Diffuse large B cell lymphoma (DLBCL) is an aggressive B cell malignancy and the most common type of non-Hodgkin lymphoma. The standard of care for many years has been a combination of chemotherapy and a monoclonal antibody called rituximab, a treatment known as R-CHOP.
Although this treatment is very effective for many patients, for a significant proportion, R-CHOP is not successful in eliminating all the lymphoma cells, or the lymphoma returns after a period of remission. Researchers estimate that the treatment is not successful for approximately 30-40% of diffuse large B cell lymphoma patients.
Identifying new treatment options for patients
Many trials have looked at other treatments that could offer an alternative to R-CHOP, but none have yet shown any definite benefit. However, as a result of an improved understanding of the biology of lymphoma, researchers on the NCRI Lymphoma Group identified an opportunity to improve treatment outcomes for that 30-40% of patients.
Researchers observed that bortezomib, a proteasome inhibitor, was showing promising results in other lymphomas. They wanted to see if adding bortezomib to the standard R-CHOP treatment would make it more successful. They also wanted to know if they could predict who was most likely to benefit from the treatment, using real-time molecular (RNA) profiling.
NCRI Lymphoma Group: Developing studies to improve outcomes
The NCRI High-Grade Lymphoma Subgroup designed the REMoDL-B trial to compare R-CHOP treatment with R-CHOP plus the addition of bortezomib (the B in the trial name stands for bortezomib). All patients recruited into the trial received either R-CHOP or R-CHOP plus bortezomib based on molecular profiling.
The NCRI Lymphoma Group, which reviewed the study, is made up of over 30 core and additional members, who are leading clinicians and clinical researchers, as well as NCRI Consumers. Through the NCRI group structure, the group can discuss research questions and generate ideas to address them. Alternatively, members of the group will formulate ideas that the group then improves via an iterative approach before applying for funding.
The group members represent many academic centres and hospitals in the UK. During the REMoDL-B trial, group members supported the recruitment of over 1000 patients to the trial across >100 sites throughout the UK and Switzerland.
Predicting treatment response using molecular profiling
This trial, led by Professors Andrew Davies and Peter Johnson at the University of Southampton, was internationally leading in its use of real-time molecular profiling. Previous research had identified two subtypes of DLBCL, germinal center B-cell (GCB) and activated B-cell (ABC). These can be identified by looking at the molecular profile of the lymphoma cells. As part of the REMoDL-B trial, researchers used molecular profiling to identify the subtype and then looked at whether the subtype determined who would benefit from the addition of bortezomib to the treatment. Tumour biopsies were analysed at the Leeds Cancer Centre within the first weeks of a patient enrolling in the trial.
Although there was no clear clinical benefit from the addition of Bortezomib to R-CHOP treatment, this study was applauded widely for its novel design and efficient operational delivery. Moreover, further data from the REMoDL-B trial have been crucial in identifying new high-risk categories of DLBCL, who may benefit from targeted additional therapies. The clinical and translational data derived from REMoDL-B have advanced our understanding of DLBCL biology and enhanced our capabilities in trial design and delivery. The successor trial, ReMoDL-A, will open to recruitment in early 2021 and much work is ongoing within the NCRI High-Grade Lymphoma Subgroup in designing future trials in this disease area.
Dr Christopher Fox, Chair of High-Grade Lymphoma Subgroup
As a member of the trial management group for this study, it was exciting to see researchers overcoming the early challenges of real-time profiling, recruitment numbers mounting, and being part of an international partnership. Although as a patient myself, the results were disappointing, establishing that we can use molecular profiling to enable personalised treatment will help many more patients in the long term. ReMODL-B has established a methodology that can be used for other studies.
Richard Stephens, NCRI Consumer
REMoDL-B: Providing a framework for future trials
The study found that the addition of bortezomib did not improve progression-free survival. The results were published in The Lancet Oncology. There was no significant difference in treatment response between the subgroups.
However, the success of the trial design has provided a framework for future trials, allowing trial participants to initiate treatment while molecular characterisation is carried out. The design has informed REMoDL-A, which will investigate the addition of acalabrutinib to the R-CHOP treatment. The trial hopes to recruit 500 patients across 50 centres.