Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Transplant Toxicities

Improvement of overall survival after allogeneic hematopoietic stem cell transplantation for children and adolescents: a three-decade experience of a single institution

Bone Marrow Transplantation volume 51, pages 267–272 (2016)Cite this article

Subjects

Abstract

Allogeneic stem cell transplantation (allo-SCT) has become an essential component of the treatment for a variety of diseases in pediatric patients. During the past decades, advances in the transplant technology, availability of hematopoietic stem cells and supportive care not only have resulted in improved outcomes, but also have expanded the transplant options. However, these features have been studied mainly in adult populations. This investigation analyzed changes in patient profile, transplantation, graft characteristics and outcome among 250 children and adolescent patients who received allo-SCT in a single center between 1983 and 2010. In the 2000–2010, compared with the 1983–1999 period, a significantly higher 5-year overall survival (64% versus 52%, P=0.03) was observed together with a significant decrease of non-relapse mortality (27% versus 9%, P=0.0002). The progression-free survival was comparable between the two periods (49% versus 57%; P=0.17). The 5-year cumulative incidence of relapse was 24% between 1983 and 1999, and 34% between 2000 and 2010 (P=0.08). Major advances in supportive care practice have been made over the past decade, resulting in a significant survival benefit for the pediatric population undergoing allo-SCT. However, post-transplant relapse remains the leading cause of failure of this therapeutic approach, and preventing relapse represents a major challenge today.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Appelbaum FR . Hematopoietic-cell transplantation at 50. N Engl J Med 2007; 357: 1472–1475.

    Article  CAS  PubMed  Google Scholar 

  2. Copelan EA . Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354: 1813–1826.

    CAS  PubMed  Google Scholar 

  3. 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: 3214–3219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rocha V, Wagner JE Jr, Sobocinski KA, Klein JP, Zhang MJ, Horowitz MM et al. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med 2000; 342: 1846–1854.

    Article  CAS  PubMed  Google Scholar 

  5. Miano M, Labopin M, Hartmann O, Angelucci E, Cornish J, Gluckman E et al. Haematopoietic stem cell transplantation trends in children over the last three decades: a survey by the paediatric diseases working party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2007; 39: 89–99.

    Article  CAS  PubMed  Google Scholar 

  6. Gratwohl A, Brand R, Frassoni F, Rocha V, Niederwieser D, Reusser P et al. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant 2005; 36: 757–769.

    Article  CAS  PubMed  Google Scholar 

  7. Shaw PJ, Kan F, Woo Ahn K, Spellman SR, Aljurf M, Ayas M et al. Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors. Blood 2010; 116: 4007–4015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Peffault de Latour R, Peters C, Gibson B, Strahm B, Lankester A, de Heredia CD et al. Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes. Bone Marrow Transplant 2015; 50: 1168–1172.

    Article  CAS  PubMed  Google Scholar 

  9. Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B et al. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol 2006; 24: 5742–5749.

    Article  PubMed  Google Scholar 

  10. Eckert C, Henze G, Seeger K, Hagedorn N, Mann G, Panzer-Grumayer R et al. Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group. J Clin Oncol 2013; 31: 2736–2742.

    Article  PubMed  Google Scholar 

  11. Balduzzi A, Conter V, Uderzo C, Valsecchi MG . Transplantation in childhood very high risk acute lymphoblastic leukemia in first complete remission: where are we now? J Clin Oncol 2007; 25: 2625–2626; author reply 2627-8.

    Article  PubMed  Google Scholar 

  12. Passweg JR, Baldomero H, Peters C, Gaspar HB, Cesaro S, Dreger P et al. Hematopoietic SCT in Europe: data and trends in 2012 with special consideration of pediatric transplantation. Bone Marrow Transplant 2014; 49: 744–750.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Davies SM, Ramsay NK, Klein JP, Weisdorf DJ, Bolwell B, Cahn JY et al. Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. J Clin Oncol 2000; 18: 340–347.

    Article  CAS  PubMed  Google Scholar 

  14. MC P. Current use and outcome of hematopoietic stem cell transplantation. http://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/pages/index.aspx, 2010.

