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Conditioning Regimens

Treosulfan-based preparative regimens for allo-HSCT in childhood hematological malignancies: a retrospective study on behalf of the EBMT pediatric diseases working party

Abstract

This retrospective analysis evaluated 51 children (0.7–17 years; median eight) with high-risk or advanced hematological malignancies, including 18 (35%) patients undergoing second/third hematopoietic SCT (allo-HSCT), not eligible for standard myeloablative regimens and transplanted from matched sibling (MSD) (n=24) or matched unrelated (MUD) (n=27) donors. Preparative regimens were based on treosulfan (TREO) i.v., a structural analog of BU, given at total dose of 30 g/m2 (n=21) or 36–42 g/m2 (n=30) in combination with, fludarabine, cyclophosphamide, melphalan and/or VP-16 according to diagnosis, and risk factors. Deaths due to early regimen-related toxicity (RRT) did not occur. Nonrelapse mortality was 8% at 1 year and 16% after 4 years. Myeloid engraftment was achieved in 94%, complete donor chimerism in 90% of patients. A 4-year incidence of relapse was 24%, and was significantly lower after MUD-HSCT (8%) than after MSD-HSCT (39%), but similar in children undergoing first (28%) or second/third HSCT (17%). A 4-year disease-free survival was 61%, but it was significantly better in myeloid (73%), than in lymphoid malignancies (41%). Thus, children with high-risk and advanced hematological malignancies and high-risk of life-threatening RRT can be transplanted effectively and safely using TREO-based regimens. Particularly favorable results were achieved in myeloid malignancies and in children undergoing second HSCT.

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References

  1. Miano M, Faraci M, Dini G, Bordigoni P . Early complications following haematopoietic SCT in children. Bone Marrow Transplant 2008; 41 (Suppl 2): S39–S49.

    Article  PubMed  Google Scholar 

  2. Ranke MB, Schwarze CP, Dopfer R, Klingebiel T, Scheel-Walter HG, Lang P et al. Late effects after stem cell transplantation (SCT) in children—growth and hormones. Bone Marrow Transplant 2005; 35 (Suppl 1): S77–S81.

    Article  PubMed  Google Scholar 

  3. Ortega JJ, Olivé T, de Heredia CD, Llort A . Secondary malignancies and quality of life after stem cell transplantation. Bone Marrow Transplant 2005; 35 (Suppl 1): S83–S87.

    Article  PubMed  Google Scholar 

  4. Giralt S . Reduced-intensity conditioning regimens for hematologic malignancies; What have we learned over the last 10 years? In: Berliner N, Lee SJ, Linenberger M, Vogelsang GB (eds). Hematology 2005. ASH Education Program Book, ASH: Washington, DC, USA, 2005 pp 384–389.

    Google Scholar 

  5. Del Toro G, Satwani P, Harrison L, Cheung YK, Brigid Bradley M, George D et al. A pilot study of reduced intensity conditioning and allogeneic stem cell transplantation from unrelated cord blood and matched family donors in children and adolescent recipients. Bone Marrow Transplant 2004; 33: 613–622.

    Article  CAS  PubMed  Google Scholar 

  6. Casper J, Wilhelm S, Steiner B, Hammer U, Hanner U, Wegener R, Freund M . Treosulfan and fludarabine conditioning for allogeneic blood stem cell transplantation. Bone Marrow Transplant 2000; 25 (Suppl 1): S129 (abstract 377).

    Google Scholar 

  7. Casper J, Knauf W, Kiefer T, Wolff D, Steiner B, Hammer U et al. Treosulfan and fludarabine: a new toxicity-reduced conditioning regimen for allogeneic hematopoietic stem cell transplantation. Blood 2004; 103: 725–731.

    Article  CAS  PubMed  Google Scholar 

  8. Feit PW, Rastrup-Andersen N . Studies in epoxide formation from (2S, 3S)-threitol-1,4-bismethan sulfonate. The preparation and biological activity of (2S, 3S)-1,2-epoxy-3,4-butanediol-4-methansulfonate. J Med Chem 1970; 13: 1173–1175.

    Article  CAS  PubMed  Google Scholar 

  9. Fichtner I, Becker M, Baumgart J . Antileukemic activity of treosulfan in xenografted human acute lymphoblastic leukemias (ALL). Eur J Cancer 2003; 39: 801–807.

    Article  CAS  PubMed  Google Scholar 

  10. Schmidmaier R, Oellereich M, Baumgart J, Emmerich B, Meinhardt G . Treosulfan induced apoptosis in AML cells is accompanied by translocation of PKC delta and enhanced by bryostatin-1. Exp Hematol 2004; 32: 76–86.

    Article  CAS  PubMed  Google Scholar 

  11. Topaly J, Fruehauf S, Ho AD, Zeller WJ . Rationale for combination therapy of chronic myelogenous leukemia with imatinib and irradiation or alkylating agents: implication for pretransplant conditioning. Br J Cancer 2002; 86: 1487–1493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Munkelt D, Koehl U, Kloess S, Zimmermann S-Y, El Kalaa R, Wehner S et al. Cytotoxic effects of treosulfan and busulfan against leukemic cells of pediatric patients. Cancer Chemotherapy Pharmacol 2008; 62: 821–830.

