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

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.

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

References

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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. 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.

  26. 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.

  27. 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.

  28. 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.

  29. 29.

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

  30. 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.

  31. 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.

  32. 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.

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

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.

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

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 (2020). https://doi.org/10.1038/s41409-020-0847-z

Download citation