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.

  • Article
  • Published:

The role of HLA matching in unrelated donor hematopoietic stem cell transplantation for sickle cell disease in Europe

Bone Marrow Transplantation volume 55, pages 1946–1954 (2020)Cite this article

Subjects

Abstract

We report the results of an analysis of unrelated allogeneic hematopoietic stem cell transplantations (HSCT) in 71 patients with sickle cell disease (SCD) transplanted in EBMT centers between 2005 and 2017. Median age was 9.3 years; graft type was bone marrow in 79% and peripheral blood in 21%. Recipient–donor HLA match at high resolution typing was 10/10 in 31, 9/10 in 20, and 8/10 in 4 patients; the other patients had intermediate resolution typing. The most frequent conditioning regimens were fludarabine–thiotepa–treosulfan (64%) or busulfan–cyclophosphamide (12%). Cumulative incidence of neutrophil engraftment was 92%; platelet engraftment was 90%. Eleven patients (15%) experienced graft failure. Grade II–IV acute graft-vs.-host disease (GvHD) was 23%; 3-year chronic GvHD was 23%. Three-year overall survival (OS) was 88 ± 4%. GRFS was 62 ± 6%. HLA matching was the most significant risk factor for OS: 3-year OS was 96 ± 4% in 10/10 group vs. 75 ± 10% in 9–8/10 (p = 0.042); GRFS was 69 ± 9% vs. 50 ± 12% (p = 0.114), respectively. In conclusion, unrelated donor HSCT is a valid option for SCD patients who lack an HLA-identical sibling donor, preferably in the context of clinical trials. Using a 10/10 HLA-matched unrelated donor yields better survival indicating that HLA matching is an important donor selection factor in this nonmalignant disease.

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

Fig. 1: Three-year overall survival (3y-OS).

Similar content being viewed by others

References

  1. Walters MC, Storb R, Patience M, Leisenring W, Taylor T, Sanders JE, et al. Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood. 2000;95:1918–24.

    CAS  PubMed  Google Scholar 

  2. Bernaudin F, Socie G, Kuentz M, Chevret S, Duval M, Bertrand Y, et al. SFGM-TC. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007;110:2749–56.

    Article  CAS  Google Scholar 

  3. Gluckman E, Cappelli B, Bernaudin F, Labopin M, Volt F, Carreras J. Eurocord, the Pediatric Working Party of the European Society for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research et al. Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood. 2017;129:1548–56.

    Article  CAS  Google Scholar 

  4. Cappelli B, Volt F, Tozatto-Maio K, Scigliuolo GM, Ferster A, Dupont S, et al. Risk factors and outcomes according to age at transplantation with an HLA-identical sibling for sickle cell disease. Haematologica. 2019;104:e543–6. https://doi.org/10.3324/haematol.2019.216788.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using non myeloablative conditioning and high-dose, post transplantation cyclophosphamide. Biol Blood Marrow Transpl. 2008;14:641–50.

    Article  CAS  Google Scholar 

  6. Foell J, Schulte JH, Pfirstinger B, Troeger A, Wolff D, Edinger M, et al. Haploidentical CD3 or α/β T-cell depleted HSCT in advanced stage sickle cell disease. Bone Marrow Transpl. 2019;54:1859–67.

    Article  CAS  Google Scholar 

  7. Shenoy S, Eapen M, Panepinto JA, Logan BR, Wu J, Abraham A, et al. A trial of unrelated donor marrow transplantation for children with severe sickle cell disease. Blood. 2016;128:2561–7.

    Article  CAS  Google Scholar 

  8. Kamani NR, Walters MC, Carter S, Aquino V, Brochstein JA, Chaudhury S, et al. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biol Blood Marrow Transpl. 2012;18:1265–72.

    Article  Google Scholar 

  9. Ruggeri A, Eapen M, Scaravadou A, Cairo MS, Bhatia M, Kurtzberg J, et al. Umbilical cord blood transplantation for children with thalassemia and sickle cell disease. Biol Blood Marrow Transpl. 2011;17:1375–82.

