From Dr. Bruce Cheson’s electric speech on how it all started with pentostatin in hairy cell leukemia, to the introduction of bendamustine in indolent lymphoma, to the development of R-squared (an innovative chemotherapy-free approach to treating lymphoma)—the nostalgia at the International Conference on Malignant Lymphoma (ICML) 2025 was real.
Another legend, Dr. Emanuele Zucca, took us through a lymphoma time capsule—the story of the evolution of different subtypes in lymphoma—how Helicobacter pylori eradication transformed gastric MALT (mucosa-associated lymphoid tissue) lymphoma; how primary mediastinal B-cell lymphoma became a distinct entity from diffuse large B-cell lymphoma (DLBCL) and found its footing with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin plus rituximab); and how the International Extranodal Lymphoma Study Group, through unprecedented international collaboration, shaped the management of central nervous system and testicular lymphomas.
“The momentum in aggressive B-cell lymphomas was undeniable. We didn’t just see the field evolve—we saw it realign.”— KHUSHALI JHAVERI, MD
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Watching these legends—architects of the field—walk us through 4 decades of progress felt like a gift. For many of us, it was the dream: the history lesson we never got in fellowship, delivered firsthand. But ICML wasn’t just about honoring the past—it was a front-row seat to where we’re going.
Learning From Two Molecular Classifiers
We’ve long leaned on cell of origin to guide prognosis in DLBCL, splitting patients into germinal center B-cell (GCB) or activated B-cell (ABC) subtypes. However, that binary framework is starting to crack. This year, two molecular classifiers—LymphGen and DLBclass—offered a more nuanced way to look at disease biology.
DLBclass identified five molecular clusters of DLBCL. Cluster 5, a high-risk, ABC-like group marked by MYD88/CD79B mutations and extranodal tropism, has historically had poor outcomes. But when applied to the POLARIX trial,1 patients with C5 tumors treated with polatuzumab vedotin-piiq plus rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) saw the 5-year progression-free survival rate rise from 42% to 70%; the benefit held after accounting for either of individual mutations or both. These tools may finally take us beyond cell of origin—not just classifying prognosis but guiding therapy.
At the same time, LymphoMAPs offered a new lens on the tumor microenvironment. Three immune archetypes emerged: lymph node–like, T-cell–exhausted, and fibroblast/macrophage (FMAC) archetype (T-cell–excluded). In ZUMA-7,2patients with lymph node–like tumor microenvironments had the best outcomes with axicabtagene ciloleucel. The others struggled. Interferon gamma and transforming growth factor beta emerged as mediators of resistance—and potential targets. This is a reminder that response isn’t just about the tumor; it’s about the neighborhood.
Moving Beyond Rituximab Plus GemOx
But perhaps the clearest message from ICML 2025 was that rituximab plus GemOx (gemcitabine and oxaliplatin) is history. Three studies drove that point home.
In POLARGO,3 polatuzumab vedotin, an antibody-drug conjugate that combines a monoclonal antibody targeting CD79b, with monomethyl auristatin E (MMAE), added to rituximab plus GemOx more than doubled the overall response rate compared with rituximab plus GemOx alone and showed a clear efficacy edge. The objective response rate was 53% vs 25%, with progression-free survival extended by 63% (7.4 vs 2.7 months) and overall survival improved by 36% (19.5 vs 12.5 months).
In STARGLO,4 adding the bispecific T-cell engager glofitamab-gxbm to GemOx, with longer 2-year follow-up, resulted in a 2-year overall survival rate of 54%, climbing to 60% in the second-line setting compared with 39% in historical controls. Among patients who achieved end-of-treatment complete remission, the 1-year progression-free and overall survival rates were 89% and 82%, respectively.
And, perhaps most strikingly, in the phase III SUNMO trial,5 the chemotherapy-free bispecific/antibody-drug conjugate combination of mosunetuzumab-axgb and polatuzumab vedotin, crushed rituximab plus GemOx across the board. It halved the risk of disease progression (progression-free survival of 11.5 vs 3.8 months), doubled the complete response rate (51% vs 24%), and showed durable responses with a favorable safety profile. Grade ≥ 2 cytokine-release syndrome occurred in just 4.4%, and no case of immune effector cell–associated neurotoxicity syndrome was reported.
Three regimens. Three paths forward. All better than what rituximab plus GemOx could offer.
