Understanding T-Cell Lymphomas

T-cell lymphomas develop from white blood cells called T-lymphocytes (also called T-cells) or natural killer (NK) cells (a type of T-cell), and account for less than 15% of all non-Hodgkin Lymphomas (NHLs) in the United States. T-cells direct the immune response by binding and signaling the cancer cells, while NK cells directly and rapidly kill cancer cells.

Most T-cell lymphomas appear from mature T-cells (T-cells that are fully developed). T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing) and are mainly found in the skin (cutaneous T-cell lymphomas, CTCL) or throughout the body (peripheral T-cell lymphomas, PTCL):

• PTCL account for 10-15% of all cases of NHL.
• CTCL account for about 4% of all NHL.

In rare cases (about 1% of all lymphomas), T-cell lymphoma develops from immature (early stages of development) T-cells in the thymus and is called T-lymphoblastic lymphoma. When cancer develops from NK cells (which share many characteristics with T-cells), it is called NK or NK/T-cell lymphoma and is generally grouped with other T-cell lymphomas. Some subtypes of T-cell lymphoma are listed in Figure 2 and described below.

Figure 2. Relative frequencies (probability of T-cell lymphoma happening relative to all lymphomas) of T-cell lymphomas in the United States. Percentages are based on the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER, an official source for cancer statistics) data, 2008-2017. Some very rare types are not shown in the graph. NK, natural killer.

Symptoms, Staging, and Diagnostic Procedure

Some patients with T-cell lymphoma do not have any obvious signs or symptoms of the disease. Their doctors might detect lymphoma during routine blood tests and/ or a physical examination. For others, lymphoma is discovered when symptoms occur and patients go to the doctor because they are worried, uncomfortable, or not feeling well.

T-cell lymphomas may cause different signs and symptoms depending on the type of lymphoma and where it is located in the body. Keep in mind that many of these signs and symptoms are not specific to T-cell lymphoma and can be caused by other conditions. The signs and symptoms commonly found in patients with T-cell lymphoma are:

To make a definite diagnosis of T-cell lymphoma, doctors need to collect a sample of the affected lymph node. This procedure is called a biopsy (a procedure in which a piece of the abnormal tissue is removed from the body and examined under a microscope). Biopsies where an entire lymph node or tumor is removed (called excisional biopsies) are preferred to ensure there is enough sample to determine the type of lymphoma. The biopsy is typically studied by a pathologist (doctor who specializes in the diagnosis of diseases by studying the cells from a patient’s body fluids and tissue samples) and preferably a hematopathologist (pathologist who has undergone additional training in the diagnosis of blood cancers, including lymphoma) who is experienced in diagnosing lymphoma. There are multiple subtypes of T-cell lymphoma, some very uncommon, and additional tests may be needed to make an accurate diagnosis. Determining the exact T-cell lymphoma subtype helps to identify the appropriate treatment options for the patient.

After a diagnosis of T-cell lymphoma, it is important to determine if and how far the lymphoma has spread. This process is called staging, and it uses the results of the different tests (such as biopsies and scans) to determine the severity of the disease and the appropriate treatment. The Lugano staging system is used for T-cell lymphomas and is depicted in Figure 3 below. This system categorizes lymphoma from Stage I (least severe) to IV (most severe), based on whether the disease is restricted to a single group of lymph nodes, has spread to other lymph nodes, or has reached the bone marrow and/or other organs (like the liver or lungs).

Figure 3. Staging of lymphoma according to the Lugano system.

Subtypes

Common PTCLs

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), the most common subtype of PTCL (around 30% of PTCLs in the United States), and refers to a group of lymphomas that do not fit into any of the other PTCL subtypes. PTCL-NOS usually occurs in adults in their 60s. Although most patients with PTCL-NOS are diagnosed when the disease is only located in the lymph nodes, extranodal sites (sites in the body outside the lymph nodes) such as the liver, bone marrow, gastrointestinal tract, and skin are frequently involved. This group of PTCLs is generally aggressive and requires urgent treatment. Patients are most often treated with chemotherapy and may be considered for an autologous stem cell transplant (SCT, patient’s own cells are infused after high-dose chemotherapy) following initial chemotherapy. While PTCL-NOS is potentially curable, in some patients the disease tends to relapse (disease returns after treatment).

Anaplastic large cell lymphoma (ALCL) accounts for around 15% of all T-cell lymphomas. There are several different subtypes of ALCLs. All patients with ALCL have a protein called CD30 on the surface of cancer cells, which helps detect and diagnose ALCL. CD30 is characteristic of some forms of NHLs, while the majority of Hodgkin’s lymphoma cells are positive for CD30.