    Article  Google Scholar 

  10. Krishnamurti L, Neuberg DS, Sullivan KM, Kamani NR, Abraham A, Campigotto F, et al. Bone marrow transplantation for adolescents and young adults with sickle cell disease: results of a prospective multicenter pilot study. Am J Hematol. 2019;94:446–54.

    Article  CAS  Google Scholar 

  11. Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;376:848–55.

    Article  CAS  Google Scholar 

  12. Holtan SG, DeFor TE, Lazaryan A, Bejanyan N, Arora M, Brunstein CG, et al. Composite end point of graft versus host disease free, relapse free survival after allogeneic hematopoietic cell transplantation. Blood. 2015;125:1333–8.

    Article  CAS  Google Scholar 

  13. Ruggeri A, Labopin M, Ciceri F, Mohty M, Nagler A. Definition of GvHD-free, relapse-free survival for registry-based studies: an ALWP-EBMT analysis on patients with AML in remission. Bone Marrow Transpl. 2016;51:610–1.

    Article  CAS  Google Scholar 

  14. Schoemans HM, Lee SJ, Ferrara JL, Wolff D, Levine JE, Schultz KR, et al. EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. Bone Marrow Transpl. 2018;53:1401–15.

    Article  Google Scholar 

  15. Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371:339–48.

    Article  CAS  Google Scholar 

  16. Kosuri S, Wolff T, Devlin SM, Byam C, Mazis CM, Naputo K, et al. Prospective evaluation of unrelated donor cord blood and haploidentical donor access reveals graft availability varies by patient ancestry: practical implications for donor selection. Biol Blood Marrow Transpl. 2017;23:965–70.

    Article  Google Scholar 

  17. Eapen M, Brazauskas R, Walters MC, Bernaudin F, Bo-Subait K, Fitzhugh CD, et al. Effect of donor type and conditioning regimen intensity on allogeneic transplantation outcomes in patients with sickle cell disease: a retrospective multicentre, cohort study. Lancet Haematol. 2019;6:e585–96. https://doi.org/10.1016/S2352-3026(19)30154-1.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Balduzzi A, Dalle JH, Wachowiak J, Yaniv I, Yesilipek A, Sedlacek P, et al. Transplantation in children and adolescents with acute lymphoblastic leukemia from a matched donor versus an HLA-identical sibling: is the outcome comparable? Results from the International BFM ALL SCT 2007 Study. Biol Blood Marrow Transpl. 2019;25:2197–210.

    Article  CAS  Google Scholar 

  19. Ramsuran V, Naranbhai V, Horowitz A, Qi Y, Martin MP, Yuki Y, et al. Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells. Science. 2018;359:86–90.

    Article  CAS  Google Scholar 

  20. Strocchio L, Zecca M, Comoli P, Mina T, Giorgiani G, Giraldi E, et al. Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in children with sickle cell disease. Br J Haematol. 2015;169:726–36.

    Article  CAS  Google Scholar 

  21. Rangarajan HG, Abu-Arja R, Pai V, Guilcher GMT, Soni S. Outcomes of unrelated donor stem cell transplantation with post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in patients with severe sickle cell disease. Biol Blood Marrow Transpl. 2018;24:413–7.

    Article  CAS  Google Scholar 

  22. Fitzhugh CD, Cordes S, Taylor T, Coles W, Roskom K, Link M, et al. At least 20% donor myeloid chimerism is necessary to reverse the sickle phenotype after allogeneic HSCT. Blood. 2017;130:1946–8.

    Article  CAS  Google Scholar 

  23. Abraham A, Hsieh M, Eapen M, Fitzhugh C, Carreras J, Keesler D, et al. Relationship between mixed donor-recipient chimerism and disease recurrence after hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transpl. 2017;23:2178–83.

    Article  Google Scholar 

  24. Magnani A, Pondarré C, Bouazza N, Magalon J, Miccio A, Six E, et al. Extensive multilineage analysis in patients with mixed chimerism after allogeneic transplantation for sickle cell disease: insight into hematopoiesis and engraftment thresholds for gene therapy. Haematologica. 2019. https://doi.org/10.3324/haematol.2019.227561.

