A team of researchers at the National Institutes of Health (NIH) has developed a promising non-chemotherapy treatment regimen that is achieving full remissions in patients with aggressive B-cell lymphoma who have exhausted standard treatment options. The five-drug combination therapy, known as ViPOR, targets multiple molecular pathways that diffuse large B-cell lymphoma (DLBCL) tumors use to survive.
In a clinical trial conducted at the National Cancer Institute (NCI), researchers tested the combination of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide in 50 patients with DLBCL, the most common type of lymphoma. The results, published June 20, 2024, in the New England Journal of Medicine, showed significant clinical benefits.
The treatment shrank tumors substantially in 54% of evaluable patients (26 of 48), with 38% (18 patients) achieving a complete response, meaning their tumors disappeared entirely. At the two-year mark, 36% of all patients remained alive, and 34% were free of disease.
"Many of these patients who stopped responding to standard treatments would have otherwise died within a year, and now we have a good proportion who are still alive past two years, and some past four years," said Christopher J. Melani, M.D., of NCI's Center for Cancer Research, who co-led the study. "It's gratifying to see these long-term remissions and potential cures in patients."
Targeting Multiple Pathways in a Heterogeneous Disease
DLBCL is known for its genetic heterogeneity, with different molecular subtypes including activated B cell–like (ABC) DLBCL and germinal center B cell–like (GCB) DLBCL. Previous research has identified various genetic pathways involved in the development and survival of these different subtypes.
While targeted drugs have shown effectiveness in blocking some of these pathways, individual drugs rarely produced lasting responses because tumors often develop resistance through alternative survival mechanisms. Dr. Melani and colleagues hypothesized that simultaneously targeting multiple survival pathways would lead to more durable responses.
"DLBCL is one of the most genetically heterogeneous forms of cancer, and as a result we don't yet have the ability to identify exactly which combination of drugs would be most effective for any given patient," Dr. Melani explained. "By putting five drugs together, we believe there will be some drug combination—either two, three, or more drugs—that will be particularly effective against that patient's tumor."
The researchers designed the treatment protocol based on laboratory studies analyzing which targeted drugs could best be combined to kill DLBCL cells synergistically. To maximize efficacy while managing side effects, they administered the drugs simultaneously in two-week cycles with a weeklong break between each cycle.
Subtype-Specific Responses
In the phase 1b/2 trial, responses to ViPOR varied significantly by DLBCL subtype. Complete responses were concentrated in two specific subtypes:
- 62% (8 of 13) of patients with non-GCB DLBCL
- 53% (8 of 15) of patients with high-grade B-cell lymphoma "double hit," a form of GCB DLBCL
At two years, patients with these two subtypes had higher rates of both progression-free and overall survival compared to others in the study. The researchers noted that these subtypes are highly reliant on the survival mechanisms targeted by ViPOR, explaining their particularly strong response to the combination therapy.
Notably, ViPOR also helped 30% (6 of 20) of patients whose lymphomas had not responded to or had relapsed after CAR T-cell therapy—the current standard of care for relapsed DLBCL—achieve lasting remissions.
Manageable Side Effect Profile
The five-drug regimen demonstrated a relatively favorable safety profile. Side effects were generally mild to moderate compared with those of standard treatments and improved during the scheduled treatment breaks. Only five patients had to discontinue treatment early for various reasons, including side effects.
Given this manageable toxicity profile, the researchers suggested that additional drugs could potentially be added to ViPOR to further improve its efficacy. The team is also investigating the ViPOR regimen in patients with other types of lymphoma that are resistant to previous therapies.
Future Directions
Building on these promising results, the researchers have developed a larger phase 2 study to be conducted at multiple centers. This follow-up trial aims to confirm the activity of ViPOR specifically in patients with non-GCB DLBCL and double-hit GCB DLBCL.
The researchers acknowledge that more work is needed to develop effective therapies for GCB DLBCL subtypes that didn't respond as well to ViPOR. The study was co-led by NCI's Center for Cancer Research investigators Wyndham H. Wilson, M.D., Ph.D., Mark Roschewski, M.D., and Louis M. Staudt, M.D., Ph.D., along with Dr. Melani, with contributions from investigators at NIH's National Center for Advancing Translational Sciences and other institutions.
For patients with relapsed or refractory DLBCL who have limited treatment options, the ViPOR regimen represents a promising non-chemotherapy approach that could significantly extend survival and potentially offer cures for some patients with specific disease subtypes.
