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.
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ARTICLES|
June 15, 1995
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,
RA Nash
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98104–2092, USA.
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R Etzioni,
R Etzioni
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98104–2092, USA.
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R Storb,
R Storb
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98104–2092, USA.
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T Furlong,
T Furlong
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98104–2092, USA.
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T Gooley,
T Gooley
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98104–2092, USA.
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C Anasetti,
C Anasetti
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98104–2092, USA.
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FR Appelbaum,
FR Appelbaum
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98104–2092, USA.
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K Doney,
K Doney
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98104–2092, USA.
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P Martin,
P Martin
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98104–2092, USA.
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J Slattery
J Slattery
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98104–2092, USA.
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Blood (1995) 85 (12): 3746–3753.
Citation
RA Nash, R Etzioni, R Storb, T Furlong, T Gooley, C Anasetti, FR Appelbaum, K Doney, P Martin, J Slattery; 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. Blood 1995; 85 (12): 3746–3753. doi: https://doi.org/10.1182/blood.V85.12.3746.bloodjournal85123746
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June 15 1995
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