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Tacrolimus (FK506) alone or in combination with methotrexate or
methylprednisolone for the prevention of acute graft-versus-host disease
after marrow transplantation from HLA-matched siblings: a single-center
study
RA Nash, R Etzioni, R Storb, T Furlong, T Gooley, C Anasetti, FR Appelbaum, K Doney, P Martin and J Slattery
Fred Hutchinson Cancer Research Center, University of Washington School of
Medicine, Seattle, WA 98104-2092, USA.
The pharmacokinetics, safety, and efficacy in marrow transplantation of
FK506-based immunosuppression for graft-versus-host disease (GVHD)
prophylaxis was evaluated in an open label pilot study of 18 patients.
Patients more than 12 years of age (median, 35 years; range, 15 to 50
years) with advanced hematologic malignancies receiving HLA-matched sibling
marrow grafts were randomized to receive FK506 alone, FK506 and
methotrexate (MTX), or FK506 and methyl-prednisolone. Of 17 evaluable
patients, all had evidence of sustained marrow engraftment. The median time
to an absolute neutrophil count of greater than 500/microL was 15 days for
patients receiving FK506 alone or FK506 plus methylprednisolone and 23 days
for FK506 plus short MTX. Pharmacokinetic studies did not show any
significant difference in clearance of FK506 when administered alone or in
combination with methylprednisolone or MTX. The mean bioavailability after
oral administration in these same three groups was 0.49 +/- 0.1, 0.27 +/-
0.12, and 0.16 +/- 0.08, respectively (P = .003). The decrease in
bioavailability may have resulted from an exacerbation of radiation-
induced gastroenteritis by MTX. The most significant adverse effect
associated with the administration of FK506 was nephrotoxicity, which
occurred in 14 of 18 patients (78%). The mean glomerular filtration rate,
determined by clearance of (99MTc)DTPA, decreased to 56% (+/- 18%) of the
pretransplant baseline level by week 8 (P = .002). Eight of 18 patients
(44%) developed grades II-IV acute GVHD, predominantly of the skin and
gastrointestinal tract. The actuarial probability of transplant-related
mortality during the first 100 days was 24%. The actuarial probability of
1-year disease-free survival was 39%. In conclusion, although
bioavailability of FK506 may be affected in patients receiving MTX, this
study suggests that FK506 may have a role in the management of patients
after allogeneic marrow transplantation.
Volume 85,
Issue 12,
pp. 3746-3753,
06/15/1995
Copyright © 1995 by The American Society of Hematology
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