Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation.
Sirolimus is an effective agent used in graft-versus-host disease (GVHD) prophylaxis after allogeneic transplantation. It also has antiproliferative effects on vascular endothelium when used to coat coronary artery stents. We noted an excess of veno-occlusive disease (VOD) in a clinical trial, and retrospectively reviewed the records of 488 patients to determine the association between sirolimus and VOD. When used with cyclophosphamide/total body irradiation (Cy/TBI) conditioning, sirolimus is associated with an increased incidence of VOD (OR 2.35, P = .005). The concomitant use of methotrexate further increased this rate (OR 3.23, P < .001), while sirolimus without methotrexate was not associated with an increased risk of VOD (OR 1.55, P = .33). Mortality after VOD diagnosis was unaffected, and overall treatment-related mortality was lowest when sirolimus was used without methotrexate. Similar findings were noted in matched, related, and unrelated as well as mismatched donor subgroups. When used with busulfan-based conditioning, sirolimus use was associated with an even higher rate of VOD (OR 8.8, P = .008). Our findings suggest that sirolimus use is associated with VOD after TBI-based transplantation when used with methotrexate after transplantation. Sirolimus-based GVHD prophylaxis without methotrexate is associated with the greatest overall survival. Myeloablative doses of busulfan should not be used with sirolimus-based immunosuppression.
Cutler
Corey
C
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. corey_cutler@dfci.harvard.edu
Stevenson
Kristen
K
Kim
Haesook T
HT
Richardson
Paul
P
Ho
Vincent T
VT
Linden
Erica
E
Revta
Carolyn
C
Ebert
Ruth
R
Warren
Diane
D
Choi
Sung
S
Koreth
John
J
Armand
Philippe
P
Alyea
Edwin
E
Carter
Shelly
S
Horowitz
Mary
M
Antin
Joseph H
JH
Soiffer
Robert
R
D000293:Adolescent; D000328:Adult; D004338:Drug Combinations; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced* / Q000453:epidemiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D015994:Incidence; D007938:Leukemia / Q000628:therapy*; D008223:Lymphoma / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D019172:Transplantation Conditioning / Q000009:adverse effects; D014184:Transplantation, Homologous; D055815:Young Adult
D004338:Drug Combinations; D007166:Immunosuppressive Agents; D020123:Sirolimus
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