# Diffuse large B-cell lymphoma

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## TL;DR

Diffuse large B-cell lymphoma (DLBCL) is an aggressive but curable lymphoma. CAR-T cures about 40% of relapsed patients, and off-the-shelf bispecifics are now approved.

## Summary

Diffuse large B-cell lymphoma is the most common aggressive lymphoma, about 30% of all non-Hodgkin lymphoma, with a median age around 65. It is curable: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) cures roughly 60% of patients, more with low IPI and fewer with high-risk features (IPI 3-5, double-hit MYC/BCL2 rearrangement, activated B-cell origin, TP53 loss). Staging uses PET-CT and the Lugano classification; biology is read from cell of origin and FISH for MYC, BCL2 and BCL6, with genetic classifiers (LymphGen) and ctDNA emerging.

Frontline therapy stood still for twenty years until POLARIX (2022) showed that replacing vincristine with the CD79b ADC polatuzumab vedotin improves progression-free survival (5-year 64.9% vs 59.1%), and frontMIND (Lancet 2026) showed tafasitamab plus lenalidomide added to R-CHOP improves PFS in IPI 3-5 disease (HR 0.75); epcoritamab plus R-CHOP (EPCORE DLBCL-2) and golcadomide plus R-CHOP (GOLSEEK-1) follow. For the 30-40% who relapse, the sequence has been rebuilt around T-cell redirection: CD19 CAR-T (axi-cel, liso-cel) beats salvage chemotherapy and transplant for relapse within a year (ZUMA-7 with an overall survival benefit; TRANSFORM), while transplant remains for later chemosensitive relapse. Off-the-shelf CD20×CD3 bispecifics (glofitamab, epcoritamab, mosunetuzumab, odronextamab) give complete remissions in about 40% of heavily pretreated patients, and chemotherapy-free doublets such as mosunetuzumab-polatuzumab (SUNMO) beat salvage chemotherapy. CD19 ADC (loncastuximab), tafasitamab-lenalidomide, and the ROR1 ADC zilovertamab vedotin fill later lines.

The open questions are regulatory as much as scientific. EPCORE DLBCL-1 (2026) improved PFS but not overall survival against chemotherapy; STARGLO's survival benefit was rejected by the FDA because the trial was mostly enrolled in Asia. Nobody has compared bispecifics with CAR-T head to head. ctDNA (PhasED-seq) predicts cure better than PET and is the obvious tool for response-adapted frontline therapy. Primary refractory disease, CNS relapse, older and frail patients, and access to CAR-T outside major centres remain the hard problems.

## Fields

- Kind: Indication
- Last checked: 2026-09-07
- Tags: heme; spike
- Group: haematologic
- Burden: ~150,000 new cases a year worldwide; ~25,000 in the US; median age 65; about 60% cured with first-line therapy.
- Subtypes: Germinal-centre B-cell-like (GCB) vs activated B-cell-like (ABC / non-GCB); High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double hit); LymphGen genetic subtypes: MCD, BN2, N1, EZB, ST2, A53; Primary mediastinal B-cell lymphoma (distinct; PD-1 responsive); Primary CNS lymphoma (distinct; methotrexate-based); Transformed indolent lymphoma (Richter, transformed follicular); EBV-positive DLBCL of the elderly; Primary refractory vs early relapse (<12 months) vs late relapse
- Biomarkers: Cell of origin (GCB/ABC); Double-hit (MYC/BCL2); CD19/CD20; ctDNA MRD; IPI / NCCN-IPI; Cell of origin (Hans IHC, Lymph2Cx); MYC, BCL2, BCL6 FISH; TP53 mutation; CD19 and CD20 expression (loss after CAR-T or bispecific); Interim and end-of-treatment PET (Deauville); ctDNA (PhasED-seq, clonoSEQ); LDH; CNS-IPI for CNS prophylaxis decisions

## Standard of care

- Frontline: R-CHOP or Pola-R-CHP.
- Early relapse: CD19 CAR-T.
- Later: CD20×CD3 bispecifics, loncastuximab, tafasitamab.
- Limited stage (I-II, non-bulky): R-CHOP × 4 with PET-guided omission of radiation (FLYER, S1001): 4 cycles if interim PET negative; involved-site radiotherapy if PET positive. ([FDG PET](https://nuclide.cc/technologies/fdg-pet/))
- Advanced stage, IPI 0-1: R-CHOP × 6 (or Pola-R-CHP); consider 4 cycles plus 2 rituximab in young low-risk patients (FLYER).
- Advanced stage, IPI 2-5: Pola-R-CHP × 6 (POLARIX) or R-CHOP × 6; tafasitamab + lenalidomide + R-CHOP (frontMIND) pending approval for IPI 3-5; DA-EPOCH-R for double-hit lymphoma; CNS prophylaxis for high CNS-IPI (contested).
- Frail or elderly: R-mini-CHOP; epcoritamab-based regimens in trials for the elderly (EPCORE NHL-2 cohorts); tafasitamab-lenalidomide where transplant is never an option.
- Primary refractory or relapse within 12 months: CD19 CAR-T (axi-cel or liso-cel) preferred over salvage chemotherapy and transplant (ZUMA-7, TRANSFORM); bridging therapy while manufacturing; bispecific ± chemotherapy if CAR-T unavailable.
- Late relapse (>12 months), transplant-eligible: Salvage chemotherapy (R-ICE, R-DHAP, R-GemOx) → high-dose therapy and autologous transplant if chemosensitive; CAR-T if not.
- Relapse, transplant-ineligible: CD20×CD3 bispecific (glofitamab, epcoritamab) or mosunetuzumab-polatuzumab (SUNMO); pola-BR; tafasitamab-lenalidomide; loncastuximab tesirine.
- Third line and beyond: CAR-T if not yet given; bispecific after CAR-T (active in CD19-negative relapse if CD20 retained); loncastuximab; zilovertamab vedotin (trial); allogeneic transplant in selected fit patients; clinical trials.

