Main Article Content

Antonio Marzollo
Elisabetta Calore
Manuela Tumino
Marta Pillon
Maria Vittoria Gazzola
Roberta Destro
Raffaella Colombatti
Piero Marson
Tiziana Tison
Anna Colpo
Chiara Mainardi
Maria Gabelli
Maria Paola Boaro
Sara Rossin
Aurora Strano
Nadia Quaglia
Federica Menzato
Giuseppe Basso
Laura Sainati
Chiara Messina


Anemia, Stem Cell transplantation


Background and objectives  Lack of suitable donors and regimen related toxicity are major barriers for hematopoietic stem cell transplantation (HSCT) in patients with sickle cell disease (SCD) when employing the most frequently used Busulfan-based conditioning regimen. The aim of the study is the assessment of efficacy and toxicity of Treosulfan-based conditioning regimen for SCD also when alternative donors such as mismatched unrelated donor and haploidentical donor are employed.

Methods We report our single-center experience: 11 patients with sickle cell disease received HSCT with a Treosulfan/Thiotepa/Fludarabine/Anti-thymoglobulin conditioning regimen between 2010 and 2015. The donor was a matched sibling donor (n= 7), a haploidentical parent (n= 2), a matched unrelated donor (n= 1) or a mismatched unrelated donor (n=1). The haploidentical and mismatched unrelated donor grafts were manipulated by removing TCR?? and CD19 positive cells.

Results All patients survived the procedure and achieved stable engraftment. Stable mixed chimerism but no SCD manifestation was observed in 5/11 patients. Grade III-IV regimen related toxicity was limited to mucositis and no grade III-IV graft-versus-host disease (GvHD) was observed. Organ function evaluation showed no long term pulmonary, cardiac or renal toxicity; cerebral vasculopathy improved in 3/5 evaluable patients. Gonadal failure was observed in 1/4 evaluable patients.

Conclusion Our data suggest that Treosulfan retains the myeloablative potential of Busulfan while reducing the toxicity also when haploidentical or unrelated donors are employed.


Download data is not yet available.

Abstract 3135
PDF Downloads 932
HTML Downloads 1014


1. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet [Internet]. 2010 Dec;376(9757):2018–31. Available from:

2. Talano J-A, Cairo MS. Smoothing the crescent curve: sickle cell disease. Hematology [Internet]. 2014 Dec 1;2014(1):468–74. Available from:

3. Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children and adolescents with sickle cell disease. Blood [Internet]. 2010 Apr 29;115(17):3447–52. Available from:

4. Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, Davies SC, Ohene-Frempong K, Bernaudin F, Matthews DC, Storb R, Sullivan KM. Bone Marrow Transplantation for Sickle Cell Disease. N Engl J Med [Internet]. 1996 Aug 8;335(6):369–76. Available from:

5. Vermylen C, Cornu G, Ferster a, Brichard B, Ninane J, Ferrant a, Zenebergh a, Maes P, Dhooge C, Benoit Y, Beguin Y, Dresse MF, Sariban E. Haematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium. Bone Marrow Transplant. 1998;22(1):1–6.

6. Walters MC, Storb R, Patience M, Leisenring W, Taylor T, Sanders JE, Buchanan GE, Rogers ZR, Dinndorf P, Davies SC, Roberts IA, Dickerhoff R, Yeager AM, Hsu L, Kurtzberg J, Ohene-Frempong K, Bunin N, Bernaudin F, Wong WY, Scott JP, Margolis D, Vichinsky E, Wall DA, Wayne AS, Pegelow C, Redding-Lallinger R, Wiley J, Klemperer M, Mentzer WC, Smith FO, Sullivan KM. Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood [Internet]. 2000 Mar 15 [cited 2016 Jun 4];95(6):1918–24. Available from:

7. Bernaudin F, Socie G, Kuentz M, Chevret S, Duval M, Bertrand Y, Vannier J-P, Yakouben K, Thuret I, Bordigoni P, Fischer A, Lutz P, Stephan J-L, Dhedin N, Plouvier E, Margueritte G, Bories D, Verlhac S, Esperou H, Coic L, Vernant J-P, Gluckman E. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood [Internet]. 2007 Oct 1;110(7):2749–56. Available from:

8. Panepinto JA, Walters MC, Carreras J, Marsh J, Bredeson CN, Gale RP, Hale GA, Horan J, Hows JM, Klein JP, Pasquini R, Roberts I, Sullivan K, Eapen M, Ferster A. Matched-related donor transplantation for sickle cell disease: Report from the Center for International Blood and Transplant Research. Br J Haematol. 2007;137(5):479–85.