ALCL can be either systemic (occurring throughout the body), cutaneous (limited to the skin), and can rarely be seen around breast implants. Systemic ALCL is typically in an advanced stage (disease has grown in size and/or spread throughout the body) at diagnosis and can progress (grow and/ or spread) rapidly. Patients with systemic ALCL are divided into two groups, depending on whether or not the surface of their cells have an abnormal form of a protein called anaplastic lymphoma kinase (ALK):

• ALK-positive (ALK protein is present in cancer cells) disease can respond well to chemotherapy treatment and is potentially curable.
• ALK-negative (ALK protein is not present in cancer cells) disease may require stronger treatments than ALK-positive disease. It can be cured with chemotherapy but relapse occurs more frequently than in ALK positive disease.

Primary cutaneous ALCL appears only on the skin and is often less aggressive (it grows slower). A rare type of ALCL called breast implant-associated (BIA)-ALCL has been observed in some patients who have or had breast implants, especially implants with textured (non-smooth) surfaces. Most patients with BIA-ALCL may be treated with surgery alone.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and often fast-growing form of PTCL. It accounts for about 15-30% of PTCLs and is more common in older people (median age at diagnosis is 65 years), though it can affect young adults as well. Most patients with AITL are diagnosed with advanced-stage disease (Stage III or Stage IV disease). Patients are most often treated with chemotherapy and may be considered for an autologous SCT following initial chemotherapy. While AITL is potentially curable, in some patients the disease tends to relapse.

Uncommon PTCLs

Adult T-cell leukemia/lymphoma (ATLL) is a rare and often aggressive form of T-cell lymphoma that can be found in the blood (leukemia), lymph nodes (lymphoma), skin, or other areas of the body. ATLL has been linked to infection with human T-lymphotropic virus type 1 (HTLV-1). However, not all individuals that are positive for HTLV-1 will develop ATLL.

This virus is commonly found in people from the Caribbean, parts of Japan, and some areas of South and Central America, Africa, Middle East, and more rarely in Australia and Asia. The HTLV-1 virus is believed to be passed through sexual contact or contact with blood, but it is most often passed from mother to child through the placenta, at childbirth, or during breastfeeding. Only 5% of those who carry the virus will develop lymphoma. Treatment commonly includes chemotherapy and antivirals to treat the underlying HTLV-1 infection. In some patients, allogeneic SCT (patients receive stem cells from a familiar or unrelated donor) may be appropriate following remission (disappearance of signs and symptoms). The acute and lymphoma subtypes are aggressive forms of ATLL, whereas chronic and smoldering are indolent.

• Acute: Symptoms develop rapidly and may include fatigue (extreme tiredness), skin rash, and enlarged lymph nodes in the neck, underarm, or groin. The characteristics of acute ATLL are a high level of white blood cells (cells that help the body fight infections and cancer) often with hypercalcemia (elevated calcium levels in the blood), which can cause confusion, irregular heartbeat and severe constipation (a condition in which stool becomes hard, dry, and difficult to pass, and bowel movements don’t happen very often). Acute ATLL may spread to extranodal sites.
• Lymphoma: This aggressive type of ATLL is found primarily in the lymph nodes, causes swollen or enlarged lymph nodes and may cause an increase in the level of white blood cells, skin rash, and hypercalcemia.
• Chronic: This slow-growing type of ATLL can result in elevated lymphocytes in the blood, enlarged lymph nodes, skin rash, or fatigue. It can also be found in other areas of the body such as the spleen and liver.
• Smoldering: This slow-growing type of ATLL is associated with very mild symptoms, such as a few skin lesions and/or rash.

Enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma are extremely rare and aggressive subtypes of T-cell lymphoma that appear in the intestines. Patients with enteropathy-Associated T-Cell Lymphoma frequently have chronic diarrhea, gluten sensitivity (feeling sick after eating gluten), and celiac disease (autoimmune disease where the ingestion of gluten leads to damage of the small intestine). Monomorphic epitheliotropic intestinal T-cell lymphoma is not generally associated with celiac disease. Other symptoms include abdominal pain and weight loss. Both require aggressive treatment that frequently is followed by SCT in selected patients.

Hepatosplenic gamma-delta T-cell lymphoma is an extremely rare and aggressive disease that affects the liver and/or spleen. It can spread into the blood and bone marrow. It most often occurs in adolescents and young adults and is more common in males. This lymphoma is associated with immunosuppressive treatments (drugs that lower the activity of the immune system). Patients, especially children, who have been treated with immunosuppressants such as azathioprine and infliximab (Remicade) for Crohn’s disease (a type of inflammatory bowel disease), may be more susceptible to this type of lymphoma. Allogeneic SCT are also considered after initial treatment for selected patients.

