Non-Hodgkins lymphomas are a diverse group of malignancies that can behave either quite aggressively, as is the case with the intermediate- and high-grade histologies, or in a more indolent manner, as is the case with the indolent lymphomas.
The intermediate- and high-grade lymphomas have the potential for being cured even when in advanced stages. In contrast, although indolent lymphomas, or low-grade lymphomas as they were called in the Working Formulation, are generally highly responsive to a variety of therapies, there is little convincing evidence that any therapy is curative. The majority of patients with indolent lymphomas will relapse and suffer substantial morbidity as well as mortality related to the persistence or recurrence of their disease.
This article discusses various aspects of the natural history and current therapeutic approaches to the more indolent lymphomas, as defined in the recently proposed Revised European-American Lymphoma (REAL) classification. The intent of this classification scheme was to place identifiable lymphoid malignancies into categories that are biologically similar, thus facilitating the study of these entities.
A major contribution of the REAL classification scheme is the incorporation of several recently described entities that have not had specified niches in previous classification schemes (eg, mantle cell lymphomas and marginal zone lymphomas, including the mucosa-associated lymphoid tissue [MALT] lymphomas). The REAL classification also utilizes information beyond pure histopathology, such as immunophenotyping, cytogenetics, and molecular characteristics, to help define the entities. Using this type of classification, studies leading to a greater understanding of more specific disease processes may be planned.
The classification schemes of lymphomas used most commonly in recent years have been the Kiel classification, which is used predominantly in Europe, and the Working Formulation. The Kiel classification originated from an attempt to classify lymphoid malignancies based on the normal counterpart or cell of origin, whereas the Working Formulation relied heavily on histology, resulting in a classification that correlates well with natural history and response to treatment. The Working Formulation also facilitated translation of tumor type among various classifications.
This article reviews entities that have generally been encompassed under the category of indolent lymphomas in various classifications, including the Working Formulation, although many were not specifically identified or labeled as separate entities. These include small-lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma, the follicle center cell lymphomas, mantle cell lymphoma, and nodal and extranodal marginal zone lymphomas, including MALT lymphoma.
Mantle cell lymphoma carries a poorer prognosis than most of the other disease processes discussed in this review and is not an indolent disease in the true sense. It has, however, been grouped with the other indolent or low-grade lymphomas in the past and is frequently confused with some of the other indolent entities. Table 1 provides information about immunophenotyping and the translation of histologic types between the REAL Classification and Working Formulation.
The predominant cell type seen in SLL is a small, benign-appearing lymphocyte with a round nucleus, condensed chromatin, and sometimes a small nucleolus. Larger cells are present and pseudofollicles may be seen.
In the past, some MALT and mantle cell lymphomas were included in this classification, in part, because they were not recognized as distinct pathologic entities and, in part, because of similar histologic appearances. However, the International Lymphoma Study Group for the REAL Classification recommended that only those lymphomas with morphology and immunophenotyping similar to that of chronic lymphocytic leukemia (CLL) be included in this group.
Immunoglobulin gene rearrangements are seen in SLL, and trisomy 12 and abnormalities of chromosome 13 may be present. Selected immunophenotypic features of this entity are shown in Table 1.[1,3,4]
Small lymphocytic lymphoma accounts for approximately 4% to 5% of the non-Hodgkins lymphomas.[4,5] The male-to-female ratio is approximately 1.3:1, and the median age at diagnosis is 60 years.[4-6] This disease is quite rare in patients under 30 years of age. Small lymphocytic lymphoma is the nodal counterpart of CLL, and patients with evidence of blood involvement are generally considered to have leukemia.[4-6]
Clinical Features and Natural History
The great majority (greater than 60% to 80%) of patients with SLL are diagnosed with stage IV disease, most often based on bone marrow involvement.[3,4,6] Over time, many patients also develop peripheral blood involvement, which, again, suggests the relationship to CLL. So-called B-symptoms (fever, weight loss, and night sweats) generally are not present but may be seen in 15% of cases. Extranodal involvement of the liver, lung, spleen, gastrointestinal (GI) tract, and other sites may occur, but clinical problems at these sites are unusual.
The disease process is generally indolent, median survival exceeds 5 to 8 years, and involved nodes may spontaneously regress and increase in size at various intervals.[3,4] Transformation to large-cell lymphoma does occur, and the prognosis in this situation is poor.
Few studies have specifically addressed the treatment of SLL, and therefore, most information is derived from studies of either CLL or indolent lymphomas in aggregate.
Need for Early TreatmentEvidence from studies of CLL suggests that early treatment of patients at the presymptomatic stage does not prolong survival and may actually be associated with shorter overall survival.
Catovsky et al reviewed the results of a number of clinical trials initiated by the Medical Research Council Working Party on Leukemia in Adults. Two randomized studies (CLL trials 1 and 2) compared treatment with chlorambucil(Drug information on chlorambucil) (Leukeran) vs no initial therapy in a total of 306 patients with early-stage CLL. Results of both studies suggested that patients on the early-treatment arms experienced shorter overall survival.
The French Cooperative Group on Chronic Lymphocytic Leukemia conducted a randomized clinical trial comparing initial treatment with daily oral chlorambucil vs observation in 612 patients with early-stage CLL. This trial indicated that early treatment imparted no benefit in terms of patient survival.
In one of the studies included in the review published by Catovsky et al, 61 patients were randomized to receive chlorambucil alone or one of two regimens of cyclophosphamide(Drug information on cyclophosphamide), vincristine, and prednisone(Drug information on prednisone) (CVP); the CVP arms differed with respect to the cyclophosphamide dose. Overall response rates were 61% to 63% for the chlorambucil arm and 53% to 73% for the CVP arm, with the higher response rate seen in the arm using the higher cyclophosphamide dose.
There appear to be no significant advantages to treating patients with CLL in the early stages, before symptoms develop and before there is evidence of real or threatened organ dysfunction. Patients treated earlier do not gain any survival benefit, and the natural history of the disease is such that treatment directed toward symptom relief or amelioration of organ dysfunction may not be necessary for months to years. Single-agent alkylator therapy is quite effective, as is other low-intensity therapy such as CVP, and these therapies carry lower risks of treatment-related morbidity than do higher-intensity regimens.
Similar trials have been conducted in patients with indolent B-cell non-Hodgkins lymphomas. Again, these studies generally showed no important advantages to the use of multiple agents in treating these diseases, although response rates may be higher with regimens of higher intensity. Presumably, the results described above, although not derived from patients with SLL, may be used to guide treatment choices.
Fludarabine (Fludara) may be a drug of special promise in CLL and, by extension, possibly in SLL as well. Several trials have confirmed the efficacy of fludarabine in the treatment of CLL. Response rates of 20% to 70% have been seen in previously treated patients, and response rates of 70% to 100% have been reported in untreated patients.
A large study of fludarabine vs chlorambucil in 233 previously untreated patients revealed an overall response rate of 71% with a complete response rate of 33% for fludarabine, as compared with an overall response rate of 43% with a complete response rate of 8% for chlorambucil. No influence on survival was reported, but this may reflect the relatively short follow-up of less than 5 years in these patients.
Thus, fludarabine has promise as a first-line agent in CLL, but it is not clear that its use prolongs survival. Moreover, there have been several reports of an increased incidence of opportunistic infections in patients treated with fludarabine.