  25. Bhatia M, Kolva E, Cimini L, Jin Z, Satwani P, Savone M, et al. Health-related quality of life after allogeneic hematopoietic stem cell transplantation for sickle cell disease. Biol Blood Marrow Transpl. 2015;21:666–72.

    Article  Google Scholar 

  26. Saraf SL, Oh AL, Patel PR, Jalundhwala Y, Sweiss K, Koshy M, et al. Nonmyeloablative stemcell transplantation with alemtuzumab/low-dose irradiation to cure and improve the quality of life of adults with sickle cell disease. Biol Blood Marrow Transpl. 2016;22:441–8.

    Article  CAS  Google Scholar 

  27. Shenoy S, Gaziev J, Angelucci E, King A, Bhatia M, Smith A, et al. Late effects screening guidelines after hematopoietic cell transplantation (HCT) for hemoglobinopathy: consensus statement from the second pediatric blood and marrow transplant consortium international conference on late effects after pediatric HCT. Biol Blood Marrow Transpl. 2018;24:1313–21.

    Article  Google Scholar 

  28. Martelli MF, Di Ianni M, Ruggeri L, Pierini A, Falzetti F, Carotti A, et al. “Designed” grafts for HLA-haploidentical stem cell transplantation. Blood. 2014;123:967–73.

    Article  CAS  Google Scholar 

  29. Mc Curdy SR, Luznik L. How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide. Blood 2019;134:1802–10.

    Google Scholar 

  30. Foell J, Pfirstinger B, Rehe K, Wolff D, Holler E, Corbacioglu S. Haploidentical stem cell transplantation with CD3(+)-/CD19(+)- depleted peripheral stem cells for patients with advanced stage sickle cell disease and no alternative donor: results of a pilot study. Bone Marrow Transpl. 2017;52:938–40.

    Article  CAS  Google Scholar 

  31. de la Fuente J, Dhedin N, Koyama T, Bernaudin F, Kuentz M, Karnik L, et al. Haploidentical Bone marrow transplantation with post-transplantation cyclophosphamide plus thiotepa improves donor engraftment in patients with sickle cell anemia: results of an international learning collaborative. Biol Blood Marrow Transpl. 2019;25:1197–209.

    Article  Google Scholar 

  32. Kurzay M, Hauck F, Schmid I, Wiebking V, Eichinger A, Jung E, et al. T-cell replete haploidentical bone marrow transplantation and post-transplant cyclophosphamide for patients with inborn errors. Haematologica. 2019;104:e478–82.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Arnaud Dalissier from the EBMT for helping collecting and preparing the data, the EBMT centers who collaborated in updating the database, patients and families. We thank Monaco Government, the “Centre Scientifique de Monaco” and the association “Cordons de vie” who supported this work. We also thank all the participating transplant centers below: Austria: St. Anna Kinderspital, Vienna. Belgium: University Hospital Gasthuisberg, Leuven. France: Centre Hospitalier Universitaire Pontchaillou, Rennes. Germany: Medical School Hannover, Hannover; Dr. von Haunersches University Children’s Hospital, Munich; University of Regensburg, Regensburg; Klinikum der Johann-Wolfgang Goethe Universitaet, Frankfurt am Main; Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Ulm; Klinik Hamatologie/Onkologie, Idar-Oberstein; University Hospital Erlangen, Erlangen; Tübingen University Hospital, Tubingen. Greece: Aghia Sophia Children’s Hospital, Thivon and Papadiamantopoulou, Athens. Italy: Fondazione IRCCS Policlinico San Matteo, Pavia; Azienda Ospedaliera-University of Padova, Padova; University of Milano-Bicocca, MBBM Foundation c/o San Gerardo Hospital, Monza; IRCCS Ospedale Pediatrico Bambino Gesù, Roma; Meyer Children Hospital, Firenze; Centro Trapianti di Midollo Osseo PO Microcitemico, Cagliari. Netherlands: Leiden University Medical Center, Leiden. Spain: Hospital de la Santa Creu i de Sant Pau, Barcelona. Sweden: Sahlgrenska University Hospital, Goeteborg; Karolinska University Hospital Children’s Hospital, Stockholm. United Kingdom: Department of Paediatrics, St. Mary’s Hospital, London, United Kingdom; Birmingham Children's Hospital, Birmingham.

