Feasibility of salvage cord blood transplantation using a fludarabine, melphalan, and low-dose anti-thymocyte globulin conditioning regimen

Abstract

Primary graft failure (PGF) is a lethal complication that occurs early after allogeneic stem cell transplantation (allo-SCT). Cord blood transplantation (CBT) is a potential re-transplantation option. Total body irradiation (TBI) is often incorporated into the pre-salvage CBT conditioning regimen following PGF; however, patients experiencing PGF are not always amenable to TBI, and non-TBI regimens for salvage CBT should be established. Here, we report five patients with hematologic malignancies who received salvage CBT for PGF following a non-TBI regimen using fludarabine (Flu), melphalan (Mel), and low-dose anti-thymocyte globulin (ATG). The median intervals between the failed allo-SCT and salvage CBT, as well as between the diagnosis of PGF and salvage CBT, were 37 days and 8 days, respectively. The median neutrophil recovery period was 21 days (range 18–21 days). Four of five patients achieved neutrophil engraftment following salvage CBT; all four exhibited sustained engraftment with complete donor chimerism. Three of the five patients were alive after a median follow-up time of 907 days (range 315–909 days) post-salvage CBT; two patients died of causes unrelated to recurrence. These data suggest that CBT following the non-TBI regimen described here is feasible in patients with PGF.

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References

  1. 1.

    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 Transpl. 2010;16:1099–106.

    Article  Google Scholar 

  2. 2.

    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 Transpl. 2011;17:841–51.

    Article  Google Scholar 

  3. 3.

    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 Transpl. 2012;18:1407–14.

    Article  Google Scholar 

  4. 4.

    Yoshihara S, Ikegame K, Taniguchi K, Kaida K, Kim EH, Nakata J, et al. Salvage haploidentical transplantation for graft failure using reduced-intensity conditioning. Bone Marrow Transpl. 2012;47:369–73.

    Article  CAS  Google Scholar 

  5. 5.

    Ishiyama K, Takeda J, Kondo T, Sugimoto N, Kawabata H, Kitano T, et al. Feasibility of salvage cord blood transplantation following fludarabine, melphalan and low-dose TBI for graft rejection after hematopoietic stem cell transplantation. Bone Marrow Transpl. 2016;51:985–7.

    Article  CAS  Google Scholar 

  6. 6.

    Sumi M, Shimizu I, Sato K, Ueki T, Akahane D, Ueno M, et al. Graft failure in cord blood transplantation successfully treated with short-term reduced-intensity conditioning regimen and second allogeneic transplantation. Int J Hematol. 2010;92:744–50.

    Article  PubMed  Google Scholar 

  7. 7.

    Mattsson J, Ringdén O, Storb R. Graft failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transpl. 2008;14(1Suppl 1):165–70.

    Article  Google Scholar 

  8. 8.

    Koyama M, Hashimoto D, Nagafuji K, Eto T, Ohno Y, Aoyama K, et al. Expansion of donor-reactive host T cells in primary graft failure after allogeneic hematopoietic SCT following reduced-intensity conditioning. Bone Marrow Transpl. 2014;49:110–5.

    Article  CAS  Google Scholar 

  9. 9.

    Georges G, Storb R. Failure of sustained engraftment: clinical manifestations and treatment. In: Atkinson K, editor. Clinical Bone Marrow and Blood Stem Cell Transplantation. 3rd ed. New York: Cambridge University Press; 2000. pp. 1088–188.

    Google Scholar 

  10. 10.

    Storb R, Weiden PL, Sullivan KM, Appelbaum FR, Beatty P, Buckner CD, et al. Second marrow transplants in patients with aplastic anemia rejecting the first graft: use of a conditioning regimen including cyclophosphamide and antithymocyte globulin. Blood. 1987;70:116–21.

    CAS  PubMed  Google Scholar 

  11. 11.

    Nakasone H, Fuji S, Yakushijin K, Onizuka M, Shinohara A, Ohashi K, et al. Impact of total body irradiation on successful neutrophil engraftment in unrelated bone marrow or cord blood transplantation. Am J Hematol. 2017;92:171–8.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    McCann SR, Bacigalupo A, Gluckman E, Hinterberger W, Hows J, Ljungman P, et al. Graft rejection and second bone marrow transplants for acquired aplastic anaemia: a report from the Aplastic Anaemia Working Party of the European Bone Marrow Transplant Group. Bone Marrow Transpl. 1994;13:233–7.

