Diffuse Large B Cell Lymphoma: Biology, Classification, and Emerging Treatments

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, accounting for approximately 30-40% of all lymphoma diagnoses. It is aggressive but curable in many patients with modern treatment.

Cell of Origin: GCB vs. ABC Subtypes

Gene expression profiling has revealed two major DLBCL subtypes. The germinal center B cell-like (GCB) subtype arises from centroblasts/centrocytes and is characterized by BCL2 translocation, EZH2 mutations, and PTEN deletion with generally better prognosis. The activated B cell-like (ABC) subtype resembles post-germinal center B cells and is characterized by chronic active BCR signaling, MYD88 mutations, and NF-kappaB activation with generally worse prognosis.

Key Oncogenic Drivers

DLBCL harbors a complex genomic landscape. MYC translocations drive proliferation—particularly dangerous in combination with BCL2 rearrangement (double-hit lymphoma). BCL2 is anti-apoptotic; BCL6 is a transcriptional repressor frequently rearranged; and MYD88 L265P provides constitutive NF-kappaB signaling in ~30% of ABC-DLBCL.

Treatment: R-CHOP and Beyond

Rituximab plus CHOP chemotherapy remains the backbone of DLBCL treatment with ~60-70% cure rate. Recent advances include polatuzumab vedotin (anti-CD79b antibody-drug conjugate), tafasitamab combined with lenalidomide, and CAR-T cell therapies (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) for relapsed/refractory disease.

Bispecific Antibodies

Bispecific antibodies simultaneously engaging CD20 on tumor cells and CD3 on T cells show impressive activity in relapsed DLBCL. Epcoritamab and glofitamab have both received approval for relapsed/refractory DLBCL, offering off-the-shelf options with manageable toxicity. The rapid evolution of DLBCL treatment reflects deeper understanding of its biology.

Read more about lymphoma research on our blog.