Overview of DLBCL Treatment

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma, representing approximately 30% of all NHL cases. Treatment has evolved dramatically with R-CHOP (rituximab plus CHOP chemotherapy) remaining the backbone for most patients, achieving cure in 60-70% of cases. For relapsed/refractory disease, the landscape has transformed with CAR T-cell therapies, bispecific antibodies, and antibody-drug conjugates providing unprecedented response rates. Cell-of-origin subtyping (GCB vs ABC) and molecular profiling increasingly guide treatment selection.

Treatment Approach by Setting

Newly Diagnosed DLBCL

  • Standard: R-CHOP × 6 cycles (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone)
  • High-risk (IPI 3-5): Consider Pola-R-CHP (polatuzumab vedotin replacing vincristine)
  • CNS prophylaxis for high-risk patients (testicular, breast, kidney, adrenal involvement)
  • Consolidation radiation for bulky or residual PET-positive disease

First Relapse - Transplant Eligible

  • Standard: Salvage chemotherapy (R-ICE, R-DHAP, GDP-R) followed by autologous SCT
  • CAR T-cell therapy (axi-cel, tisa-cel, liso-cel) as alternative to auto-SCT in chemosensitive disease
  • Epcoritamab or glofitamab (CD20×CD3 bispecific antibodies) for earlier line therapy

Second+ Relapse or CAR T Failure

  • CAR T-cell therapy if not previously used (preferred)
  • Bispecific antibodies: Epcoritamab, glofitamab, odronextamab
  • Loncastuximab tesirine (ADC targeting CD19)
  • Polatuzumab vedotin + bendamustine + rituximab
  • Selinexor, tafasitamab + lenalidomide, or clinical trial

Epidemiology & Impact

NHL encompasses over 60 distinct lymphoid malignancies, collectively the seventh most common US cancer with approximately 83,570 new cases in 2025. DLBCL (30%) and follicular lymphoma (20%) are the most common subtypes. Risk factors include immunodeficiency, autoimmune conditions, and certain infections. Five-year survival across all subtypes is approximately 75%.

Molecular Biology & Biomarkers

Subtypes are defined by characteristic molecular alterations: DLBCL divides into GCB and ABC subtypes; MYC/BCL2/BCL6 rearrangements define high-grade lymphomas; FL has t(14;18); MCL has t(11;14). Molecular subtyping increasingly guides therapy selection.

Evolving Treatment Landscape

Polatuzumab vedotin-R-CHP has shown superiority over R-CHOP for DLBCL in POLARIX. CAR-T therapy revolutionized relapsed aggressive NHL with 40-50% CR rates. Bispecific antibodies (glofitamab, epcoritamab, mosunetuzumab) provide off-the-shelf alternatives. Treatment continues evolving rapidly with subtype-specific agents.

Approved DLBCL Therapies

Yescarta
axicabtagene ciloleucel (axi-cel)
FDA Approved 2017 CAR T-cell
Approved Indications (US/FDA)
Treatment of adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy (2L); Treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy (3L+).
Treatment Process
Single infusion of 2 × 10⁶ CAR+ T cells/kg after lymphodepleting chemotherapy (cyclophosphamide 500 mg/m² + fludarabine 30 mg/m² × 3 days). Requires leukapheresis, manufacturing time (~2-3 weeks), and bridging therapy if needed. Must be administered at certified treatment centers with REMS program.
Clinical Evidence
ZUMA-7 trial: Axi-cel superior to salvage chemo + auto-SCT in 2L DLBCL (median EFS 8.3 vs 2.0 months, HR 0.40). Complete response 65% vs 32%. This established CAR T as preferred option over auto-SCT in eligible patients. ZUMA-1: 52% ORR, 40% CR in heavily pretreated R/R DLBCL. Main toxicities include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) requiring tocilizumab and corticosteroids.
Manufacturer
Kite/Gilead
Approval Year
2017
Pivotal Trial
NCT03391466 ↗
Epkinly
epcoritamab
FDA Approved 2023 Bispecific 3L+
Approved Indications (US/FDA)
Treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from indolent lymphoma, after two or more lines of systemic therapy.
Dosing Schedule
Cycle 1: 0.16 mg SC day 1, 0.8 mg day 8, 48 mg days 15, 22
Cycles 2-3: 48 mg SC days 1, 8, 15, 22 (weekly)
Cycles 4+: 48 mg SC days 1, 15 (every 2 weeks)
Continue until disease progression. Requires hospitalization for cycle 1 doses due to CRS risk. Premedicate with corticosteroids, acetaminophen, antihistamine.
Clinical Evidence
EPCORE NHL-1 trial: Epcoritamab achieved 63% ORR (39% CR) in heavily pretreated R/R DLBCL after ≥2 prior lines including CAR T failure. Median DOR 12 months. Epcoritamab is a CD20×CD3 bispecific antibody that redirects T cells to kill B cells. Advantages include off-the-shelf availability (unlike CAR T), subcutaneous administration, and activity post-CAR T. Main toxicities are CRS (mostly grade 1-2), ICANS (infrequent), infections, and cytopenias.
Manufacturer
Genmab/AbbVie
Approval Year
2023
Pivotal Trial
NCT03625037 ↗
Polivy
polatuzumab vedotin
FDA Approved 2019/2023 R/R & Frontline
Approved Indications (US/FDA)
In combination with rituximab and cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) for treatment of adult patients with previously untreated DLBCL; In combination with bendamustine and rituximab for treatment of adult patients with relapsed or refractory DLBCL after at least two prior therapies.
Dosing Schedule
Frontline (Pola-R-CHP): 1.8 mg/kg IV day 1 every 21 days × 6 cycles with R-CHP
R/R (with BR): 1.8 mg/kg IV day 1 every 21 days × 6 cycles with bendamustine 90 mg/m² days 1-2 + rituximab 375 mg/m² day 1
Clinical Evidence
POLARIX trial: Pola-R-CHP improved PFS vs R-CHOP in frontline DLBCL (77% vs 70% at 2 years, HR 0.73), particularly in high-risk patients (IPI 3-5). Similar OS but less neurotoxicity than R-CHOP. This established Pola-R-CHP as new option for frontline therapy. Polatuzumab vedotin is an anti-CD79b antibody-drug conjugate delivering MMAE. Main toxicities include cytopenias, peripheral neuropathy (less than vincristine), and infections.
Manufacturer
Genentech
Approval Year
2023
Pivotal Trial
NCT03274492 ↗