Emerging Bispecifics and Antibody-Drug Conjugates
The chemotherapy-free momentum didn’t stop there. In LOTIS-7,6 the bispecific/antibody-drug conjugate combination of glofitamab and loncastuximab tesirine-lpyl achieved an objective response rate of 93% and a complete response rate of 87% in heavily pretreated patients—numbers rarely seen in this population. Responses came fast (median time to response was 42 days), and early safety looked manageable. It’s the kind of data that hint bispecific/antibody-drug conjugate combinations may offer speed, depth, and safety—all off the shelf.
And although much of the bispecific buzz has focused on the relapsed or refractory setting, front-line trials this year made it clear: these agents are coming for day 1.
In EPCORE NHL-5,7 the bispecific T-cell engager epcoritamab-bysp added to polatuzumab vedotin plus R-CHP achieved a 100% objective response rate and a 97% complete response rate, with more than 80% of patients achieving undetectable measurable residual disease (MRD) by cycle 3. Glofitamab joined the fight too. When glofitamab was added after two cycles of polatuzumab vedotin plus R-CHP in patients with an International Prognostic Index ≥ 2, it delivered a 95% objective response rate, a 90% complete response rate, and a 95% MRD negativity rate at the end of treatment. It’s early, but the message is perhaps suggesting that front-line DLBCL may soon have a new standard?
And, finally, bispecifics also found their place as bridging therapy8 prior to chimeric antigen receptor (CAR) T-cell therapy. In a small cohort, agents such as glofitamab and epcoritamab led to objective response rates over 80%, with strong progression-free survival and overall survival at 100 days and no signals of impaired CAR T-cell efficacy. It’s yet another sign that these drugs are no longer on the margins. They’re integrating into the very structure of how we think about DLBCL management.
Although I could go on about the many updates at ICML, the momentum in aggressive B-cell lymphomas was undeniable. We didn’t just see the field evolve—we saw it realign. From molecular classifiers to chemotherapy-free combinations, from off-the-shelf depth in late lines to bispecifics knocking at the front line—the ground is shifting. Not slowly. Not someday. Now.
DISCLOSURE: Dr. Jhaveri reported no conflicts of interest.
REFERENCES
- Calabretta E, Lu K, Zhao X, et al: The benefit of pola-R-CHP in DLBclass-defined molecular subsets of newly diagnosed DLBCL in the POLARIX trial. Hematol Oncol 43(S3):eLBA_70110, 2025.
- Russler-Germain DA, Li X, Singhal K, et al: Large B-cell lymphoma microenvironment archetype profiles (LymphoMAPS) identify subgroups with greatest benefit from CD19 CAR T-cell therapy. Hematol Oncol 43(S3):e5_70093, 2025.
- Sancho J, Li Z, Vassilakopoulos TP, et al: Polatuzumab vedotin, rituximab, gemcitabine and oxaliplatin (POLA-R-GEMOX) for relapsed/refractory diffuse large b-cell lymphoma: Phase III POLARGO trial. Hematol Oncol 43(S3):e7_70093, 2025.
- Abramson JS, Ku M, Hertzberg M, et al: Glofitamab plus gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma: 2-Year follow-up of STARGLO. Hematol Oncol 43(S3):e76_70093, 2025.
- Westin J, Zhang H, Kim W, et al: Mosunetuzumab plus polatuzumab vedotin is superior to R-GemOx in transplant-ineligible patients with R/R LBCL: Primary results of the phase III SUNMO trial. Hematol Oncol 43(S3):eLBA3_70100.
- Alderuccio JP, Okada C, Crochet G, et al: Initial results from LOTIS-7: A phase 1b study of loncastuximab tesirine plus glofitamab in patients with relapsed/refractory diffuse large B-cell lymphoma. Hematol Oncol 43(S3):e78_70093, 2025.
- Lavie D, Kerr DA, Avigdor A, et al: Durable efficacy with fixed-duration epcoritamab + polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone for 1l DLBCL (EPCORE NHL-5). Hematol Oncol 43(S3):e282_70094, 2025.
- Zieger HK, Neumann MAC, Shumilo E, et al: Bispecific antibodies as holding or bridging therapy before CAR-T in large B-cell lymphoma. Hematol Oncol 43(S3):e448_70094, 2025.
Dr. Jhaveri, India-bred and recently transplanted to Indiana via Tampa, Florida, and Washington, DC, is a lymphoma specialist at Indiana University in Indianapolis.
