Targeted Combination Therapy Leads to Durable Response in Patients With Relapsed Diffuse Large B-Cell Lymphoma


Combining multiple drugs to induce a deep response in patients with diffuse large B-cell lymphoma could open curative pathways for those affected.

Treatment with venetoclax, ibrutinib, prednisone, obinutuzumab and lenalidomide (ViPOR) in relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) was associated with durable remissions and had mainly reversible adverse events (AEs), according to results from a new study published in The New England Journal of Medicine.1

Photomicrograph of a diffuse large B-cell lymphoma (DLBCL) a type of non-Hodgkin lymphoma.

Image credit: David A Litman |

Chemoimmunotherapy can be curative for DLBCL. However, patients with R/R disease have poor outcomes with conventional treatments such as anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy, for which only 30% to 40% of patients are cured.

There have been genetic and functional genomic studies that led to the development of drugs against actionable targets in DLBCL, though they rarely induce a cure or deep responses despite some molecular subtypes occasionally responding exceptionally well to these agents.

Previously published literature has found synergy among targeted drugs in DLBCL models. One study, conducted by Griner et al., used a combinatorial screening platform to identify drug combinations that could be effective against DLBCL.

Griner et al. discovered that ibrutinib (Imbruvica; Pharmacyclics, Johnson & Johnson) reacted favorably with a wide range of drugs; findings such as these led the authors of the current study to hypothesize that inhibiting multiple survival pathways at the same time could be curative in R/R DLBCL.2

Phase 1b of this study included patients with R/R B-cell lymphoma, while the phase 2 expansion focused on those with R/R DLBCL. To be eligible, patients had to have received anti-CD20 antibodies on a previous occasion.

Sixty patients with R/R B-cell lymphoma were enrolled in the study, with 20 in phase 1b and 40 in phase 2. In total, 50 patients had DLBCL, with 10 of these patients enrolled in phase 1b. In more than two-thirds of patients, hematologic AEs of any grade occurred, including grade 3 or 4 neutropenia, thrombocytopenia, and anemia.

Among 48 evaluable patients with DLBCL, ViPOR caused a response in 54% of patients (26), while 38% of patients (18) had a complete response (CR) of entirely disappearing tumors, according to the investigators. Among those patients with CR, 78% were durable and without consolidation.

Two-year progression free survival (PFS) was 34% (95% CI: 21-47) in all patients with DLBCL. In patients who had a response, 2-year duration was 65% overall. A subtype analysis showed that 2-year PFS was highest in those with HGBCL-DH-BCL2 (47%), T-cell histiocyte-rich large B-cell lymphoma (40%) and non-GCB DLBCL not otherwise specified (39%), the study authors wrote.

“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 2 years, and some past 4 years,” Christopher J. Melani, MD, who co-led the study, said in a news release, noting that it was “gratifying” to see durable responses and potentially curative effects in patients.3

Despite hematologic toxic effects being common, the investigators noted serious AEs occurred in less than a quarter of the cycles. Additionally, the method of intermittent drug dosing resulted in fewer nonhematologic toxic effects; specifically, high-grade rash, which had been seen in prior continuous targeted-therapy regimens.

About the Trial

Trial Name: Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma Identifier: NCT03223610

Sponsor: National Cancer Institute (NCI)

Estimated Completion Date: December 1, 2026

In patients who had previously undergone CAR-T therapy, ViPOR was associated with 2-year PFS in 30% of them, which the investigators said suggests the drug combination may alter the poor prognosis in these patients.

Furthermore, ViPOR led to higher percentages of CRs and PFS when used as a second-line therapy. This observation suggests that the combination drug should be administered early in the treatment of patients with R/R DLBCL, the study authors noted.

“By putting 5 drugs together, we believe that there will be some drug combination—either 2, 3, or more drugs—that will be particularly effective against that patient's tumor,” Melani said.

  • Melani C, Lakhotia R, Pittaluga S, et al. Combination targeted therapy in relapsed diffuse large B-cell lymphoma. N Engl J Med. 2024;390(23):2143-2155. doi:10.1056/NEJMoa2401532.
  • Griner L, Guha R, Shinn P, et al. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Pro Natl Acad Sci. 2014;111(6):2349-2354. doi:10.1073/pnas.1311846111.
  • EurekAlert! Combination targeted treatment produces lasting remissions in people with resistant aggressive B-cell lymphoma. News release. Released June 19, 2024. Accessed June 20, 2024.
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