Comparison of immunosuppressant regimens in salvage cord blood transplantation for graft failure after allogeneic hematopoietic stem cell transplantation

Abstract

Graft failure (GF) is a life-threatening complication after allogeneic stem cell transplantation. Although salvage cord blood transplantation (CBT) is a curative therapy for GF, the optimal immunosuppression after salvage CBT remains unknown. Using nationwide registration data, we compared the transplant outcomes of patients who developed GF and underwent salvage CBT using immunosuppressants, including calcineurin (CNI) alone (n = 177); CNI plus methotrexate (CNI+MTX, n = 150); and CNI plus mycophenolate mofetil (CNI+MMF, n = 161). The CNI+MMF group, in comparison with the CNI+MTX and CNI alone groups, demonstrated better neutrophil recovery at 30 days (62.7 vs. 42.7 vs. 53.1%, P < 0.001); better overall survival (OS) at 12 months (48.4 vs. 33.5 vs. 28.3%, P < 0.001); and lower non-relapse mortality (NRM) at 12 months (35.2 vs. 53.9 vs. 56.5%, P < 0.001). On multivariate analysis, CNI+MMF had the best neutrophil recovery (hazard ratio (HR), 1.71; P < 0.001) and OS (HR, 0.64; P = 0.002) and the lowest NRM (HR, 0.53; P < 0.001). Hemorrhage was relatively less frequent in the CNI+MMF group. CNI+MMF can be a promising immunosuppressant regimen after salvage CBT for GF, with better engraftment and survival outcomes, compared with CNI alone and CNI+MTX.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Cumulative incidence of hematologic recoveries after salvage transplantation according to the immunosuppressants.
Fig. 2: Survival rates after salvage transplantation according to the graft-vs.-host disease prophylaxis.
Fig. 3: Cumulative incidence of each extent of GVHD after salvage transplantation, according to the prophylaxis.
Fig. 4: Subgroup analyses for transplant outcomes according to the immunosuppressants in patients who received antithymocyte or antilymphocyte globulin.

References

  1. 1.

    Olsson R, Remberger M, Schaffer M, Berggren DM, Svahn BM, Mattsson J, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transpl. 2013;48:537–43.

    CAS  Article  Google Scholar 

  2. 2.

    Cluzeau T, Lambert J, Raus N, Dessaux K, Absi L, Delbos F, et al. Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI. Bone Marrow Transplant. 2016;51:687–91.

    CAS  Article  Google Scholar 

  3. 3.

    Narimatsu H, Kami M, Miyakoshi S, Murashige N, Yuji K, Hamaki T, et al. Graft failure following reduced-intensity cord blood transplantation for adult patients. Br J Haematol. 2006;132:36–41.

    Article  Google Scholar 

  4. 4.

    Wobma H, Jin Z, Moscoso S, Bhatia M, Broglie L, George D, et al. Risk factors, clinical outcomes, and cost-of-care related to graft failure in pediatric allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2020;S1083-8791:30146–4.

    Google Scholar 

  5. 5.

    Kawashima N, Terakura S, Nishiwaki S, Koyama D, Ozawa Y, Ito M, et al. Increase of bone marrow macrophages and CD8+ T lymphocytes predict graft failure after allogeneic bone marrow or cord blood transplantation. Bone Marrow Transplant. 2017;52:1164–70.

    CAS  Article  Google Scholar 

  6. 6.

    Ciurea SO, Thall PF, Milton DR, Barnes TH, Kongtim P, Carmazzi Y, et al. Complement-binding donor-specific anti-HLA antibodies and risk of primary graft failure in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21:1392–8.

    CAS  Article  Google Scholar 

  7. 7.

    Kongtim P, Cao K, Ciurea SO. Donor specific anti-HLA antibody and risk of graft failure in haploidentical stem cell transplantation. Adv Hematol. 2016;2016:4025073.

    Article  Google Scholar 

  8. 8.

    Martin PJ. Prevention of allogeneic marrow graft rejection by donor T cells that do not recognize recipient alloantigens: potential role of a veto mechanism. Blood. 1996;88:962–9.

    CAS  Article  Google Scholar 

  9. 9.

    Kong Y, Wang YT, Hu Y, Han W, Chang YJ, Zhang XH, et al. The bone marrow microenvironment is similarly impaired in allogeneic hematopoietic stem cell transplantation patients with early and late poor graft function. Bone Marrow Transplant. 2016;51:249–55.

    CAS  Article  Google Scholar 

  10. 10.

    Selleri C, Sato T, Anderson S, Young NS, Maciejewski JP. Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol. 1995;165:538–46.