9. McPherson ME, Hutcherson D, Olson E, Haight A, Horan J, Chiang K-Y. Safety and efficacy of targeted busulfan therapy in children undergoing myeloablative matched sibling donor BMT for sickle cell disease. Bone Marrow Transplant [Internet]. 2011 Jan 22;46(1):27–33. Available from:

10. Dedeken L, Lê PQ, Azzi N, Brachet C, Heijmans C, Huybrechts S, Devalck C, Rozen L, Ngalula M, Ferster A. Haematopoietic stem cell transplantation for severe sickle cell disease in childhood: a single centre experience of 50 patients. Br J Haematol [Internet]. 2014 May;165(3):402–8. Available from:

11. Locatelli F, Pagliara D. Allogeneic hematopoietic stem cell transplantation in children with sickle cell disease. Pediatr Blood Cancer [Internet]. 2012 Aug;59(2):372–6. Available from:

12. Walters MC, Patience M, Leisenring W, Eckman JR, Buchanan GR, Rogers ZR, Olivieri NE, Vichinsky E, Davies SC, Mentzer WC, Powars D, Scott JP, Bernaudin F, Ohene-Frempong K, Darbyshire PJ, Wayne A, Roberts IA, Dinndorf P, Brandalise S, Sanders JE, Matthews DC, Appelbaum FR, Storb R, Sullivan KM. Barriers to bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant [Internet]. 1996 May [cited 2016 Jun 1];2(2):100–4. Available from:

13. Gluckman E. Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease. Hematology [Internet]. 2013 Dec 1;2013(1):370–6. Available from:\n\n

14. Krishnamurti L, Abel S, Maiers M, Flesch S. Availability of unrelated donors for hematopoietic stem cell transplantation for hemoglobinopathies. Bone Marrow Transplant [Internet]. 2003 Apr;31(7):547–50. Available from:

15. Justus D, Perez-Albuerne E, Dioguardi J, Jacobsohn D, Abraham A. Allogeneic donor availability for hematopoietic stem cell transplantation in children with sickle cell disease. Pediatr Blood Cancer [Internet]. 2015 Jul;62(7):1285–7. Available from:

16. Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R, Hartzman R, Rizzo JD, Horowitz M, Confer D, Maiers M. HLA Match Likelihoods for Hematopoietic Stem-Cell Grafts in the U.S. Registry. N Engl J Med [Internet]. 2014 Jul 24;371(4):339–48. Available from:

17. Ruggeri A, Eapen M, Scaravadou A, Cairo MS, Bhatia M, Kurtzberg J, Wingard JR, Fasth A, Lo Nigro L, Ayas M, Purtill D, Boudjedir K, Chaves W, Walters MC, Wagner J, Gluckman E, Rocha V. Umbilical Cord Blood Transplantation for Children with Thalassemia and Sickle Cell Disease. Biol Blood Marrow Transplant [Internet]. 2011 Sep;17(9):1375–82. Available from:

18. Locatelli F, Kabbara N, Ruggeri A, Ghavamzadeh A, Roberts I, Li CK, Bernaudin F, Vermylen C, Dalle J-H, Stein J, Wynn R, Cordonnier C, Pinto F, Angelucci E, Socie G, Gluckman E, Walters MC, Rocha V. Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling. Blood [Internet]. 2013 Aug 8;122(6):1072–8. Available from:

19. King AA, Kamani N, Bunin N, Sahdev I, Brochstein J, Hayashi RJ, Grimley M, Abraham A, Dioguardi J, Wah Chan K, Douglas D, Adams R, Andreansky M, Anderson E, Gilman A, Chaudhury S, Yu L, Dalal J, Hale G, Cuvelier G, Jain A, Krajewski J, Gillio A, Kasow KA, Delgado D, Hanson E, Murray L, Shenoy S. Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies. Am J Hematol [Internet]. 2015 Dec;90(12):1093–8. Available from:

