Hematological Malignancies: Diffuse Large B-Cell Lymphoma (DLBCL)

Jordan Fortunato, PharmD -

Introduction

Lymphoma represents a heterogeneous group of hematologic malignancies originating from lymphoid tissues. It is broadly categorized into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), with NHL being the more prevalent form. Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive subtype of NHL, accounting for 30-40% of NHL cases worldwide (Coiffier et al., 2019). DLBCL is characterized by heterogeneous genetic and molecular features, contributing to variations in prognosis and response to therapy (Alizadeh et al., 2020). This article provides a high-level overview of the evolution of DLBCL treatment, unmet clinical needs, diagnosis, immunophenotyping, and future therapeutic innovations.

Background of Lymphoma

Lymphomas arise from the malignant transformation of lymphocytes, which are critical components of the immune system (Padala et al., 2020). This transformation leads to uncontrolled proliferation and accumulation of abnormal lymphoid cells in lymph nodes, bone marrow, spleen, and extranodal sites. Lymphomas can be broadly classified into two main categories:

  • Hodgkin Lymphoma (HL): Characterized by the presence of Reed-Sternberg cells, HL typically follows a predictable pattern of spread and is highly curable with standard therapy. Represents ~10% of all lymphomas; incidence peaks in young adults and again in later life.
  • Non-Hodgkin Lymphoma (NHL): A diverse group of lymphoid malignancies, further classified based on cell origin (B-cell, T-cell, or NK-cell) and clinical behavior (indolent or aggressive).
    • Diffuse Large B-Cell Lymphoma (DLBCL): The most common aggressive NHL, accounting for ~30-40% of cases.
    • Follicular Lymphoma (FL): An indolent lymphoma, comprising ~20% of NHL cases.
    • Mantle Cell Lymphoma (MCL): A rare but aggressive lymphoma associated with poor prognosis.
    • Burkitt Lymphoma: A highly aggressive form with characteristic MYC translocations.
    • T-Cell Non-Hodgkin Lymphomas (T-NHL): Less common but often more aggressive, including peripheral T-cell lymphoma (PTCL) and anaplastic large cell lymphoma (ALCL).
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Pathophysiology of DLBCL

DLBCL arises from malignant B lymphocytes, which are crucial components of the adaptive immune system. The transformation of normal B-cells into malignant cells occurs due to genetic and molecular alterations that drive uncontrolled proliferation, impaired apoptosis, and resistance to immune surveillance.

The pathophysiology of DLBCL is complex and involves multiple genetic and molecular abnormalities:

  • Cell of Origin (COO) Classification: Based on gene expression profiling (GEP), DLBCL is categorized into:
    • Germinal Center B-cell-like (GCB) DLBCL: Arises from germinal center B-cells and is characterized by BCL2 translocations and mutations in chromatin-modifying genes (e.g., EZH2, CREBBP).
    • Activated B-cell-like (ABC) DLBCL: Originates from post-germinal center B-cells and exhibits chronic B-cell receptor (BCR) signaling, NF-κB pathway activation, and mutations in MYD88 and CARD11, leading to aggressive clinical behavior.
    • Unclassified DLBCL: A small subset of cases that do not fit into either category.
  • Genetic Abnormalities:
    • BCL2, BCL6, and MYC Rearrangements: These contribute to the aggressive "double-hit" or "triple-hit" lymphomas, which exhibit poor responses to standard treatments.
    • TP53 Mutations: Associated with resistance to chemotherapy and poor prognosis.
    • Epigenetic Dysregulation: Mutations in histone-modifying enzymes (e.g., EZH2, KMT2D) disrupt gene expression and promote lymphoma progression.

