The disease we now call diffuse large B-cell lymphoma (DLBCL) has gone by the names of reticulum cell sarcoma, diffuse histiocytic lymphoma, and diffuse large cell lymphoma, and included both lymphomas of B cells and T cells. We now know DLBCL is still heterogenous and some subtypes might benefit from specific therapies. The latest efforts to further optimize outcomes were described at the 2024 Debates in Hematology and Oncology Conference, sponsored by Emory University Winship Cancer Center, by lymphoma expert James O. Armitage, MD, FASCO. Dr. Armitage is the Joe Shapiro Professor of Medicine at the University of Nebraska and the Editor-in-Chief of The ASCO Post.
Primary Therapy
Many patients with DLBCL are either elderly or present as unwell and have a reduced performance status. For this group, a simple treatment—so-called prephase therapy developed by the German High-Grade Lymphoma Study Group—may be started before definitive therapy and has been shown to reduce first-cycle deaths. The treatment is prednisone at 100 mg/day for 5 to 7 days, with or without vincristine at 1 mg (less important than prednisone). Using this approach, Dr. Armitage has observed significant improvement in the clinical status of patients who had become “dangerously ill,” convincing him that “we have something that can make a real difference for at least for some patients.”
Looking back over the list of DLBCL treatments over the years, Dr. Armitage noted that most ultimately proved to be no better than CHOP, with the exception the addition of rituximab to CHOP. However, the antibody-drug conjugate polatuzumab vedotin-piiq, yielded strong single-agent activity in relapsed or refractory DLBCL; a response rate of 56% and a complete response rate of 16.1% were reported.1 As initial therapy, polutuzumab vedotin was substituted for vincristine in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine; Pola-R-CHP).2 The overall improvement in progression-free survival, over R-CHOP, was 7%, but the benefit was not uniform.
“The most significant were the 8% absolute improvement with Pola-R-CHP in patients older than 60; absolute 10% improvement in men; absolute 10% improvement in patients with higher International Prognostic Index (IPI) scores (IPI 3–5); and, most strikingly, a 25% absolute improvement in patients with the ABC (activated B-cell) rather than GCB-NOS (germinal center B-cell subtype, not otherwise specified). “The drug is approved for all DLBCL, and that’s fine, as it’s better than R-CHOP on average, but you certainly don’t want to not give it to the patients with the ABC subtype,” Dr. Armitage emphasized.
Curing Patients Who Fail to Respond to Primary Therapy
“Things are changing in patients who have failed to respond to primary therapy,” Dr. Armitage noted. “DLBCL is one of those diseases where it is not unheard of for patients who have failed to respond to two or three treatments and look quite ill can respond to the next treatment and be cured.” He described, as an example, two patients with highly refractory disease with robust responses to salvage interferon. The patients never relapsed and remain well 20 to 30 years later.
Clearly, there are more reliable options than interferon, as Dr. Armitage explained, citing autologous stem cell transplant, chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies, and a novel regimen that avoids conventional chemotherapy.
First in terms of transplantation, he noted that long-term follow-up of a 1987 study3 showed autologous transplant can clearly cure some patients. In optimal candidates—those who relapsed after a complete remission and then responded to salvage therapy—approximately 40% were alive and still in remission at 12 years.
More recently, CAR T-cell therapy has demonstrated the ability to induce prolonged remissions, though follow-up remains short. “We are all becoming increasingly confident that CAR T-cell therapy cures people with recurrent DLBCL, and that it seems to work in people who never got into remission, and people who failed to respond to auto-transplant, and/ or people who were not candidates for auto-transplant,” he said.
The most recent findings for the cellular immunotherapy lisocabtagene maraleucel in TRANSCEND-NHL,4 where median follow-up was 20 months, showed an objective response rate of 73%, a complete response rate of 53%, median progression-free survival of 7 months, median overall survival of 27 months, and 2-year overall survival of 50%. In ZUMA-7, at a median follow-up of 25 months, treatment with the immunotherapy axicabtagene ciloleucel led to a response rate of 83%, a complete response rate of 65%, median event-free survival of 8 months, 24-month event-free survival of 41%, and estimated overall survival at 2 years of 61%.5
There are no prospective studies to determine the relative efficacy of autologous transplant vs CAR T-cell therapy, but retrospective data suggest that auto-transplant is not less effective than CAR T-cell therapy in optimal transplant candidates.6 Auto-transplant also may be more readily approved than transplant, and, should it fail, subsequent CAR T-cell therapy can be effective.
The newer bispecific antibodies are more or less “off-the-shelf” T-cell therapies that are simpler to give and somewhat less toxic. The bispecific T-cell engager glofitamab-gxbm in patients with relapsed or refractory DLBCL produced complete responses in 39% overall and in 35% with prior CAR T-cell therapy.7 The median duration of response was 18 months, and for complete responders, it was not reached. At 12 months, 78% of complete responses were ongoing, and the median progression-free survival was about 5 months.