20. Matthes-Martin S, Lawitschka A, Fritsch G, Lion T, Grimm B, Breuer S, Boztug H, Karlhuber S, Holter W, Peters C, Minkov M. Stem cell transplantation after reduced-intensity conditioning for sickle cell disease. Eur J Haematol [Internet]. 2013 Apr;90(4):308–12. Available from:

21. Burroughs LM, Nemecek ER, Torgerson TR, Storer BE, Talano J-A, Domm J, Giller RH, Shimamura A, Delaney C, Skoda-Smith S, Thakar MS, Baker KS, Rawlings DJ, Englund J a., Flowers MED, Deeg HJ, Storb R, Woolfrey AE. Treosulfan-Based Conditioning and Hematopoietic Cell Transplantation for Nonmalignant Diseases: A Prospective Multi-Center Trial. Biol Blood Marrow Transplant [Internet]. 2014 Sep [cited 2014 Sep 9]; Available from:

22. Slatter MA, Boztug H, Pötschger U, Sykora K-W, Lankester A, Yaniv I, Sedlacek P, Glogova E, Veys P, Gennery AR, Peters C. Treosulfan-based conditioning regimens for allogeneic haematopoietic stem cell transplantation in children with non-malignant diseases. Bone Marrow Transplant [Internet]. 2015 Dec 10;50(12):1536–41. Available from:

23. Strocchio L, Zecca M, Comoli P, Mina T, Giorgiani G, Giraldi E, Vinti L, Merli P, Regazzi M, Locatelli F. Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in children with sickle cell disease. Br J Haematol [Internet]. 2015 Jun;169(5):726–36. Available from:

24. Feit PW, Rastrup-Andersen N, Matagne R. Studies on epoxide formation from (2S,3S)-threitol 1,4-bismethanesulfonate. The preparation and biological activity of (2S,3S)-1,2-epoxy-3,4-butanediol 4-methanesulfonate. J Med Chem [Internet]. 1970 Nov [cited 2016 Jun 2];13(6):1173–5. Available from:

25. Sjöö F, Hassan Z, Abedi-Valugerdi M, Griskevicius L, Nilsson C, Remberger M, Aschan J, Concha H, Gaughan U, Hassan M. Myeloablative and immunosuppressive properties of treosulfan in mice. Exp Hematol [Internet]. 2006 Jan;34(1):115–21. Available from:

26. Bernardo ME, Piras E, Vacca A, Giorgiani G, Zecca M, Bertaina A, Pagliara D, Contoli B, Pinto RM, Caocci G, Mastronuzzi A, La Nasa G, Locatelli F. Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan. Blood [Internet]. 2012 Jul 12;120(2):473–6. Available from:

27. Slatter MA, Rao K, Amrolia P, Flood T, Abinun M, Hambleton S, Nademi Z, Goulden N, Davies G, Qasim W, Gaspar HB, Cant A, Gennery AR, Veys P. Treosulfan-based conditioning regimens for hematopoietic stem cell transplantation in children with primary immunodeficiency: United Kingdom experience. Blood [Internet]. 2011 Apr 21;117(16):4367–75. Available from:

28. Beier R, Schulz A, Hönig M, Eyrich M, Schlegel P-G, Holter W, Stachel KD, Ehlert K, Greil J, Nürnberger W, Wößmann W, Bader P, Urban C, Müller I, Suttorp M, Sauer M, Gruhn B, Meisel R, Zimmermann M, Sykora K-W. Long-term follow-up of children conditioned with Treosulfan: German and Austrian experience. Bone Marrow Transplant [Internet]. 2013 Apr 22;48(4):491–501. Available from:\n

29. Lehmberg K, Albert MH, Beier R, Beutel K, Gruhn B, Kroger N, Meisel R, Schulz A, Stachel D, Woessmann W, Janka G, Muller I. Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis. Haematologica [Internet]. 2014 Jan 1;99(1):180–4. Available from:

