SILVER SPRING, MD — Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma (NHL), characterized by its aggressive nature. While frontline therapies achieve remission in the majority of patients, many of those diagnosed with the lymphoid malignancy will ultimately experience relapsed or refractory (R/R) disease, necessitating novel therapeutic approaches.
The standard initial treatment for DLBCL involves a combination chemotherapy regimen that includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This regimen induces durable remission in approximately 60% of patients. However, about 40% of patients either do not respond to initial therapy or relapse after an initial response, with about 15% not responding at all and 20% to 25% relapsing, typically within 24 months following initial response.
For these individuals, one of several high-dose chemotherapy regimens followed by autologous stem cell transplantation (ASCT) has been the standard treatment recommendation.
Yet, only 10% percent of patients with R/R DLBCL receive long-term benefit from ASCT. The math is brutal: up to half of patients with R/R DLBCL are ineligible for ASCT because of advanced age, comorbidities or poor performance status. Of those eligible for ASCT, about half prove refractory to the salvage chemotherapy and are unable to continue to transplantation. Of those who complete the grueling treatment, 40% achieve lasting remission.1
Patients who do not respond or cannot withstand the intensive chemotherapy required before transplantation or become ineligible for ASCT after the salvage therapy, have had few options, little hope and less time until recently.
A burst of U.S. Food and Drug Administration approvals for novel therapies in the last five years has significantly expanded options for patients with R/R DLBCL and for selected patients in the first line.
In a change for initial treatment, the VA Oncology Clinical Pathways for DLBCL and the National Comprehensive Cancer Network (NCCN) now recommend using polatuzumab plus vedotin piiq, rituximab, cyclophosphamide, doxorubicin, prednisone (pola-R-CHP) for most patients diagnosed with stage III or IV disease who have International Prognostic Index of 2 or higher and non-germinal center B-cell cell of origin.
Polatuzumab, a monoclonal antibody, received FDA approval in this setting in April 2023 based on the POLARIX trial. While the 879-person study did not demonstrate a difference in overall survival or complete response rate for Pola-R-CHP compared to R-CHOP, progression-free survival was 27% longer.2
For patients with R/R DLBCL who relapsed within 12 months of initial treatment or had primary refractory disease, NCCN recommends chimeric antigen receptor T-cell (CAR-T)-mediated therapies using axicabtagene ciloleucel or lisocabtagene maraleucel, both CD19-directed therapies, with several options for bridging therapies.
CAR-T therapies face numerous challenges, however. Physicians are often reluctant to use them in patients over age 70 or 75 or in those with significant co-morbidities because of their toxicity and the high risk of cytokine release syndrome and potentially life-threatening neurological events. In addition, because they are customized to the patient, they are very expensive and are not available outside of major academic centers. These therapies are only available through Risk Evaluation and Mitigation Strategy (REMS) programs because of their risks. Further, they can take three-to-four weeks to produce, which is often too long for a patient with a quickly progressing disease that has already been demonstrated to be refractory to high-intensity immunochemotherapy.
For patients who are not eligible for or choose not to proceed with CAR T-cell therapy, the NCCN recommends five newer therapies.
Tafasitamab-cxix
Tafasitamab-cxix is a humanized monoclonal antibody targeting the CD19 antigen on B cells. In July 2020, the FDA granted accelerated approval for tafasitamab-cxix in combination with lenalidomide for adult patients with R/R DLBCL who are not eligible for ASCT. The VA added tafasitamab to its formulary in 2024 for patients who meet the agency’s criteria for use.
This approval was based on the L-MIND study, which demonstrated an overall response rate of 57.5% at a median of 44 months follow up, including a complete response rate of 41.3%. The median duration of response was 21.7 months. Median progression-free survival was 11.6 months and overall survival was 33.5 months. Neutropenia and thrombocytopenia were the most common adverse events.3
A subsequent real-world analysis of 181 patients supported these findings, reporting a progression-free survival of 11.3 months and an overall survival of 24.8 months in patients treated with tafasitamab-cxix and lenalidomide. The overall response rate (ORR) was 73.5%, of which 23.2% achieved complete response. Factors such as treatment line, disease stage, and comorbidities significantly influenced outcomes, with use of the tafasitamab-cxix/lenalidomide combination in earlier lines associated with better results than in later lines.4
Epcoritamab-bysp
A bispecific antibody that engages CD3 and CD20, epcoritamab-bysp received accelerated approval from the FDA in May 2023 for patients with R/R DLBCL after two or more lines of systemic therapy. NCCN recommends using epcoritamab-bysp with gemcitabine and oxaliplatin (GemOx) as a second line therapy.
