoff on February 10, 2025, the median follow-up was 12.5 months, and the median number of treatment cycles received was 14.
The 12-month progression-free survival rate was 68.8%, and the 12-month overall survival rate was 77.2%. The objective response rate was 73.5%, with a complete response rate of 59.2%. Responses occurred rapidly, with a median time to response of 2.7 months. Among patients achieving complete response, response durability was notable, with high rates of ongoing remission at 12 months. In evaluable complete responders, 68.8% achieved MRD negativity.
The most common adverse events were injection-site reactions, which were predominantly grade 1. Grade 3–4 adverse events occurred in approximately two-thirds of patients, most commonly infections and neutropenia. Serious adverse events were reported in 42.9% of patients. Four grade 5 events occurred, all deemed unrelated to mosunetuzumab by investigators. Cytokine release syndrome occurred in 12.2% of patients and was limited to grade 1–2 events, all of which resolved. No immune effector cell–associated neurotoxicity syndrome was observed.
These interim results indicate that fixed-duration subcutaneous mosunetuzumab monotherapy demonstrates meaningful clinical activity, encouraging efficacy, and manageable safety in treatment-naïve elderly or chemotherapy-ineligible patients with DLBCL. Importantly, the regimen is suitable for outpatient administration in community practice settings, addressing a critical unmet need in this vulnerable population.
Expert Profile
Jeff Sharman, MD Research Director, Willamette Valley Cancer Institute Medical Director of Hematology Research, The US Oncology Network
Dr. Sharman is a leading hematologist-oncologist with extensive experience across multiple cancer types. He has played a key role in advancing innovative therapies and has published widely in top-tier journals such as The New England Journal of Medicine, Journal of Clinical Oncology, and Blood. His research programs have gained international recognition, and he is a frequent speaker at major academic conferences in the United States, Asia, and Europe.
Dr. Sharman’s work has positioned the Willamette Valley Cancer Institute at the forefront of emerging fields including immunotherapy, targeted therapy, and personalized medicine. He emphasizes that, while scientific progress continues to open new possibilities, the most important aspect of his work remains supporting patients when they need it most—a commitment that forms the foundation of meaningful and enduring physician–patient relationships.