Extranodal NK/T-cell lymphomas (ENKTL) develop from NK cells. This aggressive lymphoma is relatively rare in the United States, but common in Asia and parts of Latin America. It typically develops in the interior of the nose or upper airway (nose, nasal cavity, mouth, throat, and larynx) at the back of the throat (in which case it is referred to as nasal type) but may appear in the gastrointestinal tract, skin, bone marrow, and other organs. The NK/T-cell lymphomas seem to be related to infections with Epstein-Barr virus.

Treatment-related T-cell lymphomas sometimes referred to as post-transplant lymphoproliferative disorder (PTLD), appear in patients who received immunosuppressants after an organ or bone marrow transplant (to prevent rejection of the transplanted organ). These treatments put patients at risk for this type of lymphoma. While PTLD is more commonly from B-cells, it can sometimes come from T-cells.

Lymphoblastic lymphoma can appear from either immature B-cells or T-cells (B-or T-cells that are not fully developed), but more commonly comes from T-cells, making up to 80% of all lymphoblastic lymphomas. This type of lymphoma is most often diagnosed in adolescents and young adults and is a bit more common in males.

Common CTCL

Cutaneous T-cell lymphoma (CTCL) describes a group of typically indolent lymphomas that appear on, and most often only affect the skin. Some patients may develop lymphoma in their blood, lymph nodes and, more rarely, other organs.

Mycosis fungoides (MF) is the most common subtype of CTCL (around 60% of all cases). It usually appears as skin patches (flat and often scaly rashes), plaques (thick, raised and often itchy lesions, similar to those found in eczema, psoriasis or dermatitis), or tumors (raised bumps or nodules with a diameter or height ≥ 1cm, which may turn into an open sore). More than one type of lesion may be present at any time.

Sézary syndrome (SS) is a less common and more aggressive form of CTCL that affects both the skin and the blood. Most individuals with SS are adults between the ages of 55 and 60 years. The most common symptoms are swollen lymph nodes and a red, very itchy rash that covers large portions of the body. Cancer T-cells, called Sézary cells, can be seen under a microscope and are present in both the skin and blood. There are other rarer forms of CTCL as well.

For more information, view the Cutaneous Lymphomas fact sheet on the Foundation’s website (visit lymphoma.org/publications).

First Line Therapies

Because there are so many different subtypes of T-cell lymphoma, treatment types vary widely, but initial treatment for the more common types of PTCL typically includes combination chemotherapy regimens usually for curative intent. Standard lymphoma therapies include:

• Chemotherapy (drugs that stop the growth of or kill cancer cells):
  • CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone).
  • CHOEP (CHOP plus etoposide).
  • Dose-adjusted EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone).
• Chemoimmunotherapy: a combination of chemotherapy (drugs that stop the growth of or kill cancer cells) with immunotherapy (drugs that use the body’s immune system to fight cancer):
  • An ADC is a monoclonal antibody (a protein made in the laboratory that binds to cancer cells and helps the immune system destroy them) attached to a chemotherapy drug. The monoclonal antibody in the ADC recognizes and binds to a protein on the cancer cell surface. Once the ADC is inside the cell, the chemotherapy drug separates from the ADC and kills the cancer cell by targeting cell multiplication.
  • BV-CHP is a combination of the ADC brentuximab vedotin (Adcetris) and the chemotherapy regimen cyclophosphamide, doxorubicin, and prednisone (CHP). This combination is used for the treatment of lymphomas that are positive for CD30 (molecule present on the surface of certain lymphomas) and has been approved for ALCL and CTCL.
• Immunotherapy such as:
  • Immunomodulatory agents, drugs that work on the immune system directly by regulating (activating or slowing down) the activity of specific proteins.
• Radiation which uses high-energy radiation to kill cancer cells.
• SCT (the patient is treated with high-dose chemotherapy or radiation to remove their blood-forming cells or stem cells and then receives healthy stem cells to restore the immune system and the bone marrow’s ability to make new blood cells). For more information about SCT, please view the Understanding Cellular Therapy Guide, also on the Foundation’s website (lymphoma.org/publications).
  • Allogeneic SCT (patients receive stem cells from a familiar or unrelated donor)
  • Autologous SCT (patient receives own stem cells)
• Antiviral therapy (treatment of infections caused by a virus). Zidovudine (Retrovir, AZT) in combination with interferon-alpha, to treat the underlying HTLV-1 infection (in patients with slow-growing ATLL).

Patients diagnosed with rare forms of lymphoma should consult their medical team to find new promising therapies or to enroll in clinical trials.