    CAS  Article  Google Scholar 

  11. 11.

    Alcazer V, Conrad A, Valour F, Bachy E, Salles G, Huynh A, et al. Early-onset severe infections in allogeneic hematopoietic stem cell transplantation recipients with graft failure. Am J Hematol. 2019;94:E109–11.

    Article  Google Scholar 

  12. 12.

    Masouridi-Levrat S, Simonetta F, Chalandon Y. Immunological basis of bone marrow failure after allogeneic hematopoietic stem cell transplantation. Front Immunol. 2016;7:362.

    Article  Google Scholar 

  13. 13.

    Ozdemir ZN, Civriz Bozdağ S. Graft failure after allogeneic hematopoietic stem cell transplantation. Transfus Apher Sci. 2018;57:163–7.

    Article  Google Scholar 

  14. 14.

    Sun YQ, He GL, Chang YJ, Xu LP, Zhang XH, Han W, et al. The incidence, risk factors, and outcomes of primary poor graft function after unmanipulated haploidentical stem cell transplantation. Ann Hematol. 2015;94:1699–705.

    CAS  Article  Google Scholar 

  15. 15.

    Shimada K, Narimatsu H, Morishita Y, Kohno A, Saito S, Kato Y. Severe regimen-related toxicity of second transplantation for graft failure following reduced-intensity cord blood transplantation in an adult patient. Bone Marrow Transplant. 2006;37:787–8.

    CAS  Article  Google Scholar 

  16. 16.

    Schriber J, Agovi MA, Ho V, Ballen KK, Bacigalupo A, Lazarus HM, et al. Second unrelated donor hematopoietic cell transplantation for primary graft failure. Biol Blood Marrow Transplant. 2010;16:1099–106.

    Article  Google Scholar 

  17. 17.

    Fuji S, Nakamura F, Hatanaka K, Taniguchi S, Sato M, Mori S, et al. Peripheral blood as a preferable source of stem cells for salvage transplantation in patients with graft failure after cord blood transplantation: a retrospective analysis of the registry data of the Japanese Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2012;18:1407–14.

    Article  Google Scholar 

  18. 18.

    Waki F, Masuoka K, Fukuda T, Kanda Y, Nakamae M, Yakushijin K, et al. Feasibility of reduced-intensity cord blood transplantation as salvage therapy for graft failure: results of a nationwide survey of adult patients. Biol Blood Marrow Transplant. 2011;17:841–51.

    Article  Google Scholar 

  19. 19.

    Lund TC, Liegel J, Bejanyan N, Orchard PJ, Cao Q, Tolar J, et al. Second allogeneic hematopoietic cell transplantation for graft failure: poor outcomes for neutropenic graft failure. Am J Hematol. 2015;90:892–6.

    Article  Google Scholar 

  20. 20.

    Onishi Y, Mori T, Kako S, Koh H, Uchida N, Kondo T, et al. Outcome of second transplantation using umbilical cord blood for graft failure after allogeneic hematopoietic stem cell transplantation for aplastic anemia. Biol Blood Marrow Transplant. 2017;23:2137–42.

    Article  Google Scholar 

  21. 21.

    Harada K, Fuji S, Seo S, Kanda J, Ueki T, Kimura F, et al. Comparison of the outcomes after haploidentical and cord blood salvage transplantations for graft failure following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2020. https://doi.org/10.1038/s41409-020-0821-9.

  22. 22.

    Singh H, Nikiforow S, Li S, Ballen KK, Spitzer TR, Soiffer R, et al. Outcomes and management strategies for graft failure after umbilical cord blood transplantation. Am J Hematol. 2014;89:1097–101.

    Article  Google Scholar 

  23. 23.

    Tang BL, Zhu XY, Zheng CC, Liu HL, Geng LQ, Wang XB, et al. Successful early unmanipulated haploidentical transplantation with reduced-intensity conditioning for primary graft failure after cord blood transplantation in hematologic malignancy patients. Bone Marrow Transplant. 2015;50:248–52.

    CAS  Article  Google Scholar 

  24. 24.

    Prata PH, Resche-Rigon M, Blaise D, Socié G, Rohrlich PS, Milpied N, et al. Outcomes of salvage haploidentical transplant with post-transplant cyclophosphamide for rescuing graft failure patients: a report on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2019;25:1798–802.

    Article  Google Scholar 

  25. 25.

    Hoshino T, Takada S, Hatsumi N, Sakura T. Feasibility of salvage cord blood transplantation using a fludarabine, melphalan, and low-dose anti-thymocyte globulin conditioning regimen. Int J Hematol. 2019;109:463–9.

