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Modulation of acute graft-versus-host-disease after allogeneic bone marrow
transplantation by tumor necrosis factor alpha (TNF alpha) release in the
course of pretransplant conditioning: role of conditioning regimens and
prophylactic application of a monoclonal antibody neutralizing human TNF
alpha (MAK 195F)
E Holler, HJ Kolb, J Mittermuller, M Kaul, G Ledderose, T Duell, B Seeber, M Schleuning, R Hintermeier-Knabe and B Ertl
Medizinische Klinik III, Klinikum Grosshadern, Munchen, Germany.
Contribution of host-related cytokine release in the course of
pretransplant conditioning to early tissue damage and induction of acute
graft-versus-host disease (GVHD) after allogeneic bone marrow
transplantation (BMT) has been shown in experimental models. We performed a
clinical phase I/II trial applying a monoclonal antibody neutralizing human
tumor necrosis alpha (TNF alpha) during pretransplant conditioning as
additional prophylaxis in high-risk patients admitted to allogeneic BMT;
TNF alpha serum levels and clinical courses in 21 patients receiving
anti-TNF alpha prophylaxis were compared with data from 22 historical
controls. Absence of significant release of TNF alpha in the period of
busulphan (BUS) treatment, but significant induction of TNF alpha by total
body irradiation (TBI) and cyclophosphamide (CY) conditioning were
correlated with significantly earlier onset of acute GVHD in patients
receiving TBI/CY regimens as compared with BUS/CY-treated patients.
Prophylactic application of monoclonal anti-TNF alpha seemed to postpone
onset of acute GVHD from day 15 to day 25 (P < .05) after TBI/CY and
from day 33 to day 53 after BUS/CY (P < .10) conditioning. Application
of monoclonal anti-TNF alpha in low and intermediate doses was safe and not
associated with an increased incidence of infectious or hematologic
complications. Thus, our data provide indirect and direct evidence for
involvement of conditioning-related cytokine release in induction of early
acute GVHD in the clinical setting and support further investigation of
this novel approach in randomized trials.
Volume 86,
Issue 3,
pp. 890-899,
08/01/1995
Copyright © 1995 by The American Society of Hematology
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