The results from a phase Ib/II study of a five-drug regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) show the treatment produced durable remissions in patients with specific molecular DLBCL subtypes and was associated with mild to moderate adverse events. Durable complete responses were observed in patients who were heavily pretreated with chemotherapy or chimeric antigen receptor (CAR) T-cell therapy, according to the researchers at the National Institutes of Health who developed ViPOR. The study was published by Melani et al in The New England Journal of Medicine.

DLBCL is the most common form of non-Hodgkin lymphoma in the United States, comprising more than 25% of all lymphomas diagnosed in the United States. Each year more than 25,000 people in the United States are diagnosed with the cancer. Although chemoimmunotherapy for DLBCL can be curative, patients with early relapsed or refractory disease have poor outcomes with conventional treatments.

Study Methodology

The researchers enrolled 60 patients with relapsed or refractory B-cell lymphoma into the trial from February 2018 to June 2021, including 20 patients (10 with DLBCL) in phase Ib and 40 patients (all with DLBCL) in phase II. Among the 50 patients with DLBCL, the median age was 61 years, and 92% had stage III or IV disease. The median number of previous systemic therapies received was three, including in 20 patients who had received previous CAR T-cell therapy and 29 patients with refractory disease.

A total of 25 patients had DLBCL–not otherwise specified, including 12 with germinal center B-cell (GCB) subtypes and 13 with non-GCB subtypes. Twenty patients had high-grade B-cell lymphoma, double hit (HGBCL-DH), including 17 with MYC and BCL2 translocations (HGBCL-DH-BCL2) and three with MYC and BCL6 translocations (HGBCL-DH-BCL6), and 5 patients had T-cell histiocyte-rich large B-cell lymphoma.

In the phase Ib portion of the trial, patients received the ViPOR regimen; a phase II expansion in patients with GCB and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles.

Results

The researchers found in the phase Ib portion, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established the recommended phase II dose of venetoclax as 800 mg. Phase II of the study included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%).

Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were seen exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI] = 21%–47%) and 36% (95% CI = 23%–49%), respectively.

“Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events,” concluded the study authors.

Clinical Significance

“This multiagent regimen simultaneously targets multiple key survival pathways that are important for B-cell lymphoma to grow and survive,” said lead study author Christopher J. Melani, MD, Staff Clinician and a clinical researcher specializing in lymphoma at the Lymphoid Malignancies Branch, Center for Cancer Research at the National Cancer Institute. During a media briefing detailing the results of the ViPOR study, Dr. Melani explained, “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.”

Christopher J. Melani, MD

To minimize treatment adverse events in the study participants, ViPOR was administered over six cycles, or 18 weeks of therapy, explained Dr. Melani. “ViPOR is given in noncontinuous cycles, so all the medications, including the four oral agents as well as the one intravenous agent (obinutuzumab) are given in 2-week cycles with a 1-week break of all medications to try to maximize the effectiveness of the regimen, but also minimize some of these potentially added side effects that can occur when you are giving multiple study agents simultaneously…. Additionally, unlike other targeted therapy regimens that are given indefinitely, or at least for prolonged periods of time such as 1 or 2 years, ViPOR is given for a fixed duration, with no prolonged maintenance or consolidation built into it,” he said.

The simultaneous targeting of multiple survival pathways in these patients has resulted in very durable remissions, with one-third of the patients alive and experiencing no evidence of disease after 2 years following therapy, and several patients potentially cured of their disease, according to Dr. Melani.

“In [patients] with non-GCB DLBCL, there were 39% of patients alive and without evidence of disease at the 2-year time point, with several of these patients now out after 5 years in continued remission, so we think they are likely cured of their disease at this point in time,” he concluded.

Wyndham Wilson, MD, PhD, of the National Cancer Institute, is the corresponding author for The New England Journal of Medicine article.

Disclosure: Funding for this study was provided by the National Cancer Institute, the National Institutes of Health, and others. For full disclosures of the study authors, visit nejm.org.