Double Hit Lymphoma

Double hit lymphoma is an aggressive form of cancer that develops from white blood cells called B lymphocytes, characterized by specific genetic changes that make it particularly challenging to treat.

Table of contents

• What is Double Hit Lymphoma?
• What Causes This Disease?
• Signs and Symptoms
• How Doctors Identify the Disease
• Treatment Approaches
• Outcomes and Survival

high-grade B-cell lymphoma, HGBCL, DHL

What is Double Hit Lymphoma?

Double hit lymphoma is an aggressive type of B-cell non-Hodgkin lymphoma (a cancer that develops from white blood cells that normally help fight infection). The disease is now officially known as high-grade B-cell lymphoma, though many doctors and patients still use the term “double hit lymphoma.”^[3]

This form of lymphoma is relatively rare. Approximately 5 percent of people with diffuse large B-cell lymphoma (DLBCL, a common type of lymphoma) have double hit lymphoma.^[4] The disease primarily affects older adults and is slightly more common in males.^[4]

The World Health Organization designated this as its own category of B-cell non-Hodgkin lymphoma in 2016, recognizing that it differs in several important ways from other lymphomas that do not have the same genetic characteristics.^[3]

What Causes This Disease?

Double hit lymphoma is caused by specific genetic changes called translocations, which occur when pieces of chromosomes (structures in cells that contain DNA) break off and combine in an abnormal way.^[4]

The disease is most commonly caused by a translocation involving a gene called MYC and another gene called BCL2. These changes are known as MYC rearrangements and BCL2 rearrangements.^[4] One rearrangement involves the MYC gene, and the other involves the BCL2 gene or, less commonly, the BCL6 gene.^[3]

When all three genes are involved (MYC, BCL2, and BCL6), the cancer is known as triple-hit lymphoma.^[4] The term “double hit” comes from the presence of two adverse gene markers that make the disease particularly aggressive.^[19]

The BCL2 and BCL6 genes normally play a role in controlling cell death, while the MYC gene promotes cell multiplication. When these genes are rearranged, they cause too much cell division and decreased cell death, resulting in cancer.^[4] The combination of dysregulation of both MYC with BCL2 and BCL6 rearrangements promotes the development of lymphoma and increases resistance to chemotherapy.^[12]

Signs and Symptoms

Patients with double hit lymphoma usually present with rapidly progressive disease that has already reached an advanced stage. The disease commonly involves areas outside the lymph nodes.^[12] These fast-growing lymphomas typically are not detected by a general exam but instead announce their presence suddenly with specific symptoms.^[9]

Some symptoms, called B symptoms, are common in many forms of lymphoma. These include:^[4]

• Fevers
• Night sweats
• Sudden weight loss

Other common signs and symptoms include:^[4]

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

How Doctors Identify the Disease

Molecular tests that allow doctors to check for gene rearrangements in chromosomes under a microscope are used to confirm a diagnosis of double hit lymphoma.^[3] A tissue sample is typically obtained through a biopsy (removal of a small piece of tissue for examination). The diagnosis requires identifying the presence of MYC rearrangements along with BCL2 or BCL6 rearrangements.^[9]

During the diagnostic process, doctors use a technique called fluorescence in situ hybridization (FISH) to detect these specific genetic changes in the cancer cells.^[9] Additional tests, such as imaging scans, help doctors determine how far the disease has spread in the body.

Treatment Approaches

People diagnosed with double hit lymphoma are typically advised to undergo an intensive treatment plan due to its aggressive and high-risk nature.^[4] Studies have demonstrated that this group of diseases leads to poor outcomes following standard treatment, so more intensive approaches are recommended.^[9]

Chemotherapy

The initial approach to treat double hit lymphoma is often chemotherapy (drugs that kill rapidly dividing cells, including cancer cells). Combinations of chemotherapy drugs are typically used with an antibody drug called rituximab (Rituxan). Rituximab recognizes a specific molecule on the surface of B cells, allowing it to target the cancer cells in particular.^[4]

In the past, double hit lymphoma was commonly treated with a chemotherapy regimen known as R-CHOP, which is commonly used to treat diffuse large B-cell lymphoma. R-CHOP gets its name from the drugs that make up the regimen:^[4]

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

However, current approaches favor more intensive treatment regimens due to poor outcomes for double hit lymphoma treated with R-CHOP.^[4] More aggressive treatment combinations may include dose-intense platforms that have shown better results in retrospective studies.^[9]

Stem Cell Transplant

Based on the results of intensive chemotherapy, some patients may be candidates for a bone marrow transplant (also called stem cell transplant). This procedure involves replacing the patient’s blood-forming cells with healthy ones, either from the patient’s own body or from a donor.^[19]

Advanced Therapies

In the relapsed and refractory setting (when the disease comes back or does not respond to initial treatment), novel approaches have demonstrated high effectiveness. These include anti-CD19 chimeric antigen receptor T cells (CAR T-cell therapy, a treatment that uses modified immune cells to attack cancer) and antibodies against CD19.^[9] Recent studies suggest that CAR T-cell therapy may overcome the poor outcomes traditionally associated with double hit lymphoma.^[11]

Outcomes and Survival

Double hit lymphoma has historically been associated with an aggressive clinical course and resistance to conventional chemotherapy.^[5] Without the dual gene rearrangements present in double hit lymphoma, similar lymphomas tend to have better survival rates. The presence of these genetic changes makes the disease less responsive to therapy and lowers the likelihood of long-term survival.^[19]

Despite the poor prognosis historically associated with this disease, recent evidence suggests that newer treatment approaches, particularly CAR T-cell therapy, can overcome the poor prognostic impact of double hit lymphoma in the relapsed or refractory setting.^[11] However, patients with double hit lymphoma who relapse after CAR T-cell therapy have a very poor prognosis.^[11]

There currently remains no evidence for a single best risk-adapted treatment strategy, and no clinical, pathologic, or genetic factors have been identified that reliably predict response to therapy.^[5] Large, multicenter studies are still needed to define relevant clinical, genetic, and pathologic variables and to characterize appropriate treatment strategies.^[5]