Diffuse Large B-cell Lymphoma

The most common aggressive NHL — GCB vs ABC molecular subtypes, R-CHOP and pola-R-CHP frontline therapy, and CAR-T and bispecific antibodies in relapsed disease

Key Points

• DLBCL is the most common non-Hodgkin lymphoma worldwide, accounting for ~25–30% of all NHL cases; approximately 25,000 new cases are diagnosed annually in the United States.
• Two major cell-of-origin (COO) subtypes — Germinal Center B-cell (GCB) and Activated B-cell (ABC/non-GCB) — differ in molecular drivers, prognosis, and emerging targeted therapy sensitivity; COO is determined by gene expression profiling or surrogate IHC (Hans algorithm).
• Double-hit lymphoma (DHL, concurrent MYC + BCL2 and/or BCL6 rearrangements) defines the highest-risk DLBCL subtype; DA-EPOCH-R (dose-adjusted) is preferred over R-CHOP, and CNS prophylaxis is mandatory.
• R-CHOP × 6 cycles remains the standard frontline backbone; pola-R-CHP (polatuzumab vedotin + rituximab + CHP) demonstrated superior 2-year PFS in the POLARIX trial and is now a preferred option for IPI ≥2 DLBCL.
• CAR-T cell therapy (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) is approved for relapsed/refractory DLBCL and has demonstrated superiority over salvage chemo + ASCT as 2nd-line therapy in high-risk early relapse (ZUMA-7, TRANSFORM trials).
• Bispecific T-cell engagers epcoritamab (CD20×CD3) and glofitamab are FDA-approved for multiply relapsed DLBCL, offering a chemotherapy-free option with durable responses in heavily pretreated patients.

Epidemiology, Classification, and Molecular Biology

DLBCL is a morphologically and biologically heterogeneous aggressive B-cell lymphoma defined by diffuse sheets of large lymphoid cells with vesicular nuclei, prominent nucleoli, and brisk mitotic activity. It arises de novo (~60%) or by transformation from an indolent lymphoma (follicular lymphoma, CLL/SLL, marginal zone — "transformed" DLBCL, ~40%). **Cell-of-Origin (COO) Classification:** The Activated B-cell (ABC) and Germinal Center B-cell (GCB) subtypes, identified by gene expression profiling (GEP) or IHC algorithms (Hans, Choi), reflect fundamentally different biology: - **GCB-DLBCL…

Clinical Presentation and Diagnosis

DLBCL presents with rapidly progressive lymphadenopathy — often growing over days to weeks — or a rapidly enlarging extranodal mass. B symptoms (fever, night sweats, weight loss) are present in ~30–40%. Elevated LDH (reflecting high tumor burden) is common and prognostically important. **Nodal disease:** Cervical, mediastinal, retroperitoneal, and mesenteric adenopathy. Mediastinal involvement is prominent in PMBCL. **Extranodal involvement (~40% at presentation):** - GI tract (most common extranodal site — stomach, small bowel, ileocecal) - Bone marrow (~15–30%; may cause cytopenias) - CNS…

Staging and Risk Stratification

Staging follows the Lugano Classification (Ann Arbor modified). PET/CT is the standard staging modality. **International Prognostic Index (IPI):** Five factors each scored 1 point — age >60, ECOG PS ≥2, elevated LDH, >1 extranodal site, stage III–IV: - Low risk (0–1): 5-year OS ~73% - Low-intermediate (2): 5-year OS ~51% - High-intermediate (3): 5-year OS ~43% - High (4–5): 5-year OS ~26% **R-IPI (revised IPI for rituximab era):** Stratifies into very good (0), good (1–2), and poor (3–5) risk groups with 4-year OS of 94%, 79%, and 55%, respectively. **NCCN-IPI:** Refines age and LDH…

Treatment

**Frontline Therapy:** *Standard DLBCL (non-DHL, IPI ≥2):* - **Pola-R-CHP** (polatuzumab vedotin + rituximab + cyclophosphamide + doxorubicin + prednisone, vincristine omitted) × 6 cycles: POLARIX trial (N=879) demonstrated improved 2-year PFS (76.7% vs. 70.2%) vs. R-CHOP; OS improvement seen at 4-year follow-up; preferred for IPI ≥2 patients - **R-CHOP** × 6 cycles: Remains acceptable for low-risk (IPI 0–1) DLBCL - Stage I–II limited disease (non-bulky): R-CHOP × 4 cycles ± ISRT; or R-CHOP × 6 cycles *Double-hit / High-grade B-cell lymphoma:* - **DA-EPOCH-R** (dose-adjusted etoposide,…

CNS Prophylaxis and Primary CNS DLBCL

**CNS Prophylaxis:** CNS relapse occurs in ~5% of DLBCL overall but reaches 10–30% in high-risk patients (CNS-IPI ≥4, testicular DLBCL, >1 extranodal site + elevated LDH, double-hit biology). Prophylaxis strategies: - Intrathecal (IT) MTX: 4–6 doses during systemic chemotherapy cycles; standard approach but limited CNS penetration for parenchymal disease - IV high-dose MTX (3–3.5 g/m²): Superior CNS penetration; used at many centers for DHL and very high-risk DLBCL; schedule between R-CHOP cycles **Primary CNS DLBCL (PCNSL):** A distinct entity requiring specialized treatment; standard…