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.

[1]  A. Qureshi,et al.  Defibrotide in the prevention and treatment of veno‐occlusive disease in autologous and allogeneic stem cell transplantation in children , 2008, Pediatric blood & cancer.

[2]  A. LaCasce,et al.  54: Inclusion of Sirolimus in the GVHD Prophylaxis Regimen is Associated with Improved Survival in Patients with Lymphoma Undergoing Allogeneic Transplantation , 2008 .

[3]  P. Richardson,et al.  Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies , 2008, Bone Marrow Transplantation.

[4]  L. Gesualdo,et al.  Rapamycin Inhibits PAI-1 Expression and Reduces Interstitial Fibrosis and Glomerulosclerosis in Chronic Allograft Nephropathy , 2008, Transplantation.

[5]  P. Armand,et al.  Tacrolimus and Sirolimus without Methotrexate as Acute GVHD Prophylaxis after Matched Related Donor Reduced Intensity Conditioning (RIC) Stem Cell Transplantation (SCT). , 2007 .

[6]  I. Bassett,et al.  Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis. , 2007, Blood.

[7]  R. Soiffer,et al.  Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. , 2007, Blood.

[8]  M. Noshiro,et al.  OE-277 DEC1, a Member of the Fifth Clock-Gene Family, is Induced by Angiotensin II, Growth Factors, and Hypoxia in Vascular Cells(Hypertension, basic-1, The 71st Annual Scientific Meeting of the Japanese Circulation Society) , 2007 .

[9]  K. Maekawa,et al.  Impaired endothelial vasomotor function after sirolimus-eluting stent implantation. , 2007, Circulation journal : official journal of the Japanese Circulation Society.

[10]  I. Rozenberg,et al.  Effects of Tacrolimus or Sirolimus on Proliferation of Vascular Smooth Muscle and Endothelial Cells , 2006, Journal of cardiovascular pharmacology.

[11]  A. Kiani,et al.  Graft Versus Host Disease Prophylaxis with Everolimus and Tacrolimus in Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukaemia (AML) Receiving Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT). , 2006 .

[12]  T. Akasaka,et al.  Sirolimus accelerates senescence of endothelial progenitor cells through telomerase inactivation. , 2006, Atherosclerosis.

[13]  S. Ogawa,et al.  Influence of glutathione S-transferase A1 polymorphism on the pharmacokinetics of busulfan. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[14]  S. Rodenhuis,et al.  High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy , 2006, British Journal of Cancer.

[15]  P. Birembaut,et al.  Sirolimus‐Induced Thrombotic Microangiopathy is Associated with Decreased Expression of Vascular Endothelial Growth Factor in Kidneys , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  R. Soiffer,et al.  Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[17]  R. Soiffer,et al.  Mucositis after allogeneic hematopoietic stem cell transplantation: a cohort study of methotrexate- and non-methotrexate-containing graft-versus-host disease prophylaxis regimens. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[18]  Moo-Song Lee,et al.  Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation , 2005, Annals of Hematology.

[19]  R. Nagai,et al.  Potent Inhibitory Effect of Sirolimus on Circulating Vascular Progenitor Cells , 2005, Circulation.

[20]  J. Gribben,et al.  Sirolimus, Tacrolimus and Reduced-Dose Methotrexate as Graft Versus Host Disease (GVHD)Prophylaxis after Non-Myeloablative Stem Cell Transplantation: Low Incidence of Acute GVHD Compared with Tacrolimus/Methotrexate or Cyclosporine/Prednisone. , 2004 .

[21]  B. Chapuis,et al.  Prevention of veno-occlusive disease with defibrotide after allogeneic stem cell transplantation. , 2004, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[22]  J. Gaynor,et al.  A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. Ii. Survival, function, and protocol compliance at 1 year , 2004, Transplantation.

[23]  A. Marks.  Sirolimus for the prevention of in-stent restenosis in a coronary artery. , 2003, The New England journal of medicine.

[24]  Catherine J. Wu,et al.  Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. , 2003, Blood.

[25]  P. Richardson,et al.  Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. , 2003, Blood.

[26]  J. Trotter,et al.  Sirolimus in liver transplantation. , 2003, Transplantation proceedings.

[27]  A. Marks.  Rapamycin: signaling in vascular smooth muscle. , 2003, Transplantation Proceedings.

[28]  A. Macdonald.  Rapamycin in combination with cyclosporine or tacrolimus in liver, pancreas, and kidney transplantation. , 2003, Transplantation proceedings.

[29]  G. Everson,et al.  Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications , 2003, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[30]  Allen R. Chen,et al.  Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. , 2002, Blood.

[31]  Robert W. G. Johnson.  Sirolimus (Rapamune) in renal transplantation , 2002, Current opinion in nephrology and hypertension.

[32]  J. Niland,et al.  Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. , 2002, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[33]  Je-Hwan Lee,et al.  Plasminogen activator inhibitor‐1 is an independent diagnostic marker as well as severity predictor of hepatic veno‐occlusive disease after allogeneic bone marrow transplantation in adults conditioned with busulphan and cyclophosphamide , 2002, British journal of haematology.

[34]  T. Resink,et al.  Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR) ‐dependent signaling , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  N. Tygstrup,et al.  Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin). , 2001, Pharmacology & toxicology.

[36]  Vivian Charles McAlister,et al.  Orthotopic liver transplantation using low‐dose tacrolimus and sirolimus , 2001, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[37]  M. Scholl,et al.  Busulfan levels are influenced by prior treatment and are associated with hepatic veno-occlusive disease and early mortality but not with delayed complications following marrow transplantation , 2001, Bone Marrow Transplantation.

[38]  M. Zern,et al.  Rapamycin inhibits hepatic stellate cell proliferation in vitro and limits fibrogenesis in an in vivo model of liver fibrosis. , 1999, Gastroenterology.

[39]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[40]  R. Calne,et al.  Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. , 1999, Transplantation.

[41]  G. Alexander,et al.  Sirolimus: a potent new immunosuppressant for liver transplantation. , 1999, Transplantation.

[42]  G. Rosti,et al.  Increased plasma level of vascular endothelial glycoprotein thrombomodulin as an early indicator of endothelial damage in bone marrow transplantation. , 1996, Bone marrow transplantation.

[43]  J. Wingard,et al.  Association of busulfan area under the curve with veno-occlusive disease following BMT. , 1996, Bone marrow transplantation.

[44]  P. Ljungman,et al.  A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group. , 1994, Blood.

[45]  L. Grochow,et al.  VENOOCCLUSIVE DISEASE OF THE LIVER FOLLOWING BONE MARROW TRANSPLANTATION , 1987, Transplantation.

[46]  J. Peto,et al.  Asymptotically Efficient Rank Invariant Test Procedures , 1972 .

[47]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[48]  A. Schulz,et al.  Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention , 2004, Bone Marrow Transplantation.

[49]  J. Klein,et al.  Risk factors for hepatic veno-occlusive disease following HLA-identical sibling bone marrow transplants for leukemia. , 1996, Bone marrow transplantation.

[50]  R. Gray.  A Class of $K$-Sample Tests for Comparing the Cumulative Incidence of a Competing Risk , 1988 .