Understanding Double-Hit Lymphoma: Causes, Symptoms & Treatment

Introduction

Double-hit lymphoma (DHL) is a rare and aggressive form of non-Hodgkin lymphoma, a type of cancer that originates in the lymphatic system. It is defined by genetic abnormalities involving two specific genes—MYC and BCL2 and/or BCL6—that drive the rapid growth and survival of cancerous cells. First identified in the early 2000s, DHL has been recognized as a distinct subtype of lymphoma due to its unique genetic profile and challenging treatment course. Despite its aggressive nature, advancements in diagnostic tools and treatment options have led to improved outcomes for some patients.

This article provides a comprehensive overview of Double-hit lymphoma, including its risk factors, symptoms, diagnostic tests, treatment options, and strategies for managing symptoms at home. Whether you or a loved one has been diagnosed with DHL or you are seeking to learn more about this condition, this guide offers clear, patient-friendly information to help you better understand and navigate your care.

What is Double-hit Lymphoma?

Double-hit lymphoma is a rare subtype of non-Hodgkin lymphoma characterized by genetic mutations affecting the MYC and BCL2 and/or BCL6 genes. This article explores its risk factors, symptoms, diagnostic tests, treatments (including medications and procedures), and self-care strategies to help manage symptoms at home.

Description of Double-hit Lymphoma

Double-hit lymphoma (DHL) is a high-grade B-cell lymphoma, meaning it originates from B-lymphocytes, a type of white blood cell responsible for producing antibodies. What sets DHL apart from other lymphomas is the presence of genetic rearrangements in at least two genes: MYC, which promotes cell growth, and BCL2 and/or BCL6, which prevent programmed cell death. These mutations lead to the rapid and uncontrolled growth of cancer cells, making the disease particularly aggressive.

DHL progresses quickly, with symptoms developing and worsening over weeks to months. Common symptoms include swollen lymph nodes, unexplained weight loss, night sweats, fever, and fatigue. Without timely diagnosis and treatment, the disease can spread to other organs, including the bone marrow, liver, and central nervous system.

Although rare, DHL accounts for approximately 5-10% of all cases of diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma. It is more frequently diagnosed in older adults, with the average age of diagnosis being around 60. Men are slightly more likely than women to develop the condition. Despite its aggressive nature, early diagnosis and advances in treatment have improved survival rates for some patients.

Risk Factors for Developing Double-hit Lymphoma

Lifestyle Risk Factors

While lifestyle factors are not direct causes of Double-hit lymphoma, certain behaviors may increase the risk of developing non-Hodgkin lymphoma in general. For example, smoking has been linked to a higher risk of lymphomas due to its ability to weaken the immune system and cause genetic damage to cells. Chronic exposure to chemicals such as pesticides or industrial solvents may also elevate risk. Additionally, a diet low in fruits and vegetables and high in processed foods may negatively impact overall immune health, potentially increasing vulnerability to cancers like DHL.

Medical Risk Factors

Several medical conditions and treatments can increase the risk of developing Double-hit lymphoma. Individuals with a history of immunosuppressive therapy, such as those who have undergone organ transplantation or are being treated for autoimmune diseases, are at greater risk. Similarly, people with HIV/AIDS or other conditions that compromise the immune system are more susceptible. Previous cancer treatments, including chemotherapy or radiation, may also heighten the likelihood of developing secondary cancers like DHL.

Genetic and Age-Related Risk Factors

Genetic predisposition plays a significant role in the development of Double-hit lymphoma. While the specific genetic mutations in MYC, BCL2, and BCL6 are not inherited, a family history of lymphoma or other blood cancers may indicate a higher risk. Age is another critical factor, as DHL is most commonly diagnosed in individuals over 60. The aging process can lead to genetic changes in cells, increasing the likelihood of mutations that contribute to aggressive cancers like DHL. Men are also slightly more likely than women to develop this condition, though the reasons for this gender disparity remain unclear.