Author information

Authors and Affiliations

  1. Eurocord, Hôpital Saint Louis, Université Paris, Paris, France

    Eliane Gluckman, Barbara Cappelli, Graziana M. Scigliuolo, Fernanda Volt, Karina Tozatto-Maio, Vanderson Rocha & Annalisa Ruggeri

  2. Monacord, Centre Scientifique de Monaco, Monaco, Monaco

    Eliane Gluckman, Barbara Cappelli, Graziana M. Scigliuolo, Fernanda Volt, Karina Tozatto-Maio, Vanderson Rocha & Annalisa Ruggeri

  3. Department of Paediatrics, St. Mary’s Hospital, London, UK

    Josu de la Fuente & Farah O’Boyle

  4. Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, Brazil

    Karina Tozatto-Maio

  5. Bone Marrow Transplant Unit, Hospital Sirio Libanes, São Paulo, Brazil

    Vanderson Rocha

  6. Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Mina Tommaso & Marco Zecca

  7. Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands

    Frans Smiers & Arjan C. Lankester

  8. Department of Pediatric Hematology and Oncology, Medical School Hannover, Hannover, Germany

    Claudia Bettoni Da Cunha-Riehm

  9. Pediatric Hematology–Oncology Unit, Department of Women’s and Children’s Health, Azienda Ospedaliera-University of Padova, Padova, Italy

    Elisabetta Calore

  10. Pediatric Clinic—Hemato–Oncology Department, University of Milano-Bicocca, MBBM Foundation c/o San Gerardo Hospital, Monza, Italy

    Sonia Bonanomi

  11. Stem Cell Transplant Unit, Aghia SophiaChildren’s Hospital, Thivon and Papadiamantopoulou, Athens, Greece

    Stelios Graphakos & Anna Paisiou

  12. Pediatric Hematology and Oncology, Dr. von Haunersches University Children’s Hospital, Munich, Germany

    Michael H. Albert

  13. Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy

    Annalisa Ruggeri

  14. Cellular Therapy and Immunobiology WP of EBMT, Leiden, The Netherlands

    Annalisa Ruggeri

  15. Department of Pediatric Hematology Oncology and Stem Cell Transplantation, University of Regensburg, Regensburg, Germany

    Selim Corbacioglu

Authors
  1. Eliane Gluckman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Josu de la Fuente
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barbara Cappelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Graziana M. Scigliuolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fernanda Volt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karina Tozatto-Maio
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vanderson Rocha
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mina Tommaso
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Farah O’Boyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Frans Smiers
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Claudia Bettoni Da Cunha-Riehm
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Elisabetta Calore
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sonia Bonanomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Stelios Graphakos
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Anna Paisiou
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Michael H. Albert
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Annalisa Ruggeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Marco Zecca
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Arjan C. Lankester
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Selim Corbacioglu
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of Paediatric Diseases (PDWP) and Inborn Errors Working Parties (IEWP) of the EBMT

Contributions

EG, BC, GMS, and FV reviewed the literature, analyzed the data, and wrote the manuscript. All authors were involved in collecting patients’ data, contributed to the intellectual content of the paper and approved the final manuscript.

Corresponding author

Correspondence to Eliane Gluckman.

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gluckman, E., Fuente, J.d.l., Cappelli, B. et al. The role of HLA matching in unrelated donor hematopoietic stem cell transplantation for sickle cell disease in Europe. Bone Marrow Transplant 55, 1946–1954 (2020). https://doi.org/10.1038/s41409-020-0847-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-020-0847-z

This article is cited by

Search

Advanced search

Quick links