Disease Overview

Diffuse Large B-Cell lymphoma, also known as DLBCL, is a type of cancer where B-cells, a type of white blood cell,  become abnormal and spread throughout tissues and organs. DLBCL can often be fatal if left untreated due to its aggressive growth rate across multiple organ systems and tissues. It is one of the most prevalent forms of cancer in the lymphatic system, responsible for 30% to 40% of cases. The estimated incidence rate is 4.68 cases per 100,000 per year. 

Classification

DLBCL encompasses a spectrum of diverse subtypes, each characterized by unique clinical and molecular features. Various subtypes of DLBCL arise based on the maturity stage of B-cell differentiation when genetic alterations first occur and the specific genetic mutations involved. The World Health Organization has categorized DLBCL into several subtypes. The most prevalent subtype is DLBCL, not otherwise specified (DLBCL, NOS). There are DLBCL subtypes found in specific anatomic sites such as primary CNS DLBCL, primary cutaneous DLBCL, leg type, and intravascular large B-cell lymphoma. In addition, there is T cell/histiocyte rich large B-cell lymphoma (T/HRLBCL), Epstein-Barr virus (EBV)-positive DLBCL, DLBCL associated with chronic inflammation, Primary mediastinal (thymic) large B-cell lymphoma (PMBL), DLBCLs with plasma cell immunophenotype, ALK-positive large B-cell lymphoma, Plasmablastic lymphoma (PBL), Primary effusion lymphoma (PEL), DLBCL arising in HHV-8 associated multicentric Castleman Disease (MCD), B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (B-UNC/BL/DLBCL), Double-hit lymphomas, Triple-hit lymphomas, and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (B-UNC/cHL/DLBCL). The majority of DLBCL cases are classified as DLBCL, NOS (not otherwise specified), reflecting their varied and heterogeneous nature.

Majority of DLBCL cases fall under the DLBCL, NOS category. Within this category, researchers have identified two main molecular subtypes based on gene expression profiling: germinal center B-cell (GCB) and activated B-cell (ABC) subtypes. These molecular subtypes arise from genetic alterations occurring during B-cell maturation. Mutations occurring in the dark zone of the germinal center lead to GCB-DLBCLs, whereas mutations in the light zone or after leaving the germinal center result in ABC-DLBCLs.

DLBCL development involves over 700 genetic variations and 150 genetic drivers, often involving chromosomal translocations affecting BCL2, BCL6, and MYC genes. Researchers developed an algorithm identifying four genetic subtypes of DLBCL, which collectively constitute approximately 46.6% of all DLBCL cases. These subtypes include MCD (MYD88 and CD79B mutations), BN2 (BCL6 fusion and NOTCH2 mutation), N1 (NOTCH1 mutations), and EZB (EZH2 mutations and BCL2 translocations).

Signs and Symptoms

Common signs and symptoms of DLBCL include heavy night sweats, weight loss, fluctuating pyrexia, generalized pruritus, fatigue, anorexia, splenomegaly, pedal edema secondary to pelvic lymphadenopathy, chest discomfort or dyspnea secondary to mediastinal lymphadenopathy, and lymphadenopathy of the cervical, axillary, and inguinal lymph nodes. Lymphadenopathy, the swelling of lymph nodes, may be associated with pain, which can vary depending on the size or rate of enlargement of the mass.

Diagnosis and Prognosis

DLBCL can be diagnosed using imaging, laboratory studies, and various procedures. Imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), bone scan, gallium-67 scan, positron emission tomography (PET) with fluorodeoxyglucose, and multigated acquisition scan are employed to assess the severity of the disease. These imaging modalities can evaluate lymphadenopathy in areas including the upper and lower gastrointestinal system, central nervous system (CNS), bones, neck, chest, abdomen, and pelvis. Imaging provides insight into the severity of lymphadenopathy and extent of organ involvement where the disease has spread. Laboratory tests are used to detect specific markers or comorbidities that are associated with DLBCL. Complete Blood Cell count (CBC) tests are used to detect anemia, thrombocytopenia, and/or leukopenia indicative of bone marrow involvement. Serum electrolyte is collected to assess renal function. Lactate dehydrogenase and uric acid concentrations are collected because they serve as markers that reflect the amount of tumor in the body. Hepatitis B testing serves to detect Hep B for patients receiving chemoimmunotherapy combined with rituximab and flow cytometry is used to differentiate between the DLBCL subtypes of B-or T-cell origin. Confirmation of DLBCL diagnosis often requires lymph node biopsy, and procedures such as bone marrow aspiration and biopsy are conducted to determine cancer staging.

Clinicians use the International Prognostic Index (IPI) to predict prognosis in patients with DLBCL, relying on factors such as age, stage of disease, number of extranodal sites, performance status, and lactate dehydrogenase level. Additionally, prognosis in DLBCL is influenced by its subtypes. ABC subtypes generally have a poorer prognosis compared to GCB subtypes when treated with standard initial chemoimmunotherapy. Moreover, double- and triple-hit lymphomas exhibit greater resistance to standard treatment protocols.

Disease Management

Depending on the disease stage at diagnosis, the primary treatment goal is either achieving long-term complete remission or preventing or delaying metastasis. Additionally, molecular classification of DLBCL subtypes predicts prognosis and enables customized therapy with the use of novel agents that target specific subtypes. 

First-line therapy for DLBCL is R-CHOP (Rituxan® with cyclophosphamide, doxorubicin hydrochloride liposome injection (Doxil® or Lipodox®), vincristine, and prednisone), administered on either a 14- or 21-day cycle, commonly followed by radiation therapy. R-CHOP achieves disease remission in approximately 50% to 60% of DLBCL patients. An alternative therapy for patients who cannot use anthracyclines is R-CEOP. This medication substitutes doxorubicin with etoposide (Toposar® or Etopophos®). 

Options for patients with relapsed DLBCL or those resistant to standard treatment include Xpovio®, Monjuvi® with Revlimid®, high-dose chemotherapy followed by autologous stem cell rescue with or without radiation, and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. Other regimens include Rituximab plus dexamethasone, cytarabine, and cisplatin (R-DHAP), Rituximab plus ifosfamide, carboplatin, and etoposide (R-ICE), Rituximab plus etoposide, methylprednisolone, cytarabine, and cisplatin (R-ESHAP), and Rituximab plus gemcitabine, cisplatin, and methylprednisolone (R-GEM-P). Another targeted combination therapy is Polivy® with Bendeka® and rituximab, an antibody-drug conjugate that targets C79D using microtubule inhibitor monomethyl auristatin E (MMAE). 

Current therapies in development are Monjuvi, Zynlonta®, Breyanzi®, Monjuvi and Revlimid. These therapies target the C19 antigen, which is expressed by B-cells and involved in B-cell development. 

Venous access devices are necessary to facilitate repeated chemotherapy administration and blood sample collection. Patients will have hemoglobin levels monitored to assess the need for red blood cell transfusions or hematopoietic growth factor administration. This will only be required in the case that there is persistent low hemoglobin levels due to chemotherapy or disease progression. Monitoring with complete blood cell count, biochemistry panel, liver and renal function tests will be necessary to assess for potential hypersensitivity reactions, infections, and other chemotherapy-related adverse effects during treatment.