In a phase Ib/II study conducted in patients with relpased or refractory diffuse large B-cell lymphoma (DLBCL), use of a regimen consisting of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) with simultaneous targeting of multiple pathways was shown as potentially curative in specific molecular subtypes. To optimise multiagent drug synergy, the study team designed a schedule reminiscent of combination chemotherapy, in which all targeted agents were concurrently administered in a noncontinuous fashion for a maximum of six cycles.
This strategy avoided the cumulative side effects that are associated with continuous or indefinite drug dosing and thereby allowed the safe administration of multiple targeted agents. The findings are reported by Dr. Wyndham H. Wilson of the Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health in Bethesda, MD, US and colleagues on 19 June 2024 in The New England Journal of Medicine.
Patients with early relapsed or refractory DLBCL have poor outcomes with conventional treatments. Although anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has improved outcomes, only approximately 30-40% of patients with relapsed or refractory disease are cured with such therapy. Genetic and functional genomic studies have revealed oncogenic driver pathways in DLBCL. Although many of targeted agents are active as monotherapy, they rarely induce deep responses or a cure.
The authors wrote in the study background that pathways in the activated B-cell subtype of DLBCL include BCR signalling to activate the NF-κB and PI3K, prevention of apoptosis by BCL2, and expression of the IRF4, Ikaros, and Aiolos. In the germinal-centre B-cell subtype of DLBCL, cell viability is maintained by constitutive BCR-dependent PI3K signalling, BCL2, Ikaros, and Aiolos.
The study team developed a regimen with venetoclax, ibrutinib, prednisone, and lenalidomide to target these pathways and included obinutuzumab to trigger innate immune responses to malignant B-cells. To maximise potential synergy while minimising the cumulative drug-related side effects, the study investigators administered all the agents in noncontinuous cycles for a fixed duration.
In the latest article, they present the results of a single-centre phase Ib study of ViPOR involving patients with relapsed or refractory B-cell lymphoma and an efficacy analysis for the phase II expansion involving patients with relapsed or refractory DLBCL. ViPOR was administered every 21 days for six cycles.
In a phase Ib of the study, involving 20 patients of whom 10 with DLBCL, a single dose-limiting side effect of grade 3 intracranial haemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase II included 40 patients with DLBCL. Side effects that were observed among all the patients included grade 3 or 4 neutropenia in 24% of the cycles, thrombocytopenia in 23%, anaemia 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 exclusively in patients with non-germinal-centre B-cell subtype of DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumour DNA was undetectable in 33% of the patients at the end of treatment with ViPOR. With a median follow-up of 40 months, 2-year progression-free survival (PFS) and overall survival were 34% and 36%.
Among patients who had previously undergone CAR T-cell therapy, ViPOR was associated with 2-year PFS in 30%, suggesting the treatment may alter the poor prognosis in these patients. Additionally, ViPOR allowed successful bridging to radiotherapy, CAR T-cell therapy, or allogeneic transplantation in more than one third of the patients who had a partial response.
Although haematologic side effects were common and occurred in more than two thirds of the patients, serious haematologic adverse events occurred in less than a quarter of the cycles, with febrile neutropenia observed in only 1% of the cycles. Intermittent drug dosing also resulted in fewer non-haematologic side effects, such as high-grade rash, than had been seen in continuous targeted therapy regimens.
Despite an initial concern about possible tumour lysis syndrome and hyperkalaemia occurring in patients who received ViPOR, diarrhoea and hypokalaemia were more commonly observed than tumour lysis syndrome and hyperkalaemia, with most patients receiving antidiarrhoeal medication and electrolyte support, in contrast to the one event of tumour lysis syndrome that was observed. In addition, adverse events frequently resolved during the off-treatment week, and most patients received all treatment cycles on schedule and without dose reductions.
The activity of ViPOR in patients with relapsed or refractory non-germinal-centre B-cell subtype of DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both) is a topic for future study.
In an accompanied editorial article, Drs. Jordan S. Goldstein and Ash A. Alizadeh of the Divisions of Oncology and Hematology, Department of Medicine, Stanford University in Stanford, CA, US wrote that the interpretation of the results is limited by single-group, single-centre design. Future multicentre studies are needed to confirm the results.
Access to CAR T-cell therapy remains an issue for many patients and providers. As a combination of oral and intravenous targeted therapies, ViPOR can be easily administered in the community setting. However, combining multiple targeted agents is costly. In addition, although all the component agents are approved by the Food and Drug Administration for other haematologic malignancies, none are currently approved for treatment of patients with DLBCL, which poses a potential impediment to on-label access.
Rationally designed targeted combination therapies such as ViPOR represent a key step forward in biology-based, chemotherapy-free treatment approaches to the treatment of large B-cell lymphomas according to the editorialists.
This study was supported by the Intramural Research Program of the US National Cancer Institute and the National Center for Advancing Translational Sciences of the US National Institutes of Health. Genentech provided venetoclax and obinutuzumab and Bristol Myers Squibb–Celgene provided lenalidomide under clinical trial agreements with the National Cancer Institute, and the National Institutes of Health Clinical Center Pharmacy Department provided ibrutinib and prednisone.
The study findings were previously presented in part at the International Conference on Malignant Lymphoma in 2019, and ASH Annual Meetings in 2019, 2020 and 2023.
References
- Melani C, Lakhotia R, Pittaluga S, et al. Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma. N Engl J Med 2024;390:2143-2155.
- Goldstein JS, Alizadeh AA. ViPOR’s Venom — Rationally Targeting DLBCL with Precision. N Engl J Med 2024;390:2209-2211.