Skip to main content
Top
Published in: International Journal of Hematology 1/2017

01-01-2017 | Original Article

Comparison of cyclosporine and tacrolimus combined with mycophenolate mofetil in prophylaxis for graft-versus-host disease after reduced-intensity umbilical cord blood transplantation

Authors: Toshihiro Miyamoto, Shuichiro Takashima, Koji Kato, Ken Takase, Goichi Yoshimoto, Shuro Yoshida, Hideho Henzan, Koichi Osaki, Tomohiko Kamimura, Hiromi Iwasaki, Tetsuya Eto, Takanori Teshima, Koji Nagafuji, Koichi Akashi

Published in: International Journal of Hematology | Issue 1/2017

Login to get access

Abstract

Umbilical cord blood transplantation with a reduced-intensity conditioning regimen (RIC-UCBT) is used increasingly in patients who have comorbid organ functions and lack human leukocyte antigen-identical donors. We compared the outcomes in 35 patients who received mycophenolate mofetil plus cyclosporine (MMF/CSP, n = 17) or MMF plus tacrolimus (MMF/TAC, n = 18) for graft-versus-host disease (GVHD) prophylaxis after RIC-UCBT. Cumulative incidence of neutrophil engraftment was 94 and 89 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.34). The incidence of pre-engraftment immune reaction did not differ between the MMF/CSP (41 %) and MMF/TAC (39 %, p = 1.00) groups; however, patients in the MMF/TAC group tended to have a lower incidence of grade II–IV acute GVHD than those in MMF/CSP group (28 vs 53 %, p = 0.11). Overall survival (OS) at 1 year was 43 and 60 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.39). Progression-free survival, non-relapse mortality, and relapse rate were comparable between the two groups (p = 0.76, 0.59, and 0.88, respectively). In multivariate analyses, MMF/TAC GVHD prophylaxis was closely associated with improved OS, but not with incidence of engraftment and acute GVHD. These results suggest that more intensive GVHD prophylaxis with MMF/TAC decreased acute GVHD without affecting other clinical outcomes, resulting in improved OS after RIC-UCBT.
Appendix
Available only for authorised users
Literature
1.
2.
go back to reference Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91(3):756–63.PubMed Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91(3):756–63.PubMed
3.
go back to reference Giralt S, Thall PF, Khouri I, Wang X, Braunschweig I, Ippolitti C, et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood. 2001;97(3):631–7.CrossRefPubMed Giralt S, Thall PF, Khouri I, Wang X, Braunschweig I, Ippolitti C, et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood. 2001;97(3):631–7.CrossRefPubMed
4.
go back to reference Goggins TF, Rizzieri DR. Nonmyeloablative allogeneic stem cell transplantation using alternative donors. Cancer Control. 2004;11(2):86–96.PubMed Goggins TF, Rizzieri DR. Nonmyeloablative allogeneic stem cell transplantation using alternative donors. Cancer Control. 2004;11(2):86–96.PubMed
5.
go back to reference Brunstein CG, Barker JN, Weisdorf DJ, DeFor TE, Miller JS, Blazar BR, et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007;110(8):3064–70.CrossRefPubMedPubMedCentral Brunstein CG, Barker JN, Weisdorf DJ, DeFor TE, Miller JS, Blazar BR, et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007;110(8):3064–70.CrossRefPubMedPubMedCentral
6.
go back to reference Uchida N, Wake A, Takagi S, Yamamoto H, Kato D, Matsuhashi Y, et al. Umbilical cord blood transplantation after reduced-intensity conditioning for elderly patients with hematologic diseases. Biol Blood Marrow Transplant. 2008;14(5):583–90.CrossRefPubMed Uchida N, Wake A, Takagi S, Yamamoto H, Kato D, Matsuhashi Y, et al. Umbilical cord blood transplantation after reduced-intensity conditioning for elderly patients with hematologic diseases. Biol Blood Marrow Transplant. 2008;14(5):583–90.CrossRefPubMed
7.
