Prophylaxis and treatment with mycophenolate mofetil in children with graft-versus-host disease undergoing allogeneic hematopoietic stem cell transplantation: a nationwide survey in Japan

Abstract

We investigated the safety and efficacy of mycophenolate mofetil (MMF) in the prevention and treatment of graft-versus-host disease (GVHD) using a nationwide retrospective survey in Japanese children undergoing hematopoietic stem cell transplantation (HSCT). Overall, 141 children undergoing allogeneic HSCT for hematological malignancy (n = 84), non-malignancy (n = 52), and solid tumors (n = 5) were administered MMF orally (median 8 years; range 0–15 years; 89 males and 52 females) during 1995–2011. Donors were primarily unrelated and mismatched related. In the GVHD prophylaxis group, 29% and 8.6% of patients developed grade II–IV and III–IV GVHD, respectively. Of the 32 evaluable patients, 16% developed chronic [limited (n = 4) and extensive (n = 1)] GVHD. In the acute GVHD treatment group, 61% had decreased grade. In the chronic GVHD treatment group, 36% had improved symptoms. Combined immunosuppressant was reduced or discontinued in 61% patients. Major adverse events (AEs) were neutropenia (4.3%), infection (3.5%), thrombocytopenia (2.1%), myelosuppression (2.1%), and diarrhea (1.4%). MMF dosage was reduced in two children due to grade ≥ 3 AEs; two children died from infection. MMF thus may be well tolerated in children, and may be an effective option for prophylaxis and treatment of acute and chronic GVHD.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Kato K, Sakaguchi H, Muramatsu H, Sekiya Y, Kawashima N, Narita A, et al. Danaparoid reduces transplant-related mortality in stem cell transplantation for children. Pediatr Transplant. 2018;22:e13099.

    Article  CAS  Google Scholar 

  2. 2.

    Dhir S, Slatter M, Skinner R. Recent advances in the management of graft-versus-host disease. Arch Dis Child. 2014;99:1150–7.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Baird K, Cooke K, Schultz KR. Chronic graft-versus-host disease (GVHD) in children. Pediatr Clin N Am. 2010;57:297–322.

    Article  Google Scholar 

  4. 4.

    Okamoto S, Teshima T, Kosugi-Kanaya M, Kahata K, Kawashima N, Kato J, et al. Extracorporeal photopheresis with TC-V in Japanese patients with steroid-resistant chronic graft-versus-host disease. Int J Hematol. 2018;108:298–305.

    Article  PubMed  Google Scholar 

  5. 5.

    Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47:85–118.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Miyamoto T, Takashima S, Kato K, Takase K, Yoshimoto G, Yoshida S, et al. Comparison of cyclosporine and tacrolimus combined with mycophenolate mofetil in prophylaxis for graft-versus-host disease after reduced-intensity umbilical cord blood transplantation. Int J Hematol. 2017;105:92–9.

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Nakane T, Nakamae H, Yamaguchi T, Kurosawa S, Okamura A, Hidaka M, et al. Use of mycophenolate mofetil and a calcineurin inhibitor in allogeneic hematopoietic stem-cell transplantation from HLA-matched siblings or unrelated volunteer donors: Japanese multicenter phase II trials. Int J Hematol. 2017;105:485–96.

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Iida M, Fukuda T, Ikegame K, Yoshihara S, Ogawa H, Taniguchi S, et al. Use of mycophenolate mofetil in patients received allogeneic hematopoietic stem cell transplantation in Japan. Int J Hematol. 2011;93:523–31.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Iida M, Fukuda T, Uchida N, Murata M, Aotsuka N, Minagawa K, et al. Mycophenolate mofetil use after unrelated hematopoietic stem cell transplantation for prophylaxis and treatment of graft-vs.-host disease in adult patients in Japan. Clin Transplant. 2014;28:980–9.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A, et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol. 2007;86:269–74.

    Article  PubMed  Google Scholar 

  11. 11.

    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Niederwieser D, Maris M, Shizuru JA, Petersdorf E, Hegenbart U, Sandmaier BM, et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood. 2003;101:1620–9.

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Osunkwo I, Bessmertny O, Harrison L, Cheung YK, Van de Ven C, del Toro G, et al. A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients. Biol Blood Marrow Transplant. 2004;10:246–58.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Urban C, Benesch M, Sykora KW, Schwinger W, Lackner H. Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Bone Marrow Transplant. 2005;35:591–4.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Bhatia M, Militano O, Jin Z, Figurski M, Shaw L, Moore V, et al. An age-dependent pharmacokinetic study of intravenous and oral mycophenolate mofetil in combination with tacrolimus for GVHD prophylaxis in pediatric allogeneic stem cell transplantation recipients. Biol Blood Marrow Transplant. 2010;16:333–43.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Styczynski J, Tallamy B, Waxman I, van de Ven C, Milone MC, Shaw LM, et al. A pilot study of reduced toxicity conditioning with BU, fludarabine and alemtuzumab before the allogeneic hematopoietic SCT in children and adolescents. Bone Marrow Transplant. 2011;46:790–9.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Zhang D, Renbarger JL, Chow DS. Pharmacokinetic variability of mycophenolic acid in pediatric and adult patients with hematopoietic stem cell transplantation. J Clin Pharmacol. 2016;56:1378–86.