Clinical Manifestations of Double-hit Lymphoma

Fever

Fever occurs in approximately 30-40% of patients with Double-hit lymphoma (DHL). This symptom often results from the body’s immune response to cancerous cells. As the lymphoma progresses, the rapid growth of malignant cells can trigger inflammation, leading to elevated body temperatures. Fevers in DHL may be persistent or intermittent and are often more pronounced in advanced stages. Patients may also experience chills alongside fever, indicating systemic involvement.

Night Sweats

Night sweats are reported in about 20-30% of DHL cases. These episodes involve excessive sweating during sleep, often soaking bedclothes and sheets. The exact cause is not fully understood but is believed to be linked to the release of inflammatory cytokines by lymphoma cells. These chemical messengers can disrupt the body’s temperature regulation, particularly during rest. Night sweats may be more common in patients with advanced-stage disease or systemic symptoms.

Weight Loss

Unintentional weight loss of more than 10% of body weight over six months is observed in approximately 25-35% of DHL patients. This symptom often results from the body’s increased metabolic demands due to the aggressive growth of lymphoma cells. Additionally, certain proteins released by cancer cells can suppress appetite and alter metabolism. Weight loss is a concerning symptom that typically indicates systemic disease progression.

Fatigue

Fatigue is a common symptom, affecting about 50-60% of individuals with DHL. This profound tiredness is not relieved by rest and can significantly impact daily activities. Fatigue in DHL is often multifactorial, caused by anemia, systemic inflammation, and the body’s effort to combat the disease. It may be more pronounced in patients undergoing treatment or those with advanced disease.

Swollen Lymph Nodes

Swollen lymph nodes, or lymphadenopathy, are present in nearly 80-90% of DHL patients. These nodes may feel firm, rubbery, and painless, commonly appearing in the neck, armpits, or groin. The swelling results from the accumulation of malignant B-cells within the lymphatic system. Enlarged lymph nodes are often one of the first noticeable signs of DHL and may persist or grow over time.

Abdominal Pain

Abdominal pain occurs in about 20-30% of DHL patients, particularly when the lymphoma involves abdominal lymph nodes or organs such as the spleen or liver. This pain can range from mild discomfort to severe cramping and may be accompanied by bloating or a feeling of fullness. The symptom arises due to pressure exerted by enlarged lymph nodes or organ involvement.

Chest Pain

Chest pain is reported in approximately 10-15% of DHL cases and may occur when the lymphoma affects the mediastinal lymph nodes or chest cavity. This symptom can present as a dull ache, sharp pain, or pressure in the chest and may worsen with deep breaths or physical activity. Chest pain in DHL warrants immediate medical attention to rule out complications such as pleural effusion or cardiovascular involvement.

Itching

Itching, or pruritus, affects about 15-20% of DHL patients. This symptom is thought to result from the release of inflammatory cytokines or direct skin involvement by lymphoma cells. The itching may be localized or widespread and can significantly impact quality of life. It is often resistant to over-the-counter remedies and may require specific treatments targeting the underlying lymphoma.

Loss of Appetite

Loss of appetite, or anorexia, is experienced by approximately 20-30% of DHL patients. It is often linked to systemic inflammation, metabolic changes, or abdominal involvement causing a sensation of fullness. This symptom can contribute to weight loss and nutritional deficiencies, further complicating the patient’s condition.

Anemia

Anemia, or a low red blood cell count, is present in about 40-50% of DHL cases. This condition can cause symptoms such as fatigue, shortness of breath, and pale skin. Anemia in DHL is often due to bone marrow involvement, where malignant cells interfere with the production of healthy blood cells. It may also result from chronic inflammation or blood loss.

Health Conditions with Similar Symptoms to Double-Hit Lymphoma

Hodgkin Lymphoma

Hodgkin lymphoma is a type of cancer that begins in the lymphatic system, a crucial component of the immune system. It involves the abnormal growth of lymphocytes, a kind of white blood cell, which can form tumors in lymph nodes or other parts of the body. A hallmark of Hodgkin lymphoma is the presence of Reed-Sternberg cells, a distinctive type of abnormal cell visible under a microscope.