go back to reference Kishi Y, Kami M, Miyakoshi S, Kanda Y, Murashige N, Teshima T, et al. Early immune reaction after reduced-intensity cord-blood transplantation for adult patients. Transplantation. 2005;80(1):34–40.CrossRefPubMed Kishi Y, Kami M, Miyakoshi S, Kanda Y, Murashige N, Teshima T, et al. Early immune reaction after reduced-intensity cord-blood transplantation for adult patients. Transplantation. 2005;80(1):34–40.CrossRefPubMed
8.
go back to reference Wang X, Liu H, Li L, Geng L, Ding K, Liu X, et al. Pre-engraftment syndrome after unrelated donor umbilical cord blood transplantation in patients with hematologic malignancies. Eur J Haematol. 2012;88(1):39–45.CrossRefPubMed Wang X, Liu H, Li L, Geng L, Ding K, Liu X, et al. Pre-engraftment syndrome after unrelated donor umbilical cord blood transplantation in patients with hematologic malignancies. Eur J Haematol. 2012;88(1):39–45.CrossRefPubMed
9.
go back to reference Bolwell B, Sobecks R, Pohlman B, Andresen S, Rybicki L, Kuczkowski E, et al. A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004;34(7):621–5.CrossRefPubMed Bolwell B, Sobecks R, Pohlman B, Andresen S, Rybicki L, Kuczkowski E, et al. A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004;34(7):621–5.CrossRefPubMed
10.
go back to reference Pohlreich D, Vitek A, Maalouf J, Cetkovsky P. Decreased risk of acute gastrointestinal toxicity when substituting methotrexate with mycophenolate mofetil in the prevention of graft-versus-host disease in stem cell transplantation following myeloablative conditioning regimens. Bone Marrow Transplant. 2006;37(2):235–6 (author reply 6–7).CrossRefPubMed Pohlreich D, Vitek A, Maalouf J, Cetkovsky P. Decreased risk of acute gastrointestinal toxicity when substituting methotrexate with mycophenolate mofetil in the prevention of graft-versus-host disease in stem cell transplantation following myeloablative conditioning regimens. Bone Marrow Transplant. 2006;37(2):235–6 (author reply 6–7).CrossRefPubMed
11.
go back to reference Cutler C, Li S, Kim HT, Laglenne P, Szeto KC, Hoffmeister L, et al. Mucositis after allogeneic hematopoietic stem cell transplantation: a cohort study of methotrexate- and non-methotrexate-containing graft-versus-host disease prophylaxis regimens. Biol Blood Marrow Transplant. 2005;11(5):383–8.CrossRefPubMed Cutler C, Li S, Kim HT, Laglenne P, Szeto KC, Hoffmeister L, et al. Mucositis after allogeneic hematopoietic stem cell transplantation: a cohort study of methotrexate- and non-methotrexate-containing graft-versus-host disease prophylaxis regimens. Biol Blood Marrow Transplant. 2005;11(5):383–8.CrossRefPubMed
12.
go back to reference Uchida N, Wake A, Nakano N, Ishiwata K, Takagi S, Tsuji M, et al. Mycophenolate and tacrolimus for graft-versus-host disease prophylaxis for elderly after cord blood transplantation: a matched pair comparison with tacrolimus alone. Transplantation. 2011;92(3):366–71.CrossRefPubMed Uchida N, Wake A, Nakano N, Ishiwata K, Takagi S, Tsuji M, et al. Mycophenolate and tacrolimus for graft-versus-host disease prophylaxis for elderly after cord blood transplantation: a matched pair comparison with tacrolimus alone. Transplantation. 2011;92(3):366–71.CrossRefPubMed
13.
go back to reference Kanda J, Kaynar L, Kanda Y, Prasad VK, Parikh SH, Lan L, et al. Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: risk factors and response to treatment. Bone Marrow Transplant. 2013;48(7):926–31.CrossRefPubMedPubMedCentral Kanda J, Kaynar L, Kanda Y, Prasad VK, Parikh SH, Lan L, et al. Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: risk factors and response to treatment. Bone Marrow Transplant. 2013;48(7):926–31.CrossRefPubMedPubMedCentral
14.
go back to reference Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998;92(7):2303–14.PubMed Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998;92(7):2303–14.PubMed
15.
