Triple-hit lymphoma (THL) is an aggressive cancer that forms in tissues of the immune system. The cancer affects white blood cells called B lymphocytes (B cells). It is a form of non-Hodgkin lymphoma. THL is very rare and makes up approximately 2 percent of B-cell lymphomas. It primarily affects elderly adults and is slightly more common in males.

THL is related to two other types of aggressive non-Hodgkin lymphoma: diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. More rarely, THL might start out as an indolent (slow-growing) lymphoma called follicular lymphoma. While gene mutations are common in these cancers, “triple-hit” lymphomas have mutations involving three genes instead of just one. Double-hit lymphoma (DHL) has mutations in two genes and is often studied with THL. The term “double-hit lymphoma” is often used in a broader sense to include THL.

What Causes Triple-Hit Lymphoma?

DNA is organized in cells as chromosomes. A genetic mutation called a translocation occurs when pieces of chromosomes break off and are rearranged in a new way. THL is caused by rearrangements involving three genes: MYC, BCL2, and BCL6.

BCL2 and BCL6 both control cell death, while MYC promotes cell division. When these genes mutate, they cause too much cell division and too little cell death, resulting in cancer. While rearrangements involving MYC or BCL2 are often observed in other lymphomas, THL has rearrangements in both genes, plus a BCL6 rearrangement. In contrast, DHL usually has rearrangements in BCL2 and MYC.

Symptoms of Triple-Hit Lymphoma

Because THL shares features with DLBCL and Burkitt lymphoma, it may cause many of the same signs and symptoms. Some symptoms, including fevers, night sweats, and sudden weight loss, are known as B symptoms. B symptoms are associated with many forms of lymphoma.

Other common signs and symptoms shared by THL, DLBCL, and Burkitt lymphoma include:

• Swollen lymph nodes
• Fatigue
• Trouble breathing
• Loss of appetite

How Is Triple-Hit Lymphoma Diagnosed?

Diagnosing THL requires several medical tests. Many of these tests are also used to diagnose aggressive non-Hodgkin lymphoma.

Lymph Node Biopsy

A lymph node biopsy is the removal and examination of lymph node tissue. A biopsy can involve removal of part of a lymph node (a needle biopsy) or removal of an entire lymph node (a surgical biopsy). A pathologist examines the tissue under a microscope to confirm the presence of cancer cells.

Fluorescence in Situ Hybridization

THL is definitively diagnosed using fluorescence in situ hybridization (FISH). FISH uses fluorescent molecules that bind to specific regions of chromosomes. This allows a doctor to see the MYC, BCL2, and BCL6 rearrangements that are found in THL.

Bone Marrow Testing

THL is often found in the bone marrow of people with THL. Doctors use bone marrow biopsies and bone marrow aspirations to check the bone marrow for cancer cells. A bone marrow biopsy involves taking a small tissue sample from the bone marrow. In a bone marrow aspiration, a doctor uses a thin needle to remove liquid from the bone marrow.

Imaging Technologies

CT scans, positron emission tomography (PET) scans, and combination PET and CT (PET-CT) scans are used to see the tissues within the body. CT or PET-CT scans can look for evidence of enlarged lymph nodes.

Blood Tests

Blood tests can be used to check for signs of high-grade B-cell lymphoma, which often includes low levels of red blood cells (anemia). A blood test can also reveal high levels of the protein lactate dehydrogenase (LDH), which is a common feature of THL.

Spinal Tap

Also known as a lumbar puncture, a spinal tap involves using a needle to collect fluid from the spinal canal. Your doctor may perform this test because THL often affects the central nervous system, or the CNS (the brain and spinal cord).

Treatments for Triple-Hit Lymphoma

Because THL is an aggressive disease, it is typically treated as soon as possible with an intensive treatment plan.

Chemotherapy

Chemotherapy is generally the standard approach to treating THL. Chemotherapeutic drugs are often given in combination, usually with a drug called rituximab (Rituxan). Rituximab recognizes a specific molecule on the surface of B cells and helps the chemotherapy target THL cancer cells specifically.

THL was previously treated with a chemotherapy regimen known as R-CHOP, which is a combination of cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), vincristine (Oncovin), and prednisone plus rituximab. While R-CHOP is still used, treatment often calls for more intensive regimens. These can include:

• DA-EPOCH-R — Etoposide (VP-16), prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab
• R-Hyper-CVAD — Rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone
• R-CODOX-M or R-IVAC — Rituximab plus cyclophosphamide, vincristine, doxorubicin, and methotrexate, alternating with rituximab plus ifosfamide (Ifex), etoposide, and cytarabine (Ara-C)

Stem Cell Transplant

Also called a bone marrow transplant, a stem cell transplant may be recommended for some people being treated for THL. A stem cell transplant replaces the cells of the bone marrow with healthy cells, allowing a person to tolerate higher doses of chemotherapy. This transplant can be an allogeneic stem cell transplant, which uses stem cells from a donor, or an autologous stem cell transplant, which uses stem cells from elsewhere in the person’s own body.

CNS Prophylaxis

THL often causes additional problems by spreading to the CNS. To reduce the risk of a more serious situation, a doctor may treat a person with CNS prophylaxis. CNS prophylaxis involves administering chemotherapy directly to the CNS intravenously or through a lumbar puncture. The chemotherapeutic drugs most commonly given for CNS prophylaxis are methotrexate and cytarabine.

Emerging Treatments

There are many ongoing clinical trials to evaluate the effectiveness of existing drugs for treating THL. Bortezomib (Velcade) and ibrutinib (Imbruvica) — both targeted drugs that are approved to treat other forms of non-Hodgkin lymphoma — are being evaluated as potential treatment options for THL.

Also under investigation is a new type of therapy called chimeric antigen receptor T-cell therapy, or CAR T-cell therapy. CAR T-cell therapy involves removing immune cells called T cells from a person and engineering them to contain CARs on the surface of the cells. The CAR T cells are then put back into the person’s body, where they can bind to molecules on the cancer cells and attack them.

Outlook for Triple-Hit Lymphoma

Compared to DLBCL and Burkitt lymphoma, THL is often refractory, meaning it does not respond as well to conventional treatments. As a result, THL often has a poor prognosis. The overall survival time is generally less than two years. Because it is so rare and aggressive, THL is challenging to study. Further investigation is needed to identify more effective therapies to treat THL.

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