How to Differentiate Hodgkin Lymphoma from Double-Hit Lymphoma

Both Hodgkin lymphoma and double-hit lymphoma can present with symptoms such as swollen lymph nodes, night sweats, fever, and unexplained weight loss. However, Hodgkin lymphoma typically spreads in a predictable, orderly pattern from one group of lymph nodes to the next. In contrast, double-hit lymphoma, a high-grade B-cell lymphoma, often involves multiple lymph nodes or organs simultaneously and progresses more aggressively.

A lymph node biopsy is critical for distinguishing between the two. Hodgkin lymphoma is identified by the presence of Reed-Sternberg cells, while double-hit lymphoma is characterized by genetic mutations, including MYC and BCL2 and/or BCL6 rearrangements. Additional diagnostic tools, such as PET and CT scans and blood tests, help assess the extent of the disease and confirm the diagnosis.

Diffuse Large B-Cell Lymphoma (DLBCL)

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. This aggressive cancer originates in B cells, which are responsible for producing antibodies. DLBCL can develop within lymph nodes or in other areas of the body, such as the stomach, skin, or brain.

How to Differentiate DLBCL from Double-Hit Lymphoma

DLBCL and double-hit lymphoma share symptoms like rapidly enlarging lymph nodes, fever, night sweats, and weight loss. However, double-hit lymphoma is a specific subtype of DLBCL defined by genetic mutations involving MYC and BCL2 and/or BCL6, which make it more aggressive.

Diagnosis requires a biopsy. Standard DLBCL does not exhibit the dual genetic rearrangements seen in double-hit lymphoma. Genetic testing methods, such as fluorescence in situ hybridization (FISH), are used to identify these abnormalities. Due to its aggressive nature, double-hit lymphoma often necessitates more intensive treatment than standard DLBCL.

Burkitt Lymphoma

Burkitt lymphoma is a rare and highly aggressive form of non-Hodgkin lymphoma that originates in B cells. It is frequently associated with genetic changes involving the MYC gene. While it is most common in children and young adults, it can also affect older individuals.

How to Differentiate Burkitt Lymphoma from Double-Hit Lymphoma

Both Burkitt lymphoma and double-hit lymphoma are aggressive cancers that cause rapidly growing lymph nodes, fever, night sweats, and weight loss. However, Burkitt lymphoma often involves the abdomen, leading to symptoms such as abdominal pain, swelling, or bowel obstruction. Double-hit lymphoma, on the other hand, may affect a wider range of organs and tissues.

Biopsy and genetic testing are essential for differentiation. Burkitt lymphoma is characterized by a specific translocation involving the MYC gene on chromosome 8 but lacks the additional BCL2 or BCL6 rearrangements seen in double-hit lymphoma. Imaging studies and bone marrow biopsies are also used to determine the extent of the disease.

Chronic Lymphocytic Leukemia (CLL)

Chronic lymphocytic leukemia (CLL) is a slow-growing cancer that begins in the bone marrow and affects lymphocytes. It primarily occurs in older adults and weakens the immune system, making individuals more susceptible to infections.

How to Differentiate CLL from Double-Hit Lymphoma

CLL and double-hit lymphoma can both cause swollen lymph nodes, fatigue, and weight loss. However, CLL progresses slowly, whereas double-hit lymphoma is highly aggressive. Additionally, CLL often leads to elevated white blood cell counts, a feature less common in double-hit lymphoma.

Blood tests, including a complete blood count (CBC) and flow cytometry, are used to diagnose CLL by identifying abnormal lymphocytes in the blood. In contrast, double-hit lymphoma is diagnosed through a lymph node biopsy and genetic testing to detect MYC and BCL2 and/or BCL6 rearrangements.

Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is a rapidly progressing cancer of the bone marrow and blood. It primarily affects children but can also occur in adults. ALL results in the overproduction of immature white blood cells, known as lymphoblasts, which crowd out healthy blood cells.

How to Differentiate ALL from Double-Hit Lymphoma

ALL and double-hit lymphoma can both cause fatigue, fever, night sweats, and swollen lymph nodes. However, ALL often presents with symptoms related to low blood counts, such as frequent infections, easy bruising, or bleeding. Double-hit lymphoma is more likely to involve extranodal sites, such as the brain or gastrointestinal tract.

Blood tests, including a CBC and peripheral blood smear, reveal lymphoblasts in ALL. A bone marrow biopsy and flow cytometry confirm the diagnosis. In contrast, double-hit lymphoma is identified through a lymph node biopsy and genetic testing for MYC and BCL2 and/or BCL6 rearrangements.

Non-Hodgkin Lymphoma (NHL)

Non-Hodgkin lymphoma (NHL) is a broad category of cancers that originate in the lymphatic system. It encompasses many subtypes, ranging from slow-growing to highly aggressive forms. NHL can develop in lymph nodes or other parts of the body, such as the spleen, stomach, or skin.

How to Differentiate NHL from Double-Hit Lymphoma

Double-hit lymphoma is a specific subtype of NHL, so the two share many symptoms, including swollen lymph nodes, fever, night sweats, and weight loss. However, double-hit lymphoma is distinguished by its aggressive behavior and specific genetic abnormalities involving MYC and BCL2 and/or BCL6.

To differentiate double-hit lymphoma from other NHL subtypes, a biopsy and genetic testing are necessary. Standard NHL subtypes lack the dual rearrangements seen in double-hit lymphoma. Imaging studies and additional laboratory tests help determine the specific type and extent of NHL.

Multiple Myeloma

Multiple myeloma is a cancer of plasma cells, a type of white blood cell responsible for producing antibodies. It often causes bone pain, anemia, kidney problems, and elevated calcium levels in the blood. Multiple myeloma primarily affects older adults.

How to Differentiate Multiple Myeloma from Double-Hit Lymphoma

Both multiple myeloma and double-hit lymphoma can cause fatigue, weight loss, and bone pain. However, multiple myeloma is more likely to result in symptoms related to bone damage, such as fractures or high calcium levels, as well as kidney dysfunction. These symptoms are uncommon in double-hit lymphoma.

Blood tests, such as serum protein electrophoresis (SPEP) and free light chain assays, detect abnormal proteins produced by myeloma cells. A bone marrow biopsy confirms the diagnosis. In contrast, double-hit lymphoma is diagnosed through a lymph node biopsy and genetic testing for MYC and BCL2 and/or BCL6 rearrangements.

Granulomatosis with Polyangiitis (GPA)

Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis, is a rare autoimmune disease that causes inflammation of blood vessels. This inflammation can damage organs, particularly the lungs, kidneys, and sinuses.

How to Differentiate GPA from Double-Hit Lymphoma

Both GPA and double-hit lymphoma can cause fatigue, fever, and weight loss. However, GPA is more likely to produce respiratory symptoms, such as sinus pain, nasal congestion, or coughing up blood, as well as kidney problems. These symptoms are not typical of double-hit lymphoma.

Blood tests for GPA include antineutrophil cytoplasmic antibodies (ANCA), which are often positive in this condition. A biopsy of affected tissue, such as the lungs or kidneys, confirms the diagnosis. Double-hit lymphoma, on the other hand, requires a lymph node biopsy and genetic testing.

Infections

Infections, particularly viral or bacterial, can sometimes mimic the symptoms of double-hit lymphoma. Common infections include mononucleosis, tuberculosis, and HIV.

How to Differentiate Infections from Double-Hit Lymphoma

Infections and double-hit lymphoma can both cause fever, night sweats, and swollen lymph nodes. However, infections often present with additional symptoms, such as a sore throat, cough, or localized pain, depending on the type of infection. These symptoms are less common in double-hit lymphoma.

