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:
- Cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome)
- Follicular lymphoma (FL)
- Lymphoplasmacytic lymphoma and Waldenström macroglobulinemia
- Marginal zone lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma
- Small cell lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL)
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 individua and depends on factors that include the patient’s
- Prognostic factors
- Stage of disease
- Age and other medical conditions.
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.
- Two agents that belong to the class of drugs called “histone deacetylase (HDAC)” inhibitors are used to treat CTCL:
- Romidepsin (Istodax®)
- Vorinostat (Zolinza®)
If there is widespread involvement of lymph nodes and other sites, either single- or multidrug chemotherapy or photopheresis can be used, depending on the objective of therapy and the rate of disease progression. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that uses PUVA. Leukocytes are removed by leukapheresis, then treated with psoralen, exposed to UVA and then returned to the patient. Extracorporeal photopheresis is recommended for patients either with, or at risk for, blood involvement, such as that seen in Sézary syndrome. Allogeneic stem cell transplantation may be considered for selected patients and this option can be potentially curative for some of them.
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) 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®) followed by radiation therapy
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
- Idelalisib (Zydelig®)
- Copanlisib (Aliqopa®)
- Immunotherapy with monoclonal antibodies, either alone or in combination
- Yttrium-90+ibritumomab tiuxetan (Zevalin®)
- Obinutuzumab (Gazyva®)
- Rituximab and the endoglycosidase hyaluronidase human (Rituxan Hycela™)
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 high-dose therapies along with autologous stem cell transplantation. A clinical trial may be a good option for patients with disease that transforms after several different treatment approaches. Other options include
- Chemotherapy, either with or without rituximab (Rituxan®)
- Yttrium-90+ibritumomab tiuxetan (Zevalin®)
- Radiation therapy
- Supportive care
- Autologous stem cell transplantation within a clinical trial. When an autologous stem cell transplant is an option, stem cells should be collected before treatment with radioimmunotherapy.
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 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.
Most patients with WM are treated with combination chemotherapy. R-CHOP (rituximab [Rituxan®] plus cyclophosphamide [Cytoxan®], doxorubicin [hydroxydoxorubicin], vincristine [Oncovin®] and prednisone) has been reported to produce excellent response rates.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica®), given by mouth, is approved by the FDA for the treatment of patients with WM.
For more about Waldenström macroglobulinemia and treatment options, download or order LLS's free fact sheet Waldenström Macroglobulinemia Facts.
Marginal zone lymphoma can develop in either the lymph nodes (nodal) or outside the lymph nodes (extranodal). It begins in B lymphocytes in a part of the lymph tissue called the "marginal zone." The disease tends to remain localized.
Marginal zone lymphoma includes several subtypes, 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.
- Extragastric MALT lymphoma begins outside the stomach and may form in almost any part of the body including other areas of the GI tract, salivary glands, thyroid, lung, skin and around the eye.
- 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)
Small cell lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) are highly similar subtypes with regard to
- Incidence—median age of patients is 65 years
- Signs and symptoms—usually widespread enlarged lymph nodes (lymphadenopathy) and slight marrow and blood involvement
- Disease progression—may be very slow
Chronic lymphocytic leukemia is primarily a disease of the blood and marrow; however, CLL cells may travel to the lymph nodes. SLL primarily involves lymph nodes or lymphoid tissue. Treatments include:
- Ibrutinib (Imbruvica®)
- Venetoclax (Venclexta®)
- Bendamustine hydrochloride (Bendeka®)
- FCR (fludarabine, cyclophosphamide and rituximab)
To read more about CLL and its treatment options, download or order LLS's free booklet Chronic Lymphocytic Leukemia.