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Bone marrow graft engineering by counterflow centrifugal elutriation:
results of a phase I-II clinical trial
JE Wagner, GW Santos, SJ Noga, SD Rowley, J Davis, GB Vogelsang, ER Farmer, BA Zehnbauer, R Saral and AD Donnenberg
Johns Hopkins Oncology Center, Johns Hopkins School of Medicine, Baltimore,
MD 21205.
In an attempt to reduce the incidence and severity of acute graft-
versus-host disease (GVHD), we have decreased the number of bone marrow
(BM) lymphocytes in the donor marrow graft before bone marrow
transplantation (BMT) using counterflow centrifugal elutriation (CCE). In a
phase I-II clinical trial, 23 patients received lymphocyte- depleted BM
allografts from their HLA-identical, mixed lymphocyte culture
(MLC)-nonreactive sibling donors. The patients entered in the study were
deemed to be at high risk for treatment failure on the basis of age
(greater than 30 years; median, 39 years) and the result of our skin
explant assay predictive of acute GVHD. Patients predicted not to develop
acute GVHD by this assay were excluded from this study. All patients
received a standard lymphocyte dose of 0.5 x 10(6) morphologic lymphocytes
per kilogram ideal body weight (IBW) in the marrow graft and were
maintained on cyclosporine A (CsA) immunosuppression for 170 days after
BMT. Prompt hematopoietic recovery occurred in 22 of 23 patients with a
median time to an absolute neutrophil count (ANC) greater than or equal to
500/microL of 21 days. Donor cell engraftment was subsequently verified by
cytogenetic and/or DNA analysis in all of 21 evaluable patients. No patient
developed systemic acute GVHD. Only five (22%) developed cutaneous GVHD
(clinical stage 1) that required steroid treatment, including one patient
who failed to engraft. The median follow-up of the patients enrolled in
this study is 14 months (range, 5 to 20 months). Actuarial survival 1 year
after BMT is 83%. Thus, in two consecutive clinical trials using CCE to
deplete donor BM of alloreactive lymphocytes (1.0 x 10(6) versus 0.5 x
10(6) lymphocytes/kg), we have demonstrated that the procedure does not
interfere with BM engraftment and is effective in decreasing the incidence
and severity of acute GVHD. Furthermore, comparison of these studies has
revealed a differential dose response relationship between the number of
graft lymphocytes, protection of engraftment, and induction of acute GVHD.
Although there appears to be a modest relationship between lymphocyte dose
and time to hematopoietic recovery, the 50% reduction in lymphocyte dose
from that used in our previous trial resulted in a marked decrease in acute
GVHD without compromising engraftment.
Volume 75,
Issue 6,
pp. 1370-1377,
03/15/1990
Copyright © 1990 by The American Society of Hematology
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