A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation.
Improvement of graft-versus-host disease prophylaxis remains an important goal in allogeneic hematopoietic stem cell transplantation. Based on reports of possibly preferential properties of sirolimus, we compared the standard regimen of cyclosporine and methotrexate (n=106) with a combination of tacrolimus and sirolimus (n=103) as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation in a prospective, open, randomized trial. The hypothesis was that the tacrolimus/sirolimus regimen would lead to less acute graft-versus-host disease and reduced transplant-related mortality. There was no significant difference in the cumulative incidence of acute graft-versus-host disease of grades II-IV (41% vs. 51%; P=0.19) or grades III-IV (13% vs. 7%; P=0.09) between the groups. Time to neutrophil engraftment (18 days vs. 17 days; P=0.24) was similar, but time to platelet engraftment was longer in cyclosporine/methotrexate patients (14 vs. 12 days; P<0.01). No significant differences in incidence of oropharyngeal mucositis, time to full donor chimerism, or number of cytomegalovirus infections were seen between the two treatment arms, and transplant-related toxicities were equally distributed. Triglyceride (P=0.005) and cholesterol (P=0.009) levels were higher in tacrolimus/sirolimus patients. Transplant-related mortality (18% vs. 12%; P=0.40) and 5-year overall survival (72% vs. 71%; P=0.71) were similar. Five-year relapse-free survival in patients with malignant diagnoses was 65% in the cyclosporine/methotrexate group and 63% in the tacrolimus/sirolimus group (P=0.73). We conclude that tacrolimus/sirolimus remains a valid and safe alternative to cyclosporine/methotrexate as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation, with comparable transplant-related outcomes. The trial was registered at clinicaltrials.gov identifier: 00993343.
Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden johan.karlsson-torlen@karolinska.se.|Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Johan
J
Törlén
Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden.
Olle
O
Ringdén
Division of Oral and Maxillofacial Surgery, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
Karin
K
Garming-Legert
Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden.|Department of Hematology, Karolinska University Hospital and Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Per
P
Ljungman
Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
Jacek
J
Winiarski
Department of Internal Medicine, Turku University Hospital, Finland.|Turku University, Finland.
Kari
K
Remes
Department of Internal Medicine, Turku University Hospital, Finland.
Maija
M
Itälä-Remes
Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden.|Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Mats
M
Remberger
Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden.|Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Jonas
J
Mattsson
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D006801:Humans; D007223:Infant; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology; D010976:Platelet Count; D011292:Premedication / Q000379:methods* / Q000401:mortality; D020123:Sirolimus / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus; D008727:Methotrexate
Bone Marrow Transplant. 2015 Aug;50(8):1037-56
25798672
Hematology Am Soc Hematol Educ Program. 2009;:593-601
20008244
Clin Adv Hematol Oncol. 2012 Oct;10(10):663-5
23187772
Blood. 2014 Jul 17;124(3):307
24914141
Blood. 2003 Jun 1;101(11):4457-63
12531798
Br J Haematol. 1990 Apr;74(4):547-8
2346739
Biol Blood Marrow Transplant. 2004 May;10(5):328-36
15111932
Transplantation. 2004 Jul 15;78(1):122-7
15257050
J Gen Virol. 2014 Oct;95(Pt 10):2260-6
24986086
Blood. 2002 Jun 15;99(12):4618-25
12036896
Blood. 2008 Dec 1;112(12):4425-31
18776081
BMJ. 2014 Nov 24;349:g6679
25422259
Biol Blood Marrow Transplant. 2005 Aug;11(8):571-5
16041306
Bone Marrow Transplant. 1999 Oct;24(8):823-30
10516691
Biol Blood Marrow Transplant. 2011 Nov;17(11):1688-97
21620989
Transplantation. 2006 Oct 15;82(7):913-9
17038906
Bone Marrow Transplant. 2002 Aug;30(3):141-7
12189531
Blood. 2007 May 15;109(10):4582-5
17272503
Scand J Infect Dis. 2006;38(11-12):970-6
17148063
Tissue Antigens. 1992 May;39(5):225-35
1357775
Blood. 1994 May 1;83(9):2723-30
8167351
PLoS One. 2014 Dec 08;9(12):e114735
25485632
Cancer Lett. 2012 Jun 1;319(1):1-7
22261336
Blood. 2014 Mar 27;123(13):2017-25
24497539
Clin Transplant. 2015 Jun;29(6):555-9
25851741
Blood. 1993 Feb 15;81(4):1094-101
8427991
Bone Marrow Transplant. 2014 May;49(5):684-90
24566710
Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56
16338616
Bone Marrow Transplant. 1995 Jun;15(6):825-8
7581076
Expert Rev Clin Immunol. 2007 May;3(3):423-36
20477684
Bone Marrow Transplant. 2003 Feb;31(3):145-55
12621474
Transplantation. 2003 May 15;75(9):1581-90
12792519
Blood. 1988 Feb;71(2):293-8
3276360
Lancet Oncol. 2009 Sep;10(9):855-64
19695955
Haematologica. 2006 Aug;91(8):1059-67
16885046
Blood. 2014 Aug 21;124(8):1372-7
24982504
Haematologica. 2015 Jul;100(7):970-7
25840599
Eur J Haematol. 2000 May;64(5):281-91
10863974
Blood. 2003 Feb 15;101(4):1620-9
12393457
Blood. 2007 Apr 1;109(7):3108-14
17138818
Transplant Proc. 2003 May;35(3 Suppl):7S-14S
12742462
Stem Cells. 2013 Mar;31(3):592-601
23307526
Biol Blood Marrow Transplant. 2010 Jul;16(7):937-47
20102746
N Engl J Med. 2010 Nov 25;363(22):2091-101
21105791
Cell Metab. 2014 Mar 4;19(3):373-9
24508508
Blood. 2007 May 15;109(10):4119-26
17234737
Blood. 1998 Feb 1;91(3):756-63
9446633
Transfusion. 2015 Sep;55(9):2134-41
25857725
Eur J Haematol. 2011 Dec;87(6):503-9
22974354