Growing evidence supports the proposition that high dose therapy requiring hematopoietic support (transplantation) is a curative procedure for some patients with non-Hodgkin's lymphoma (NHL) who fail to achieve a remission or who relapse following conventional doses of chemotherapy. Furthermore, there is an indication that the source of hematopoietic support employed, autologous bone marrow (ABMT) versus autologous peripheral blood stem cells obtained by leukapheresis (PSCT) is also a determinant of outcome. In a non-randomized study, PSCT patients had a significantly better long- term disease free survival. In preliminary studies we have shown, using a sensitive culture technique to amplify lymphoma cells followed by Southern analysis to detect clonal populations, that histologically normal appearing bone marrow harvests were contaminated with tumor in about 30- 40% of patients. In contrast, using the same approach, blood stem cell harvests were contaminated in only 5-10% of patients. When the clinical outcome was analyzed for those patients who were recipients of tumor-free PSCT and ABMT they did much better than recipients of minimally contaminated marrow harvests. Therefore, it is our hypothesis that minimal disease in the harvest is a critical determinant of outcome in transplantation for lymphoma. In association with a proposed multicenter prospective randomized trial of ABMT versus PSCT for NHL patients with histologically uninvolved marrow, we will employ culture techniques as well as molecular biology, including Southern analysis and PCR analysis of appropriate sequences defined by the genetic rearrangement of the patient's primary tumor to detect lymphoma cells in the harvests. We will correlate the outcome and sensitivities of our methodological approaches to the clinical outcome of the patients in an attempt to confirm that minimal lymphoma in the harvest is a key determinant of outcome. We will evaluate if the extent of tumor contamination is a predictor of time to disease progression. These data should answer questions such as what is the optimum methodological approach for detection of minimal lymphoma and whether purging of marrow or selection of CD34 positive cells for transplantation is necessary or does the use of PSCT rather than AMBT suffice? This information should further improve the curative ability of transplantation for otherwise incurable NHL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA061453-02
Application #
2102203
Study Section
Special Emphasis Panel (SRC (57))
Project Start
1993-09-30
Project End
1997-07-31
Budget Start
1994-09-30
Budget End
1995-07-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Vose, Julie M; Sharp, Graham; Chan, Wing C et al. (2002) Autologous transplantation for aggressive non-Hodgkin's lymphoma: results of a randomized trial evaluating graft source and minimal residual disease. J Clin Oncol 20:2344-52
Demirkazik, A; Kessinger, A; Armitage, J O et al. (2001) Progenitor and lymphoma cells in blood stem cell harvests: impact on survival following transplantation. Bone Marrow Transplant 28:207-12
Greiner, T C; Abou-Elella, A A; Smir, B N et al. (2000) Molecular epidemiology of EBNA-1 substrains of Epstein-Barr virus in posttransplant lymphoproliferative disorders which have infrequent p53 mutations. Leuk Lymphoma 38:563-76
Sharp, J G; Chan, W C (1999) Detection and relevance of minimal disease in lymphomas. Cancer Metastasis Rev 18:127-42
Weekes, C D; Pirruccello, S J; Vose, J M et al. (1998) Lymphoma cells associated with bone marrow stromal cells in culture exhibit altered growth and survival. Leuk Lymphoma 31:151-65
Wu, G Q; Sharp, J G; Wu, G et al. (1997) The detection of minimal lymphoma by molecular and combined culture-molecular methods. Br J Haematol 99:873-81
Ohno, T; Stribley, J A; Wu, G et al. (1997) Clonality in nodular lymphocyte-predominant Hodgkin's disease. N Engl J Med 337:459-65
Wu, G; Greiner, T C; Chang, W C (1997) Obtaining clone-specific primer and probe for the immunoglobulin heavy-chain gene from paraffin-embedded tissue of B-cell lymphoma: technical considerations. Diagn Mol Pathol 6:147-53
Sharp, J G (1996) Micrometastases and transplantation. J Hematother 5:519-24
Greiner, T C; Moynihan, M J; Chan, W C et al. (1996) p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. Blood 87:4302-10

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