Treatment of Low grade B cell Lymphoid Malignancies

For many decades the standard therapy for symptomatic Low Grade B Cell Lymphoid Malignancies (low grade lymphoma and chronic lymphatic leukemia) was based on alkylating agents (usually Chlorambucil) with or without prednisone. The chemotherapy combinations using Cyclophosphamide, Vincristine and Prednisone (CVP) or Adriamycine based regimens with or without external beam radiotherapy have been recommended if rapid response is required for relief of severe symptoms. Such therapeutic approaches though effective symptomatically could not change the natural history of the disease as almost all patients eventually relapse and die because of the disease.
Attempts to improve overall survival by using more intensive therapy failed to do so inspite of the initial encouraging results (higher complete remission rate and prolonged median time to progression). In fact, the curative potential of combination chemotherapy observed in aggressive lymphoma was not reproducible in Low Grade B Cell Lymphoid Malignancies (LGBLM).
The progressive nature of LGBLM may be (at least in part) attributed to the genetic defect in programmed cell death (apoptosis), leading to accumulation of neoplastic B cells and hence disease progression. Therefore, a rationale therapeutic approach in this group of disease may be via the use of agents which can induce or enhance apoptosis.
The introduction of purine analogues (Fludarabine and Cladribine) during the late 1980s with their ability to enhance apoptosis could provide a more rationale treatment for LGBLM. Early phase II studies did show the high activity of Fludarabine in patients with LGBLM.
Results of 3 large phase III studies in previously untreated CLL patients have further confirmed the superiority of Fludarabine over both Chlorambucil and a Doxorubicin based regimen (CAP) in terms of complete remission rate and progression free survival. Whether this will be translated into a true improvement in overall survival is still to be seen. Nevertheless, these studies have moved Fludarabine to be the standard front line therapy in symptomatic CLL.
Owing to the synergistic interaction between alkylating agents and the new purine analogs, many investigations have explored the combination of Fludarabine and Cyclophosphamide in LGBLM, with extremely favorable outcome (response rate ranges between 90-100% in previously untreated patients).
Although data on purine analogs in low grade lymphomas are relatively less mature compared to CLL, however the last few years have witnessed very encouraging outcome of Fludarabine based regimen in refractory and relapsing indolent lymphoma especially, the combination of Fludarabine / Mitaxantrone (FM) and Fludarabine /Mitaxantrone/ Cyclophosphamide (FMC).
In addition to promises made by purine analogs in LGBLM, 2 chimeric antibodies have demonstrated efficacy in different categories of this group of disease: Rituximab (anti CD20) and CAMPATH-1H (anti CD52). Rituximab, which is known to enhance apoptosis, has already demonstrated remarkable activity in all subtypes of B cell lymphoma. Furthermore, Rituximab has shown true synergy with many chemotherapy agents with improved treatment outcome in terms of response rate, disease free survival and occasionally overall survival (with CHOP in aggressive B cell lymphoma and with Fludarabine/Mitaxontrone in low grade B cell lymphoma).
CAMPATH-1H is an anti CD52 antibody. It has been shown that CD52 surface antigen is expressed by the vast majority of T and B lymphocytes. In phase II studies,
CAMPATH-1H has demonstrated response rate of 30-40% in previously treated and 69% in previously untreated patients with CLL. A unique feature of this agent in its preferential effect in the spleen, bone marrow and peripheral blood compared to nodal sites. As expected treatment by CAMPATH-1H would lead to immuno-suppression which may be severe if the treatment period exceeds 6 weeks or given during Fludarabine therapy. Its role in treating minimal residual disease after Fludarabine cytoreduction is the subject of prospective studies.

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