  15. Diaz MA, Gonzalez-Vicent M, Gonzalez ME, Verdeguer A, Martinez A, Perez-Hurtado M et al. Long-term outcome of allogeneic PBSC transplantation in pediatric patients with hematological malignancies: a report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON) and the Spanish Group for Allogeneic Peripheral Blood Transplantation (GETH). Bone Marrow Transplant 2005; 36: 781–785.

    Article  CAS  PubMed  Google Scholar 

  16. Satwani P, Jin Z, Duffy D, Morris E, Bhatia M, Garvin JH et al. Transplantation-related mortality, graft failure, and survival after reduced-toxicity conditioning and allogeneic hematopoietic stem cell transplantation in 100 consecutive pediatric recipients. Biol Blood Marrow Transplant 2013; 19: 552–561.

    Article  PubMed  Google Scholar 

  17. Pulsipher MA, Boucher KM, Wall D, Frangoul H, Duval M, Goyal RK et al. Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood 2009; 114: 1429–1436.

    Article  CAS  PubMed  Google Scholar 

  18. Bitan M, He W, Zhang MJ, Abdel-Azim H, Ayas MF, Bielorai B et al. Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens. Blood 2014; 123: 1615–1620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nash RA, Johnston L, Parker P, McCune JS, Storer B, Slattery JT et al. A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft-versus-host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2005; 11: 495–505.

    Article  CAS  PubMed  Google Scholar 

  20. Mohty M, de Lavallade H, Faucher C, Bilger K, Vey N, Stoppa AM et al. Mycophenolate mofetil and cyclosporine for graft-versus-host disease prophylaxis following reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 2004; 34: 527–530.

    Article  CAS  PubMed  Google Scholar 

  21. Brissot E, Chevallier P, Guillaume T, Delaunay J, Ayari S, Dubruille V et al. Prophylaxis with mycophenolate mofetil and CsA can decrease the incidence of severe acute GVHD after antithymocyte globulin-based reduced-intensity preparative regimen and allo-SCT from HLA-matched unrelated donors. Bone Marrow Transplant 2010; 45: 786–788.

    Article  CAS  PubMed  Google Scholar 

  22. 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: 246–258.

    Article  CAS  PubMed  Google Scholar 

  23. Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576–4583.

    Article  CAS  PubMed  Google Scholar 

  24. Frangoul H, Najjar J, Simmons J, Domm J . Long-term follow-up and management guidelines in pediatric patients after allogenic hematopoietic stem cell transplantation. Semin Hematol 2012; 49: 94–103.

    Article  PubMed  Google Scholar 

  25. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363: 2091–2101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gratwohl A, Stern M, Brand R, Apperley J, Baldomero H, de Witte T et al. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer 2009; 115: 4715–4726.

    Article  PubMed  Google Scholar 

  27. Davies SM, Rowe JM, Appelbaum FR . Indications for hematopoietic cell transplantation in acute leukemia. Biol Blood Marrow Transplant 2008; 14 (1 Suppl 1): 154–164.

    Article  PubMed  Google Scholar 

  28. Pinkel D . 'Allogeneic marrow transplantation in children with acute leukemia: a practice whose time has gone': twenty years later. Leukemia 2009; 23: 2189–2196.

    Article  CAS  PubMed  Google Scholar 

  29. Chaidos A, Kanfer E, Apperley JF . Risk assessment in haemotopoietic stem cell transplantation: disease and disease stage. Best Pract Res Clin Haematol 2007; 20: 125–154.

    Article  PubMed  Google Scholar 

  30. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009; 15: 1628–1633.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Heslop HE . How I treat EBV lymphoproliferation. Blood 2009; 114: 4002–4008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  PubMed  Google Scholar 

  33. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.

    Article  CAS  PubMed  Google Scholar 

  34. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.

    Article  PubMed  Google Scholar 

  35. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  PubMed  Google Scholar 

  36. Gratwohl A, Baldomero H, Frauendorfer K, Rocha V, Apperley J, Niederwieser D . The EBMT activity survey 2006 on hematopoietic stem cell transplantation: focus on the use of cord blood products. Bone Marrow Transplant 2008; 41: 687–705.

