Indolent NHL is not curable; however, it is responsive to radiation therapy, chemotherapy, and immunotherapy. Patients tend to live an average of 10 years with the disease. The goal of treatment, therefore, is symptom management.

Any treatment that causes clinically significant toxicity is generally stopped or switched to a more tolerable regimen. In contrast, aggressive NHL and HD are curable with chemotherapy in a large proportion of patients (30 to 60%, depending on other risk factors). Treatment is therefore continued, even in the face of significant side effects, because the goal in most patients is cure.

Many patients diagnosed with lymphoma have bone marrow involvement. Since most chemotherapy causes bone marrow suppression, it can be tricky to treat these patients aggressively without causing life-threatening cytopenias. White blood cell colony-stimulating factors are often administered in order to keep the patient on schedule with chemotherapy and decrease the risk of serious infections.

This is most often done with aggressive lymphomas, which are curable. Drugs include filgrastim (G-CSF, Neupogen), pegfilgrastim (Neulasta), and sargramostim (GM-CSF, Leukine). Red blood cell colony-stimulating factors may be given under certain circumstances to treat anemia, with drugs such as erythropoietin (Epogen, Procrit), darbepoietin (Aranesp). Transfusions of red blood cells may also be given, as can transfusions of platelets for patients with thrombocytopenia.

Common Treatment Options

RADIATION

Lymphomas are very responsive to radiation therapy. Radiation therapy is used alone for stage I indolent NHL. It is used in combination with chemotherapy for stages I and II HD, stage II NHL, and for CNS lymphoma. Stages III and IV lymphoma have extensive disease on both sides of the diaphragm. In these patients, radiation therapy is only used after systemic chemotherapy, to treat sites of previous bulky disease. This minimizes the risk of serious toxicity to normal organs.

CHEMOTHERAPY

Chemotherapy is the cornerstone of treatment for bulky or high-risk stage II and all stages III and IV lymphoma. It may even be used for stage I NHL if the patient has numerous risk factors. Chemotherapy is particularly important for more aggressive lymphoma histologies.

There are many drugs with significant activity in lymphoma. This includes:

• Bleomycin
• Dacarbazine
• Mechlorethamine
• Carboplatin
• Doxorubicin
• Methotrexate
• Chlorambucil
• Etoposide
• Mitoxantrone
• Cisplatin
• Fludarabine
• Oxaliplatin
• Cladribine
• Gemcitabine
• Procarbazine
• Cyclophosphamide
• Ifosfamide
• Vinblastine
• Cytarabine
• Vincristine

Chemotherapy may be administered as single agents. However, the more usual approach is to give combinations of agents. The most common combination chemotherapy regimens for lymphoma are listed below:

• Aggressive NHL: CHOP, DHAP, ESHAP, ICE, MINE, ProMACE-CytaBOM, m-BACOD, MACOP-B, EPOCH
• Indolent NHL: FC, CVP, CHOP, FM, FND
• HD: ABVD, MOPP, COPP, Stanford V

Note that almost all combination chemotherapy regimens include corticosteroids (e.g., prednisone, dexamethasone, methylprednisolone). These drugs are toxic to lymphocytes but do not cause additive bone marrow suppression.

IMMUNOTHERAPY

Immunotherapy for lymphoma is also highly effective and synergistic with chemotherapy. The most commonly used agent is rituximab, an anti-CD20 monoclonal antibody. Recall that CD20 is a common B-cell antigen. Rituximab may be used as monotherapy or in combination with chemotherapy for indolent B-cell NHL. It is also used with chemotherapy for aggressive B-cell NHL. Rituximab is used both as first-line therapy and in patients with relapsed lymphoma.

In addition to rituximab, there are several other monoclonal antibodies commercially available to treat lymphomas. Alemtuzumab is an anti-CD52 monoclonal antibody. CD52 is expressed on most normal and malignant lymphocytes. It is most often used to treat chronic lymphocytic leukemia and small cell lymphoma. It causes a high incidence of opportunistic infections due to toxicity to normal lymphocytes, therefore use of prophylactic antibiotics is critical.

