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.

Inherited and Genetic Disorders

Hematopoietic stem cell transplantation for homozygous β-thalassemia and β-thalassemia/hemoglobin E patients from haploidentical donors

Bone Marrow Transplantation volume 51, pages 813–818 (2016)Cite this article

Subjects

Abstract

Thalassemia-free survival after allogeneic stem cell transplantation (SCT) is about 80–90% with either matched-related or -unrelated donors. We explored the use of a mismatched-related (‘haplo- ’) donor. All patients received two courses of pretransplant immunosuppressive therapy (PTIS) with fludarabine (Flu) and dexamethasone (Dxm). After two courses of PTIS, a conditioning regimen of rabbit antithymocyte globulin, Flu and IV busulfan (Bu) was given followed by T-cell-replete peripheral blood progenitor cells. GvHD prophylaxis consisted of cyclophosphamide (Cy) on days SCT +3 and +4 (post-Cy), and on day SCT +5 tacrolimus or sirolimus was started together with a short course of mycophenolate mofetil. Thirty-one patients underwent haplo-SCT. Their median age was 10 years (range, 2–20 years). Twenty-nine patients engrafted with 100% donor chimerism. Two patients suffered primary graft failure. Median time to neutrophil engraftment was 14 days (range, 11–18 days). Five patients developed mild to moderate, reversible veno-occlusive disease, while nine patients developed acute GvHD grade II. Only five patients developed limited-chronic GvHD. Projected overall and event-free survival rates at 2 years are 95% and 94%, respectively. The median follow up time is 12 months (range, 7–33 months).

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1
Figure 2

References

  1. Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio GC, Forni GL, Gamberini MR et al. Survival and complications in thalassemia. Ann N Y Acad Sci 2005; 1054: 40–47.

    Article  CAS  Google Scholar 

  2. Lucarelli G, Clift RA, Galimberti M, Polchi P, Angelucci E, Baronciani D et al. Marrow transplantation for patients with thalassemia: results in class 3 patients. Blood 1996; 87: 2082–2088.

    CAS  PubMed  Google Scholar 

  3. Angelucci E, Matthes-Martin S, Baroninciani D, Bernaudin F, Bonanoni S, Cappelleni MD et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica 2014; 99: 811–820.

    Article  Google Scholar 

  4. Leelahavarong P, Chaikledkaew U, Hongeng S, Kasemsup V, Lubell Y, Teerawattananon Y . A cost-utility and budget impact analysis of allogeneic hematopoietic stem cell transplantation for severe thalassemic patients in Thailand. BMC Health Serv Res 2010; 10: 209–220.

    Article  Google Scholar 

  5. Sruamsiri R, Chaiyakunapruk N, Pakakasama S, Sirireung S, Sripaiboonkij N, Bunworasate U et al. Cost utility analysis of reduced intensity hematopoietic stem cell transplantation in adolescence and young adult with severe thalassemia compared to hypertransfusion and iron chelation program. BMC Health Serv Res 2013; 13: 45–57.

    Article  Google Scholar 

  6. Sodani P, Gaziev D, Polchi P, Erer B, Giardini C, Angelucci E et al. New approach for bone marrow transplantation in patients with class 3 thalassemia aged younger than 17 years. Blood 2004; 104: 1201–1203.

    Article  CAS  Google Scholar 

  7. Gaziev J, Nguyen L, Puozzo C, Mozzi AF, Casella M, Perrone Donnorso M et al. Novel pharmacokinetic behavior of intravenous busulfan in children with thalassemia undergoing hematopoietic stem cell transplantation: a prospective evaluation of pharmacokinetic and pharmacodynamics profile with therapeutic drug monitoring. Blood 2010; 115: 4597–4604.

