A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft-versus-host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation.
Abstract In a phase I/II study, the combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) was investigated as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and hematopoietic cell transplantation from an HLA-matched sibling donor. In phase I, 3 groups, each with 10 or 11 patients, received MMF (15 mg/kg) from day 0 to day 27 at decreasing dose intervals of every 12, 8, and 6 hours to determine a safe and effective total daily dose. At the 45 mg/kg/d dosage level, 4 of 11 patients developed only grade II GVHD, and a concentration at steady state of mycophenolic acid (the active moiety of MMF) consistent with a therapeutic range described for solid-organ transplantation was achieved. There was a suggestion of increased toxicity without improved efficacy at the 60 mg/kg/d dosage level. Accordingly, the 45 mg/kg/d dosage was therefore selected for phase II, and another 15 patients were added to this group from the phase I study (n=26). The concentrations at steady state for this dosage at days 0, 6, 13, 20, and 27 were 2.73, 3.02, 3.20, 2.62, and 2.64 microg/mL, respectively. No toxicities were attributed to MMF at this dose. The median time to engraftment after hematopoietic cell transplantation was 15 days (range, 10-20 days). The incidence of acute GVHD was 62%, which was comparable to a group of historical controls receiving CSP and methotrexate (MTX) for GVHD prophylaxis. Although a significant improvement in the prevention of GVHD was not suggested, compared with CSP and MTX, MMF in combination with CSP could be considered in cases in which MTX is contraindicated.
Nash
Richard A
RA
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. rnash@flcrc.org
Johnston
Laura
L
Parker
Pablo
P
McCune
Jeannine S
JS
Storer
Barry
B
Slattery
John T
JT
Furlong
Terry
T
Anasetti
Claudio
C
Appelbaum
Frederick R
FR
Lloid
Michele E
ME
Deeg
H Joachim
HJ
Kiem
Hans-Peter
HP
Martin
Paul J
PJ
Schubert
Mark M
MM
Witherspoon
Robert P
RP
Forman
Stephen J
SJ
Blume
Karl G
KG
Storb
Rainer
R
D000293:Adolescent; D000328:Adult; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D006086:Graft vs Host Disease / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid