Double-hit lymphoma (DHL) is an aggressive cancer that affects white blood cells called B lymphocytes or B cells. DHL is a form of non-Hodgkin lymphoma (NHL), one of the two main categories of lymphoma. DHL is relatively rare and makes up approximately 14 percent of aggressive B-cell lymphomas. It primarily affects older adults and is slightly more common in males, according to the Atlas of Genetics and Cytogenetics in Oncology and Haematology.

DHL is related to two other types of aggressive non-Hodgkin lymphoma: diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. More rarely, DHL might start as a low-grade (slow-growing) lymphoma called follicular lymphoma. Common gene mutations are often found in these types of cancer. The term double-hit comes from the presence of mutations in two genes, rather than just one.

What Causes Double-Hit Lymphoma?

DNA is organized in cells in the form of chromosomes. A genetic mutation known as a translocation occurs when pieces of chromosomes break off and combine in an abnormal way. DHL is most commonly caused by a translocation involving a gene called MYC and another gene called BCL2. Less commonly, there is a rearrangement involving another gene called BCL6 instead of BCL2. When all three genes are involved, the cancer is known as triple-hit lymphoma.

BCL2 and BCL6 normally play a role in controlling cell death, while MYC promotes cell multiplication. The genetic rearrangements cause too much cell division and decreased cell death, resulting in cancer. Although BCL2 translocations or MYC translocations are often observed in lymphoma, translocations involving both genes are present in the case of DHL.

Symptoms of Double-Hit Lymphoma

Due to its similarities to diffuse large B-cell lymphoma and Burkitt lymphoma, DHL may cause many of the same signs and symptoms. Some symptoms, called B symptoms, are experienced with many forms of lymphoma and include fevers, night sweats, and sudden weight loss. Other common signs and symptoms shared by DHL, DLBCL, and Burkitt lymphoma include:

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

How Is Double-Hit Lymphoma Diagnosed?

To diagnose DHL, doctors perform several tests, many of which are used for aggressive non-Hodgkin lymphoma in general.

Lymph Node Biopsy

A lymph node biopsy is the removal and examination of lymph node tissue. The biopsy can be a surgical biopsy, which involves the removal of an entire lymph node from the body, or a needle biopsy, which involves removal of a portion of a lymph node. A doctor examines the tissue under a microscope to confirm the presence of cancer cells.

Fluorescence In Situ Hybridization

DHL is definitively diagnosed using a molecular technique called fluorescence in situ hybridization (FISH). FISH involves the use of fluorescent molecules that bind to certain regions of the chromosomes, allowing a doctor to visualize the BCL2 translocations and MYC translocations that are found in DHL.

Bone Marrow Testing

Infiltration of cancer cells in the bone marrow is prevalent in people with DHL. Cancer cells in the bone marrow can be observed using tests such as a bone marrow biopsy and bone marrow aspiration. A bone marrow biopsy involves taking a small tissue sample from the bone marrow, whereas a bone marrow aspiration takes a sample of liquid from the bone marrow.

Imaging Technologies

Computerized tomography (CT) scans and positron emission tomography combined with CT (PET-CT scans) are used to image the tissues within the body. CT or PET-CT scans can be used to look for evidence of enlarged lymph nodes.

Blood Tests

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

Spinal Tap

Also known as a lumbar puncture, a spinal tap involves using a needle to collect fluid from the spinal canal. This test may be performed because DHL often affects the central nervous system.

Treatments for Double-Hit Lymphoma

People diagnosed with DHL can expect to undergo an intensive treatment regimen due to its aggressive nature.

Chemotherapy

The initial approach to treat DHL is often chemotherapy. Combinations of chemotherapy drugs are often used for certain treatment regimens, generally used with an antibody drug called rituximab (Rituxan). Rituximab recognizes a specific molecule on the surface of B cells, allowing it to target the DHL cancer cells in particular.

In the past, DHL was commonly treated with a chemotherapy regimen known as R-CHOP, which consists of cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), vincristine (formerly sold as Oncovin), and prednisone plus rituximab. Currently, the standard approach favors more intensive treatment regimens, such as:

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

Stem Cell Transplant

For people being treated for DHL who are responsive to chemotherapy, a stem cell transplant may be recommended. A stem cell transplant allows a person undergoing treatment to tolerate higher doses of chemotherapy by later replacing the damaged cells of the bone marrow with healthy cells. A transplant can be done using stem cells from a healthy donor, called an allogeneic stem cell transplant, or using stem cells from the person’s own body, called an autologous stem cell transplant.

Central Nervous System Prophylaxis

There is a higher risk of DHL spreading to the central nervous system (CNS) and causing a more serious situation compared to other forms of non-Hodgkin lymphoma. To reduce the risk, the medical team may recommend treatment with CNS prophylaxis. CNS prophylaxis involves administering chemotherapy directly to the CNS via either an intravenous (IV) drip or a lumbar puncture. The drug most commonly given for CNS prophylaxis is methotrexate.

New and Emerging Treatments

There are ongoing clinical trials to evaluate the effectiveness of existing drugs for treating DHL. 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 DHL. Also under investigation is a new type of therapy called chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy involves removing immune cells called T cells from a person and engineering them to contain chimeric antigen receptors on the surface of the cells. The CAR T cells are then put back into the person, where they can bind to molecules on the cancer cells and attack them.

Outlook for Double-Hit Lymphoma

Compared to DLBCL and Burkitt lymphoma, DHL is often more refractory, meaning it does not respond as well to conventional treatments. In the case of an initial response to treatment, the cancer often relapses (comes back) after a while. Relapsed DHL often occurs within a year of treatment, and the median overall survival time is less than two years.

DHL is challenging to study due to its rarity and the aggressive nature of the disease. Additional research and clinical trials are crucial to improve treatment options for individuals with DHL.

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