Bruce Hough, Maher Albitar
Clinical Lymphoma, Myeloma and Leukemia, Vol. 000, No.xxx, 1–3 © 2025 Published by Elsevier Inc.
Keywords: CD19 dim, Diffuse large b-cell lymphoma, Relapsed/Refractory, Bispecific T-cell engagers, Third line
Introduction
Diffuse Large B-cell Lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma with an estimated 80,620 new case in the US in 2024. While most patients are cured with the current standard of care treatment, a combination of the drugs rituximab, Cytoxan, doxorubicin, vincristine and prednisone (R-CHOP), 25%-30% of patients have either primary refractory disease or have a relapse of their disease.
Those patients who are either primary refractory or have a DLBCL recurrence (R/R) have a relatively poor outcome, as seen recently in a series of patients from the Netherlands. In that trial, 50% of 455 patients did not receive subsequent treatment at the first instance of R/R disease. The median OS from subsequent treatment initiation was only 3.6 months with a 2 year OS rate of 13%.
New strategies and therapies are desperately needed in this vulnerable subset of patients.
Patients who are CD20 “dim” at the time of diagnosis have inferior outcomes. In a series by Johnson et al., those patients who were deemed to be “dim” by flow cytometry had statistically significant worse outcomes with RCHOP compared to patients who were not CD20 dim. In that trial, an arbitrary distinction was made between dim and bright by defining the lowest 16% on flow cytometry as being dim.
The traditional second line therapy for patients who relapse or are refractory to front line treatment of DLBCL is CAR-T therapy, following the success of the Zuma-7 trial comparing CAR-T to the previous standard of care, autologous HCT. In Zuma-7, evaluating CD19 expression by immunohistochemistry or flow cytometry was not a requirement for enrollment. Conceptually, it is possible that some patients in that trial would be considered “CD19 dim”, or perhaps could have even been CD19 negative by IHC.
There is clear data showing negative selective pressure and clonal expansion of CD20 negative clones following rituximab therapy. A similar mechanism occurs with CD19 in patients with DLBCL treated with the anti-CD19 CART product axicabtagene ciloleucel. On July 31st, 2020, the FDA has approved a naked anti-CD19 monoclonal antibody in combination with lenalidomide for use in patients who have relapsed or refractory DLBCL and who are not eligible for autologous stem cell transplant, the standard of care at the time of approval. This approval was based on the l-MIND trial, a phase II showing an overall response rate of 43% and a complete response rate of 18%. This regimen is currently in use as the backbone for the SWOG 2207 trial comparing tafasitamab/lenalidomide alone or in combination with either zanubrutinib or tazemetostat. This trial is currently ongoing. It is being stratified by cell or origin (GCB vs. non-GCB), but does not require testing of CD19 expression for enrollment.
In another B-cell malignancy, multiple myeloma, marked improvements have been seen with the use of anti-BCMA bispecific T-cell engager (BITE) therapy. The FDA approved teclistamab on October 25th, 2022 in light of the overall response rate of 61.8% in the MajesTEC-1 trial. The patients in the MajesTEC-1 trial were all heavily pretreated including triple class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody.
Anti-CD38 antibodies have been evaluated in patients with relapsed/refractory DLBCL, however use of single agent daratumumab in the R/R DLBCL setting has been disappointing with only single agent response rates.