Advanced-stage low-grade lymphoma is not curable with conventional therapy and patients with this disease ultimately die of disease or complications of treatment. Therefore, new therapeutic approaches are needed. We have now demonstrated that radioimmunotherapy (RIT) with 131-I-labeled anti-B1 (anti-CD20) results in major and durable tumor responses in virtually all patients (13 of 13, 10 complete remissions) with chemotherapy-refractory low-grade lymphoma. We therefore propose to test the hypothesis that this treatment would be especially effective as front-line treatment for low-grade lymphoma by conducting a phase II clinical trial in patients with previously untreated advanced-stage low-grade lymphoma. To further define the efficacy of this treatment, we will seek to determine whether the detection of minimal residual disease (MRD) by molecular biological techniques help predict duration of remission. Specifically, we will test the use of PCR amplification of the t(14;18) chromosomal translocation involving the bcl-2 proto-oncogene (which represents a clonal marker for up to 85% of follicular lymphomas) to serially detect MRD in bone marrow and peripheral blood. The results of these studies will not only yield information on the cytoreductive power of this treatment, but also may help determine which patients may benefit from additional or adjunctive therapy in future studies. Finally, since the dose-limiting toxicity of this treatment is myelosuppression, we wish to take advantage of this unique opportunity to continue our studies on the effects of RIT on hematopoiesis in patients who have not been previously exposed to marrow-altering agents. We will test the hypothesis that RIT may have different effects on different components of the bone marrow by examining the short-term and long-term effects on stem cells, committed progenitor cells, and supporting stromal cells through bone marrow culture assays performed at various times after RIT. These studies should yield important and definitive information on the fundamental mechanisms of RIT-induced myelosuppression the tolerance of bone marrow to repeated doses, higher doses, or to other cytotoxic agents which might be used in combination with or used subsequent to 131-I-anti-B1. Radiodosimetric studies will be conducted concurrently to more clearly define dose-response relationships concerning marrow toxicity as well as tumor response. These proposed integrated studies should help answer important fundamental questions regarding RIT and help develop this new and promising strategy for the treatment of lymphomas in general.
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