    CAS  Google Scholar 

  13. 13.

    Deeg HJ, O’Donnell M, Tolar J, Agarwal R, Harris RE, Feig SA, et al. Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy. Blood. 2006;108:1485–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ohwada C, Nakaseko C, Ozawa S, Takeuchi M, Shono K, Koizumi M, et al. Second cord blood transplantation (CBT) with reduced-intensity conditioning for graft failure after the first CBT for AML. Bone Marrow Transpl. 2004;34:999–1000.

    Article  CAS  Google Scholar 

  15. 15.

    Jabbour E, Rondon G, Anderlini P, Giralt SA, Couriel DR, Champlin RE, et al. Treatment of donor graft failure with nonmyeloablative conditioning of fludarabine, antithymocyteglobulin and a second allogeneic hematopoietic transplantation. Bone Marrow Transpl. 2007;40:431–5.

    Article  CAS  Google Scholar 

  16. 16.

    Bolaños-Meade J, Luznik L, Muth M, Matsui WH, Huff CA, Smith BD, et al. Salvage transplantation for allograft failure using fludarabine and alemtuzumab as conditioning regimen. Bone Marrow Transpl. 2009;43:477–80.

    Article  CAS  Google Scholar 

  17. 17.

    Sanz GF, Saavedra S, Planelles D, Senent L, Cervera J, Barragán E, et al. Standardized unrelated donor cord blood transplantation in adults with hematologic malignancies. Blood. 2001;98:2332–8.

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Sanz J, Boluda JC, Martín C, González M, Ferrá C, Serrano D, et al. Single-unit umbilical cord blood transplantation from unrelated donors in patients with hematological malignancy using busulfan, thiotepa, fludarabine and ATG as myeloablative conditioning regimen. Bone Marrow Transpl. 2012;47:1287–93.

    Article  CAS  Google Scholar 

  19. 19.

    Yamamoto H, Uchida N, Matsuno N, Kon A, Nishida A, Ota H, et al. I.v. BU/fludarabine plus melphalan or TBI in unrelated cord blood transplantation for high-risk hematological diseases. Bone Marrow Transpl. 2015;50:607–9.

    Article  CAS  Google Scholar 

  20. 20.

    Yamamoto H, Uchida N, Yuasa M, Kageyama K, Ota H, Kaji D, et al. A novel reduced-toxicity myeloablative conditioning regimen using full-dose busulfan, fludarabine, and melphalan for single cord blood transplantation provides durable engraftment and remission in nonremission myeloid malignancies. Biol Blood Marrow Transpl. 2016;22:1844–50.

    Article  CAS  Google Scholar 

  21. 21.

    Thiede C, Bornhauser M, Ehuinger G. Strategies and clinical implications of chimerism diagnosis after allogeneic hematopoietic stem cell transplantation. Acta Haematol. 2004;112:16–23.

    Article  PubMed  Google Scholar 

  22. 22.

    Shimizu I, Kobayashi H, Nasu K, Otsuki F, Ueki T, Sumi M, et al. Successful engraftment of cord blood following a one-day reduced-intensity conditioning regimen in two patients suffering primary graft failure and sepsis. Bone Marrow Transpl. 2009;44:617–8.

    Article  CAS  Google Scholar 

  23. 23.

    Yamashita T, Sugimori C, Ishiyama K, Yamazaki H, Okumura H, Kondo Y, et al. Cord blood transplantation using minimum conditioning regimens for patients with hematologic malignancies complicated by severe infections. Int J Hematol. 2009;89:238–42.

    Article  PubMed  Google Scholar 

  24. 24.

    Guardiola P, Kuentz M, Garban F, Blaise D, Reiffers J, Attal M, et al. Second early allogeneic stem cell transplantations for graft failure in acute leukaemia, chronic myeloid leukaemia and aplastic anaemia. French Society of Bone Marrow Transplantation. Br J Haematol. 2000;111:292–302.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Kanda J, Horwitz ME, Long GD, Gasparetto C, Sullivan KM, Chute JP, et al. Outcomes of a 1-day nonmyeloablative salvage regimen for patients with primary graft failure after allogeneic hematopoietic cell transplantation. Bone Marrow Transpl. 2012;47:700–5.

    Article  CAS  Google Scholar 

  26. 26.

    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 Transpl. 2006;37:787–8.