    Article  CAS  Google Scholar 

  8. Chiesa R, Capelli B, Crocchiolo R, Frugnoli L, Biral E, Noe A et al. Unpredictability of intravenous busulfan pharmacokinetics in children undergoing hematopoietic stem cell transplantation for advanced beta thalassemia: limited toxicity with a dose-adjustment policy. Biol Blood Marrow Transplant 2010; 16: 622–628.

    Article  CAS  Google Scholar 

  9. Mathews V, George B, Deotare U, Lakshmi KM, Viswabandya A, Daniel D et al. A new stratification strategy that identifies a subset of class III patients with an adverse prognosis among children with beta thalassemia major undergoing a matched related allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2007; 13: 889–894.

    Article  Google Scholar 

  10. Anurathapan U, Pakakasama S, Rujkijyanont P, Sirachainan N, Songdej D, Chuansumrit A et al. Pharmacologic Immunoablation followed by reduced-toxicity conditioning and stem cell transplantation in high-risk thalassemi: a safe approach to disease control. Biol Blood Marrow Transplant 2013; 19: 1259–1262.

    Article  Google Scholar 

  11. Anurathapan U, Pakakasama S, Mekjaruskul P, Sirachainan N, Songdej D, Chuansumrit A et al. Outcomes of thalassemia patients undergoing hematopoietic stem cell transplant by using a standard myeloablative versus a novel reduced toxicity conditioning regimen according to new risk stratification. Biol Blood Marrow Transplant 2014; 20: 2066–2071.

    Article  Google Scholar 

  12. Luznik L, O’Donnell PV, Fuchs EJ . Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol 2012; 39: 683–693.

    Article  CAS  Google Scholar 

  13. Kanakry JA, Kasamon YL, Gocke CD, Tsai HL, Davis-Sproul J, Ghosh N et al. Outcomes of related donor HLA-identical or HLA-haploidentical allogeneic blood or marrow transplantation for peripheral T cell lymphoma. Biol Blood Marrow Transplant 2013; 19: 602–606.

    Article  CAS  Google Scholar 

  14. Kanakry CG, O’Donnell PV, Furlong T, de Lima MJ, Wei W, Medeot M et al. Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol 2014; 32: 3497–3505.

    Article  CAS  Google Scholar 

  15. Kanakry CG, Tsai HL, Bolanos-Meade J, Smith BD, Gojo I, Kanakry JA et al. Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-compatible BMT for AML, ALL, and MDS. Blood 2014; 124: 3817–3827.

    Article  CAS  Google Scholar 

  16. Raiola AM, Dominietto A, di Grazia C, Gualandi F, Ibatici A, Bregante S et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transplant 2014; 20: 1573–1579.

    Article  Google Scholar 

  17. Bolanos-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood 2012; 120: 4285–4291.

    Article  CAS  Google Scholar 

  18. Sodani P, Isgro A, Gaziev J, Polchi P, Paciaroni K, Marziali M et al. Purified T-depleted, CD34+ peripheral blood and bone marrow cell transplantation from haploidentical mother to child with thalassemia. Blood 2010; 115: 1296–1302.

    Article  CAS  Google Scholar 

  19. Isgro A, Marziali M, Sodani P, Gaziev J, Erer B, Polchi P et al. Immunohematologic reconstitution in pediatric patients after T cell-depleted HLA-haploidentical stem cell transplantation for thalassemia. Biol Blood Marrow Transplant 2010; 16: 1557–1566.

    Article  Google Scholar 

  20. Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Brown C et al. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant 2002; 8: 468–476.

    Article  CAS  Google Scholar 

  21. De Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood 2004; 104: 857–864.

    Article  CAS  Google Scholar 

  22. Sabloff M, Chandy M, Wang Z, Logan BR, Ghavamzadeh A, Li CK et al. HLA-matched sibling bone marrow transplantation for β-thalassemia major. Blood 2011; 117: 1745–1750.

    Article  CAS  Google Scholar 

  23. Ichinohe T, Teshima T, Matsuoka K, Maruya E, Saji H . Fetal-maternal microchimerism: impact on hematopoietic stem cell transplantation. Curr Opin Immunol 2005; 17: 546–552.