go back to reference Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood. 2000;96(6):2062–8.PubMed Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood. 2000;96(6):2062–8.PubMed
16.
go back to reference Hiraoka A, Ohashi Y, Okamoto S, Moriyama Y, Nagao T, Kodera Y, et al. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant. 2001;28(2):181–5.CrossRefPubMed Hiraoka A, Ohashi Y, Okamoto S, Moriyama Y, Nagao T, Kodera Y, et al. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant. 2001;28(2):181–5.CrossRefPubMed
17.
go back to reference Yanada M, Emi N, Naoe T, Sakamaki H, Takahashi S, Hirabayashi N, et al. Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan. Bone Marrow Transplant. 2004;34(4):331–7.CrossRefPubMed Yanada M, Emi N, Naoe T, Sakamaki H, Takahashi S, Hirabayashi N, et al. Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan. Bone Marrow Transplant. 2004;34(4):331–7.CrossRefPubMed
18.
go back to reference Sakai R, Taguri M, Oshima K, Mori T, Ago H, Adachi S, et al. A comparison of tacrolimus and cyclosporine combined with methotrexate for graft-versus-host disease prophylaxis, stratified by stem cell source: a retrospective nationwide survey. Int J Hematol. 2016;103(3):322–33.CrossRefPubMed Sakai R, Taguri M, Oshima K, Mori T, Ago H, Adachi S, et al. A comparison of tacrolimus and cyclosporine combined with methotrexate for graft-versus-host disease prophylaxis, stratified by stem cell source: a retrospective nationwide survey. Int J Hematol. 2016;103(3):322–33.CrossRefPubMed
19.
go back to reference Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15(6):825–8.PubMed Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15(6):825–8.PubMed
20.
go back to reference Miyakoshi S, Yuji K, Kami M, Kusumi E, Kishi Y, Kobayashi K, et al. Successful engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with advanced hematological diseases. Clin Cancer Res. 2004;10(11):3586–92.CrossRefPubMed Miyakoshi S, Yuji K, Kami M, Kusumi E, Kishi Y, Kobayashi K, et al. Successful engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with advanced hematological diseases. Clin Cancer Res. 2004;10(11):3586–92.CrossRefPubMed
21.
go back to reference Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.CrossRefPubMed Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.CrossRefPubMed
22.
go back to reference Long GD, Laughlin M, Madan B, Kurtzberg J, Gasparetto C, Morris A, et al. Unrelated umbilical cord blood transplantation in adult patients. Biol Blood Marrow Transplant. 2003;9(12):772–80.CrossRefPubMed Long GD, Laughlin M, Madan B, Kurtzberg J, Gasparetto C, Morris A, et al. Unrelated umbilical cord blood transplantation in adult patients. Biol Blood Marrow Transplant. 2003;9(12):772–80.CrossRefPubMed
23.
24.
go back to reference Laughlin MJ, Barker J, Bambach B, Koc ON, Rizzieri DA, Wagner JE, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med. 2001;344(24):1815–22.CrossRefPubMed Laughlin MJ, Barker J, Bambach B, Koc ON, Rizzieri DA, Wagner JE, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med. 2001;344(24):1815–22.CrossRefPubMed
25.
go back to reference Bejanyan N, Rogosheske J, DeFor T, Lazaryan A, Esbaum K, Holtan S, et al. Higher dose of mycophenolate mofetil reduces acute graft-versus-host disease in reduced-intensity conditioning double umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2015;21(5):926–33.CrossRefPubMedPubMedCentral Bejanyan N, Rogosheske J, DeFor T, Lazaryan A, Esbaum K, Holtan S, et al. Higher dose of mycophenolate mofetil reduces acute graft-versus-host disease in reduced-intensity conditioning double umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2015;21(5):926–33.CrossRefPubMedPubMedCentral
26.