“There is increasing evidence that some patients who are treated with glofitamab as salvage therapy will stay well for some time,” Dr. Armitage commented. “What’s exciting is perhaps using this in primary therapy in combination with chemotherapy.”
A Potential Cure Without Traditional Chemotherapy
The identification of oncogenic mutations in DLBCL has led to the development of drugs that target essential survival pathways. A recent study of a novel regimen suggests that targeting multiple survival pathways may be effective.8 The regimen, ViPOR, which includes venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide, was evaluated in a phase I/IIb study of 60 patients with relapsed or refractory lymphoma, including 50 with DLBCL, who were treated with ViPOR for six 3-weekly cycles.
Of note, complete responses were restricted to patients with non-GCB DLBCL (62%) and high-grade B-cell lymphoma who had rearrangements of MYC and BCL2 and/or BCL6 (ie, double-hit) (53%); no complete responses were observed among the GCB-NOS subtype. At 2 years, 34% of the study population was progression-free, and 36% were alive. These rates approached 50% for the high-grade double-hit/BCL2 subset and 40% for the non-GCB subset, but were less than 10% for the GCB-NOS group. The findings point to an evolving aim to better personalize treatments for the various subtypes of DLBCL, Dr. Armitage said.
Using ctDNA to Assess Response
The use of circulating tumor DNA (ctDNA) to assess treatment response is an emerging practice. Three currently used tests include CLONO-seq; CAPP-seq; and Phase-seq. The latter has the highest sensitivity of approximately 10-6. The tests can be used after one or two treatment cycles to predict outcome, at the end-of-treatment to identify patients who are likely cured, to monitor for relapse, and to predict prognosis before treatment based on baseline ctDNA. “This last is presumably a reflection of tumor bulk, so it is not surprising that ctDNA would work for that,” Dr. Armitage explained.
On the other hand, the tests appear particularly useful for assessing prognosis after treatment initiation, he maintained. “A two- to two-and-a-half log decrease after two treatments was highly predictive of someone who has a chance to be cured,” he said. With Phase-seq, end-of-treatment ctDNA found 2-year progression-free survival to be 33% when ctDNA was detectable but 98% when ctDNA was undetectable.9 When end of treatment PET still was still positive, the 2-year progression-free survival rate was 100%.
Although it would be fairly easy to use ctDNA to monitor for relapse, there is probably less value for this, according to Dr. Armitage. First, the test may be so sensitive it picks up cells that may not be relevant, and second, early detection of relapse has not been shown to improve outcomes in lymphoma. “We have a disease where we can rescue patients, but trying to find them a bit earlier doesn’t seem to make much difference,” he pointed out.
“The technology for ctDNA testing is exciting, but as for exactly how we’re going to use it, and how easy it is to obtain (and to be paid for), time will tell,” Dr. Armitage concluded. “It might make a difference, but there are issues that have to be addressed.”
DISCLOSURE: Dr. Armitage is on the Board of directors of Cardiff Oncology and a consultant to Syncromune.
REFERENCES
- Palanca-Wessels MCA, Czuczman M, Salles G, et al: Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: A phase 1 study. Lancet Oncol 16:704-715, 2015.
- Tilly H, Morschhauser F, Sehn LH, et al: Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med 386:351-363, 2022.
- Philip T, Armitage JO, Spitzer G, et al; High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin’s lymphoma. N Engl J Med 316:1493-1498, 1987.
- Abramson JS, Palomba ML, Gordon LI, et al: Two-year follow-up of lisocabtagene maraleucel in relapsed or refractory large B-cell lymphoma in TRANSCEND NHL 001. Blood 143:404-416, 2024.
- Locke FL, Miklos DB, Jacobson CA, et al: Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med 386:640-654, 2022.
- Shadman M, Pasquini M, Ahn KW, et al: Autologous transplant vs chimeric antigen receptor T-cell therapy for relapsed DLBCL in partial remission. Blood 139:1330-1339, 2022.
- Dickinson MJ, Carlo-Stella C, Morschhauser F, et al: Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 387:2220-2231, 2022.
- Melani C, Lakhotia R, Pittaluga S, et al: Combination targeted therapy in relapsed diffuse large B-cell lymphoma. N Engl J Med 390:2143-2155, 2024.
- Roschewski M, Lindenberg L, Mena E, et al: End-of-treatment response assessment after frontline therapy for aggressive B-cell lymphoma: Landmark comparison of a singular PET/CT scan vs ultrasensitive circulating tumor DNA. 2023 ASH Annual Meeting & Exposition. Abstract 192. Presented December 9, 2023.