30. Dinur-Schejter Y, Krauss AC, Erlich O, Gorelik N, Yahel A, Porat I, Weintraub M, Stein J, Zaidman I, Stepensky P. Bone marrow transplantation for non-malignant diseases using treosulfan-based conditioning. Pediatr Blood Cancer [Internet]. 2015 Oct;62(2):299–304. Available from:

31. Boztug H, Zecca M, Sykora K-W, Veys P, Lankester A, Slatter M, Skinner R, Wachowiak J, Pötschger U, Glogova E, Peters C. Treosulfan-based conditioning regimens for allogeneic HSCT in children with acute lymphoblastic leukaemia. Ann Hematol [Internet]. 2015 Feb 19;94(2):297–306. Available from:

32. Morillo-Gutierrez B, Beier R, Rao K, Burroughs L, Schulz A, Ewins A-M, Gibson B, Sedlacek P, Krol L, Strahm B, Zaidman I, Kalwak K, Talano J-A, Woolfrey A, Fraser C, Meyts I, Muller I, Wachowiak J, Bernardo ME, Veys P, Sykora K-W, Gennery AR, Slatter M. Treosulfan based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicentre experience. Blood [Internet]. 2016 May 23; Available from:

33. Angelucci E, Matthes-Martin S, Baronciani D, Bernaudin F, Bonanomi S, Cappellini MD, Dalle J-H, Di Bartolomeo P, de Heredia CD, Dickerhoff R, Giardini C, Gluckman E, Hussein AA, Kamani N, Minkov M, Locatelli F, Rocha V, Sedlacek P, Smiers F, Thuret I, Yaniv I, Cavazzana M, Peters C. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica [Internet]. 2014 May 1;99(5):811–20. Available from:

34. Dallas MH, Triplett B, Shook DR, Hartford C, Srinivasan A, Laver J, Ware R, Leung W. Long-Term Outcome and Evaluation of Organ Function in Pediatric Patients Undergoing Haploidentical and Matched Related Hematopoietic Cell Transplantation for Sickle Cell Disease. Biol Blood Marrow Transplant [Internet]. 2013 May;19(5):820–30. Available from:

35. Bertaina A, Merli P, Rutella S, Pagliara D, Bernardo ME, Masetti R, Pende D, Falco M, Handgretinger R, Moretta F, Lucarelli B, Brescia LP, Li Pira G, Testi M, Cancrini C, Kabbara N, Carsetti R, Finocchi A, Moretta A, Moretta L, Locatelli F. HLA-haploidentical stem cell transplantation after removal of ??+ T and B cells in children with nonmalignant disorders. Blood [Internet]. 2014 Jul 31;124(5):822–6. Available from:

36. Calore E, Marson P, Pillon M, Tumino M, Tison T, Mainardi C, De Silvestro G, Rossin S, Franceschetto G, Carraro E, Pescarin M, Varotto S, Destro R, Gazzola MV, Basso G, Messina C. Treatment of Acute Gvhd in Childhood with Extracorporeal Photochemotherapy/Phofotopheresis: the Padova Experience. Biol Blood Marrow Transplant [Internet]. 2015;1–10. Available from:

37. Walters MC, Hardy K, Edwards S, Adamkiewicz T, Barkovich J, Bernaudin F, Buchanan GR, Bunin N, Dickerhoff R, Giller R, Haut PR, Horan J, Hsu LL, Kamani N, Levine JE, Margolis D, Ohene-Frempong K, Patience M, Redding-Lallinger R, Roberts IAG, Rogers ZR, Sanders JE, Scott JP, Sullivan KM. Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease. Biol Blood Marrow Transplant [Internet]. 2010;16(2):263–72. Available from:

38. Walters M., Patience M, Leisenring W, Rogers Z., Aquino V., Buchanan G., Roberts IA., Yeager A., Hsu L, Adamkiewicz T, Kurtzberg J, Vichinsky E, Storer B, Storb R, Sullivan K. Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant [Internet]. 2001 Dec;7(12):665–73. Available from:

39. Krishnamurti L, Kharbanda S, Biernacki MA, Zhang W, Baker KS, Wagner JE, Wu CJ. Stable Long-Term Donor Engraftment following Reduced-Intensity Hematopoietic Cell Transplantation for Sickle Cell Disease. Biol Blood Marrow Transplant [Internet]. 2008;14(11):1270–8. Available from:

40. Kean LS, Manci EA, Perry J, Balkan C, Coley S, Holtzclaw D, Adams AB, Larsen CP, Hsu LL, Archer DR. Chimerism and cure: Hematologic and pathologic correction of murine sickle cell disease. Blood. 2003;102(13):4582–93.

