Key ASH 2025 Updates in Non-Hodgkin Lymphoma

Key ASH 2025 Updates in Non-Hodgkin Lymphoma

The treatment landscape for non-Hodgkin lymphoma (NHL) is rapidly evolving, with ASH 2025 delivering pivotal updates on CAR-T cell therapy, bispecific antibodies, and newly approved therapies. These advances are redefining outcomes in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), offering more durable remissions and expanding options for older and high-risk patients.

INTRODUCTION: Overview of Non-Hodgkin Lymphoma: DLBCL and Follicular Lymphoma

The landscape of non-Hodgkin's lymphoma (NHL) has undergone a remarkable transformation over the past decade, driven by the emergence of targeted immunotherapies, novel antibody-drug conjugates (ADCs), and increasingly refined understanding of disease biology. Yet as the therapeutic toolkit expands, so does the complexity of clinical decision-making. The challenge facing oncologists today is not a shortage of options — it is knowing when to combine, when to sequence, and how to tailor treatment to the individual patient without sacrificing tolerability or long-term quality of life.

Recent data from ASH 2025 have further refined the sequencing conversation in B-cell NHLs, reinforcing the role of anti-CD20 backbone therapy while introducing questions about optimal combination strategies and the management of treatment-related toxicities. For older and more vulnerable patients, these questions carry even greater weight.

Non-Hodgkin Lymphoma (NHL) is a heterogeneous group of lymphoid malignancies. This summary covers the most clinically impactful updates from ASH 2025 in the two most prevalent subtypes: Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL).

• DLBCL (31% of NHL): median age 63 yrs; poor prognosis in R/R setting — SCHOLAR-1 showed ORR 26%, median OS 6.6 months with conventional salvage therapy.
• FL (22% of NHL): relapsing-remitting course; POD24 patients face 2-year OS of 68% vs 97% in non-POD24; PFS shortens dramatically with each successive line (1L: 10.6 yrs → 5L: 0.7 yrs).
• ASH 2025 presented landmark long-term CAR-T follow-up, two Phase 3-driven 2025 FDA approvals in R/R FL, next-generation manufacturing data, and frontline immunotherapy strategies.

INTERPRETATION: CAR-T Cell Therapy in NHL: Long-Term Outcomes and Expanding Use

CAR-T Cell Therapy — R/R DLBCL & FL

• 5-year follow-up of pivotal 3L DLBCL trials confirms durable remissions: ZUMA-1 (ORR 73%, CR 53%), TRANSCEND (ORR 83%), JULIET (ORR 52%).
• 2L superiority established: ZUMA-7 (axi-cel, CR 65%) and TRANSFORM (liso-cel, CR 74%) vs SOC ± auto-HCT.
• Older/unfit patients benefit: PILOT (liso-cel, median age 74, CR 54%) and ALYCANTE (axi-cel, median age 70, CR 82.3%).
• R/R FL long-term data: ZUMA-5 (PFS 57.7 mo), ELARA (5-yr PFS 46%, ASH 2025), TRANSCEND-FL (3-yr PFS 68%, ASH 2025).

Bispecific Antibodies (BsAbs)

• Glofitamab 3-year CR follow-up: median PFS 37.3 months; 52% PFS rate at 36 months in MRD-negative patients (ASH 2025).
• Phase 3 combinations improve OS vs R-GemOx: STARGLO (glofi-GemOx, HR 0.64), SUNMO (mosun-pola, HR 0.60), POLARGO (pola-R-GemOx, HR 0.80).
• Frontline DLBCL: EPCORE NHL-2 (epco + R-CHOP): ORR 98%, CR 85%, 24-mo PFS 80%.

Phase 3 FL Approvals (2025)

• InMIND: Tafasitamab + R2 vs R2 — FDA APPROVED June 2025 for R/R FL (2L+).
• EPCOR FL-1: Epcoritamab + R2 vs R2 — FDA APPROVED November 2025 for R/R FL (2L+); benefit consistent across FL grade, FLIPI, and prior lines.