Risk Factors for DLBCL

Several known and suspected risk factors contribute to the development of DLBCL:

  • Age: The incidence of DLBCL increases with age, with most cases occurring in individuals over 60 years old.
  • Gender: Males have a slightly higher risk of developing DLBCL than females.
  • Immunodeficiency Conditions: Patients with HIV/AIDS, primary immunodeficiency syndromes, or those undergoing immunosuppressive therapy (e.g., post-transplant) have an increased risk.
  • Autoimmune Diseases: Chronic inflammatory conditions such as rheumatoid arthritis, Sjögren’s syndrome, and systemic lupus erythematosus are associated with increased lymphoma risk.
  • Infections: Epstein-Barr virus (EBV) and Helicobacter pylori infections have been implicated in certain subtypes of DLBCL.
  • Environmental and Lifestyle Factors: Exposure to pesticides, herbicides, and other carcinogens, as well as obesity and smoking, have been linked to an increased risk of NHL, including DLBCL.

Staging and Survival Rates of DLBCL

DLBCL is staged using the Ann Arbor Staging System, which classifies the disease based on the number of affected lymph node regions and whether extranodal involvement is present:

  • Stage I: Single lymph node region or single extranodal site.
  • Stage II: Two or more lymph node regions on the same side of the diaphragm.
  • Stage III: Lymph node involvement on both sides of the diaphragm.
  • Stage IV: Disseminated involvement of extranodal organs (e.g., bone marrow, liver, lungs).

The International Prognostic Index (IPI) further stratifies risk based on age, stage, LDH levels, performance status, and extranodal involvement, which helps predict prognosis and guide treatment decisions.

The survival rates for DLBCL vary based on the stage at diagnosis and risk factors:

  • Stage I: ~80%
  • Stage II: ~70-80%
  • Stage III: ~50-70%
  • Stage IV: ~40-60%

Factors such as molecular subtype (GCB vs. ABC), double-hit/triple-hit status, and response to initial therapy significantly impact prognosis. Newer therapies, including CAR-T cell therapy and bispecific antibodies, have improved outcomes for relapsed/refractory disease.

Clinical Presentation

Patients with DLBCL typically present with rapidly enlarging lymphadenopathy, often accompanied by systemic "B symptoms" such as fever, night sweats, and weight loss. Extranodal involvement occurs in 30-40% of cases, affecting the bone marrow, liver, gastrointestinal tract, and CNS (Coiffier et al., 2019). The disease can progress aggressively, necessitating timely diagnosis and intervention.

The Evolution of Treatment Options

The treatment landscape of DLBCL has evolved significantly over the years:

  • 1970s: The introduction of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) revolutionized lymphoma treatment, providing the first curative therapy for aggressive lymphomas (Coiffier et al., 2019).
  • 1990s-2000s: The addition of rituximab, a monoclonal anti-CD20 antibody, to CHOP (R-CHOP) significantly improved survival rates, reducing relapse rates and increasing overall survival (Cheson et al., 2021).
  • 2010s-Present: Advances in molecular profiling and immunotherapy have led to the emergence of chimeric antigen receptor T-cell (CAR-T) therapy, bispecific antibodies, antibody-drug conjugates (ADCs), and various targeted immunotherapies, including CD-19 (Neelapu et al., 2021).

Current NCCN Guidelines and Treatment Approaches

The National Comprehensive Cancer Network (NCCN) guidelines provide evidence-based recommendations for managing DLBCL:

  • First-Line Therapy:
    • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone): The gold standard for most patients with newly diagnosed DLBCL.
    • DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab): Preferred for high-risk molecular subtypes such as double-hit lymphoma.
    • Polatuzumab Vedotin + R-CHP (rituximab, cyclophosphamide, doxorubicin, prednisone): A newer ADC option targeting CD79b,which is expressed on the surface of B-lymphoma cells.
  • Relapsed/Refractory (R/R) Disease:
    • CAR-T Cell Therapy (axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), lisocabtagene maraleucel (Breyanzi)): A breakthrough approach for patients who relapse after second-line therapy.
    • Salvage Chemotherapy (e.g., R-ICE, R-DHAP) followed by Autologous Stem Cell Transplant (ASCT): Standard for transplant-eligible patients.
    • Bispecific Antibodies (glofitamab, epcoritamab): Emerging as an effective off-the-shelf immunotherapy.
    • Antibody-Drug Conjugates (polatuzumab vedotin, loncastuximab tesirine): Effective for patients ineligible for CAR-T therapy.
    • Targeted Immunotherapy (tafasitamab (Monjuvi)): A monoclonal antibody that targets CD19 antigen on B-cells, exerting its anti-cancer effect through antibody-dependent cellular cytotoxicity (CDCC) and antibody-dependent cell-mediated phagocytosis (ADCP).
    • Checkpoint Inhibitors (nivolumab, pembrolizumab): Investigated in select cases with high PD-L1 expression.