The EPCORE NHL-1 trial supported the agency’s decision. The multicenter, single-artm trial included 148 patients with R/R DLCBL who had previously received at least two lines of systemic therapy, including at least one with an anti-CD20 antibody-containing therapy. The ORR was 61%, with 38% of patients achieving complete response and median duration of response of 15.6 months at a median of 9.8 months of follow-up.5
At three years, EPCORE NHL-1 had an ORR of 59%, complete response of 41% and median duration of response of 20.8 months.6
Epcoritamab carries a black box warning for cytokine response syndrome (CRS) and life-threatening immune effector cell-associated neurotoxicity syndrome (ICANS). The FDA noted that more than half of the patients in the trial developed CRS and 6% developed threatening immune effector cell-associated neurotoxicity syndrome.7
Glofitamab-gxbm
Glofitamab-gxbm is another bispecific antibody targeting CD20 and CD3. It gained FDA accelerated approval in June 2023 for relapsed or refractory DLBCL following two or more lines of systemic therapy. As with epcoritamab, NCCN recommends its use in combination with GemOx.
In its pivotal study, 154 patients received glofitamab, of which 52% had an objective response and 39% had complete response. At a median follow-up of 11.6 months, the ORR was 56% with complete response in 43%. The estimated median duration of response was 18.4 months.8
Glofitamab-gxbm has a boxed warning for serious or fatal CRS and a warning for ICANS, serious infections, and tumor flare. Among 145 patients with relapsed or refractory LBCL evaluated for safety, CRS occurred in 70%, ICANS in 4.8%, serious infections in 16%, and tumor flare in 12%, the FDA noted. Nearly two-thirds of patients had an adverse event of grade 3 or higher.
Polatuzumab
Polatuzumab is also listed by NCCN as a preferred a second-line therapy either in combination with bendamustinem with or without rituximab or in combination with mosunetuzumab-axgb.
- Hoffmann MS, Hunter BD, Cobb PW, Varela JC, Munoz J. Overcoming Barriers to Referral for Chimeric Antigen Receptor T Cell Therapy in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma. Transplant Cell Ther. 2023 Jul;29(7):440-448. doi: 10.1016/j.jtct.2023.04.003. Epub 2023 Apr 7.
- US FDA. FDA DISCO Burst Edition: FDA approval of Polivy (polatuzumab vedotin-piiq) for previously untreated diffuse large B-cell lymphoma, not otherwise specified, and high grade B-cell lymphoma. June 7, 2023.
- Duell J, Abrisqueta P, Andre M, et al. Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety findings in the phase II L-MIND study. Haematologica. 2024 Feb 1;109(2):553-566. doi: 10.3324/haematol.2023.283480.
- Saverno K, Nastoupil L, Feinberg B, et al. Real-world effectiveness of tafasitamab (tafa) for the treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in the United States. Blood. 2024;144(suppl 1):2375. doi:10.1182/blood-2024-193264
- Thieblemont C, Phillips T, Ghesquieres H, Cheah CY, Clausen MR, Cunningham D, et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: dose expansion in a phase I/II trial. J Clin Oncol. 2023;41:2238–47.
- Vose, et al. 3-Year Update from the Epcore NHL-1 Trial: Epcoritamab Leads to Deep and Durable Responses in Relapsed or Refractory Large B-Cell Lymphoma. ASH Annual Meeting & Exposition Database. Dec 2024. Abstrat 4480.
- US FDA. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refratory diffuse large B-cell lymphoma nad high-grad B-cell lymphoma. May 19, 2023.
- US FDA. FDA grants accelerated approval to glofitamab-gxbm for selected relapsed or refraectory large B-cell lymphomas. June 16, 2023.