B-cell non-Hodgkins lymphomas (NHL) are an increasingly common cause of cancer morbidity and mortality. In 1996, approximately 52,700 new cases of NHL were diagnosed, representing a marked increase in incidence. Indeed, the incidence rose from 8.5 per 100,000 population in 1973 to 15.1 per 100,000 in 1992. About 20% to 30% of these are NHLs of the indolent varieties.
Clinical trials in the late 1960s and early 1970s demonstrated that the indolent lymphomas were remarkably sensitive to single alkylating agents, various regimens of combination chemotherapy, and radiotherapy administered in a variety of ways. Despite this responsiveness, however, a continuous rate of relapse is observed. Even with the advent of new chemotherapy agents, new combination chemotherapy regimens, myeloablative regimens in conjunction with bone marrow transplantation, and biologic agents, the pattern of relapse of low-grade lymphomas has not improved and the range of median survival remains at 6 to 12 years.
This article by Drs. Seng and Peterson summarizes the current state of our knowledge about indolent lymphomas and highlights some recent developments in this field. They first introduce the Revised European-American Lymphoma (REAL) classification system, which incorporates the use of molecular and cell surface marker data in distinguishing lymphoma subtypes. Data of this type are helpful for making precise diagnoses and have been useful for recognizing new subtypes such as mantle cell lymphoma (MCL) and mucosa-associated lymphoid tissue (MALT) lymphoma. However, analysis of selected cell surface markers and cytogenetics requires fresh tissue, which may not be routinely available. The Working Formulation, which the new system seeks to replace, was particularly useful to clinicians in that it divided all the lymphoma subtypes into a three-tiered system of low- grade, intermediate-grade, and high-grade lymphoma, with epidemiology, natural history, and treatment for each grade being fairly uniform. Although the new system is very thorough and no doubt adds greatly to our understanding of the distinctions and relationships among subtypes, it is designed primarily by and for pathologists, and awaits clinical validation.
Treatment Advances and Strategies
The authors also point out the advances in molecular genetics that shed light on the pathogenesis of MCL and the follicular lymphomas. In the case of MCL, as described by Drs. Seng and Peterson, a characteristic chromosomal translocation leads to inappropriate propagation of the cell cycle and, presumably, to lymphomagenesis. Similarly, the characteristic chromosomal translocation of the follicular lymphomas is believed to promote production of bcl-2, upsetting the balance of propagating and apoptotic cells. Additional factors essential for neoplastic transformation and longevity of neoplastic cells are currently under active investigation.
Some new treatment strategies are reviewed here, including the use of the purine analogs fludarabine (Fludara) and cladribine (Leustatin). These drugs seem to have activity against dividing as well as resting cells, and thus have particular appeal for use in indolent lymphomas, where most cells are not actively dividing. Their mechanism of action is not understood completely. Both drugs are taken up by lymphocytes and are selectively phosphorylated. They are resistant to adenosine deaminase, the usual first step in the metabolic degradation of excess purines. As these agents accumulate in lymphocytes, the available pool of normal purines decreases, and the analogs serve as defective deoxynucleotides, interfering with DNA strand elongation, and thus arresting mitosis. In resting cells, purine analogs interfere with normal repair of DNA strand breaks, inducing apoptosis. Again, the induction of apoptosis is particularly attractive in low-grade lymphoma, where lymphocytes may be immortalized by bcl-2 prevention of programmed cell death.
As noted by the authors, high dose chemotherapy with stem-cell support has been investigated as a treatment strategy for these lymphomas. This approach is attractive, as these diseases are initially very sensitive to a variety of treatments, but before any definitive conclusions can be drawn, more data need to be accumulated. Many patients have been excluded from this approach because of the perceived difficulty of the treatment; the fact that many patients with indolent lymphoma are beyond the maximum age accepted by high-dose programs; and because of coexisting diseases.
Antiobiotics and Other Investigative Treatments
Finally, the authors highlight the recent developments in the treatment of MALT lymphoma. It is now clear that many patients with gastric MALT lymphoma can achieve prolonged remission after treatment with antibiotics aimed at Helicobacter pylori. The relationship between an infectious agent and lymphomagenesis is tantalizing and begs the question of whether other immune system neoplasms have a viral basis.
Except for the aforementioned high-dose chemotherapy, the authors do not discuss investigative treatments for indolent lymphomascrucial to this field in which overall survival has not improved with the use of conventional treatment strategies. Immunotherapy, for instance, has generated significant interest. In particular, monoclonal antibodies targeted to pan-B cell antigens and idiotype vaccines have shown encouraging preliminary results. Trials of chimeric monoclonal antibody directed against the pan B-cell antigen CD20 in patients with relapsed low-grade lymphoma showed that the antibody was well-tolerated and that remissions could be achieved in about half of treated patients.
Monoclonal antibody linked to radioisotopes such as yttrium-90 and iodine-131 have been investigated in phase I/II trials, and high rates of response have been reported.[6-8] Kwak et al reported on nine patients who received immunoglobulin idiotype vaccines derived from their individual tumors, seven of whom developed a specific humoral or cell-mediated response. Hsu et al recently reported a pilot study in which autologous dendritic cells from patients with follicular lymphoma were pulsed ex vivo with tumor-specific idiotype vaccine and then reinfused. Patients then received a subcutaneous injection of the soluble antigen. All of the patients had measurable antitumor immunologic responses, and some also had clinical tumor responses. Clinical trials of these new vaccine approaches continue at Stanford and the National Cancer Institute.
This summary of the current understanding of the indolent lymphomas points out the need for continuing investigation of and new approaches to this diverse group of diseases.
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