go back to reference Miyakoshi S, Kusumi E, Matsumura T, Hori A, Murashige N, Hamaki T, et al. Invasive fungal infection following reduced-intensity cord blood transplantation for adult patients with hematologic diseases. Biol Blood Marrow Transplant. 2007;13(7):771–7.CrossRefPubMed Miyakoshi S, Kusumi E, Matsumura T, Hori A, Murashige N, Hamaki T, et al. Invasive fungal infection following reduced-intensity cord blood transplantation for adult patients with hematologic diseases. Biol Blood Marrow Transplant. 2007;13(7):771–7.CrossRefPubMed
27.
go back to reference Narimatsu H, Terakura S, Matsuo K, Oba T, Uchida T, Iida H, et al. Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults. Bone Marrow Transplant. 2007;39(1):31–9.CrossRefPubMed Narimatsu H, Terakura S, Matsuo K, Oba T, Uchida T, Iida H, et al. Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults. Bone Marrow Transplant. 2007;39(1):31–9.CrossRefPubMed
28.
go back to reference Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE. Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood. 2003;102(5):1915–9.CrossRefPubMed Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE. Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood. 2003;102(5):1915–9.CrossRefPubMed
29.
go back to reference Sanz J, Picardi A, Hernandez Boluda JC, Martin C, Ferra C, Nozzoli C, et al. Impact of graft-versus-host disease prophylaxis on outcomes after myeloablative single-unit umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2013;19(9):1387–92.CrossRefPubMed Sanz J, Picardi A, Hernandez Boluda JC, Martin C, Ferra C, Nozzoli C, et al. Impact of graft-versus-host disease prophylaxis on outcomes after myeloablative single-unit umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2013;19(9):1387–92.CrossRefPubMed
30.
go back to reference Miyakoshi S, Kami M, Tanimoto T, Yamaguchi T, Narimatsu H, Kusumi E, et al. Tacrolimus as prophylaxis for acute graft-versus-host disease in reduced intensity cord blood transplantation for adult patients with advanced hematologic diseases. Transplantation. 2007;84(3):316–22.CrossRefPubMed Miyakoshi S, Kami M, Tanimoto T, Yamaguchi T, Narimatsu H, Kusumi E, et al. Tacrolimus as prophylaxis for acute graft-versus-host disease in reduced intensity cord blood transplantation for adult patients with advanced hematologic diseases. Transplantation. 2007;84(3):316–22.CrossRefPubMed
31.
go back to reference Kanda Y, Kobayashi T, Mori T, Tanaka M, Nakaseko C, Yokota A, et al. A randomized controlled trial of cyclosporine and tacrolimus with strict control of blood concentrations after unrelated bone marrow transplantation. Bone Marrow Transplant. 2016;51(1):103–9.CrossRefPubMed Kanda Y, Kobayashi T, Mori T, Tanaka M, Nakaseko C, Yokota A, et al. A randomized controlled trial of cyclosporine and tacrolimus with strict control of blood concentrations after unrelated bone marrow transplantation. Bone Marrow Transplant. 2016;51(1):103–9.CrossRefPubMed
32.
go back to reference Jacobson P, Rogosheske J, Barker JN, Green K, Ng J, Weisdorf D, et al. Relationship of mycophenolic acid exposure to clinical outcome after hematopoietic cell transplantation. Clin Pharmacol Ther. 2005;78(5):486–500.CrossRefPubMed Jacobson P, Rogosheske J, Barker JN, Green K, Ng J, Weisdorf D, et al. Relationship of mycophenolic acid exposure to clinical outcome after hematopoietic cell transplantation. Clin Pharmacol Ther. 2005;78(5):486–500.CrossRefPubMed
Metadata
Title
Comparison of cyclosporine and tacrolimus combined with mycophenolate mofetil in prophylaxis for graft-versus-host disease after reduced-intensity umbilical cord blood transplantation
Authors
Toshihiro Miyamoto
Shuichiro Takashima
Koji Kato
Ken Takase
Goichi Yoshimoto
Shuro Yoshida
Hideho Henzan
Koichi Osaki
Tomohiko Kamimura
Hiromi Iwasaki
Tetsuya Eto
Takanori Teshima
Koji Nagafuji
Koichi Akashi
Publication date
01-01-2017
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 1/2017
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-016-2093-0

Other articles of this Issue 1/2017

International Journal of Hematology 1/2017 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine