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Treatment for Indolent NHL Subtypes

Indolent non-Hodgkin lymphoma (NHL) subtypes progress slowly. They make up about 40 percent of all NHL cases in the United States. Indolent subtypes include:

Treatment for indolent NHL ranges from observation with careful monitoring (the watch-and-wait approach) to aggressive therapy. Indolent NHL management or treatment is highly individual and depends on factors that include the patient’s

  • Subtype 
  • Prognostic factors
  • Stage of disease
  • Age and other medical conditions.

For information about relapsed or refractory NHL, click here

For information on the watch-and-wait approach, download the free LLS fact sheet Watch and Wait

For information about the drugs listed on this page, visit Drug Listings.

Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sézary Syndrome)

Cutaneous T-cell lymphomas (CTCLs) are a group of NHLs that develop primarily in the skin and may grow to involve lymph nodes, blood and other organs. This type of lymphoma originates in a T-cell. Mycosis fungoides is the most common type of CTCL, and is characterized by prominent skin involvement. When the malignant lymphocytes enter and accumulate in the blood, the disease is called Sézary syndrome.

Therapy for CTCL depends on the nature of the skin lesions and whether disease is present in the lymph nodes.

  • Topical therapies are among the approaches used to treat the skin lesions. These include drugs applied directly to the skin and two different forms of therapy based on exposing skin lesions to light—ultraviolet light therapy and electron beam therapy. Ultraviolet light is used in conjunction with psoralen (a drug that becomes active when it is exposed to light); the combination therapy is often referred to as “PUVA” (psoralen and ultraviolet A) therapy.
  • If there is widespread involvement of lymph nodes and other areas, chemotherapy or extracorporeal photopheresis can be used. Photopheresis is a process in which white blood cells are removed by apheresis, treated with psoralen, exposed to ultraviolet A light and then returned to the patient’s bloodstream.
  • Two histone deacetylase (HDAC) inhibitors, romidepsin (Istodax®), given by IV infusion and vorinostat (Zolinza®), given by mouth, as well as one monoclonal antibody, mogamulizumab (Poteligeo®), given by IV, are indicated for the treatment of adult patients with either relapsed or refractory disease who have received previous systemic therapy.

To read more about cutaneous T-cell lymphoma and treatment options, download or order The Leukemia & Lymphoma Society's (LLS's) free booklet, Cutaneous T-Cell Lymphoma.

Follicular lymphoma (FL)

Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL), making up about 22 percent of all NHL cases. Most follicular lymphoma cells have a specific chromosomal abnormality (a translocation between parts of chromosomes 14 and 18) that causes the production (overexpression) of the gene, BCL-2, which can make the cells resistant to therapy. 

FL is a very slow-growing disease. Some patients may not need treatment for several years, whereas others may have extensive lymph node or organ involvement and need treatment right away. In a small percentage of patients, FL may transform into a more aggressive disease.

Stage I or stage II FL may be treated with:

  • Watch-and-wait approach; patients with less advanced disease can be observed with periodic examinations and imaging tests.
  • Radiation therapy
  • Chemotherapy with rituximab (Rituxan®) 
  • Rituximab alone

For patients with stage II FL who have large lymph nodes, stage III or stage IV FL or advanced-stage relapsed FL, treatment will be based on symptoms, the patient's age and health status, the extent of disease and the patient’s choice. Taking part in a clinical trial may also be a good treatment option. Other treatment options include:

  • The watch-and-wait approach
  • Radiation therapy to lymph nodes that are causing symptoms, or to a large localized mass, if one is present
  • Chemotherapy plus immunotherapy (rituximab)
  • Single chemotherapy drugs in combination with rituximab. Examples of drugs used for treatment include cyclophosphamide, chlorambucil or bendamustine hydrochloride (Bendeka®)
  • Chemotherapy combinations plus rituximab, such as R-CVP (rituximab plus cyclophosphamide [Cytoxan®], hydroxydoxorubicin [doxorubicin], vincristine [Oncovin®] and prednisone) or R-CHOP (rituximab [Rituxan®] plus cyclophosphamide [Cytoxan®], doxorubicin [hydroxydoxorubicin], Oncovin® [vincristine] and prednisone)
  • Maintenance rituximab after completion of initial therapy with either rituximab alone or rituximab in combination with chemotherapy. This involves a single dose of rituximab administered on a prescribed schedule (generally every 2 to 3 months). Rituximab maintenance may be continued for 2 years.
  • Autologous and allogeneic stem cell transplantation for selected patients
  • Targeted therapy, using kinase inhibitors, such as copanlisib (Aliqopa®) and EZH2 inhibitors, such as tazemetostat (Tazverik™)
  • Immunomodulatory drugs, such as lenalidomide (Revlimid®)
  • Immunotherapy with monoclonal antibodies, either alone or in combination
    • Yttrium-90+ibritumomab tiuxetan (Zevalin®)
    • Obinutuzumab (Gazyva®)
    • The combination of the monoclonal antibody rituximab and the enzyme endoglycosidase hyaluronidase human (Rituxan Hycela™)
  • Axicabtagene ciloleucel (Yescarta®)

Transformed B-Cell Follicular Lymphoma (FL). Follicular lymphoma has a small risk of transforming into an aggressive large B-cell lymphoma, such as DLBCL. Patients with transformed B-cell FL appear to benefit from rituximab therapy, either alone or in combination with chemotherapy. Other options include chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel (Yescarta®), lisocabtagene maraleucel (Breyanzi®) or tisagenlecleucel (Kymriah®).

For more information about CAR T-cell therapy, see the free LLS booklet Chimeric Antigen Receptor (CAR) T-Cell Therapy.

Reduced-intensity transplantation, within a clinical trial, may also be considered in cases of FL transformation. Several novel drug combinations are being studied for the treatment of refractory/relapsed FL.

The Follicular Lymphoma International Prognostic Index (FLIPI). The FLIPI is a scoring system used to predict which patients with follicular lymphoma may be at higher risk for disease recurrence. One point is assigned for each of the following risk factors (known by the acronym NoLASH):

  • Nodes involved—5 or more
  • Lactate dehydrogenase (LDH) level—higher than the upper limit of normal
  • Age older than 60 years
  • Stage III or stage IV disease
  • Hemoglobin concentration—less than 12 g/dL

Low risk:  0 to 1 point
Intermediate risk: 2 points
High risk: 3 to 5 points

Lymphoplasmacytic Lymphoma and Waldenström Macroglobulinemia

Lymphoplasmacytic lymphoma and Waldenström macroglobulinemia are both slow-growing types of lymphoma that originate in a B-lymphocyte precursor. Waldenström macroglobulinemia is a type of lymphoplasmacytic lymphoma.

In lymphoplasmacytic lymphoma, the lymph nodes are more involved than they are in WM. Both disorders show malignant lymphoplasmacytic cells in the marrow and spleen.

Patients may experience increased blood viscosity (thickening of the blood), inadequate blood flow, and symptoms and signs of limited blood flow (eg, headache, visual blurring, mental confusion). This is referred to as “hyperviscosity syndrome” which may require urgent intervention. Hyperviscosity syndrome can be treated by plasmapheresis (a process in which plasma is separated from whole blood and the rest is returned to the patient). Plasmapheresis can reverse acute symptoms and signs, but long-term control requires a reduction in the mass of lymphoma cells that make the protein.

One option for patients without symptoms of WM is to take a watch-and-wait approach. Active treatment begins for these patients only if symptoms develop. Progressive disease may also involve the lungs, the gastrointestinal (GI) tract and other organs.

Several different therapies are effective against WM, but no single or combination standard treatment is used for all patients. Patients are advised to discuss with their doctors the most appropriate treatment for their situation. Specific treatments include drug therapy, combinations of drugs, stem cell transplantation, and involvement in clinical trials.

For more about Waldenström macroglobulinemia and treatment options, download or order LLS's free fact sheet Waldenström Macroglobulinemia Facts.

Marginal Zone Lymphoma (MZL)

This indolent B-cell lymphoma subtype may be extranodal (disease outside of the lymph nodes) or nodal (disease within the lymph nodes). It begins in B lymphocytes in a part of the lymph tissue called the “marginal zone.” The disease tends to remain localized.