## State of the art

- CAR-T second line.
- Bispecifics as off-the-shelf T-cell therapy.
- Frontline has moved: Pola-R-CHP (POLARIX) is standard for IPI 2-5, and frontMIND (tafasitamab-lenalidomide-R-CHOP) is the first phase 3 to beat R-CHOP in IPI 3-5 disease since rituximab.
- CD19 CAR-T is second-line standard for early relapse, with an overall survival benefit in ZUMA-7 (4-year OS 54.6% vs 46.0%).
- Four CD20×CD3 bispecifics approved or conditionally approved worldwide give ~40% complete remissions off the shelf; chemotherapy-free doublets (mosun-pola) beat salvage chemotherapy.
- ctDNA by phased-variant sequencing detects residual lymphoma below PET sensitivity and is entering response-adapted trials.
- Regulators now scrutinise generalisability (STARGLO CRL) and demand overall survival for confirmatory bispecific trials (EPCORE DLBCL-1 missed OS).

## Open problems

- Primary refractory disease.
- CAR-T access and cost.
- Primary refractory disease (~10-15%) still has poor outcomes even with CAR-T; CD19-negative and CD20-negative escape after targeted therapy.
- No head-to-head comparison of bispecifics and CAR-T; sequencing is by access rather than evidence.
- Overall survival is hard to demonstrate for bispecifics against chemotherapy with crossover and effective later lines (EPCORE DLBCL-1).
- Trial generalisability: STARGLO's rejection shows regional enrolment can decide approvals.
- CNS relapse: prophylaxis with high-dose methotrexate is of uncertain benefit and CNS-penetrant options are few.
- Older and frail patients are underrepresented; R-mini-CHOP cure rates lag and cellular therapies carry toxicity.
- Cost and access: CAR-T requires certified centres; bispecific CRS management needs infrastructure; lenalidomide-based triplets add expense.
- Response-adapted therapy: interim PET is unreliable and ctDNA is not yet a regulatory endpoint.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Diffuse_large_B-cell_lymphoma
- Wikipedia: https://en.wikipedia.org/wiki/Diffuse_large_B-cell_lymphoma

## Connected records

- indications: [Follicular lymphoma](https://nuclide.cc/indications/follicular-lymphoma/)
- technologies: [FDG PET](https://nuclide.cc/technologies/fdg-pet/), [PET-adapted (response-adapted) therapy](https://nuclide.cc/technologies/pet-adapted-therapy/)
- targets: [CD20](https://nuclide.cc/targets/cd20/)
- companies: [Bristol Myers Squibb](https://nuclide.cc/companies/bms/), [Merck & Co. (MSD)](https://nuclide.cc/companies/merck/), [Novartis](https://nuclide.cc/companies/novartis/)
- institutions: [Chinese PLA General Hospital](https://nuclide.cc/institutions/pla-general-hospital/), [Comprehensive Cancer Center Mainfranken, University Hospital Würzburg](https://nuclide.cc/institutions/ccc-wuerzburg/), [Dana-Farber Brigham Cancer Center](https://nuclide.cc/institutions/dana-farber/), [Institut Jules Bordet](https://nuclide.cc/institutions/institut-jules-bordet/), [IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico Sant'Orsola](https://nuclide.cc/institutions/sant-orsola-bologna/), [King Faisal Specialist Hospital and Research Centre](https://nuclide.cc/institutions/kfshrc/), [Mayo Clinic](https://nuclide.cc/institutions/mayo-clinic/), [MD Anderson Cancer Center](https://nuclide.cc/institutions/md-anderson/), [Memorial Sloan Kettering Cancer Center](https://nuclide.cc/institutions/mskcc/), [University Hospital Zurich / Comprehensive Cancer Center Zurich](https://nuclide.cc/institutions/usz-zurich/)
- drugs: [Rituximab](https://nuclide.cc/drugs/rituximab/)
- trials: [Study of Iopofosine I-131 (CLR 131) in Select B-Cell Malignancies (CLOVER-1) With Expansion in Waldenstrom](https://nuclide.cc/trials/nct02952508/)
- bottlenecks: [Manufacturing cost and time for living and radioactive medicines](https://nuclide.cc/bottlenecks/b-manufacturing-cell-therapy/)
- pairings: [Rituximab pretreatment before ibritumomab tiuxetan (Zevalin)](https://nuclide.cc/pairings/rituximab-then-ibritumomab-tiuxetan/)
- terms: [Deauville five-point scale for PET](https://nuclide.cc/terms/deauville-for-pet/)

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