title: Prolonged sirolimus administration after allogeneic hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft-versus-host disease.
abstract: Effective pharmacological strategies employed in allogeneic hematopoietic cell transplantation should prevent serious chronic graft-versus-host disease and facilitate donor-recipient immune tolerance. Based on demonstrated pro-tolerogenic activity, sirolimus (rapamycin) is an agent with promise to achieve these goals. In a long-term follow-up analysis of a randomized phase II trial comparing sirolimus/tacrolimus versus methotrexate/tacrolimus for graft-versus-host disease prevention in matched sibling or unrelated donor transplant, we examined the impact of prolonged sirolimus administration (≥ 1 year post-transplant). Median follow-up time for surviving patients at time of this analysis was 41 months (range 27-60) for sirolimus/tacrolimus and 49 months (range 29-63) for methotrexate/tacrolimus. Sirolimus/tacrolimus patients had significantly lower National Institutes of Health Consensus moderate-severe chronic graft-versus-host disease (34% vs. 65%; P=0.004) and late acute graft-versus-host disease (20% vs. 43%; P=0.04). While sirolimus/tacrolimus patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to tacrolimus discontinuation 368 days vs. 821 days; P=0.002), there was no significant difference in complete immune suppression discontinuation (60-month estimate: 43% vs. 31%; P=0.78). Prolonged sirolimus administration represents a viable approach to mitigate risk for moderate-severe chronic and late acute graft-versus-host disease. Further study of determinants of successful immune suppression discontinuation is needed.
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA joseph.pidala@moffitt.org.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pidala
authors.affiliation: Oncologic Sciences, College of Medicine at University of South Florida, USA Biostatistics, Moffitt Cancer Center; USA.
authors.forename: Jongphil
authors.initials: J
authors.lastname: Kim
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Alsina
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Ayala
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Betts
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Hugo F
authors.initials: HF
authors.lastname: Fernandez
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Field
authors.affiliation: Oncologic Sciences, College of Medicine at University of South Florida, USA Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Fl, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Jim
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Kharfan-Dabaja
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Frederick L
authors.initials: FL
authors.lastname: Locke
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Asmita
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Taiga
authors.initials: T
authors.lastname: Nishihori
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Leonel
authors.initials: L
authors.lastname: Ochoa-Bayona
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Lia
authors.initials: L
authors.lastname: Perez
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Marcie
authors.initials: M
authors.lastname: Riches
authors.affiliation: Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
mesh_terms: D000208:Acute Disease; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D002908:Chronic Disease; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008727:Methotrexate / Q000627:therapeutic use*; D012720:Severity of Illness Index; D035781:Siblings; D020123:Sirolimus / Q000627:therapeutic use*; D016019:Survival Analysis; D016559:Tacrolimus / Q000627:therapeutic use; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D061349:Unrelated Donors
chemical_list: D000964:Antimetabolites, Antineoplastic; D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus; D008727:Methotrexate
references.citation: Leukemia. 2009 Jan;23(1):78-84
references.pmid: 18830253
references.citation: J Clin Oncol. 2008 Dec 10;26(35):5767-74
references.pmid: 19001324
references.citation: Blood. 2009 Jul 16;114(3):702-8
references.pmid: 19470693
references.citation: Lancet Oncol. 2009 Sep;10(9):855-64
references.pmid: 19695955
references.citation: Blood. 2010 Apr 22;115(16):3224-30
references.pmid: 20124511
references.citation: Biol Blood Marrow Transplant. 2010 Jul;16(7):937-47
references.pmid: 20102746
references.citation: Biol Blood Marrow Transplant. 2011 Jan;17(1):124-32
references.pmid: 20601033
references.citation: Blood. 2011 Apr 28;117(17):4651-7
references.pmid: 21355084
references.citation: Biol Blood Marrow Transplant. 2011 Sep;17(9):1343-51
references.pmid: 21320619
references.citation: Biol Blood Marrow Transplant. 2011 Oct;17(10):1528-36
references.pmid: 21440079
references.citation: Blood. 2011 Oct 13;118(15):4242-9
references.pmid: 21791424
references.citation: Haematologica. 2011 Nov;96(11):1678-84
references.pmid: 21791465
references.citation: Haematologica. 2012 Mar;97(3):451-8
references.pmid: 22058206
references.citation: Bone Marrow Transplant. 2012 Apr;47(4):581-8
references.pmid: 21552302
references.citation: Biol Blood Marrow Transplant. 2012 Jul;18(7):1099-107
references.pmid: 22198540
references.citation: N Engl J Med. 2012 Oct 18;367(16):1487-96
references.pmid: 23075175
references.citation: Haematologica. 2012 Dec;97(12):1882-9
references.pmid: 22689677
references.citation: Blood. 2013 Mar 21;121(12):2340-6
references.pmid: 23321253
references.citation: Haematologica. 2014 Mar;99(3):548-53
references.pmid: 24241491
references.citation: Blood. 2014 Aug 21;124(8):1372-7
references.pmid: 24982504
references.citation: Haematologica. 2014 Oct;99(10):1624-31
references.pmid: 25085357
references.citation: Bone Marrow Transplant. 1995 Jun;15(6):825-8
references.pmid: 7581076
references.citation: Blood. 1998 Oct 1;92(7):2303-14
references.pmid: 9746768
references.citation: Blood. 2000 Sep 15;96(6):2062-8
references.pmid: 10979948
references.citation: Blood. 2001 Dec 15;98(13):3868-70
references.pmid: 11739201
references.citation: Blood. 2002 Aug 1;100(3):1084-7
references.pmid: 12130531
references.citation: Haematologica. 2003 Mar;88(3):315-23
references.pmid: 12651271
references.citation: Transplant Proc. 1988 Jun;20(3):491-3
references.pmid: 3289191
references.citation: Br J Haematol. 1990 Apr;74(4):547-8
references.pmid: 2346739
references.citation: J Immunol. 2007 Jun 1;178(11):7018-31
references.pmid: 17513751
references.citation: Blood. 2004 Dec 1;104(12):3501-6
references.pmid: 15292060
references.citation: Am J Transplant. 2005 Feb;5(2):228-36
references.pmid: 15643982
references.citation: Blood. 2005 Jun 15;105(12):4743-8
references.pmid: 15746082
references.citation: Biol Blood Marrow Transplant. 2005 Aug;11(8):571-5
references.pmid: 16041306
references.citation: Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56
references.pmid: 16338616
references.citation: Transplantation. 2006 Mar 27;81(6):818-25
references.pmid: 16570002
references.citation: Biol Blood Marrow Transplant. 2006 May;12(5):560-5
references.pmid: 16635791
references.citation: J Immunol. 2007 Feb 15;178(4):2163-70
references.pmid: 17277121
references.citation: Bone Marrow Transplant. 2007 May;39(9):537-45
references.pmid: 17351648
references.citation: J Immunol. 1999 Mar 1;162(5):2775-84
references.pmid: 10072524
references.citation: Am J Transplant. 2007 Jul;7(7):1722-32
references.pmid: 17511761
references.citation: Biol Blood Marrow Transplant. 2007 Oct;13(10):1207-15
references.pmid: 17889358
references.citation: Bone Marrow Transplant. 2009 Jan;43(2):149-53
references.pmid: 18794869