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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA056794-06
Application #
2608087
Study Section
Special Emphasis Panel (ZRG2-IVP (03))
Program Officer
Wu, Roy S
Project Start
1992-06-01
Project End
2000-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Kaminski, Mark S; Tuck, Melissa; Estes, Judith et al. (2005) 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352:441-9
Koral, Kenneth F; Dewaraja, Yuni; Li, Jia et al. (2003) Update on hybrid conjugate-view SPECT tumor dosimetry and response in 131I-tositumomab therapy of previously untreated lymphoma patients. J Nucl Med 44:457-64
Koral, Kenneth F; Francis, Isaac R; Kroll, Stewart et al. (2002) Volume reduction versus radiation dose for tumors in previously untreated lymphoma patients who received iodine-131 tositumomab therapy. Conjugate views compared with a hybrid method. Cancer 94:1258-63
Nordoy, T; Kolstad, A; Tuck, M K et al. (2001) Radioimmunotherapy with iodine-131 tositumomab in patients with low-grade non-Hodgkin's B-cell lymphoma does not induce loss of acquired humoral immunity against common antigens. Clin Immunol 100:40-8
Koral, K F; Dewaraja, Y; Clarke, L A et al. (2000) Tumor-absorbed-dose estimates versus response in tositumomab therapy of previously untreated patients with follicular non-Hodgkin's lymphoma: preliminary report. Cancer Biother Radiopharm 15:347-55
Koral, K F; Dewaraja, Y; Li, J et al. (2000) Initial results for Hybrid SPECT--conjugate-view tumor dosimetry in 131I-anti-B1 antibody therapy of previously untreated patients with lymphoma. J Nucl Med 41:1579-86
Kaminski, M S; Estes, J; Zasadny, K R et al. (2000) Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 96:1259-66
Koral, K F; Li, J; Dewaraja, Y et al. (1999) I-131 anti-B1 therapy/tracer uptake ratio using a new procedure for fusion of tracer images to computed tomography images. Clin Cancer Res 5:3004s-3009s
Wahl, R L (1998) Iodine-131 anti-B1 antibody therapy in non-Hodgkin's lymphoma: dosimetry and clinical implications. J Nucl Med 39:1S
Wahl, R L; Zasadny, K R; MacFarlane, D et al. (1998) Iodine-131 anti-B1 antibody for B-cell lymphoma: an update on the Michigan Phase I experience. J Nucl Med 39:21S-27S

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