Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation.
We report the results of a phase III open-label, randomized, multicenter trial comparing tacrolimus/methotrexate to cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis after HLA-identical sibling marrow transplantation in patients with hematologic malignancy. The primary objective of this study was to compare the incidence of moderate to severe (grade II-IV) acute GVHD. Secondary objectives were to compare the relapse rate, disease-free survival, overall survival, and the incidence of chronic GVHD. Patients were stratified according to age (<40 v >/=40) and for male recipients of a marrow graft from an alloimmunized female. There was a significantly greater proportion of patients with advanced disease randomized to tacrolimus arm (P = . 02). The incidence of grade II-IV acute GVHD was significantly lower in patients who received tacrolimus than patients in the cyclosporine group (31.9% and 44.4%, respectively; P = .01). The incidence of grade III-IV acute GVHD was similar, 17.1% in cyclosporine group and 13.3% in the tacrolimus group. There was no difference in the incidence of chronic GVHD between the tacrolimus and the cyclosporine group (55.9% and 49.4%, respectively; P = .8). However, there was a significantly higher proportion of patients in the cyclosporine group who had clinical extensive chronic GVHD (P = . 03). The relapse rates of the two groups were similar. The patients in the cyclosporine arm had a significantly better 2-year disease-free survival and overall survival than patients in the tacrolimus arm, 50.4% versus 40.5% (P = .01) and 57.2% versus 46.9% (P = .02), respectively. The significant difference in the overall and disease-free survival was largely the result of the patients with advanced disease, 24.8% with tacrolimus versus 41.7% with cyclosporine (P = .006) and 20.4% with tacrolimus versus 28% with cyclosporine (P = .007), respectively. There was a higher frequency of deaths from regimen-related toxicity in patients with advanced disease who received tacrolimus. There was no difference in the disease-free and overall survival in patients with nonadvanced disease. These results show the superiority of tacrolimus/methotrexate over cyclosporine/methotrexate in the prevention of grade II-IV acute GVHD with no difference in disease-free or overall survival in patients with nonadvanced disease. The survival disadvantage in advanced disease patients receiving tacrolimus warrants further investigation.
Ratanatharathorn
V
V
University of Michigan, Ann Arbor; Fred Hutchinson Cancer Research Center, Seattle, WA, USA. vratanat@umich.edu
Nash
R A
RA
Przepiorka
D
D
Devine
S M
SM
Klein
J L
JL
Weisdorf
D
D
Fay
J W
JW
Nademanee
A
A
Antin
J H
JH
Christiansen
N P
NP
van der Jagt
R
R
Herzig
R H
RH
Litzow
M R
MR
Wolff
S N
SN
Longo
W L
WL
Petersen
F B
FB
Karanes
C
C
Avalos
B
B
Storb
R
R
Buell
D N
DN
Maher
R M
RM
Fitzsimmons
W E
WE
Wingard
J R
JR
D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D002648:Child; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D005260:Female; D006086:Graft vs Host Disease / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000401:mortality / Q000628:therapy; D006648:Histocompatibility; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D006973:Hypertension / Q000139:chemically induced; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015994:Incidence; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009679:Nuclear Family; D012008:Recurrence; D016019:Survival Analysis; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000009:adverse effects*; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus; D008727:Methotrexate