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Basara N, Blau WI, Römer E, Rudolphi M, Bischoff M, Kirsten D, et al. Mycophenolate mofetil for the treatment of acute and chronic GVHD in bone marrow transplant patients. Bone Marrow Transplant. 1998;22:61–5.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Inagaki J, Kodama Y, Fukano R, Noguchi M, Okamura J. Mycophenolate mofetil for treatment of steroid-refractory acute graft-versus-host disease after pediatric hematopoietic stem cell transplantation. Pediatr Transplant. 2015;19:652–8.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Busca A, Saroglia EM, Lanino E, Manfredini L, Uderzo C, Nicolini B, et al. Mycophenolate mofetil (MMF) as therapy for refractory chronic GVHD (cGVHD) in children receiving bone marrow transplantation. Bone Marrow Transplant. 2000;25:1067–71.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Basara N, Blau WI, Kiehl MG, Römer E, Rudolphi M, Bischoff M, et al. Efficacy and safety of mycophenolate mofetil for the treatment of acute and chronic GVHD in bone marrow transplant recipient. Transplant Proc 1998;30:4087-4089

    Article  Google Scholar 

  22. 22.

    Krejci M, Doubek M, Buchler T, Brychtova Y, Vorlicek J, Mayer J. Mycophenolate mofetil for the treatment of acute and chronic steroid-refractory graft-versus-host disease. Ann Hematol. 2005;84:681–5.

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Minagawa K, Yamamori M, Katayama Y, Matsui T. Mycophenolate mofetil: fully utilizing its benefits for GvHD prophylaxis. Int J Hematol. 2012;96:10–25.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Burroughs LM, Storb R, Leisenring WM, Pulsipher MA, Loken MR, Torgerson TR, et al. Intensive postgrafting immune suppression combined with nonmyeloablative conditioning for transplantation of HLA-identical hematopoietic cell grafts: results of a pilot study for treatment of primary immunodeficiency disorders. Bone Marrow Transplant. 2007;40:633–42.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Chen HR, Ji SQ, Wang HX, Yan HM, Zhu L, Liu J, et al. Humanized anti-CD25 monoclonal antibody for prophylaxis of graft-vs-host disease (GVHD) in haploidentical bone marrow transplantation without ex vivo T-cell depletion. Exp Hematol. 2003;31:1019–25.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Windreich RM, Goyal RK, Joshi R, Kenkre TS, Howrie D, Venkataramanan R. A pilot study of continuous infusion of mycophenolate mofetil for prophylaxis of graft-versus-host-disease in pediatric patients. Biol Blood Marrow Transplant. 2016;22:682–9.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Militano O, Ozkaynak MF, Mehta B, van deVen C, Hamby C, Cairo MS. Mycophenolate mofetil administered every 8 hours in combination with tacrolimus is efficacious in the prophylaxis of acute graft versus host disease in childhood, adolescent, and young adult allogeneic stem cell transplantation recipients. Pediatr Blood Cancer. 2018;65:e27091.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the following collaborating institutions for collecting patient data: Hokkaido University, Sapporo Medical University, Jichi Medical University, Narita Red Cross Hospital, Tokyo Metropolitan Children’s Medical Center, Tokyo Medical Dentinal University, Yokohama City University, Kanagawa Cancer Center, Tokai University, Niigata University, Kanazawa University, Shinshu University, Hamamatsu Medical University, Shizuoka Children’s Hospital, Kyoto University, Kinki University, Osaka University, Osaka City University, Osaka City General Hospital, Osaka Women’s and Children’s Hospital, Matsushita Memorial Hospital, Kobe University, Okayama University, Hiroshima University, Yamaguchi University, Kagawa Children’s Hospital, Kyushu University, and Kyushu Cancer Center (listed from north to south).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Nozomu Kawashima.

Ethics declarations

Conflict of interest

There are no relevant conflicts of interest to disclose.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplemental Figure

: The cumulative incidence of transplantation-related morality. The overall transplantation-related mortality (TRM) rate was 0.31, with a median follow-up of 5 years. The TRM rate was 0.28 in the GVHD prophylaxis group, 0.30 in the acute GVHD treatment group, and 0.35 in the chronic GVHD treatment group. TRM was not significantly different among the GVHD prophylaxis and treatment groups. (PDF 426 KB)

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kawashima, N., Iida, M., Suzuki, R. et al. Prophylaxis and treatment with mycophenolate mofetil in children with graft-versus-host disease undergoing allogeneic hematopoietic stem cell transplantation: a nationwide survey in Japan. Int J Hematol 109, 491–498 (2019). https://doi.org/10.1007/s12185-019-02601-5

Download citation

Keywords

  • Mycophenolate mofetil
  • Graft-versus-host disease
  • Prophylaxis
  • Treatment
  • Pediatric