Relapsed or Refractory

Some patients with aggressive B-cell lymphomas respond to initial treatment and go into remission. In other cases, the disease may relapse (disease returns after treatment) or become refractory (does not respond to treatment). For these patients, different therapies may result in improved treatment outcomes.

Some patients with T-cell lymphomas respond to initial treatment and go into remission. In other cases, the disease may relapse or become refractory (does not respond to treatment). For these patients, different therapies may result in improved treatment outcomes.

In some patients with PTCL, SCT is considered the next step in therapy after combined chemotherapy. However, for some patients, chemotherapy regimens or SCT might not be recommended because of their side effects. Single-agent therapies with less side effects are also available and might cause a long-lasting remission in such patients. These drugs are approved by the FDA for patients who have relapsed or become refractory to first line chemotherapy:

Table 1. FDA-approved treatments for relapsed/refractory T-cell lymphomas.

Agent (Drug)	Indication
Belinostat (Beleodaq) Pralatrexate (Folotyn) Mogamulizumab (Poteligeo) Brentuximab vedotin (Adcetris) Crizotinib (Xalkori) Vorinostat (Zolinza) Denileukin diftitox (Lymphir)	Indicated for PTCL.
	Indicated for PTCL.
	Indicated for CTCL.
	Indicated for PTCL
	Indicated for relapsed or refractory ALK-positive ALCL.
	Indicated for CTCL
	Indicated for CTCL

Some other drugs used in other types of lymphoma that may occasionally be considered for the treatment of patients with AITL include targeted therapies like romidepsin (Istodax), duvelisib (Copiktra), and chemotherapies like gemcitabine (Gemzar), bendamustine (Treanda), and azacitidine (Vidaza). Immunosuppressive agents like cyclosporin can also be used in patients who have autoimmune disorders. Alemtuzumab (Campath) is a monoclonal antibody also occasionally considered, although it is no longer commercially available and is provided only through the Campath Distribution Program.

Treatment options for the different types of newly diagnosed and relapsed/refractory T-cell lymphomas are expanding as new treatments are discovered, and current treatments are improved. Treatments currently being investigated alone or in combination are described in the table below.

Table 2. Selected agents under investigation for T-cell lymphomas in Phase 2-3 clinical trials

Agent (Drugs)	Class (Type of treatment)	Type of Lymphoma
Azacitidine (CC-486)	Chemotherapy	R/R PTCL, untreated PTCL-NOS, untreated nTFHL
Bendamustine (Treanda)	Chemotherapy	R/R nTFHL
Cemiplimab (Libtayo)	Immunotherapy; immune checkpoint inhibitor, anti-PD-1	Untreated MF, untreated ENKTL
Durvalumab (Imfinzi)	Immunotherapy; immune checkpoint inhibitor, anti-PD-1	untreated MF, R/R MF, untreated SS, R/R CTCL, R/R ENKTL, R/R PTCL-NOS
Duvelisib (Copiktra)	Targeted therapy; PI3K inhibitor	R/R PTCL, untreated PTCL
Linperlisib	Targeted therapy; PI3K inhibitor	Untreated PTCL
Golidocitinib (AZD4205)	Targeted therapy; JAK1 inhibitor	R/R ENKTL, untreated PTCL
Lacutamab (IPH4102)	Immunotherapy; monoclonal antibody, anti-KIR3DL2	Untreated PTCL
Lenalidomide (Revlimid)	Immunotherapy; immunomodulator drug	R/R PTCL, untreated MF, R/R MF, untreated SS, untreated CTCL, untreated ENKTL
Nivolumab (Opdivo)	Immunotherapy; immune checkpoint inhibitor, anti-PD-1	R/R ALCL
Pembrolizumab (Keytruda)	Immunotherapy; immune checkpoint inhibitor, anti-PD-1	R/R ALCL, R/R AITL, R/R nTFHL
Ruxolitinib (Jakafi)	Targeted therapy; JAK1/2 inhibitor	Untreated ATLL
Soquelitinib (CPI-818)	Targeted therapy; ITK inhibitor	R/R PTCL
Valemetostat (DS-3201b)	Targeted therapy; EZH1/2 dual inhibitor	R/R ATLL
Venetoclax (Venclexta)	Targeted therapy; BCL-2 inhibitor	R/R PTCL

In addition, a number of promising clinical trials are studying combinations (two or more drugs given at the same time) of these new treatments which in some cases may be more effective than the single agent (one drug) alone. It is critical to remember that scientific research is always evolving. Treatment options may change as new treatments are discovered, and current treatments are improved. Therefore, it is important that patients check with their physician or with the Foundation for any treatment updates that may have recently appeared. It is also very important that all patients with T-cell lymphoma consult a specialist to clear up any questions.

