Understanding Triple-Hit Lymphoma, a Rare Type of Non-Hodgkin’s Lymphoma

Triple-hit lymphoma (THL) is a rare and aggressive subtype of lymphoma. Treatment for THL typically involves strong chemotherapy. Sometimes, stem cell transplants and clinical trials are good options for people with THL.

THL has been linked to mutations in three particular genes responsible for cell splitting and growth. When these genes don’t function correctly, uncontrolled abnormal cell division, or cancer, can occur.

Researchers believe these gene mutations are acquired and not inherited. More research is needed to confirm.

This article reviews the causes, symptoms, and treatment for THL, and the outlook for people with this type of cancer.

Triple-hit lymphoma (THL) is an aggressive type of lymphoma. Lymphomas are cancers that form in your body’s lymphatic system, a part of your immune system.

THL is a rare subtype of non-Hodgkin’s lymphoma. It is found in two smaller subtypes of non-Hodgkin’s:

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• diffuse large B-cell lymphoma
• Burkitt’s lymphoma

About 2% of all diffuse large B-cell lymphoma diagnoses are THL.

Both diffuse large B-cell lymphoma and Burkitt’s lymphoma are commonly linked to a gene mutation. THL is called “triple-hit” because it’s linked to three gene mutations.

Often, doctors discuss THL under the broader umbrella of “double-hit” lymphomas. A double-hit lymphoma is a lymphoma that involves two, or three, if THL is included, gene mutations. These multigene mutations are rare. They can make these forms of lymphoma difficult to treat.

THL shares symptoms with Burkitt’s lymphoma and diffuse large B-cell lymphoma. Often, this includes what’s known as “B symptoms.”

B symptoms are symptoms found across many types of lymphoma. They include:

Additional symptoms might include:

• swollen lymph nodes
• trouble breathing
• loss of appetite
• weakness throughout the body
• chronic low blood pressure
• anemia
• abdominal pain and swelling
• constipation
• back pain
• swollen legs

THL is slightly more common in people assigned male at birth and in older adults.

THL is caused by mutations in three genes: MYC, BCL2, and BCL6. These genes are important for controlling how your cells grow and reproduce. When they don’t work correctly, it can lead to cancer.

Researchers don’t know exactly what causes these genes to mutate. It’s believed the mutations are primarily acquired, not inherited . But it’s unclear what environmental, aging, or other factors might lead to this change.

The first step to receiving a diagnosis of THL is a medical appointment. Your doctor will likely diagnose lymphoma before diagnosing any specific subtype.

If your doctor believes you have lymphoma, they will order tests that will include:

• Blood work:Blood tests look for the levels of blood cells and specific protein levels in your blood because lymphoma can change these levels.
• Imaging:CT scans and PET scans can get an up-close look at your lymph nodes and other areas affected by lymphoma.
• Lymph node biopsy: During a lymph node biopsy, lymph node tissue is removed and tested for cancer cells. Sometimes, an entire lymph node is removed in a surgical procedure. Other times, a small sample is removed with a needle.
• Bone marrow biopsy: A bone marrow biopsy is done by inserting a long and hollow needle into the hip bone to remove bone marrow fluid and fragments. This sample is then tested for cancer.
• Lumbar puncture: A lumbar puncture, otherwise known as a spinal tap, is a test done by inserting a needle into the base of the spine to remove spinal fluid so it can be tested for cancer cells.
• Fluorescence in situ hybridization (FISH):FISH is a genetic test on a blood sample that confirms a diagnosis of THL. It allows doctors to examine specific pieces of chromosomes to see the gene abnormalities that cause THL.

THL is a fast-moving and aggressive form of lymphoma. Treatment often starts with strong chemotherapy to kill cancer cells and stop their growth.

Often, chemotherapy is given with a medication called rituximab (Rituxan). The medication helps chemotherapy treatments target B cells involved in lymphoma.

Some people with THL might be good candidates for a stem cell transplant. A stem transplant is a procedure that replaces a person’s bone marrow with new bone marrow stem cells so healthy bone marrow can grow in place of the cancerous bone marrow.

Donor stem cells can come from the person receiving the transplant or from a closely related donor. There are benefits and drawbacks to each option.

Clinical trials may also be an option for some people with THL. Doctors are currently evaluating the effectiveness of treatments used for other forms of cancer, such as targeted therapy and immunotherapy for THL.

People with THL can talk with their doctors about clinical trials and whether they might be good candidates to participate in these tests.

THL is rare and aggressive. It’s associated with worse outcomes than more standard forms of Burkitt’s lymphoma or diffuse large B-cell lymphoma.

This type of lymphoma doesn’t typically respond well to conventional treatments. Additional research into better treatments for THL is needed.

Since THL is rare, it’s difficult to predict exact outcomes, but the average survival time is typically fewer than 2 years. However, as new treatments emerge, this survival time may improve.

Triple-hit lymphoma (THL) is a rare and aggressive form of non-Hodgkin’s lymphoma. It’s linked to three gene abnormalities.

Symptoms include swollen lymph nodes, fever, fatigue, and anemia.

THL is confirmed through genetic testing that looks at the genes and chromosomes. Treatment involves strong chemotherapy. People with THL may be good candidates for stem cell transplants and clinical trials.

Last medically reviewed on April 12, 2023