    Article  CAS  Google Scholar 

  24. Patriarca F, Luznik L, Medeot M, Zecca M, Bacigalupo A, Di Bartolomeo P et al. Experts’ considerations on HLA-haploidentical stem cell transplantation. Eur J Haematol 2014; 93: 187–197.

    Article  CAS  Google Scholar 

  25. Cutler C, Kim HT, Sun L, Sese D, Glotzbecker B, Armand P et al. Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation. Blood 2011; 118: 6691–6697.

    Article  CAS  Google Scholar 

  26. Yoshihara S, Maruya E, Taniguchi K, Kaida K, Kato R, Inoue T et al. Risk and prevention of graft failure in patients with preexisting donor-specific HLA antibodies undergoing unmanipulated haploidentical SCT. Bone Marrow Transplant 2012; 47: 508–515.

    Article  CAS  Google Scholar 

  27. Socie G, Lawler M, Gluckman E, McCann SR, Brison O . Studies on hemopoietic chimerism following allogeneic bone marrow transplantation in the molecular biology era. Leuk Res 1995; 19: 497–504.

    Article  CAS  Google Scholar 

  28. Kaplan EL, Meier P . Nonparametric estimator from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  29. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M et al. Venoocclusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118: 255–267.

    Article  CAS  Google Scholar 

  30. Bearman SI . The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 1995; 85: 3005–3020.

    CAS  PubMed  Google Scholar 

  31. Chandy M, Balasubramanian SV, Ramachandran SV, Mathews V, George B, Dennison D et al. Randomized trial of two different conditioning regimens for bone marrow transplantation in thalassemia—the role of busulfan pharmacokinetics in determining outcome. Bone Marrow Transplant 2005; 36: 839–845.

    Article  CAS  Google Scholar 

  32. Bernado ME, Piras E, Vacca A, Giorgiani G, Zecca M, Bertaina A et al. Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan. Blood 2012; 120: 473–476.

    Article  Google Scholar 

  33. Mathews V, George B, Viswabandya A, Abraham A, Ahmed R, Ganapule A et al. Improved clinical outcomes of high risk beta thalassemia major patients undergoing a HLA matched related allogeneic stem cell transplant with a treosulfan based conditioning regimen and peripheral blood stem cell grafts. PLoS ONE 2013; 8: e61637.

    Article  CAS  Google Scholar 

  34. Ruggeri A, Labopin M, Sanz G, Piemontese S, Arcese W, Bacigalupo A et al. Comparison of outcomes after unrelated cord blood and unmanipulated haploidentical stem cell transplantation in adults with acute leukemia. Leukemia 2015; 29: 1891–1900.

    Article  CAS  Google Scholar 

  35. Wang Y, Liu QF, Xu LP, Liu KY, Zhang XH, Ma X et al. Haploidentical- versus identical-sibling transplant for AML in remission: a multi-centre, prospective study. Blood 2015; 125: 3956–3962.

    Article  CAS  Google Scholar 

  36. Poonkuzhali B, Chandy M, Srivastava A, Dennison D, Krishnamoorthy R . Glutathione S-transferase activity influences busulfan pharmacokinetics in patients with beta thalassemia major undergoing bone marrow transplantation. Drug Metab Dispos 2001; 29: 264–267.

    CAS  PubMed  Google Scholar 

  37. Malar R, Sjoo F, Rentsch K, Hassan M, Gungor T . Therapeutic drug monitoring is essential for intravenous busulfan therapy in pediatric hematopoietic stem cell recipients. Pediatr Transplant 2011; 15: 580–588.

    CAS  PubMed  Google Scholar 

  38. Andersson BS, Thall PF, Madden T, Couriel D, Wang X, Tran HT et al. Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant 2002; 8: 477–485.