Both ibritumomab and tositumomab are anti-CD20 monoclonal antibodies with a radioactive substance attached. Ibritumomab contains yttrium-90, and tositumomab contains iodine-131. Administration of these compounds results in localized radiation to the sites of lymphoma throughout the body. These agents can cause tremendous toxicity to the bone marrow and are currently used for refractory/relapsed indolent B-cell NHL.

Other Treatment Options

WATCHFUL WAITING

This approach is primarily used with indolent NHL, especially in patients without significant associated symptoms. Watchful waiting does not mean patients are not cared for. Rather, patients receive regular, careful monitoring, and treatment is initiated once symptoms arise or end-organ function is compromised. The average time to treatment in these patients is 2 to 3 years.

SURGERY

Surgery is not a cornerstone of lymphoma treatment, as it is for many cancers in earlier stages. Surgery is used in selective, rare lymphoma subtypes, such as gastric NHL and splenic marginal zone lymphoma.

BONE MARROW TRANSPLANT

Bone marrow transplant is also called hematopoietic stem cell transplant. The most common procedure is autologous BMT, in which the patientís own blood stem cells are harvested, then re-infused following very-high-dose chemotherapy. This is standard treatment for aggressive NHL or HD that has relapsed after first-line chemotherapy. Autologous BMT may be used as first-line therapy in select high-risk NHL and HD patients who are remission following first-line chemotherapy. Autologous BMT is still considered experimental for indolent NHL.

A newer approach is so-called tandem transplants, in which the patient receives two autologous BMTs, usually several months apart. This tactic has been well documented as a treatment for another hematopoietic cancer, multiple myeloma, but it has been used successfully in relapsed HD as well.

Allogeneic BMT is infusion of blood stem cells from another person, usually a sibling. It may be used for younger lymphoma patients who relapsed after an autologous BMT or who have extensive bone marrow involvement of lymphoma. It is reserved for this small subtype of patients because the 100-day mortality may be as high as 40%, and it is unclear if overall survival is prolonged.

For Cutaneous T-Cell Lymphomas

Although disseminated cutaneous lymphomas are usually treated with systemic therapies, topical therapies predominate for early stage disease. This includes topical corticosteroids, bexarotene (a retinoid), ultraviolet light plus psoralen (PUVA therapy), and topical mechlorethamine. Denileukin difititox (a recombinant toxin containing human interleukin-2 and diphtheria toxin) is also used for cutaneous T-cell NHL, as are other systemic immunomodulators such as interferon-alpha.

Clinical Trials and Novel Treatments

There are many novel treatment approaches being investigated for lymphoma in clinical trials. Treatment with antiangiogenesis drugs theoretically decreases tumor blood vessel formation, leading to tumor necrosis and decreased tumor spread. Agents that are approved in the U.S. for other cancer and are being studied as anti-lymphoma treatments include bevacizumab (a monoclonal antibody) and thalidomide and lenalidomide, which are oral anti-angiogenesis agents.

Vaccines may be designed for lymphomas using tumor-specific immunoglobulins or dendritic cells loaded with tumor-specific proteins. The goal is to induce an immune response against the lymphoma. Most trials have been done in patients with follicular NHL.

This approach is time consuming and costly due to the need to manufacture patient-specific vaccines. Bortezomib (Velcade) is a proteosome inhibitor that disrupts cellular homeostasis and leads to programmed cell death. It has primarily been studied in indolent NHL and may be combined with chemotherapy.

Finally, oblimersen is an anti-sense oligonucleotide that targets the bcl-2 protein. This is a potentially useful approach in follicular and mantle cell NHL, in which bcl-2 is mutated. Oblimersen can be given alone or with rituximab and/or chemotherapy.