Novel Agents & Next-Gen CAR-T

• Golcadomide (CELMoD) + R: ORR 45–58% in R/R DLBCL (4–5 prior lines, 58–67% prior TCE); ctDNA clearance in 30% of CRs (ASH 2025).
• BMS-986458 (BCL6 degrader, Phase 1): ORR 65–80% in heavily pretreated R/R NHL (62% prior CAR-T, 58% prior BsAbs).
• Rapcabtagene autoleucel (YTB323, rapid-manufacture CD19 CAR-T): ORR 89%, CR 74% in high-risk 1L LBCL; CRS G>3: 0% (ASH 2025).
• Dual CD19/CD20 CARs (KTE-363, LYL1314, zamto-cel, JNJ-90014496): ORR 72–91%, CR 50–78% across R/R DLBCL trials.

CLINICAL IMPLICATIONS: Bispecific Antibodies in NHL—Advancing Combination Strategies

• All R/R DLBCL patients should be evaluated for CAR-T candidacy and referred to specialized centers early to avoid delays.
• CAR-T (axi-cel, liso-cel) is standard of care at 1st relapse in eligible DLBCL patients — do not default to salvage chemotherapy alone.
• BsAbs (glofitamab, epcoritamab) offer durable CRs and are validated for CAR-T-ineligible patients or post-CAR-T failure; fixed-duration glofitamab achieves sustained MRD-negative remissions.
• Phase 3-backed BsAb + chemo combinations (STARGLO, POLARGO) are new standards for transplant-ineligible relapsed LBCL.
• Golcadomide and BCL6 degraders address a critical unmet need in the post-CAR-T/post-BsAb space; enroll eligible patients on trials.
• Two new FDA-approved 2L+ FL regimens (tafasitamab + R2; epcoritamab + R2): apply regardless of FL grade, FLIPI score, or prior therapy lines.
• Rapid-manufacturing and dual-target CAR-Ts are maturing — anticipate shifts in eligibility criteria and turnaround logistics.
• Age alone should not exclude patients from CAR-T or BsAb therapy; comorbidity-adjusted selection (PILOT, ALYCANTE) supports broader use in older adults.

SUMMARY: How ASH 2025 Changes Practice

• NHL is a cancer of the lymphatic system. When it comes back or stops responding to treatment, standard chemotherapy has limited benefit. Two major advances were highlighted at ASH 2025:
• CAR-T cell therapy — a one-time personalized treatment where a patient's immune cells are engineered to attack the cancer — now has 5-year data showing roughly half of DLBCL responders remain in remission. In Follicular Lymphoma, nearly 70% remain disease-free at 3 years with one product.
• Bispecific antibodies — outpatient infusions that connect cancer cells to immune cells — are now proven in Phase 3 trials to work better in combination, with two new FDA approvals in 2025 transforming second-line Follicular Lymphoma care.
• Newer oral and injectable agents (CELMoDs, BCL6 degraders) are showing meaningful responses even after CAR-T and bispecific antibody failure.
• Faster-manufacturing CAR-T (days vs weeks) and two-target CAR-T products are in clinical trials, aiming to make treatment more accessible and harder for the cancer to escape.

Bottom line for patients: if lymphoma returns, ask about CAR-T referral and clinical trials at every step. More options exist today than ever before.