    Article  CAS  Google Scholar 

  39. Andersson BS, de Lima MJ, Saliba RM, Shpall EJ, Popat U, Jones R et al. Pharmacokinetic dose guidance of IV busulfan with fludarabine with allogeneic stem cell transplantation improves progression free survival in patients with AML and MDS; results of a randomized phase III study. Blood 2011; 118: 892.

    Google Scholar 

  40. Popat U, Bassett R, Chen J, Alousi AM, Anderlini P, Ciurea SO et al. Allogeneic transplantation for myelofibrosis: final analysis of a prospective study after a median follow up of 5 years. J Clin Oncol 2015; 33 (suppl; abstr 7008)..

  41. Furst S, Bernit E, El Cheikh J, Granata A, Harbi S, Mohty B et al. Successful engraftment and clearance of donor specific antibodies after haploidentical related stem cell transplantation for an adult patient with sickle cell disease. Blood 2014; 124: 5792.

    Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants from the Ramathibodi Foundation, the National Research University Grant, the Mahidol University Research Grant, the Office of the Higher Education Commission and Mahidol University under the National Research University Initiative, Thailand Research Fund, Research Chair Grant from the National Science and Technology Development Agency (NSTDA) and the National Institutes of Health of United States (CCSG CA16672).

Author contributions

SH and BSA designed the research. SH, SP and UA performed the research. SH, UA, RS and BSA analyzed the data and performed the statistical analyses. SH, SP, UA, RS and BSA wrote the manuscript. NS, DS, AC, PC, AJ, KS, PR, AM, YL, PI, PS, WS, SS, PA, AU and SI enrolled the patients.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    U Anurathapan, S Hongeng, S Pakakasama, N Sirachainan, D Songdej, A Chuansumrit & S Sirireung

  2. Department of Pediatrics, Chiangmai University Hospital, Chiangmai, Thailand

    P Charoenkwan

  3. Department of Pediatrics, Khonkaen University, Khonkaen, Thailand

    A Jetsrisuparb

  4. Department of Pediatrics, Siriraj Hospital, Mahidol University, Bangkok, Thailand

    K Sanpakit

  5. Department of Pediatrics, Phramongkutklao Hospital, Bangkok, Thailand

    P Rujkijyanont

  6. Queen Sirikit National Institute of Child Health, Bangkok, Thailand

    A Meekaewkunchorn

  7. Sunpasitthiprasong Hospital, Ubon Ratchathani, Thailand

    Y Lektrakul

  8. Samitivej Hospital, Bangkok, Thailand

    P Iamsirirak

  9. Department of Pediatrics, Thammasat University, Pathum Thani, Thailand

    P Surapolchai & W Satayasai

  10. Department of Pharmacy Practice, Center of Pharmaceutical Outcomes Research, Naresuan University, Phitsanulok, Thailand

    R Sruamsiri

  11. Department of Child Health, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia

    P A Wahidiyat

  12. Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    A Ungkanont

  13. Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

    S Issaragrisil

  14. Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    B S Andersson

Authors
  1. U Anurathapan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Hongeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Pakakasama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Sirachainan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Songdej
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Chuansumrit
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P Charoenkwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Jetsrisuparb
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K Sanpakit
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P Rujkijyanont
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Meekaewkunchorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Y Lektrakul
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. P Iamsirirak
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. P Surapolchai
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. W Satayasai
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. S Sirireung
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. R Sruamsiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. P A Wahidiyat
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. A Ungkanont
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. S Issaragrisil
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. B S Andersson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to S Hongeng or S Pakakasama.

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

Anurathapan, U., Hongeng, S., Pakakasama, S. et al. Hematopoietic stem cell transplantation for homozygous β-thalassemia and β-thalassemia/hemoglobin E patients from haploidentical donors. Bone Marrow Transplant 51, 813–818 (2016). https://doi.org/10.1038/bmt.2016.7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2016.7

This article is cited by

Search

Advanced search

Quick links