    Article  CAS  Google Scholar 

  27. 27.

    Staba SL, Escolar ML, Poe M, Kim Y, Martin PL, Szabolcs P, et al. Cord-blood transplants from unrelated donors in patients with Hurler’s syndrome. N Engl J Med. 2004;350:1960–9.

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Fujisaki G, Kami M, Kishi Y. Cord-blood transplants from unrelated donors in Hurler’s syndrome. N Engl J Med. 2004;351:506–7.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Kusumi E, Kami M, Yuji K, Hamaki T, Murashige N, Hori A, et al. Feasibility of reduced intensity hematopoietic stem cell transplantation from an HLA-matched unrelated donor. Bone Marrow Transpl. 2004;33:697–702.

    Article  CAS  Google Scholar 

  30. 30.

    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  PubMed  Google Scholar 

  31. 31.

    Kawamura K, Kanda J, Fuji S, Murata M, Ikegame K, Yoshioka K, et al. Impact of the presence of HLA 1-locus mismatch and the use of low-dose antithymocyte globulin in unrelated bone marrow transplantation. Bone Marrow Transpl. 2017;52:1390–8.

    Article  CAS  Google Scholar 

  32. 32.

    Kanda J, Brazauskas R, Hu ZH, Kuwatsuka Y, Nagafuji K, Kanamori H, et al. Graft-versus-host disease rates after HLA-matched sibling bone marrow or peripheral blood hematopoietic cell transplantation: Comparison of North American Caucasian versus Japanese populations. Biol Blood Marrow Transpl. 2016;22:744–51.

    Article  CAS  Google Scholar 

  33. 33.

    Oh H, Loberiza FR Jr, Zhang MJ, Ringdén O, Akiyama H, Asai T, et al. Comparison of graft-versus-host-disease and survival after HLA-identical sibling bone marrow transplantation in ethnic populations. Blood. 2005;105:1408–16.

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Morishima Y, Kawase T, Malkki M, Morishima S, Spellman S, Kashiwase K, et al. Significance of ethnicity in the risk of acute graft-versus-host disease and leukemia relapse after unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2013;19:1197–203.

    Article  Google Scholar 

  35. 35.

    Kim HJ, Min WS, Cho BS, Eom KS, Kim YJ, Min CK, et al. Successful prevention of acute graft-versus-host disease using low-dose antithymocyte globulin after mismatched, unrelated, hematopoietic stem cell transplantation for acute myelogenous leukemia. Biol Blood Marrow Transpl. 2009;15:704–17.

    Article  CAS  Google Scholar 

  36. 36.

    Davies SM, Weisdorf DJ, Haake RJ, Kersey JH, McGlave PB, Ramsay NK, et al. Second infusion of bone marrow for treatment of graft failure after allogeneic bone marrow transplantation. Bone Marrow Transpl. 1994;14:73–7.

    CAS  Google Scholar 

  37. 37.

    Kuriyama K, Fuji S, Inamoto Y, Tajima K, Tanaka T, Inoue Y, et al. Impact of low dose rabbit anti-thymocyte globulin in unrelated hematopoietic stem cell transplantation. Int J Hematol. 2016;103:453–60.

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10:855–64.

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117:3214–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Yang F, Lu D, Hu Y, Huang X, Huang H, Chen J, et al. Risk factors for graft-versus-host disease after transplantation of hematopoietic stem cells from unrelated donors in the China marrow donor program. Ann Transpl. 2017;22:384–401.

    Article  CAS  Google Scholar 

  41. 41.

    Ozawa S, Nakaseko C, Nishimura M, Maruta A, Cho R, Ohwada C, et al. Chronic graft-versus-host disease after allogeneic bone marrow transplantation from an unrelated donor: incidence, risk factors and association with relapse. A report from the Japan Marrow Donor Program. Br J Haematol. 2007;137:142–51.

    Article  PubMed  Google Scholar 

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Correspondence to Takumi Hoshino.

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Hoshino, T., Takada, S., Hatsumi, N. et al. Feasibility of salvage cord blood transplantation using a fludarabine, melphalan, and low-dose anti-thymocyte globulin conditioning regimen. Int J Hematol 109, 463–469 (2019). https://doi.org/10.1007/s12185-019-02610-4

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Keywords

  • Primary graft failure
  • Total body irradiation
  • Cord blood transplantation
  • Anti-thymocyte globulin
  • Salvage