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Autologous bone marrow transplantation in high-risk remission T-lineage
acute lymphoblastic leukemia using immunotoxins plus 4-
hydroperoxycyclophosphamide for marrow purging
FM Uckun, JH Kersey, DA Vallera, JA Ledbetter, D Weisdorf, DE Myers, R Haake and NK Ramsay
Department of Therapeutic Radiology-Radiation Oncology; University of
Minnesota Health Sciences Center, Minneapolis 55455.
Fourteen patients with high-risk T-lineage acute lymphoblastic leukemia
(ALL) in complete remission underwent autologous bone marrow
transplantation (BMT) in an attempt to eradicate their residual disease
burden. A combined immunochemotherapy protocol using a cocktail of two
immunotoxins directed against CD5/Tp67 and CD7/Tp41 T-lineage
differentiation antigens in combination with the in vitro active
cyclophosphamide congener 4-hydroperoxy-cyclophosphamide (4-HC) was used to
purge autografts. Despite high dose pretransplant radiochemotherapy and
effective purging of autografts, 9 of 14 patients relapsed at a median of
2.5 months (range, 1.2 to 16.8 months) post BMT. Two patients remain alive
and disease free at 26 and 28 months post BMT. We used a novel quantitative
minimal residual disease (MRD) detection assay, which combines fluorescence
activated multiparameter flow cytometry and cell sorting with leukemic
progenitor cell (LPC) assays, to analyze remission bone marrow (BM) samples
from T-lineage ALL patients for the presence of residual LPCs. Notably,
high numbers of residual LPC detected in remission BM before BMT
constituted a poor prognostic indicator, providing the first evidence for
the biologic significance and clinical value of in vitro T-lineage ALL LPC
assays. The median value for the residual leukemia burden before BMT, was
approximately 8.6 x 10(3) LPC/10(8) mononuclear cells (MNC) (approximately
0.0086% LPC). Patients with a residual leukemia burden less than this
median value appeared to have a better outlook for remaining free of
relapse after autologous BMT than patients with a greater leukemia burden
(53 +/- 25% v 14 +/- 13%, P = .006, Mantel- Cox). By comparison, the log
kill efficacy of purging, the remaining numbers of LPC in purged
autografts, or the estimated numbers of reinfused LPC, did not correlate
with the probability of disease-free survival (DFS). These results indicate
that the primary reason for the recurrence of leukemia was inefficient
pretransplant radiochemotherapy rather than inefficient purging of
autografts.
Volume 76,
Issue 9,
pp. 1723-1733,
11/01/1990
Copyright © 1990 by The American Society of Hematology
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