    Article  CAS  PubMed  Google Scholar 

  37. Kurtzberg J, Prasad VK, Carter SL, Wagner JE, Baxter-Lowe LA, Wall D et al. Results of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies. Blood 2008; 112: 4318–4327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. MacMillan ML, Davies SM, Nelson GO, Chitphakdithai P, Confer DL, King RJ et al. Twenty years of unrelated donor bone marrow transplantation for pediatric acute leukemia facilitated by the National Marrow Donor Program. Biol Blood Marrow Transplant 2008; 14 (9 Suppl): 16–22.

    Article  PubMed  Google Scholar 

  39. Strullu M, Rialland F, Cahu X, Brissot E, Corradini N, Thomas C et al. Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning regimen in children: a single-center experience. Eur J Haematol 2012; 88: 504–509.

    Article  CAS  PubMed  Google Scholar 

  40. Paillard C, Rochette E, Lutz P, Bertrand Y, Michel G, Bordigoni P et al. Reduced-intensity conditioning followed by allogeneic transplantation in pediatric malignancies: a report from the Societe Francaise des Cancers de l'Enfant and the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Bone Marrow Transplant 2013; 48: 1401–1408.

    Article  CAS  PubMed  Google Scholar 

  41. Geyer MB, Jacobson JS, Freedman J, George D, Moore V, van de Ven C et al. A comparison of immune reconstitution and graft-versus-host disease following myeloablative conditioning versus reduced toxicity conditioning and umbilical cord blood transplantation in paediatric recipients. Br J Haematol 2011; 155: 218–234.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Mateos MK, O'Brien TA, Oswald C, Gabriel M, Ziegler DS, Cohn RJ et al. Transplant-related mortality following allogeneic hematopoeitic stem cell transplantation for pediatric acute lymphoblastic leukemia: 25-year retrospective review. Pediatr Blood Cancer 2013; 60: 1520–1527.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Paganin M, Fabbri G, Conter V, Barisone E, Polato K, Cazzaniga G et al. Postinduction minimal residual disease monitoring by polymerase chain reaction in children with acute lymphoblastic leukemia. J Clin Oncol 2014; 32: 3553–3558.

    Article  PubMed  Google Scholar 

  44. Fossat C, Roussel M, Arnoux I, Asnafi V, Brouzes C, Garnache-Ottou F et al. Methodological aspects of minimal residual disease assessment by flow cytometry in acute lymphoblastic leukemia: a french multicenter study. Cytometry B Clin Cytom (e-pub ahead of print 1 October 2014; doi: 10.1002/cytob.21195).

  45. Russell LJ, Enshaei A, Jones L, Erhorn A, Masic D, Bentley H et al. IGH@ translocations are prevalent in teenagers and young adults with acute lymphoblastic leukemia and are associated with a poor outcome. J Clin Oncol 2014; 32: 1453–1462.

    Article  PubMed  Google Scholar 

  46. Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grumayer R, Moricke A et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010; 115: 3206–3214.

    Article  CAS  PubMed  Google Scholar 

  47. Biondi A, Valsecchi MG, Seriu T, D'Aniello E, Willemse MJ, Fasching K et al. Molecular detection of minimal residual disease is a strong predictive factor of relapse in childhood B-lineage acute lymphoblastic leukemia with medium risk features. A case control study of the International BFM study group. Leukemia 2000; 14: 1939–1943.

    Article  CAS  PubMed  Google Scholar 

  48. Dvorak CC, Steinbach WJ, Brown JM, Agarwal R . Risks and outcomes of invasive fungal infections in pediatric patients undergoing allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2005; 36: 621–629.

    Article  CAS  PubMed  Google Scholar 

  49. Dvorak CC, Fisher BT, Sung L, Steinbach WJ, Nieder M, Alexander S et al. Antifungal prophylaxis in pediatric hematology/oncology: new choices & new data. Pediatr Blood Cancer 2012; 59: 21–26.

    Article  PubMed  Google Scholar 

  50. Lehrnbecher T, Groll AH . Micafungin: a brief review of pharmacology, safety, and antifungal efficacy in pediatric patients. Pediatr Blood Cancer 2010; 55: 229–232.