Unmet Needs in DLBCL Treatment

Despite advances, several challenges remain:

  • Relapsed/Refractory (R/R) Disease: Approximately 30-40% of patients relapse or are refractory to initial therapy, requiring alternative strategies such as CAR-T cell therapy or novel targeted agents (Wilson et al., 2020).
  • Molecular Heterogeneity: DLBCL is composed of multiple genetic subtypes with distinct responses to therapy. For example, double-hit lymphomas (MYC, BCL2, and/or BCL6 rearrangements) have poorer prognoses and require intensive treatment strategies (Alizadeh et al., 2020).
  • CNS Involvement: CNS involvement in DLBCL is associated with poor outcomes, necessitating better prophylactic and treatment strategies such as high-dose methotrexate (Cheson et al., 2021).
  • Toxicity and Tolerability: Chemotherapy regimens like R-CHOP and DA-EPOCH-R are associated with severe toxicities, limiting their use in elderly or comorbid patients (Coiffier et al., 2019).

Future Directions and Pipeline Therapies

The DLBCL treatment landscape is rapidly evolving with novel therapeutic strategies:

  • Next-Generation CAR-T Cell Therapies: Improved persistence, reduced toxicity, and allogeneic CAR-T cell approaches are under investigation (Neelapu et al., 2021).
  • Bispecific T-Cell Engagers (BiTEs): Targeting CD20/CD3 (e.g., odronextamab, mosunetuzumab) to enhance T-cell-mediated cytotoxicity.
  • Epigenetic and Metabolic Targeting: Agents targeting EZH2 mutations and histone deacetylases are being tested for patients with specific genetic alterations (Alizadeh et al., 2020).
  • RNA-Based Therapies: Small interfering RNA (siRNA) drugs targeting oncogenic pathways represent a promising strategy for resistant cases (Wilson et al., 2020).
  • Personalized Medicine and AI-Driven Approaches: Using molecular profiling and artificial intelligence to tailor therapies for individual patients.

Conclusion

DLBCL remains a highly heterogeneous and evolving field, with continual advancements in molecular diagnostics, targeted treatments, and immunotherapy. The integration of these innovations into clinical practice is improving patient outcomes and redefining the standard of care for this aggressive lymphoma subtype. Ongoing research efforts are essential to address remaining unmet needs and optimize personalized treatment approaches.

References

  • Padala SA, Kallam A. Cancer, Diffuse Large B Cell Lymphoma. PubMed. Published 2020. https://www.ncbi.nlm.nih.gov/books/NBK557796/.
  • Alizadeh, A. A., et al. (2020). "Genetic insights into DLBCL pathogenesis." Blood, 136(12), 1413-1425.
  • Cheson, B. D., et al. (2021). "Updated diagnostic criteria for lymphoma subtypes." Journal of Clinical Oncology, 39(7), 850-860.
  • Coiffier, B., et al. (2019). "Epidemiology and treatment of DLBCL: A global perspective." The Lancet Oncology, 20(1), e42-e55.
  • National Comprehensive Cancer Network (2025). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): B-Cell Lymphomas [v.1.2025].
  • Neelapu, S. S., et al. (2021). "CAR-T cell therapy in R/R DLBCL: Real-world efficacy and safety." Nature Reviews Clinical Oncology, 18(2), 78-94.
  • Wilson, W. H., et al. (2020). "DA-EPOCH-R for double-hit DLBCL: An updated perspective." Journal of Clinical Oncology, 38(3), 261-272.

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