Non-Hodgkin’s lymphomas (NHLs) are a very heterogeneous group of cancers that develop in the lymph nodes present throughout the body. There are over 25 subtypes of NHL, although most are diagnosed infrequently. Small lymphocytic lymphoma (SLL) is the third most commonly diagnosed subtype, after diffuse large B-cell and follicular lymphomas. It accounts for 5 to 6% of NHL cases or approximately 400 cases per year in the United States.
Although some NHLs are very aggressive in nature, SLL is considered an indolent lymphoma. This means that the disease progresses very slowly, and patients tend to live many years after diagnosis. However, most patients are diagnosed with advanced disease, and although SLL responds well to a variety of chemotherapy drugs, it is generally considered to be incurable.
Although some cancers tend to occur more often in one gender or the other, cases and deaths due to SLL are evenly split between men and women. The average age at the time of diagnosis is 60 years.
Note that SLL and chronic lymphocytic leukemia (CLL) are considered to be different manifestations of the same disease. They behave the same clinically, with SLL presenting primarily in the lymph nodes and CLL manifesting as circulating cancer cells in the blood. Treatment for these two malignancies, however, is generally the same.
The exact cause of SLL is most often unknown. Unlike lung cancer, in which smoking is a clear contributor in the majority of patients diagnosed, there has been no single carcinogen or risk identified that is present in the majority of SLL cases. As with most cancers, a family history increases a patient’s risk to some extent.
Occupational exposures, notably pesticides, also increase the risk of SLL. In fact, the Midwest, where farming is prevalent, has the highest incidence of NHL in the United States. Finally, infection with viruses, such as hepatitis C and the Epstein-Barr virus, may increase the risk of developing SLL.
Signs and Symptoms
Enlarged (swollen) lymph nodes are the most common presenting sign in patients with SLL. The swollen lymph nodes are usually hard, fixed in place, and painless to the touch. In addition, some patients also have non-specific symptoms, such as fevers, drenching night sweats, and unexplained weight loss greater than 10% of body weight. These are termed B symptoms and indicate the presence of more advanced disease.
If patients have lymphoma involving the bone marrow (about 40% of SLL patients at diagnosis), then low red blood cell and/or platelet counts may be present. Liver involvement is also common in patients with SLL and may lead to abdominal pain and elevations in liver function tests.
Diagnosis and Staging
The most important diagnostic procedure in patients suspected of having lymphoma is the lymph node biopsy. Many cancers can be diagnosed by inserting a small needle into the tumor mass and withdrawing cells for examination under a microscope. This is called a “fine needle aspiration” or FNA.
For a lymphoma diagnosis, however, the preferred technique is removal of the entire affected lymph node for examination by a pathologist. It is of the utmost importance that these biopsies be examined by a pathologist who is experienced in diagnosing lymphomas. Knowing the subtype of NHL is crucial for determining long-term prognosis and treatment options.
Once the diagnosis of SLL is established, patients should undergo tests to determine the extent of disease. This should include CT scans of the chest, abdomen, and pelvis, a bone marrow biopsy, a complete blood count, serum chemistries (including lactate dehydrogenase (LDH) and uric acid), and an HIV test. Hepatitis B testing is also recommended due to reports of hepatitis reactivation during chemotherapy.
If patients experience recurrent infections, clinicians will often measure quantitative immunoglobulins to be sure that patients have adequate immunity to fight infections.
All of the above testing leads physicians to establish a stage of SLL for each patient.
Stages for SLL include the following:
Stage I: One involved lymph node group
Stage II: Two or more involved lymph node groups on the same side of the diaphragm
Stage III: Multiple lymph node groups involved on both sides of the diaphragm
Stage IV: Disseminated involvement of extra-nodal sites, such as the liver or bone marrow
An A or B is added to the stage number to indicate the presence or absence of the B symptoms previously described. For example, a person with SLL with involvement of the bone marrow, as well as with recurrent night sweats and weight loss, would be considered to have stage IVB disease.
When considering all stages, the average survival for patients with SLL may be as long as 10 years. Although SLL is indolent, it is persistently progressive. The usual pattern of this disease is one of high response rates to radiation therapy and/or chemotherapy, with a period of disease remission.
This is followed months or years later by an inevitable relapse. Re-treatment leads to a response again, but again the disease will relapse. This means that although the short-term prognosis of SLL is quite good, over time, many patients develop fatal complications of recurrent disease.
Stage at the time of diagnosis is by far the most important prognostic factor in patients with SLL. A higher stage indicates more advanced SLL, and therefore has a worse prognosis. Other poor prognostic factors include presence of B symptoms, presence of extra-nodal lymphoma involvement, concurrent HIV/AIDS infection, age greater than 60 years, high LDH level time of diagnosis (indicative of more advanced disease), and poor performance status (inability to care for oneself). Patients with two or more of these risk factors have less than a 50% chance of surviving five years.
Patients with SLL may have transformation of their lymphoma to a more aggressive histology after several years. This is termed Richter’s syndrome. The risk is approximately 30% after 10 years of SLL. When transformation occurs, it portends a very poor prognosis, with an average survival of only 1 to 2 years.
First-Line Treatment of Small Lymphocytic Lymphoma
The benefit of SLL being an indolent lymphoma is that it tends to respond well initially a variety of chemotherapy drugs, and patients generally live many years with the disease. The disadvantage is that although SLL responds to chemotherapy, it invariably recurs, and it is considered in most patients to be an incurable lymphoma.
