Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation

Author:

Cutler Corey12,Stevenson Kristen3,Kim Haesook T.3,Richardson Paul1,Ho Vincent T.1,Linden Erica1,Revta Carolyn1,Ebert Ruth1,Warren Diane1,Choi Sung24,Koreth John1,Armand Philippe1,Alyea Edwin1,Carter Shelly25,Horowitz Mary26,Antin Joseph H.12,Soiffer Robert12

Affiliation:

1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;

2. Blood and Marrow Transplant Clinical Trials Network, Rockville, MD;

3. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;

4. University of Michigan Medical Center, Ann Arbor;

5. EMMES Corporation, Rockville, MD; and

6. The Center for International Blood and Marrow Transplant Research, Milwaukee, WI

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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