41. Andreani M, Testi M, Gaziev J, Condello R, Bontadini A, Tazzari PL, Ricci F, De Felice L, Agostini F, Fraboni D, Ferrari G, Battarra M, Troiano M, Sodani P, Lucarelli G. Quantitatively different red cell/nucleated cell chimerism in patients with long-term, persistent hematopoietic mixed chimerism after bone marrow transplantation for thalassemia major or sickle cell disease. Haematologica [Internet]. 2011 Jan 1;96(1):128–33. Available from:

42. Iannone R, Casella JF, Fuchs EJ, Chen AR, Jones RJ, Woolfrey A, Amylon M, Sullivan KM, Storb RF, Walters MC. Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and ?-thalassemia. Biol Blood Marrow Transplant [Internet]. 2003 Aug;9(8):519–28. Available from:

43. Horan JT, Liesveld JL, Fenton P, Blumberg N, Walters MC. Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. Bone Marrow Transplant [Internet]. 2005 Jan 8;35(2):171–7. Available from:

44. Hsieh MM, Kang EM, Fitzhugh CD, Link MB, Bolan CD, Kurlander R, Childs RW, Rodgers GP, Powell JD, Tisdale JF. Allogeneic Hematopoietic Stem-Cell Transplantation for Sickle Cell Disease. N Engl J Med [Internet]. 2009 Dec 10;361(24):2309–17. Available from:

45. Saraf SL, Oh AL, Patel PR, Jalundhwala Y, Sweiss K, Koshy M, Campbell-Lee S, Gowhari M, Hassan J, Peace D, Quigley JG, Khan I, Molokie RE, Hsu LL, Mahmud N, Levinson DJ, Pickard a S, Garcia JG, Gordeuk VR, Rondelli D. Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease. Biol Blood Marrow Transplant [Internet]. 2016 Mar;22(3):441–8. Available from:
46. Schattman GL. Cryopreservation of Oocytes. Solomon CG, editor. N Engl J Med [Internet]. 2015 Oct 29;373(18):1755–60. Available from:

47. Manara R, Talenti G, Rampazzo P, Ermani M, Montanaro M, Baracchini C, Teso S, Basso G, Sainati L, Colombatti R. Longitudinal evaluation of cerebral white matter hyperintensities lesion volume in children with sickle cell disease. Br J Haematol [Internet]. 2016 Mar;i:n/a-n/a. Available from:

48. Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, Brodsky R a. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood [Internet]. 2012;120(22):4285–91. Available from:

49. Kang EM. Mobilization, collection, and processing of peripheral blood stem cells in individuals with sickle cell trait. Blood [Internet]. 2002 Feb 1;99(3):850–5. Available from:
50. Fitzhugh CD, Hsieh MM, Bolan CD, Saenz C, Tisdale JF. Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium? Cytotherapy [Internet]. 2009 Jan;11(4):464–71. Available from:

51. Maschan M, Shelikhova L, Ilushina M, Kurnikova E, Boyakova E, Balashov D, Persiantseva M, Skvortsova Y, Laberko A, Muzalevskii Y, Kazachenok A, Glushkova S, Bobrynina V, Kalinina V, Olshanskaya Y, Baidildina D, Novichkova G, Maschan A. TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant [Internet]. 2016 May 25;51(5):668–74. Available from:

52. Mainardi C, Tumino M, Gazzola M V, Rampazzo A, Scarpa M, Messina C. TCR?? CD19 depletion in allogeneic haematopoietic stem cell transplantation performed for Hurler syndrome. Bone Marrow Transplant [Internet]. 2016 Mar 9;51(3):438–9. Available from:

Similar Articles

1 2 3 4 5 6 7 8 9 10 > >> 

You may also start an advanced similarity search for this article.