Radiation therapy alone is often an effective treatment for localized Small Lymphocytic Lymphoma. This includes patients with stage I SLL and patients with stage II SLL, in which the disease is localized to one radiation field. Although this is the minority of SLL patients, these are the few with SLL that may be cured. The benefit of giving chemotherapy after definitive radiation therapy has not been proven.
Advanced SLL (some stage II and all stages III and IV) is considered incurable; therefore, the goal of treatment is symptom management. In patients with asymptomatic SLL without organ compromise, so-called watchful waiting is the first-line treatment of choice. Patients are closely monitored, and treatment is initiated only when meaningful signs or symptoms occur.
The average time to treatment from diagnosis in these patients is 2 to 3 years. Indications for treatment of advanced SLL include: painfully enlarged lymph nodes, low blood counts due to bone marrow involvement, threatened organ function (such as the liver), recurrent infections due to suppressed immune function, and transformation to a more aggressive subtype of lymphoma.
Systemic treatment is standard-of-care for advanced, symptomatic SLL. This includes single-agent chemotherapy, combination chemotherapy, or chemoimmunotherapy, which is chemotherapy plus a monoclonal antibody.
First-line regimens may include the following:
Chlorambucil with or without prednisone
Cyclophosphamide with or without prednisone
2-CDA: cladribine monotherapy
FAMP: fludarabine monotherapy
FC: fludarabine, cyclophosphamide
FM: fludarabine, mitoxantrone
FND: fludarabine, mitoxantrone, dexamethasone
CVP: cyclophosphamide, vincristine, prednisone
CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone
In advanced SLL, the addition of rituximab to any of the above chemotherapy combinations improves survival in patients. This medication is a monoclonal antibody that specifically kills B-cell lymphomas. It is synergistic with chemotherapy, meaning that the two types of medications work better together. Rituximab alone or with any of the aforementioned chemotherapy is therefore considered standard first-line therapy for SLL.
If a complete or partial response is obtained after first-line therapy, patients are monitored with labs and CT scans periodically. Recurrence of SLL typically occurs within several years. Patients who experience progressive disease on first-line treatment should be treated as described below.
Treatment of Recurrent/Refractory SLL
Many salvage chemotherapy regimens have been studied for recurrent SLL. Any of the first-line therapies discussed may be used as salvage therapy as well. The choice is often based upon the anticipated regimen-specific side effects in the patient to be treated. For example, a patient with underlying heart disease would be advised to avoid regimens containing doxorubicin or mitoxantrone, due to the risk of cardiac toxicity.
None of these regimens has proven superior to another for recurrent SLL. In fact, patients whose disease recurs more than one year after first-line treatment are often re-treated with the original regimen. As an alternative, participation in a clinical trial is always a good choice for patients with relapsed SLL.
Radioimmunotherapy is a novel option for relapsed indolent lymphomas such as SLL. This involves treatment with a radioactive substance that is linked to a lymphocyte-specific monoclonal antibody. The drugs are given by vein, and the net effect is localized radiation to all the lymphoma masses.
The two agents available in the United States are Bexxar (iodine-131 plus tositumomab) and Zevalin (yttrium-90 plus ibritumomab). SLL patients with extensive bone marrow involvement should not receive these agents due to the risk of prolonged immune suppression.
Hematopoietic stem cell transplant (so-called bone marrow transplant) is the standard of care in patients with a good performance status who have recurrent or refractory aggressive lymphomas, such as diffuse large B-cell. In the case of recurrent indolent NHL, however, the role of bone marrow transplant is less clear.
The most common procedure for aggressive NHL is an autologous transplant, in which the patient’s own blood stem cells are harvested, then re-infused following very-high-dose chemotherapy. However, this option is not viable in most patients with SLL, as the bone marrow is usually contaminated with lymphoma cells.
In SLL, the best transplant option is an allogeneic bone marrow transplant, in which the blood stem cells from another person, usually a sibling, are used. This is still considered an investigational treatment for SLL and should be done only in the setting of a clinical trial.
Supportive Care Issues
Tumor lysis syndrome leading to kidney failure and heart arrhythmias is a risk in SLL patients with advanced disease. These patients can be identified by a high LDH level, high uric acid level, and/or bulky disease. Patients at high risk for tumor lysis syndrome usually receive their cycle or two of chemotherapy in the hospital.
Infections due to bone marrow involvement with lymphoma and/or chemotherapy immune suppression are common in SLL patients. This is especially true in patients receiving rituximab as part of their therapy. Prophylaxis with antibiotics may be appropriate in some, and patients should always contact their oncologist if they develop a fever.
Recurrent infections in patients with SLL may also be related to decreased amounts of normal antibodies in the blood. If this is the case, patients may receive monthly supplemental intravenous immunoglobulin (IVIG).
Although more common as a complication of CLL, autoimmune cytopenias may be present in patients with SLL. This includes autoimmune hemolytic anemia (destruction of the red blood cells), immune thrombocytopenic purpurea (ITP; destruction of platelets), and pure red cell aplasia. In addition to treating the underlying lymphoma, treatment of these autoimmune complications usually includes corticosteroids such as prednisone and/or IVIG.