The origins of chemotherapy for non-Hodgkin lymphoma (NHL) date back to the 20th century, when observations on the toxic effects of chemical weapons led Louis S. Goodman, MD, and Alfred Gilman Sr., PhD, to experiment with nitrogen mustards, demonstrating their ability to induce lymphoid tumor regressions in mice. This discovery paved the way for intensive combination chemotherapies, with the CHOP regimen (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) becoming the cornerstone of treatment. The addition of rituximab, forming the R-CHOP regimen, revolutionized care for patients with diffuse large B-cell lymphoma (DLBCL); however, survival rates remain suboptimal and building upon frontline treatment continues to be a great challenge. Highlighting the need to learn from past efforts to drive future innovations will be Aggressive Lymphomas: Pharmacologic Therapies (12:00 p.m. - 1:30 p.m., Convention Center, Ballroom 20AB), which will consider novel frontline treatment combinations for newly diagnosed DLBCL. These state-of-the-art approaches seek to rethink R-CHOP, challenge the status quo, and offer new hope for improving patient outcomes.
“Will I be cured?” is a question I’m frequently asked by patients with newly diagnosed NHL. While I can reassure them that a cure is possible for most with standard treatment, the outlook for the small subset who don’t respond is not as good. There is no one-size-fits-all solution, and we are still far from being able to individualize the treatment up front. The answer to the need for better strategies to address the complexities and heterogeneity of the disease’s biology comes in the form of the COALITION study (Abstract 582), a randomized phase II trial developed by Michael J. Dickinson, MBBS, DMedSci, and Adrian Minson, MBBS. This study explores the incorporation of glofitamab, a bispecific antibody, into standard immunochemotherapy for DLBCL. “Patients with DLBCL and high-risk features remain in need of improved treatments and continue to have poor outcomes with existing therapies,” Dr. Minson said. “These patients have the most to gain from novel approaches to treatment.”
Bispecific antibodies (BsAbs) have shown promising results in heavily pretreated populations. “I'm excited about the potential of this and other BsAb combinations in the first line,” Dr. Dickinson said. “The history of R-CHOP+X studies has rarely led to success, but here we show that glofitamab can be added to R-CHOP or [pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone)] without compromising the treatment backbone, safely producing excellent outcomes even in patients with extremely high-burden disease. International trials of BsAbs being added to chemotherapy in the first line are running at the moment, and I very much hope they will be positive.” Be sure to also check out the Epcore NHL-2 study (Abstract 581), which evaluates fixed-duration epcoritamab combined with R-CHOP in first-line treatment. Lorenzo Falchi, MD, will present long-term data. Both the COALITION and Epcore NHL-2 trials, with their incorporation of early-stage BsAbs into frontline therapy, give me hope for improved outcomes for high-risk patients.
Several other oral presentations will feature data from phase I/II studies exploring new combination strategies with R-CHOP and pola-R-CHP for untreated DLBCL patients. These include venetoclax for high-risk B-cell lymphoma 2-positive DLBCL (Abstract 577); the Waveline-007 phase II trial evaluating zilovertamab vedotin, an antibody-drug conjugate targeting the extracellular region of ROR receptor tyrosine kinases (Abstract 578); and a promising combination adding golcadomide, an oral cereblon E3 ligase modulator, to R-CHOP (Abstract 579). Many of these trials also incorporate innovative methods to measure minimal residual disease in response to treatment, such as circulating and cell-free DNA.
Also today, a symposia on aggressive lymphomas (9:30 a.m. - 11:00 a.m., Marriott Marquis, Grand Ballroom 8-9) will feature an oral presentation of the five-year analysis of the POLARIX study (Abstract 469). This trial, which added the anti-CD79b monoclonal antibody polatuzumab vedotin to pola-R-CHP, demonstrated a higher progression-free survival than R-CHOP in untreated DLBCL patients with an International Prognostic Index score of 2 or more, later showing to be particularly beneficial for patients with non-germinal center DLBCL. Despite similar overall survival and toxicity, these findings led to U.S. Food and Drug Administration approval in 2023. Gilles Salles, MD, PhD, will present the extended results of this trial, potentially sparking a debate among the lymphoma community between those who are team R-CHOP and those who prefer pola-R-CHP.
Great strides in managing relapsed or refractory (R/R) DLBCL have reshaped the treatment landscape. Real-world studies and clinical trials provide complementary insights into therapy performance across diverse populations. Abstract 470, to be presented today (9:45 a.m. - 10:00 a.m., Marriott Marquis Marina, Grand Ballroom 8-9), focuses on real-world outcomes in patients with R/R DLBCL treated with lisocabtagene maraleucel as second-line therapy will offer valuable clinical comparisons between trial-eligible and ineligible patients. Addressing gaps in pretransplant and chimeric antigen receptor T-cell (CAR-T) bridging therapies, Abstract 987, to be presented during Monday’s symposia on pharmacologic therapies for aggressive lymphomas (4:30 p.m. - 6:00 p.m., Marriott Marquis, Pacific Ballroom Salons 18-19), will introduce a novel combination of glofitamab with the globally recognized R-ICE regimen (rituximab, ifosfamide, carboplatin, etoposide), demonstrating promising efficacy and safety for patients undergoing transplant or CAR-T therapy. Lastly, when options seem exhausted after relapsing with CD19 CAR-T, firicabtagene autoleucel, a CD22-directed CAR-T therapy, has demonstrated intriguing outcomes in heavily pretreated patients after a median follow-up of three years. Abstract 69, presented at yesterday’s session on cellular therapies for aggressive lymphomas, discussed the results of a new study of this treatment, as well as its risks and long-term complications.
In practice, when faced with a young patient with DLBCL for whom treatment has failed or one who has experienced an early relapse, I feel an overwhelming sense of helplessness. Despite efforts to think outside the box, our treatment options in Mexico are limited to high-dose chemotherapy and autologous stem cell transplant, with access to CAR-T therapy or BsAbs remaining a distant fantasy. Developing groundbreaking therapies to reshape lymphoma care must be matched with efforts to broaden access. From this side of the Rio Grande, I eagerly await results that will reveal solutions for curing these patients but also hope that they become a reality for all.
I encourage you to engage with the experts at #ASH24 during today’s malignant lymphoma sessions, where innovation and breakthroughs will deepen your knowledge and inspire you. Is the end of R-CHOP near? Come and find out.
