MINIMAL DISEASE AND OUTCOME OF TRANSPLANTS FOR LYMPHOMA

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.