Double-hit lymphoma (DHL) is an aggressive cancer that develops from white blood cells called B lymphocytes or B cells. It’s sometimes considered a rare subtype of diffuse large B-cell lymphoma (DLBCL). Approximately 5 percent of people with DLBCL develop DHL.

Like DLBCL, DHL is a form of non-Hodgkin lymphoma (NHL). DHL primarily affects older adults and is slightly more common in males, according to the Atlas of Genetics and Cytogenetics in Oncology and Haematology. Some medical scientists classify DHL as high-grade B-cell lymphoma.

Read on to learn about what causes double-hit lymphoma, how it’s treated, and the survival rates associated with it.

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 in DLBCL is most commonly caused by a translocation involving a gene called MYC and another gene called BCL2. These mutations are known as MYC rearrangements and BCL2 rearrangements. These mutations can lead to a poor outcome with cancer that is harder to treat.

Symptoms of double-hit lymphoma and DLBCL can include swollen lymph nodes, fatigue, trouble breathing, and loss of appetite.

Less commonly, there is a BCL6 rearrangement involving the gene 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, DHL may cause many of the same signs and symptoms. Some symptoms, called B symptoms, are common in many forms of lymphoma, including:

• Fevers
• Night sweats
• Sudden weight loss

Other common signs and symptoms shared by DHL and DLBCL include:

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

Treatments for Double-Hit Lymphoma

People diagnosed with DHL are typically advised to undergo an intensive treatment regimen due to its aggressive and high-risk 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 — commonly used to treat DLBCL. R-CHOP derives its name from the drugs that comprise the regimen:

• Rituximab
• Cyclophosphamide
• Doxorubicin — also called hydroxydaunomycin
• Vincristine (formerly sold as Oncovin)
• Prednisone

Most doctors recommend intensive treatment due to the aggressive nature of double-hit lymphoma.

Current approaches favor more intensive treatment regimens, due to a poor prognosis for DHL treated with R-CHOP. Treatment regimens include therapies such as:

• Dose-adjusted (or DA) EPOCH-R — Etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab
• R-Hyper-CVAD — Rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alongside two additional chemotherapy drugs, methotrexate and cytarabine
• R-CODOX-M/R-IVAC — Alternates between two drug combinations: rituximab plus cyclophosphamide, vincristine, doxorubicin, and methotrexate; and rituximab plus ifosfamide, etoposide, and cytarabine, along with cytosine arabinoside

Bone Marrow Transplant

For people being treated for DHL who are responsive to chemotherapy, a bone marrow transplant may be recommended. A bone marrow 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 bone marrow cells from a healthy donor, called an allogeneic transplant, or using bone marrow cells from the person’s own body, called an autologous transplant.

Central Nervous System Prophylaxis

Compared to other forms of non-Hodgkin lymphoma, DHL has a higher risk of spreading to the central nervous system (CNS), which comprises the brain and spinal cord. To reduce the risk, the medical team may recommend treatment with CNS prophylaxis. CNS prophylaxis involves administering chemotherapy — most often methotrexate — directly to the CNS via either an IV drip or a lumbar puncture.

New and Emerging Treatments

New treatments are showing promising results in prolonging overall survival in people with DHL, and more therapies are in development. Specifically, several immunotherapies have become available in recent years to treat advanced lymphomas. Immunotherapy harnesses your own immune system to better fight cancer.

CAR T-Cell Therapy

One newer type of immunotherapy, known as chimeric antigen receptor (CAR) T-cell therapy, is showing encouraging results in the treatment of relapsing (comes back) and refractory (resistant to treatment) forms of DLBCL. CAR T-cell therapy involves removing immune cells called T cells from the person and engineering them to specifically bind to molecules on cancer cells and attack them.

Double-hit lymphoma is often at an advanced stage when it is diagnosed.

Some examples of CAR T-cell therapy include:

• Axicabtagene ciloleucel (Yescarta)
• Lisocabtagene maraleucel (Breyanzi)
• Tisagenlecleucel (Kymriah)

Bispecific Antibodies

Bispecific antibodies are a new type of drug with two parts. One part of the drug recognizes and binds to cancer cells, while the other part attacks and kills the cancer cell.

Examples of bispecific antibodies include apcoritamab-bysp (Epkinly) and glofitamab-gxbm (Columvi).

Along with other new therapies in development, there are ongoing clinical trials to evaluate the effectiveness of new and existing drugs for treating DHL. If you’re interested in joining a clinical study to potentially access new treatments for DHL, speak to your doctor.

Outlook for Double-Hit Lymphoma

When DHL is diagnosed, it’s often at an advanced stage with extranodal cancer that has spread beyond the lymph nodes. DHL in DLBCL is also often refractory, or nonresponsive to treatment.

In the case of an initial response to treatment, the cancer often relapses and eventually returns. A 2014 study showed that after two years, 50 percent of people with DHL were still alive, and of these, 40 percent had not shown signs of disease progression.

Talk to your doctor about new treatments and how they may be improving the outlook with DHL.

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