KEY TAKEAWAYS

1. 5-year CAR-T follow-up confirms durable remissions in R/R DLBCL (~50% of CRs) and R/R FL (TRANSCEND-FL 3-yr PFS 68%; ELARA 5-yr PFS 46%).
2. CAR-T is superior to salvage chemotherapy at 1st DLBCL relapse (ZUMA-7, TRANSFORM) — early referral is essential.
3. Glofitamab achieves 36-month PFS of 52% in MRD-negative CR patients — fixed-duration BsAb with curative potential.
4. Phase 3 BsAb + chemo regimens (STARGLO HR 0.64; SUNMO HR 0.60; POLARGO HR 0.80) establish new OS benchmarks for transplant-ineligible relapsed LBCL.
5. Two FDA approvals reshape 2L+ R/R FL in 2025: Tafasitamab + R2 (June) and Epcoritamab + R2 (November).
6. CELMoDs (golcadomide) and BCL6 degraders fill a critical gap in the post-CAR-T, post-BsAb space.
7. Rapcabtagene autoleucel (rapid-manufacture): ORR 89%, CR 74% in high-risk 1L LBCL; near-immediate vein-to-vein time.
8. Dual CD19/CD20 CARs (ORR 72–91%) may overcome antigen-escape relapse, the leading mechanism of CAR-T failure.
9. Frontline BsAb strategies in FL achieve MRD-negativity in >85% at C8D1 without chemotherapy — Phase 3 development is underway.
10. Age >70 and comorbidities are not absolute contraindications to CAR-T or BsAbs — patient-level selection, not age, should guide decisions.

REFERENCES (SELECTED)

DLBCL Background: Armitage. J Clin Oncol. 1998;16:2780. | Kumar A et al. Blood Cancer Journal. 2019. | Crump M et al. Blood. 2017 [SCHOLAR-1].

FL Natural History: Casulo C et al. J Clin Oncol. 2015;33(23):2516 [POD24]. | Rivas-Delgado A et al. Br J Haematol. 2019. | Fowler NH et al. J Clin Oncol. 2021.

CAR-T Pivotal DLBCL: Neelapu SS et al. Blood. 2023 [ZUMA-1]. | Maziarz RT et al. J Clin Oncol. 2025 [JULIET]. | Abramson JS et al. ASH. 2024 [TRANSCEND].

CAR-T 2L DLBCL: Locke FL et al. NEJM. 2021 [ZUMA-7]. | Abramson JS et al. Blood. 2023 [TRANSFORM].

CAR-T Older Patients: Houot R et al. Nat Medicine. 2023 [PILOT]. | Sehgal A et al. Blood Advances. 2025 [ALYCANTE].

BsAbs DLBCL: Dickinson MJ et al. NEJM. 2023. | Thieblemont C et al. J Clin Oncol. 2022. | Karimi Y et al. ASH 2025. | Cheah CY et al. ASH 2025.

Phase 3 Chemo Combos: Abramson J et al. ASCO 2025 [STARGLO]. | Westin J et al. ICML 2025 [SUNMO]. | Sancho JM et al. EHA 2025 [POLARGO].

Novel Agents: Hoffman M et al. ASH 2025 [Golcadomide R/R DLBCL]. | Chavez J et al. ASH 2025 Abst 1006 [Golcadomide R/R FL]. | Morschhauser F et al. ASH 2025 [BCL6 degrader BMS-986458].

Next-Gen CAR-T: Westin J et al. ASH 2025 [YTB323]. | Patel K et al. ICML 2025. | Kersten MJ et al. ASCO 2025. | Merchant A et al. ICML 2025. | Shah N et al. ICML 2025.

CAR-T R/R FL: Neelapu SS et al. J Clin Oncol. 2025 [ZUMA-5]. | Schuster SJ et al. ASH 2025 [ELARA]. | Ahmed S et al. ASH 2025 [TRANSCEND-FL].

Phase 3 R/R FL Approvals: Sehn L et al. ICML 2025 [InMIND]. | Falchi L et al. ASH 2025 (Oral) [EPCOR FL-1].

Frontline FL BsAbs: Burke J et al. ASH 2025 [MorningSun]. | Falchi L et al. ASH 2024 [MITHIC FL-1]. | Finn I et al. ASCO 2025.

Treatment Algorithm: Westin J. Blood. 2022;139:2737.