A phase Ib/II study has revealed that the ViPOR regimen—comprising venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide—produced durable remissions in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The treatment demonstrated particular efficacy in specific molecular DLBCL subtypes and was associated with mild to moderate adverse events. The research, led by Christopher J. Melani, MD, at the National Institutes of Health, suggests potential cures for heavily pretreated patients, including those who had undergone CAR T-cell therapy. The findings were published in The New England Journal of Medicine.
DLBCL, the most common type of non-Hodgkin lymphoma, affects 25,000–30,000 people annually in the United States. While chemoimmunotherapy can be curative, patients with early relapsed or refractory disease often face poor outcomes with conventional treatments.
Study Design and Patient Population
The study enrolled 60 patients with relapsed or refractory B-cell lymphoma between February 2018 and June 2021. This included 20 patients (10 with DLBCL) in phase Ib and 40 patients (all with DLBCL) in phase II. Among the 50 DLBCL patients, the median age was 61 years, with 92% having stage III or IV disease. The median number of prior systemic therapies was three, with 20 patients having received prior CAR T-cell therapy and 29 having refractory disease.
The cohort included 25 patients with DLBCL–not otherwise specified (12 with germinal center B-cell [GCB] subtype and 13 with non-GCB subtype), 20 with high-grade B-cell lymphoma “double hit” (17 with MYC and BCL2 translocations, and 3 with MYC and BCL6 translocations), and 5 with T-cell histiocyte-rich large B-cell lymphoma.
In the phase Ib study, venetoclax was administered at four different dose levels to determine the recommended phase II dose. A grade 3 intracranial hemorrhage led to establishing venetoclax at 800 mg as the recommended phase II dose.
Efficacy and Safety Results
In the phase II expansion study, ViPOR was administered every 21 days for six cycles. Objective responses were observed in 54% of 48 evaluable DLBCL patients, with complete responses in 38%. Complete responses occurred exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6. Circulating tumor DNA was undetectable in 33% of patients at the end of ViPOR therapy. With a median follow-up of 40 months, the 2-year progression-free survival rate was 34% (95% CI = 21%–47%), and the overall survival rate was 36% (95% CI = 23%–49%).
Toxic effects included grade 3 or 4 neutropenia (in 24% of cycles), thrombocytopenia (23%), anemia (7%), and febrile neutropenia (1%).
Investigator Insights
"This multiagent regimen simultaneously targets multiple key survival pathways that are important for B-cell lymphoma to grow and survive," said Dr. Melani. "We hypothesized that multiple agents would be needed in patients with aggressive lymphoma in order to completely eradicate all evidence of disease and lead to a potential cure in these patients."
Louis M. Staudt, MD, PhD, Chief of the Lymphoid Malignancies Branch, Center for Cancer Research at the National Cancer Institute, added, "The two subtypes that are most curable with the ViPOR regimen are the least curable with chemotherapy. I think this says that targeted therapies, by removing these survival pathways, are achieving a fundamentally different result than the toxins we administer when we give chemotherapy."
Cost-Effectiveness
The study authors highlighted the cost-effectiveness of ViPOR compared to CAR T-cell therapy, with ViPOR costing $180,000 for six cycles versus $500,000 to $1 million for CAR T-cell therapy.
A larger phase II study of ViPOR is planned across multiple trial sites to confirm the regimen's activity in patients with non-GCB DLBCL and high-grade B-cell lymphoma with MYC and BCL2 rearrangements.