Blood tests, such as complete blood counts and specific tests for infectious agents (e.g., Epstein-Barr virus, tuberculosis skin test, or HIV test), help identify infections. Imaging studies and biopsies may also be used if the diagnosis remains unclear. Double-hit lymphoma is confirmed through genetic testing of lymph node tissue.

Autoimmune Disorders

Autoimmune disorders occur when the immune system mistakenly attacks the body’s tissues. Conditions such as lupus or rheumatoid arthritis can cause systemic symptoms, including swollen lymph nodes, fever, and fatigue.

How to Differentiate Autoimmune Disorders from Double-Hit Lymphoma

Autoimmune disorders and double-hit lymphoma can both cause fatigue, fever, and swollen lymph nodes. However, autoimmune conditions often involve joint pain, skin rashes, or other organ-specific symptoms that are not typically seen in double-hit lymphoma.

Blood tests, such as antinuclear antibodies (ANA) for lupus or rheumatoid factor (RF) for rheumatoid arthritis, are used to diagnose autoimmune disorders. A biopsy is rarely needed for autoimmune conditions but is essential for diagnosing double-hit lymphoma, which requires genetic testing to confirm MYC and BCL2 and/or BCL6 rearrangements.

Treatment Options for Double-hit Lymphoma

Medications for Double-hit Lymphoma

R-CHOP

R-CHOP is a chemotherapy regimen that combines Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone. This treatment works by targeting and destroying rapidly dividing cancer cells, including those associated with Double-hit lymphoma (DHL).

Often used as a first-line treatment for aggressive lymphomas like DHL, R-CHOP is typically administered in cycles every three weeks and can often be given in an outpatient setting. It is most effective in patients whose disease has not significantly advanced.

Many patients notice tumor shrinkage and symptom relief within the first few cycles, though achieving full remission may take several months. Treatment outcomes vary depending on individual factors, such as overall health and disease progression.

R-EPOCH

R-EPOCH combines Rituximab, Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin in an intensified chemotherapy regimen designed for aggressive lymphomas like DHL.

This treatment is often reserved for high-risk or advanced cases and involves continuous infusion over several days, making it more intensive than R-CHOP. R-EPOCH is typically chosen when the lymphoma is particularly aggressive or resistant to standard therapies.

Patients may experience significant tumor reduction and symptom relief within a few cycles, though the intensity of the regimen can lead to more pronounced side effects.

DA-EPOCH-R

DA-EPOCH-R, or dose-adjusted EPOCH with Rituximab, modifies chemotherapy dosages based on the patient’s tolerance to minimize side effects while maintaining effectiveness.

This approach is often used for patients who are frail or have other underlying health conditions. Administered similarly to R-EPOCH, DA-EPOCH-R adjusts doses in response to the patient’s progress and tolerance.

The goal is to strike a balance between treatment efficacy and reduced toxicity, improving patient tolerance and potentially leading to better outcomes.

Cytarabine

Cytarabine works by interfering with DNA synthesis, preventing cancer cells from multiplying. It is particularly effective against aggressive lymphomas.

Often used in combination with other drugs for relapsed or refractory DHL, Cytarabine is administered intravenously in cycles, either in a hospital or outpatient setting.

Patients may experience reduced cancer cell growth, though the effectiveness of the treatment depends on the stage and aggressiveness of the disease.

Methotrexate

Methotrexate inhibits cell division by targeting folic acid metabolism and is used to treat various cancers, including lymphomas.

In DHL, high-dose Methotrexate is often employed to target cancer cells in the central nervous system (CNS) or to prevent CNS involvement. It is administered intravenously under close medical supervision.

When effective, Methotrexate reduces the risk of CNS involvement and improves survival rates. However, careful monitoring is essential to manage potential side effects.

Venetoclax

Venetoclax is a targeted therapy that inhibits the BCL-2 protein, which helps cancer cells survive. By blocking this protein, Venetoclax promotes the death of cancer cells.

It is typically used for relapsed or refractory DHL, often in combination with other therapies. Venetoclax is taken orally and may be part of a long-term treatment plan.