There are several subtypes of MZL, each categorized by the type of tissue where the lymphoma forms.

  • Gastric mucosa-associated lymphoid tissue (MALT) lymphoma usually develops in the stomach. Patients with MALT lymphoma may have a history of an autoimmune disease such as Hashimoto thyroiditis or Sjögren syndrome. A higher incidence of MALT lymphoma involving the stomach is seen in patients who have been infected with the bacterium H. pylori. Bacteria have also been implicated in other forms of MALT lymphoma. Treatment often includes potent combinations of antibiotics, which both eradicate the H. pylori infection and cause the lymphoma to regress. Many patients with H. pylori have been cured of MALT lymphoma without radiation or chemotherapy. If remission is not achieved following antibiotic treatment, radiotherapy can be a curative option. For a small subset of patients, MALT lymphoma can transform into diffuse large B-cell lymphoma (DLBCL), and if this happens, patients can benefit from treatments used for DLBCL. See Diffuse Large B-cell Lymphoma.
  • Monocytoid B-cell lymphoma, also known as “nodal marginal zone B-cell lymphoma” (nodal MZL), may be found in the spleen and blood. This form of NHL is generally treated like follicular lymphoma. See Follicular Lymphoma.
  • Splenic marginal zone lymphoma (SMZL) begins in the spleen and may spread to the peripheral blood and bone marrow. One of the first signs of SMZL is an enlarged spleen; however, symptoms can be slow to develop. SMZL has been associated with hepatitis C infection. Treatment for hepatitis C with interferon (either alone or in combination with ribavirin) may result in a remission of the patient’s lymphoma.

For patients with SMZL who do not have hepatitis C or any symptoms of lymphoma, the first treatment may be the watch-and-wait approach. Treatment is generally started when an enlarged spleen starts to cause symptoms or produces low white blood cell counts. For symptomatic patients who are hepatitis-C negative, treatment may include

  • Removal of the spleen
  • Single-agent chemotherapy
  • Combination chemotherapy plus rituximab (Rituxan)
    • R-CVP (rituximab, cyclophosphamide, vincristine and prednisone)
    • R-CHOP (rituximab [Rituxan®] plus cyclophosphamide [Cytoxan®],doxorubicin [hydroxydoxorubicin], Oncovin® [vincristine] and prednisone)
    • BR (bendamustine hydrochloride (Bendeka), rituximab)

For relapsed or refractory cases, treatment may include

  • Lenalidomide (Revlimid®), given by mouth, is indicated in combination with a rituximab product for MZL patients who have been previously treated.

Researchers are evaluating new treatment approaches for MZL. Speak to your doctor or an LLS Information Specialist to find out more about clinical trials.

For more about Marginal Zone Lymphoma, download or order LLS's free booklet Marginal Zone Lymphoma

Small Cell Lymphocytic Lymphoma (SLL) and Chronic Lymphocytic Leukemia (CLL)

 Chronic lymphocytic leukemia (CLL) and SLL are different manifestations of the same disease and their treatment is very similar. 

Treatments include:

  • Ibrutinib (Imbruvica®)
  • Venetoclax (Venclexta®)
  • Bendamustine hydrochloride (Bendeka®)
  • Obinutuzumab (Gazyva®)
  • Acalabrutinib (Calquence®) 
  • Rituximab (Rituxan®)
  • Zanubrutinib (Brukinsa®)

The following drugs are used for cases of relapsed CLL or SLL: 

  • Idelalisib (Zydelig®), in combination with rituximab or in patients who received at least two prior systemic therapies
  • Duvelisib (Copiktra™), after at least two prior therapies.

The FCR (fludarabine, cyclophosphamide and rituximab) regimen is a potentially curative option for some patients with CLL/SLL. Recent reports from clinical studies indicate that chimeric antigen receptor (CAR) T-cell therapy can induce durable remissions in patients with refractory disease. This therapy is under investigation in clinical trials.

To read more about CLL and its treatment options, download or order LLS's free booklet Chronic Lymphocytic Leukemia.


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