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For some people with diffuse large B-cell lymphoma (DLBCL), the first or second round of treatments — such as chemoimmunotherapy, CAR-T cell therapy and stem cell transplants — fail to control the disease.
Some people with DLBCL have a relapse — when the lymphoma comes back after a period of remission. Others have refractory DLBCL, which is when the cancer does not improve or worsens despite treatment.
The first treatments after DLBCL diagnosis are known as first-line treatments. If the DLBCL relapses or is refractory to these therapies, another round of treatments, known as second-line treatment, may be necessary. If the cancer is still not cured at this point, healthcare teams may recommend third-line therapies.
Third-line therapies for DLBCL
Several types of third-line treatments for DLBCL are available. The treatment plan for a specific person depends on several factors, such as past therapies and overall health.
When appropriate, the preferred therapies for third-line treatment are CAR-T cell therapy and bispecific antibody therapy.
CAR-T cell therapy
CAR-T cell therapy is most often used as a second-line treatment for people with DLBCL when relapse happens during the first 12 months after initial treatment. However, if the first- and second-line treatments did not include CAR-T cell therapy, it can be used as a third-line treatment.
With CAR-T cell therapy, the healthcare team removes some of a person’s infection-fighting T cells through a blood draw. Then they genetically engineer those cells to produce special receptors called chimeric antigen receptors, or CARs. These CARs allow the T cells to recognize a protein (antigen) on the surface of cancer cells and activate the T cells’ ability to kill these cancer cells. The modified T cells are then infused back into the body.
Most people have a reaction to CAR-T cells that requires them to stay in the hospital for days to weeks for monitoring and management. Typically, the reaction happens within hours to days after the infusion. Side effects include:
- Cytokine release syndrome (CRS). As the modified T cells start targeting cancer cells, they release cytokines — proteins that can cause the immune system to overreact. This can cause fever, low blood pressure, muscle pains and flu-like symptoms.
- Neurologic effects known as neurotoxicity. This is a potentially dangerous condition in which the immune response to the treatment affects the central nervous system. While the exact cause of neurotoxicity is not well understood, some studies suggest that it is partly related to the severity of CRS. Neurotoxicity can cause confusion, tremors or difficulty with communication.
- Blood disorders. CAR-T cell therapy can result in blood changes that can lead to anemia, low platelet count (thrombocytopenia) and other blood disorders. These effects are generally short-lived and resolve themselves over time, but they can be more severe in some patients.
In most cases, these side effects can be successfully managed with close monitoring and treatment focused on the adverse effects.
Bispecific antibodies
Bispecific antibody therapy may be a third-line treatment option for people who have previously received CAR-T cell therapy.
Bispecific antibodies are based on similar technology as CAR-T cell therapy but use off-the-shelf small molecules to guide a person’s own T-cell immune response to kill cancerous tumors. However, in this treatment strategy, the person’s T cells will not be collected through a blood draw and modified.
Bispecific antibody medications attach to two separate targets. For example, the DLBCL drugs glofitamab (Columvi) and epcoritamab (Epkinly) attach to a specific protein known as CD3 on infection-fighting T cells and to a specific protein known as CD20 on lymphoma cells. This brings the T cells in direct contact with lymphoma cells, activating them to kill the lymphoma cells.
Glofitamab is an infusion given in cycles and calls for pretreatment with an infusion of the drug obinutuzumab (Gazyva). Epcoritamab is an injection administered in cycles. During specific cycles, the drugs are preceded by the steroid prednisolone, the antihistamine diphenhydramine (Benadryl, Allegra, others), and acetaminophen (Tylenol, others).
Glofitamab and epcoritamab can result in many of the same side effects as CAR-T therapy, including severe cases of cytokine release syndrome and neurotoxicity. Medications given before glofitamab and epcoritamab are meant to prevent or limit cytokine release syndrome from occurring.
Other third-line treatment options
When CART-T cell therapy and bispecific antibody therapy are unsuitable, your healthcare team may explore other options, including other antibody treatments and targeted therapy.
Other antibody treatments
Other antibody drug treatment options for DLBCL are monoclonal antibodies and antibody-drug conjugates.
Tafasitamab (Monjuvi) is a monoclonal antibody that treats relapsed or refractory DLBCL. It attaches to a protein called CD19 on the surface of lymphoma cells and triggers an immune system response that can destroy a cancer cell’s outer wall (membrane). This drug is given in cyclical infusions and with the drug lenalidomide (Revlimid), a small molecular inhibitor. It may not be a good option for those who may have CAR-T cell therapy in the future.
Antibody drug conjugates (ADC) are antibodies that are combined with a chemotherapy drug to deliver the treatment directly to the cancer cells while avoiding healthy cells. These include:
- Polatuzumab (Polivy). This infusion is administered in cycles with the chemotherapy drugs bendamustine (Belrapzo, Bendeka, others) and rituximab (Riabni, Rituxan, others). This drug may not be a good option for those who may have CAR-T cell therapy or bispecific antibody therapy in the future.
- Loncastuximab (Zynlonta). Before receiving any infusions of this drug, pretreatment with the steroid dexamethasone is needed. This medication may not be a good option for those who may have CAR-T cell therapy in the future.
These three antibody drugs commonly lead to severe side effects such as infection and low blood cell counts.
Targeted therapy
Targeted drug treatment focuses on specific proteins within cancer cells that allow them to survive. A targeted therapy option for DLBCL is the oral drug selinexor (Xpovio). This drug can also lead to severe side effects such as low blood cell counts. It also commonly leads to gastrointestinal side effects such as constipation, decreased appetite, diarrhea and nausea.
When third-line or fourth-line therapies become too much
Even with all these treatment options, it’s not always possible to recover from DLBCL. Eventually, some people choose to stop aggressive DLBCL treatment and focus on being comfortable and free from pain.
You may decide to focus on palliative care at this point, which is treatment focused on relieving symptoms and pain. Radiation treatment — and sometimes DLBCL-directed drugs — may be used at this point to help alleviate symptoms and extend your life, though they’re not intended to cure the disease.
If you have decided to stop curative treatment, have honest conversations with your healthcare team, family and friends. Be sure they understand your feelings, wishes and concerns. Write down your preferences for this stage of your life, such as your preferred hospice care options or what happens if you’re unable to make decisions for yourself.
Your healthcare team likely includes skilled experts who can make this process easier. They can provide logistical, emotional, and physical support for you and your family.
Hope on the horizon
DLBCL treatments and research constantly evolve, leading to new or improved third-line therapies.
Clinical trials are highly regulated studies about new treatments, therapy effectiveness or ways to decrease treatment side effects. Through clinical trials, people with DLBCL can get early access to an experimental therapy that may be more effective than standard treatments.
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