How to Be a Self-Advocate

Being a self-advocate and an active participant in healthcare decisions can be a positive experience. It may help patients regain a sense of control that they may have lost following the lymphoma diagnosis by making sure patients receive the best care. Patients and caregivers should remember they are partners in their treatment plan.

• Do not be afraid to ask your doctors or nurses questions about your care. An educated patient asking questions is not ‘being a challenge to your physician’ (or ‘being a difficult patient’).
• Learn more about lymphoma by asking your doctor for information and visiting reliable websites, such as the Foundation’s at www.lymphoma.org.
• Take advantage of counseling, support groups, nutritional counseling, fitness classes, expressive arts, and other services offered at your doctor’s office, cancer center, or hospital.
• Consider joining the Foundation’s Lymphoma Support Network, a nationwide peer support program that matches patients and caregivers with people who have had similar experiences. For information about the program, call (800) 500-9976 or email [email protected].
• Finally, it is important that patients not be afraid to talk with the healthcare team about nonmedical issues such as transportation, finances, insurance, working through treatment or taking time off, and childcare. There are nurses, social workers, physician’s assistants that are be able to provide the support and resources to help.

Survivorship

As a cancer survivor, it is important that you practice self-care regularly to reset your physical and emotional well-being. Adopting routines of self-care will help you recharge your batteries and stay healthy. Talk with your healthcare team about developing a wellness plan to help you stay physically and emotionally healthy and improve your mood. Consider the following suggestions:

• Watch your health. Stay up-to-date with your own medical appointments and take any medications as prescribed.
• Exercise. Stay active with short periods of daily exercise (30 minutes of power walking, jogging or biking). If not possible, take the stairs instead of the elevator or park farther away than usual.
• Eat well. Include fruits and vegetables in your meals and maintain a balanced diet.
• Cut down on risk factors. Quit smoking and reduce alcohol intake.
• Sleep. Try to get 7 hours of sleep per night, or take naps when needed.
• Rest. Meditation, deep breathing and stretching can help you relax and reduce stress.
• Write it down. Keeping a journal with thoughts and feelings may help to let go of worries and fears.

View the Foundation’s Survivorship Series factsheet on the Foundation’s website at lymphoma.org/publicationfor more info.

Care Partners

There are many ways you can help a loved one with lymphoma, as follows:

• Be present. The most important thing that a care partner can do is to “just show up.”
• Be prepared. Talk with the healthcare team so that you know what to expect throughout the treatment, how to manage symptoms and when to ask for help.
• Listen. Each person asks for help in different ways, verbally (through words) and nonverbally, and some may require more comfort while others are more action oriented.
• Avoid “cheerleading”. Do not disregard your love one’s negative feelings (sadness, anger or worry).
• Organize the help. A rush of sudden help upon diagnosis can make the situation harder to manage and create unproductive tension.
• Set up remote access with computer and/or phone access. This is helpful for regular communication with your loved one.
• Offer rides. This is important for people with decreased mobility or limited resources.
• Take notes. If you go into the appointments, write down notes with the doctor’s plan, medications, potential side effects and other relevant information.

Patients and their care partner are encouraged to keep copies of all medical records. This includes test results as well as information on the types, amounts, and duration of all treatments received. Medical records are important for keeping track of any side effects resulting from treatment or potential disease recurrences. The Foundation can help patients manage this documentation.

View the Care Partners factsheet on the Foundation’s website atl ymphoma.org/publication for more info.

• What is my exact diagnosis? What subtype of lymphoma do I have? May I have a copy of the report from the pathologist?
• What is the stage of my disease? In what area of the body is it specifically located?
• What are my treatment choices? Which do you recommend for me and why? Would choosing one treatment prevent me from getting a different kind of treatment later on? How are the different treatments administered?
• Do I need more than one type of treatment?
• What is the goal of treatment? What are the expected benefits of each type of treatment?
• How will we know if the treatment is working? What tests will I need to determine if treatment is working, and how often will I need to be tested?
• How long will the treatment last?
• What are the chances the treatment will be successful?
• What is a clinical trial? Are clinical trials available that are studying new treatments for my type of lymphoma? Would a clinical trial be appropriate for me? How would I benefit? Are there any drawbacks of participating in a clinical trial?
• Will I be able to work during treatment? Will I be able to drive or take public transportation during my treatment?
• Should I take care of other medical or dental issues before I start treatment?
• How much will the treatment cost? Will my insurance cover some or all of it? What will my out-of-pocket costs be?