    Article  PubMed  Google Scholar 

  51. Meshinchi S, Alonzo TA, Stirewalt DL, Zwaan M, Zimmerman M, Reinhardt D et al. Clinical implications of FLT3 mutations in pediatric AML. Blood 2006; 108: 3654–3661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Inaba H, Rubnitz JE, Coustan-Smith E, Li L, Furmanski BD, Mascara GP et al. Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia. J Clin Oncol 2011; 29: 3293–3300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Messinger YH, Gaynon PS, Sposto R, van der Giessen J, Eckroth E, Malvar J et al. Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Blood 2012; 120: 285–290.

    Article  CAS  PubMed  Google Scholar 

  54. Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol 2010; 11: 543–552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Handgretinger R, Zugmaier G, Henze G, Kreyenberg H, Lang P, von Stackelberg A . Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia. Leukemia 2011; 25: 181–184.

    Article  CAS  PubMed  Google Scholar 

  56. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368: 1509–1518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the nursing staff for their dedicated patient care. MM thanks Professor JV Melo (Adelaide, Australia) for critical reading of the manuscript. We also thank the Région Pays de Loire, the Association pour la Recherche sur le Cancer (ARC; grant #3175 to MM), the Fondation de France, the Fondation contre la Leucémie, the Agence de Biomédecine, the Association Cent pour Sang la Vie, the Association Laurette Fuguain, the International Research Group on Unrelated Hematopoietic Stem Cell Transplantation (IRGHET) and the Ligue contre le Cancer Grand-Ouest for their generous and continuous support for our clinical and basic research work. Our group is supported by several grants from the French National Cancer Institute (PHRC, INCa to MM). We would like to acknowledge the continuous support of the cell banking facility (‘tumorothèque’) of the CHU de Nantes. EB was supported by educational grants from Fulbright Foundation and from the Association for Training, Education and Research in Hematology, Immunology and Transplantation.

Author information

Author notes

  1. E Brissot

    Present address: Service d’Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint-Antoine, APHP, Paris, France; Université Pierre et Marie Curie, Paris France; and INSERM, UMRs 938, Paris 75012, France.,

  2. N Milpied

    Present address: Service d’hématologie, CHU de Bordeaux, Bordeaux 33604, France.,

  3. J L Harousseau

    Present address: Institut de Cancérologie de l’Ouest, Centre René Gauducheau, Nantes-St Herblain 44805, France.,

  4. F Mechinaud

    Present address: Children’s Cancer Center, The Royal Children’s Hospital, Melbourne, Victoria 3052, Australia.,

  5. M Mohty

    Present address: Service d’Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint-Antoine, APHP, Paris, France; Université Pierre et Marie Curie, Paris France; and INSERM, UMRs 938, Paris 75012, France.,

Authors and Affiliations

  1. Service d’Hématologie Clinique, CHU de Nantes, Nantes, France

    E Brissot, C Thomas, N Blin, P Chevallier, P Moreau, N Milpied, J L Harousseau & M Mohty

  2. Service d’Onco-Hématologie Pédiatrique, CHU de Nantes, Nantes, France

    F Rialland, M Strullu, N Corradini, N Blin, X Rialland, E Thebaud & F Mechinaud

  3. Service d’Hématologie Clinique, CHU de Rennes, Rennes, France

    X Cahu

  4. Centre d’Investigation Clinique en Cancérologie (CI2C), Nantes, France

    P Moreau & J L Harousseau

Authors
  1. E Brissot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Rialland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X Cahu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Strullu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Corradini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N Blin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. X Rialland
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E Thebaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P Chevallier
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P Moreau
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. N Milpied
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J L Harousseau
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. F Mechinaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M Mohty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Mohty.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brissot, E., Rialland, F., Cahu, X. et al. Improvement of overall survival after allogeneic hematopoietic stem cell transplantation for children and adolescents: a three-decade experience of a single institution. Bone Marrow Transplant 51, 267–272 (2016). https://doi.org/10.1038/bmt.2015.250

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2015.250

This article is cited by

Search

Advanced search

Quick links