    CAS  Article  Google Scholar 

  26. 26.

    Kato M, Matsumoto K, Suzuki R, Yabe H, Inoue M, Kigasawa H, et al. Salvage allogeneic hematopoietic SCT for primary graft failure in children. Bone Marrow Transplant. 2013;48:1173–8.

    CAS  Article  Google Scholar 

  27. 27.

    Terakura S, Wake A, Inamoto Y, Murata M, Sakai R, Yamaguchi T, et al. Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil. Bone Marrow Transplant. 2017;52:423–30.

    CAS  Article  Google Scholar 

  28. 28.

    Terakura S, Kuwatsuka Y, Yamasaki S, Wake A, Kanda J, Inamoto Y, et al. GvHD prophylaxis after single-unit reduced intensity conditioning cord blood transplantation in adults with acute leukemia. Bone Marrow Transplant. 2017;52:1261–7.

    CAS  Article  Google Scholar 

  29. 29.

    Kharfan-Dabaja M, Mhaskar R, Reljic T, Pidala J, Perkins JB, Djulbegovic B, et al. Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation. Cochrane Database Syst Rev. 2014;7:CD010280.

    Google Scholar 

  30. 30.

    Atsuta Y. Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol. 2016;103:3–10.

    Article  Google Scholar 

  31. 31.

    Kanda J. Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation. Int J Hematol. 2016;103:11–9.

    CAS  Article  Google Scholar 

  32. 32.

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

    CAS  Article  Google Scholar 

  33. 33.

    Murata M, Nakasone H, Kanda J, Nakane T, Furukawa T, Fukuda T, et al. Clinical factors predicting the response of acute graft-versus-host disease to corticosteroid therapy: an analysis from the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2013;19:1183–9.

    CAS  Article  Google Scholar 

  34. 34.

    Pascal L, Tucunduva L, Ruggeri A, Blaise D, Ceballos P, Chevallier P, et al. Impact of ATG-containing reduced-intensity conditioning after single- or double-unit allogeneic cord blood transplantation. Blood. 2015;126:1027–32.

    CAS  Article  Google Scholar 

  35. 35.

    Yanada M, Konuma T, Kuwatsuka Y, Kondo T, Kawata T, Takahashi S, et al. Unit selection for umbilical cord blood transplantation for adults with acute myeloid leukemia in complete remission: a Japanese experience. Bone Marrow Transplant. 2019;54:1789–98.

    CAS  Article  Google Scholar 

  36. 36.

    Konuma T, Kato S, Oiwa-Monna M, Tanoue S, Ogawa M, Isobe M, et al. Cryopreserved CD34+ cell dose, but not total nucleated cell dose, influences hematopoietic recovery and extensive chronic graft-versus-host disease after single-unit cord blood transplantation in adult patients. Biol Blood Marrow Transplant. 2017;23:1142–50.

    CAS  Article  Google Scholar 

  37. 37.

    Fuji S, Tada Y, Nakata R, Nakata K, Koike M, Kida S, et al. GVHD prophylaxis by tacrolimus and mini-MTX in single-unit CBT: a single institute experience. Int J Hematol. 2020;111:278–83.

    CAS  Article  Google Scholar 

  38. 38.

    Fuji S, Oshima K, Ohashi K, Sawa M, Saito T, Eto T, et al. Impact of pretransplant donor-specific anti-HLA antibodies on cord blood transplantation on behalf of the Transplant Complications Working Group of Japan Society for Hematopoietic Cell Transplantation. Bone Marrow Transplant. 2019. https://doi.org/10.1038/s41409-019-0712-0.

Download references

Acknowledgements

We thank all the physicians and staff at the transplant centers who provided the clinical data to the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. This work was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from the Japan Agency for Medical Research and Development, AMED under Grant Number 18ek0510023h0002.

Transplant Complications Working Group of the Japan Society for Hematopoietic Cell Transplantation

Kaito Harada1, Shigeo Fuji2, Sachiko Seo3, Makoto Onizuka1, Hideki Nakasone17

GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation

Naoyuki Uchida4, Shingo Yano6, Sachiko Seo3, Hideki Nakasone17, Seitaro Terakura16

Author information

Affiliations

Authors

Consortia

Corresponding author

Correspondence to Kaito Harada.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

Members of the Transplant Complications Working Group of the Japan Society for Hematopoietic Cell Transplantation and GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation are listed below Acknowledgements

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Harada, K., Fuji, S., Seo, S. et al. Comparison of immunosuppressant regimens in salvage cord blood transplantation for graft failure after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant (2020). https://doi.org/10.1038/s41409-020-00999-9

Download citation

Search