An Insight into Diffuse Large B-Cell Lymphoma (DLBCL)

Receiving a diagnosis of cancer will cause everyone to be horrified and Diffuse Large B-Cell Lymphoma (DLBCL) is one such.  DLBCL is a type of blood cancer and a basic knowledge of this condition will help the victim as well as the near and dear ones to overcome the situation of emotional stress.

Understanding Diffuse Large B-Cell Lymphoma (DLBCL):

DLBCL is the most common and fast growing (aggressive) type of Non Hodgkin Lymphoma (NHL), a cancer that originates in the lymphatic system. Though it is fast growing, DLBCL is often curable especially when diagnosed and treated early.

What is DLBCL?

The name by itself helps to explain the condition:

Diffuse: The cancerous cells are spread out in the tissue rather than being clustered together.

Large B-Cell: The cancer develops from abnormal B-lymphocytes (a type of white blood cell), which are larger than healthy B cells.

Lymphoma: It is a cancer of lymphatic system, a network of organ and tissues (including lymph node, spleen, and bone marrow) that helps the body fight infection.

Etiology and Risk factors of DLBCL:

For the vast majority of patients, the specific cause of DLBCL is unknown and the risk factors include:

Genetic Mutation: DLBCL development is heavily linked to acquired genetic mutations within B-cells. These mutations are generally developed during a person's lifetime (somatic) rather than being inherited, though a family history of lymphoma can slightly increase risk.

The genetic changes in DLBCL cells are now considered the most important identifier for classification, prognosis, and treatment planning.

How Genetic Mutations Drive DLBCL: Normal B-cells undergo a process called the germinal center (GC) reaction to produce high-affinity antibodies. This process involves intentional DNA damage and repair mechanisms which, while essential for immune function, can lead to errors that foster the development of lymphoma. The accumulation of these errors disrupts normal B-cell life cycles, leading to uncontrolled growth and survival of cancerous cells.

Key genetic mechanisms and mutations involved include:

• Chromosomal Translocations: These are a major source of genetic damage, where pieces of chromosomes break off and reattach in the wrong places. Common translocations involve genes like MYC, BCL2, and BCL6, which are moved next to strong gene regulators (enhancers) that cause them to be over expressed.
• Double-hit lymphoma, characterized by translocations in both MYC and either BCL2 or BCL6, is an especially aggressive form associated with a very poor prognosis.
• Aberrant Somatic Hypermutation (aSHM): This is the "mistargeting" of the normal hypermutation process to genes outside the immunoglobulin loci, affecting proto-oncogenes like PIM1 and MYC in over 50% of DLBCL cases.
• Mutations in Epigenetic Modifiers: A significant number of mutations occur in genes that help control how other genes are turned on or off (epigenetics).
• KMT2D (MLL2) is the most frequently mutated gene in DLBCL, affecting about 30% of cases. Mutations here affect gene enhancer activity, impairing cell signaling and migration.
• Mutations in CREBBP and EP300 (acetyltransferases) are also common and contribute to the dysregulation of BCL6 activity and p53 tumor suppression, allowing cells to tolerate more DNA damage.
• TP53 Mutations: This critical tumor suppressor gene is mutated or deleted in 20-30% of cases, leading to uncontrolled cell proliferation and treatment resistance, and is consistently associated with inferior survival rates.

Subtypes: DLBCL is a highly diverse disease, classified into molecular subtypes (Germinal Center B-cell-like or GCB, and Activated B-cell-like or ABC) based on their gene expression profiles. The specific genetic mutations often cluster within these subtypes, which has significant implications for treatment:

• GCB-DLBCL is enriched for mutations in genes like EZH2, BCL2, and those involved in B-cell migration.
• ABC-DLBCL commonly features mutations that constitutively activate the NF-κB signaling pathway (e.g., in MYD88, CD79B, and CARD11).

Immune System Health

A weakened or dysregulated immune system is considered the most significant risk factor for DLBCL.

• Immunodeficiency: Conditions that compromise the immune system, such as HIV/AIDS or inherited immunodeficiency syndromes, significantly elevate risk.
• Immunosuppressant Drugs: Individuals who have received an organ transplant and take anti-rejection medications have an increased risk.
• Autoimmune Diseases: Certain autoimmune disorders, where the immune system mistakenly attacks healthy tissue, are associated with higher risk. Examples include rheumatoid arthritis, Sjögren's syndrome, and systemic lupus erythematosus (lupus).

Infections

Certain chronic viral infections have been linked to the development of DLBCL.

• Epstein-Barr virus (EBV): Associated with some specific subtypes of DLBCL, particularly in older adults or those with weakened immunity.
• Human immunodeficiency virus (HIV): The risk of DLBCL is significantly higher in individuals with untreated HIV.
• Hepatitis B and C viruses: These chronic infections have also been associated with an increased risk of DLBCL.

Demographics and Medical History

Some non-modifiable factors can influence risk and these include

• Age: Risk increases with age; most people are diagnosed in their 60s or older (median age around 64-65).
• Sex: DLBCL is slightly more common in men than in women.
• Family History: Having a first-degree relative (parent or sibling) with lymphoma may slightly increase your risk, possibly due to shared genetic predispositions or environmental exposures.
• Previous Cancer Treatment: Prior exposure to certain chemotherapy or radiation therapy regimens for other cancers may increase the risk of developing DLBCL later in life.

Lifestyle and Environmental Exposures

Some external factors may play a role and these include:

• Sedentary life style
• Obesity: An increased body mass index (BMI), particularly in young adults, has been identified as a potential risk factor.
• Exposure to Toxic Substances: Exposure to chemicals such as pesticides, herbicides, solvents, and benzene (found in industry and some products) has been linked to an increased risk.

Symptoms of DLBCL

The symptoms of DLBCL vary depending on the region where lymphoma develops, but the most common initial symptom will be the fast growing painless lump in the lymph node (armpit, neck etc). A significant proportion of patients experience systemic symptoms called “B symptoms”, which are key indicators for staging and diagnosis:

• Unexplained fever
• Drenching night sweats (Soaking through clothes)
• Unintended weight loss (up to 10% of body weight in 6 months)
• Persistent fatigue
• Coughing or shortness of breath (if in the chest)
• Abdominal pain or swelling (if in the abdomen)

If any of the symptoms persist or worsen, it is essential to consult your doctor for thorough evaluation.

Diagnosis and Staging

Diagnosis is confirmed by biopsy of the affected lymph node or tissue. Additional tests are done to determine the extent of disease (staging) and assess the other related health parameters.

Imaging tests:  PET/ CT scans are gold standard for visualizing the extent of the disease (stage).

Blood tests: These check for cell counts, elevated Lactate Dehydrogenase (LDH) levels, a marker associated with cell turnover.

Bone marrow biopsy: This checks if the cancer has spread to the bone marrow.

Lumbar puncture: In high risk cases, this checks for lymphoma cells in the fluid around the brain and spinal cord.

The International Prognostic Index (IPI) is a tool doctors use to estimate prognosis based on factors like age, stage, performance status, LDH levels, and number of extranodal sites involved.

Treatment

The primary goal of DLBCL treatment is cure, with approaches tailored to the individual.

First line Therapy

The standard treatment is R-CHOP, a combination of:

• Rituximab (monoclonal antibody)
• Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), and Vincristine
• Prednisone (a steroid)

Typically, patients receive 6 cycles of R-CHOP. For early-stage disease, R-CHOP may be followed by radiation therapy.

New Standard: Polatuzumab vedotin is an anti-CD79b antibody conjugated to the monomethyl auristatin E microtubule inhibitor. The molecule has recently been under the spotlight for the promising results of the frontline combination with rituximab, cyclophosphamide, doxorubicin and prednisone in the phase III POLARIX study, demonstrating improved progression-free survival over standard R-CHOP.

For Relapsed or Refractory (R/R) DLBCL

If the lymphoma returns or doesn't respond, options include salvage chemotherapy followed by an Autologous Stem Cell Transplant, Chimeric Antigen Receptor (CAR) T-cell therapy, targeted therapies, and clinical trials. Remarkable improvements have also been achieved with polatuzumab vedotin by combining the antibody with the standard rituximab and bendamustine regimen for relapsed/refractory patients. Based on the results of these studies, health authorities in several countries granted approval for polatuzumab vedotin to be used as treatment both for patients with previously untreated DLBCL and for those with relapsed/refractory DLBCL.

Prognosis and Outlook

The prognosis for DLBCL has improved significantly, with a five-year survival rate around 60% to 70%. Survival is higher for early-stage disease and younger patients. Many patients who are cancer-free after two years have a normal life expectancy. Living with DLBCL involves managing treatment side effects, maintaining a healthy lifestyle, and having regular follow-ups. Support from healthcare teams and organizations is important.