Patients may notice gradual tumor reduction and symptom relief, though response times can vary.

Ibrutinib

Ibrutinib is a targeted therapy that blocks the Bruton’s tyrosine kinase (BTK) pathway, which is essential for the survival of certain lymphoma cells.

Used in relapsed or refractory DHL cases, Ibrutinib is often combined with other treatments. It is taken orally and may be prescribed for extended periods.

Patients can expect improved disease control and symptom relief, though outcomes depend on the specific characteristics of the lymphoma.

Rituximab

Rituximab is a monoclonal antibody that targets the CD20 protein on B-cells, including cancerous B-cells in DHL. It helps the immune system destroy these cells.

A cornerstone of many chemotherapy regimens, including R-CHOP and R-EPOCH, Rituximab is administered intravenously, often in combination with other drugs.

Patients typically experience tumor reduction and symptom relief within weeks to months of starting treatment.

Dexamethasone

Dexamethasone, a corticosteroid, reduces inflammation and suppresses the immune system. It is often used to manage symptoms and enhance the effectiveness of chemotherapy.

In DHL, Dexamethasone may be included in combination regimens or used to control complications such as swelling or pain. It can be administered orally or intravenously.

Patients often experience rapid symptom relief, though its effects are generally supportive rather than curative.

Cyclophosphamide

Cyclophosphamide damages cancer cell DNA, preventing division and growth. It is a key component of many chemotherapy regimens for DHL, including R-CHOP and R-EPOCH.

Administered intravenously in cycles, Cyclophosphamide often leads to tumor reduction and symptom relief within the first few cycles of treatment.

Procedures for Advanced Double-hit Lymphoma

For advanced Double-hit lymphoma, procedures such as stem cell transplants or biopsies may be necessary to monitor disease progression or provide additional treatment options. These interventions are typically reserved for patients who do not respond to initial treatments or experience relapse.

Improving Double-hit Lymphoma Outcomes and Seeking Medical Help

Home Remedies and Lifestyle Changes

While medical treatments are essential for managing Double-hit lymphoma, certain lifestyle changes and home remedies can support overall health and improve quality of life:

1. Nutrition: A balanced diet rich in fruits, vegetables, lean proteins, and whole grains helps maintain energy levels and supports the immune system.
2. Hydration: Staying well-hydrated is crucial, especially during chemotherapy, to help flush toxins from the body.
3. Stress Management: Practices such as meditation, yoga, or deep breathing can reduce stress and improve mental well-being.
4. Physical Activity: Light exercise, such as walking, can boost energy levels and enhance mood.
5. Rest: Adequate sleep and rest are vital for recovery and overall health.

While these strategies cannot cure Double-hit lymphoma, they can complement medical treatments, enhance outcomes, and help patients feel more in control of their health. Always consult your healthcare provider before making significant lifestyle changes.

When to Seek Medical Help

If you experience symptoms such as persistent fatigue, unexplained weight loss, night sweats, or swollen lymph nodes, seek medical attention promptly. Early diagnosis and treatment significantly improve outcomes in Double-hit lymphoma. Telemedicine offers a convenient way to consult healthcare providers, discuss symptoms, receive guidance, and begin the diagnostic process from home.

Living with Double-hit Lymphoma: Tips for Better Quality of Life

Living with Double-hit lymphoma can be challenging, but these steps can help improve your quality of life:

1. Stay Informed: Understanding your condition and treatment options empowers you to make informed decisions about your care.
2. Build a Support Network: Connect with family, friends, or support groups to share experiences and receive emotional support.
3. Follow Your Treatment Plan: Adhering to prescribed therapies and attending follow-up appointments is crucial for managing your condition effectively.
4. Communicate with Your Healthcare Team: Inform your doctors about new symptoms or side effects to ensure timely adjustments to your treatment plan.

Telemedicine plays an important role in managing care, offering convenient access to medical advice and monitoring without the need for frequent in-person visits.

James Kingsley

Learn More