    Article  CAS  Google Scholar 

  13. Lanvers-Kaminsky C, Bremer A, Dirksen U, Jürgens H, Boos J . Cytotoxicity of treosulfan and busulfan on pediatric tumor cell lines. Anticancer Drugs 2006; 17: 657–662.

    Article  CAS  PubMed  Google Scholar 

  14. Ploemacher RE, Westerhof GR, Blokland I, Baumgart J, Down JD . Treosulfan as an alternative conditioning agent in bone marrow transplantation. Bone Marrow Transplant 2000; 25 (Suppl 1): S141 (abstract 421).

    Google Scholar 

  15. Westerhof GR, Pleomacher RE, Boudewijn A, Blokland I, Dillingh JH, McGown AT et al. Comparison of different busulfan analogues for depletion of hematopoietic stem cells and promotion of donor-type chimerism in murine bone marrow transplant recipients. Cancer Res 2000; 60: 5470–5478.

    CAS  PubMed  Google Scholar 

  16. Scheulen ME, Hilger RA, Oberhoff C, Casper J, Freund M, Josten KM et al. Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies. Clin Cancer Res 2000; 6: 4209–4216.

    CAS  PubMed  Google Scholar 

  17. Glowka FK, Karazniewicz-Lada M, Grund G, Wrobel T, Wachowiak J . Pharmacokinetics of high-dose i.v. treosulfan in children undergoing treosulfan-based preparative regimen for allogeneic haematopoietic SCT. Bone Marrow Transplant 2008; 42 (Suppl 2): S67–S70.

    Article  CAS  PubMed  Google Scholar 

  18. Harstrick A, Wilke H, Eberhardt W . Phase I dose escalation trial of intravenous treosulfan in refractory cancer. Onkologie 1996; 19: 153–156.

    Google Scholar 

  19. Wachowiak J, Chybicka A, Boruczkowski D, Gorczynska E, Kalwak K, Leda M et al. Intravenous treosulfan in conditioning before allogeneic HSCT from MSD in children with high risk of toxic complications related to conventional preparative regimen. Bone Marrow Transplant 2002; 30 (Suppl 1): S12. (abstract 16).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host disease syndrome in man. A long term clinical pathological study of 20 Seattle patients. Am J Med 1980; 69: 204–212.

    Article  CAS  PubMed  Google Scholar 

  22. Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA, Thomas ED . Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6: 1562–1568.

    Article  CAS  PubMed  Google Scholar 

  23. Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  24. Beelen DW, Trenschel R, Casper J, Freund M, Hilgar RA, Scheulen ME et al. Dose-escalated treosulphan in combination with cyclophosphamide as a new preparative regimen for allogeneic hematopoietic stem cell transplantation in patients with an increased risk for regimen-related complications. Bone Marrow Transplant 2005; 35: 233–241.

    Article  CAS  PubMed  Google Scholar 

  25. Kröger N, Shimoni A, Zabelina T, Schieder H, Panse J, Ayuk F et al. Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acte myeloid leukemia (sAML) or myelodysplastic syndrome (MDS). Bone Marrow Transplant 2006; 37: 339–344.

    Article  PubMed  Google Scholar 

  26. Besinger WI, Spielberger R . Preparative regimens and modification of regimen related toxicities. In: Blume KG, Forman SJ, Appelbaum FR (eds). Thomas’ Hematopoietic Cell Transplantation, 3rd edn. Blackwell Publishing Ltd: Malden, MA, 2004, pp 158–177.

    Google Scholar 

  27. Ulrich CM, Yasui Y, Storb R, Schubert MM, Wagner JL, Bigler J et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001; 98: 231–234.

    Article  CAS  PubMed  Google Scholar 

  28. DeLeve LD, Shulman HM, McDonald GB . Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis 2002; 22: 27–42.

    Article  PubMed  Google Scholar 

  29. Reiss U, Cowan M, McMillan A, Horn B . Hepatic venoocclusive disease, risk factors, and outcome in a cohort of 241 patients. J Pediatr Hematol Oncol 2002; 24: 746–750.

    Article  PubMed  Google Scholar 

  30. Barker CC, Butzer JD, Anderson RA, Brant R, Sauve RS . Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2003; 32: 79–87.

    Article  CAS  PubMed  Google Scholar 

  31. Cesaro S, Pillon M, Talenti E, Toffolutti T, Calore E, Tridello G et al. A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica 2005; 90: 1396–1404.

    PubMed  Google Scholar 

  32. Michel G, Valteau-Couanet D, Esperou H, Gentet JC, Doz F, Méchinaud F et al. A new i.v. busulfan fixed dosing for conditioning before autologous or allogeneic hematopoietic stem cell transplantation (HSCT) in children with malignant and non-malignant diseases : pharmacokinetics, toxicity and clinical outcomes. Blood 2005; 106: 500a (abstract 1758).

    Google Scholar 

  33. Vassal G, Deroussent A, Hartmann O, Challines D, Benhamon E, Valteau-Couanet D et al. Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study. Cancer Res 1990; 50: 6203–6207.

