Combination therapy yields lasting remissions in resistant aggressive B-cell lymphoma

Researchers at the National Institutes of Health (NIH) have made significant strides in treating aggressive B-cell lymphoma that resists standard therapies. This novel approach, which doesn't rely on chemotherapy, has led to complete remissions in some patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The therapy, involving a five-drug combination, targets multiple molecular pathways crucial for the survival of DLBCL tumors.

In a clinical trial conducted by NIH's National Cancer Institute, 50 patients with DLBCL received a regimen named ViPOR, which includes venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide. The results were promising: tumors shrank significantly in 54% of evaluable patients, and 38% experienced complete tumor disappearance. Two years into the study, 36% of the participants were still alive, and 34% were disease-free. These positive outcomes were particularly notable in two specific subtypes of DLBCL.

The detailed findings were published on June 20, 2024, in the New England Journal of Medicine. "Patients who had stopped responding to conventional treatments often faced a bleak prognosis, with survival times less than a year. Now, a significant number are living beyond two years, with some even surpassing four years," remarked Dr. Christopher J. Melani, one of the study's co-leaders.

Research has previously identified various genetic pathways pivotal for different DLBCL subtypes, such as activated B cell-like (ABC) DLBCL and germinal center B cell-like (GCB) DLBCL. Though targeted drugs have shown potential in blocking these pathways, single-drug treatments rarely yielded long-lasting results due to tumors' ability to activate alternative survival mechanisms. Dr. Melani and his team theorized that a multi-drug regimen targeting several pathways could result in more durable responses.

After thorough laboratory studies to identify the most effective drug combinations, researchers settled on the five-drug ViPOR regimen. Patients received these drugs in two-week cycles, with a week-long break between cycles to minimize side effects. The trial demonstrated that this regimen was most effective in two DLBCL subtypes: non-GCB DLBCL and a form of GCB DLBCL known as high-grade B-cell lymphoma "double hit." Complete response rates were 62% and 53% for these subtypes, respectively.

Patients with non-GCB DLBCL and double-hit GCB DLBCL also showed higher rates of progression-free and overall survival after two years. The ViPOR regimen even benefited those who had not responded to or had relapsed after CAR T-cell therapy, a standard treatment for relapsed DLBCL. Among these patients, 30% achieved lasting remissions.

Side effects from the ViPOR regimen were generally mild to moderate and manageable during treatment breaks. Only five patients discontinued treatment due to adverse effects or other reasons. This suggests that the combination therapy is tolerable and opens the possibility of adding more drugs to enhance efficacy. Researchers are also exploring the regimen's potential in treating other lymphoma types resistant to previous therapies.

To further validate the ViPOR regimen's effectiveness, a larger phase 2 study involving multiple centers is underway, focusing on patients with non-GCB DLBCL and double-hit GCB DLBCL. Additional research is needed to develop treatments for GCB DLBCL subtypes less responsive to ViPOR.

The study was a collaborative effort, co-led by Drs. Wyndham H. Wilson, Mark Roschewski, and Louis M. Staudt from NCI's Center for Cancer Research, along with contributions from NIH's National Center for Advancing Translational Sciences and other institutions.