Teaching pack: Diffuse large B-cell lymphoma

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.

• 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.

1. 1976CHOP regimen introduced
2. 1993CHOP proves equal to more intensive regimens; IPI published
3. 1997Rituximab: first antibody for cancer
4. 1997Rituximab: first monoclonal antibody approved for cancer
5. 2000Gene-expression profiling defines GCB and ABC subtypes
6. 2002GELA LNH-98.5: R-CHOP improves survival over CHOP
7. 2014Lugano classification unifies PET-based staging and response
8. 2017Axi-cel CAR-T approved
9. 2017Axi-cel: first CAR-T approved for large B-cell lymphoma (ZUMA-1)
10. 2019Polatuzumab vedotin approved with BR for relapsed disease

• Zilovertamab vedotin (product)
• frontMIND (trial)
• Tafasitamab (product)
• EPCORE DLBCL-2 (trial)
• Epcoritamab (product)
• Golcadomide (product)
• GOLSEEK-1 (trial)
• Mosunetuzumab (product)
• SUNMO (trial)
• Odronextamab (product)
• waveLINE-003 (trial)
• ctDNA monitoring in lymphoma (PhasED-seq, clonoSEQ) (technology)

• POLARIX (phase 3, n=879): Progression-free survival at 2 years: 76.7% vs 70.2%, HR 0.73
• ZUMA-7 (phase 3, n=359): Event-free survival (median): 8.3 months vs 2 months, HR 0.4
• TRANSFORM (phase 3, n=184): Event-free survival (median): 29.5 months vs 2.4 months, HR 0.36
• frontMIND (phase 3, n=899): Progression-free survival at 2 years: 71.1% vs 62.9%, HR 0.75
• EPCORE DLBCL-1 (phase 3, n=552): Overall survival: pending
• STARGLO (phase 3, n=274): Overall survival (median): 25.5 months vs 12.9 months, HR 0.62

• 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.

1. How did CAR-T change second-line treatment of large B-cell lymphoma?
   Answer

   ZUMA-7 showed axicabtagene ciloleucel beats standard chemotherapy plus transplant for early relapse; CAR-T is now second-line standard, curing around 40% of relapsed patients.
2. What is CAR-T and which cancers is it approved for?
   Answer

   A patient's T cells are engineered with a synthetic receptor, multiplied, and returned. Approved CD19 products treat B-cell lymphomas and leukaemias; BCMA products treat multiple myeloma; the first solid-tumour approval (Claudin 18.2, gastric) is in China.
3. What is the difference between a CT scan and a PET scan?
   Answer

   CT is a fast 3D X-ray showing size and shape; PET shows biology by tracking where a radioactive tracer accumulates (for example glucose uptake with FDG or a specific protein such as PSMA). PET/CT combines both.
4. What is in vivo CAR-T and why is it exciting?
   Answer

   Targeted lipid nanoparticles or viral vectors deliver CAR-encoding mRNA or DNA to T cells inside the patient, avoiding manufacturing, lymphodepletion, and wait time and allowing redosing; first-in-human data in 2025-26 show B-cell depletion. AbbVie bought Capstan for up to $2.1B.

• Wikipedia: https://en.wikipedia.org/wiki/Diffuse_large_B-cell_lymphoma
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480