Researchers from the U.S. National Cancer Institute (NCI) have developed a chemotherapy-free, targeted treatment regimen that leads to durable remissions in people with certain types of diffuse large B-cell lymphoma (DLBCL).
The five-drug ViPOR regimen, named for its inclusion of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide, synergistically targets multiple molecular pathways that are essential for DLBCL survival.
“This regimen was based on our previous work targeting DLBCL with ibrutinib,” first author and study co-lead Christopher Melani of NCI’s Center for Cancer Research told Inside Precision Medicine. “Although this drug could shrink tumors in approximately 25% of patients, it was insufficient on its own, and the cancer would progress after only a few months.”
Melani and team therefore looked at thousands of drugs in the lab that could potentially combine with ibrutinib to kill cancer cells. Venetoclax plus lenalidomide was the most synergistic combination they found, offering a greater benefit in killing the cells together than would be expected by combining the individual activity of these two agents. “We combined this with prednisone and the CD20 antibody therapy obinutuzumab which both are effective in killing cancer cells and a standard component of most chemotherapy regimens,” said Melani.
The researchers tested the ViPOR regimen in 50 patients with relapsed or refractory DLBCL, who had received a median of three previous systemic therapies, including 20 patients (40%) who had received previous CAR T-cell therapy. To maximize potential synergy while minimizing the cumulative drug-related toxic effects the drugs were given simultaneously in six two-week cycles, with a week-long break between each cycle.
Senior author Wyndham Wilson, also from NCI’s Center for Cancer Research, explained that around 40% of all lymphomas are DLBCL. Chemotherapy is the standard of care and typically cures around 60% of newly diagnosed patients. Individuals with early relapsed or refractory disease, however, have poor outcomes with conventional treatments. Anti-CD19 CAR T-cell therapy has improved outcomes for these patients, but only 30–40% of patients with relapsed or refractory disease are cured with such therapy.
Wilson described the ViPOR regimen as a “major conceptual change” in how DLBCL is approached. He added that the novel nature meant that the regimen had to be tested in patients not cured by standard therapy, who would usually die from their disease and thus have a need for more effective therapy.
Wilson said that their study, which is published in The New England Journal of Medicine, “demonstrated for the first time that targeting multiple DLBCL survival pathways is curative in a significant number of these patients.”
Specifically, the investigators found that 54% of 48 evaluable patients responded to treatment, including 38% with a complete response. The median time to response was 0.66 months, with 78% of complete responses durable and without consolidation therapy.
Of note, the complete responses occurred exclusively in patients with two specific subtypes of DLBCL, namely non-germinal-center B-cell (GCB) DLBCL and those with a form of GCB DLBCL known as high-grade B-cell lymphoma “double hit” (HGBCL-DH) that has genetic rearrangements of MYC and BCL2 or BCL6 (or both). The complete response rate was 62% among the 13 patients with non-GCB DLBCL, 53% among the 15 with HGBCL-DH and a BCL2 mutation and 33% for the three patients with HGBCL-DH and a BCL6 mutation.
With a median follow-up of 40 months, two-year progression-free survival (PFS) and overall survival (OS) rates were 34% and 36%, respectively, in the whole cohort. For those with non-GCB DLBCL, the rates were 39% for both outcomes. Patients with HGBCL-DH and a BCL2 mutation had the best outcomes, with two-year PFS and OS rates each reaching 47%.
“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 Melani. “It’s gratifying to see these long-term remissions and potential cures in patients.”
By contrast, the 12 patients with GCB DLBCL and a subtype not otherwise specified had no complete responses, a two-year PFS of 8%, and a two-year OS of 17%.
“Given this preferential activity in certain molecular subtypes, the genetic make-up of the DLBCL could guide treatment selection with ViPOR in a precision-medicine-based treatment approach,” Melani remarked.
Among patients who had previously undergone CAR T-cell therapy, the two-year PFS was 30%, which suggests “the treatment may alter the poor prognosis in these patients,” the researchers remarked. They also reported that ViPOR allowed more than one-third of the patients who had a partial response to subsequently receive radiotherapy, CAR T-cell therapy, or allogeneic stem cell transplantation.
The regimen was well-tolerated, with hematologic adverse events the most commonly reported toxicities. Grade 3 or 4 neutropenia was reported in 24% of the cycles, thrombocytopenia in 23%, anemia in 7%, and febrile neutropenia in 1%.
Given these relatively mild to moderate side effects, additional drugs could potentially be added to ViPOR to improve its efficacy, the researchers said. Indeed, they are currently investigating whether another DLBCL-targeted agent polatuzumab further improves outcomes. Once the regimen has been fine-tuned, the team believes that it has the potential to be used as a chemotherapy-free option in the first-line setting particularly as circulating tumor DNA levels could predict which patients would respond to treatment.
In the meantime, the researchers have developed a larger Phase II study, which will be conducted at multiple centers, to confirm the activity of ViPOR in people with non-GCB DLBCL and double-hit GCB DLBCL.
Wilson believes that the regimen could change clinical practice immediately and it is “likely that it will be put into treatment guidelines as a potential, but not yet fully vetted, treatment option for these patients.”