    CAS  PubMed  Google Scholar 

  34. 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  PubMed  Google Scholar 

  35. Stein G, Dini G, Yaniv I . The hope and the reality of reduced intensity transplants in children with malignant diseases. Bone Marrow Transplant 2005; 35 (Suppl 1): S39–S43.

    Article  PubMed  Google Scholar 

  36. Satwani P, Harrison L, Morris E, Del Toro R, Cairo MA . Reduced-intensity allogeneic stem cell transplantation in adults and in children with malignant and non-malignant diseases. Biol Blood Marrow Transplant 2005; 11: 403–422.

    Article  PubMed  Google Scholar 

  37. Jacobsohn DA, Duerst R, Tse W, Ketzel M . Reduced intensity hematopoietic stem cell transplantation for treatment of non-malignant diseases in children. Lancet 2004; 364: 156–162.

    Article  PubMed  Google Scholar 

  38. Horn B, Baxter-Lowe L-A, Englert L, McMillan A, Quinn M, Desantes K, Cowan M . Reduced intensity conditioning using intravenous busulfan, fludarabine and rabbit ATG for children with nonmalignant disorders and CML. Bone Marrow Transplant 2006; 37: 263–269.

    Article  CAS  PubMed  Google Scholar 

  39. Valcárcel D, Martino R, Caballero D, Mateos VM, Perez-Simon JA, Canals C et al. Chimerism analysis following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant 2003; 31: 387–392.

    Article  PubMed  Google Scholar 

  40. Cwynarski K, Roberts IAG, Iacobelli S, vanBiazen A, Brand R, Devergie A et al. Stem cell transplantation for chronic myeloid leukemia in children. Blood 2003; 102: 1224–1231.

    Article  CAS  PubMed  Google Scholar 

  41. Locatelli F, Zecca M, Messina C, Rondelli R, Lanino E, Sacchi N et al. Improvement over time in outcome for children with acute lymphoblastic leukemia in second remisson given hematopoietic stem cell transplantation from unrelated donor. Leukemia 2002; 16: 2228–2237.

    Article  CAS  PubMed  Google Scholar 

  42. Ortega JJ, Diaz de Heredia C, Olivé T, Bastida P, Llort A, Armadans L et al. Allogeneic and autologous bone marrow transplantation after consolidation therapy in high-risk acute myeloid leukemia in children. Towards a risk-oriented therapy. Haematologica 2003; 88: 290–299.

    PubMed  Google Scholar 

  43. Locatelli F, Nöllke P, Zecca M, Korthof E, Lanino E, Peters C et al. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 2005; 105: 410–419.

    Article  CAS  PubMed  Google Scholar 

  44. Satwani P, Sather H, Ozkaynak F, Heerema NA, Schultz KR, Sanders J et al. Allogeneic bone marrow transplantation in first remission for children with ultra-high-risk features of acute lymphoblastic leukemia: a children's oncology group study report. Biol Blood Marrow Transplant 2007; 13: 218–227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Matthes-Martin S, Lamche M, Ladenstein R, Eminger W, Felsberg C, Topf R et al. Organ toxicity and quality of life after allogeneic bone marrow transplantation in pediatric patients: a single centre retrospective analysis. Bone Marrow Transplant 1999; 23: 1049–1053.

    Article  CAS  PubMed  Google Scholar 

  46. Nemecek ER, Gooley TA, Woolfrey AE, Carpenter PA, Mattwes DC, Sanders JE . Outcome of allogeneic bone marrow transplantation for children with advanced acute myeloid leukemia. Bone Marrow Transplant 2004; 34: 799–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Munoz A, Badell I, Olive T, Verdeguer A, Gomez P, Buero E . Second allogeneic hematopoietic stem cell transplantation in hematologic malignancies in children: long-term results of GETMON overall survival and long-term follow up. Haematologica 2002; 87: 331–332.

    PubMed  Google Scholar 

  48. Shah A-J, Kapoor N, Weinberg KI, Crooks GM, Kohn DB, Lemarsky C et al. Second hematopoietic stem cell transplantation in pediatric patients: overall survival and long-term follow up. Biol Blood Marrow Transplant 2002; 8: 221–228.

    Article  PubMed  Google Scholar 

  49. Wachowiak J, Bettoni C, Lange A, Malicki J, Kaczmarek-Kanold M, Głuszak B et al. Can busulfan replace fractionated total body irradiation as conditioning regimen for allogeneic bone marrow transplantation in children with acute lymphoblastic leukemia ? Acta Haematol Pol 1995; 26: 377–384.

    CAS  PubMed  Google Scholar 

  50. Bunin N, Aplenc R, Kamani N, Shaw K, Cnaan A, Simms S . Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow Transplant 2003; 32: 543–548.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to acknowledge all the participating teams for data submission and Uwe Pichlmeier for statistical evaluation.

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Correspondence to J Wachowiak.

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Dr Wachowiak and Dr Sykora have received reimbursement for attending conferences from Medac. Dr Cornish, Dr Chybicka, Dr Kowalczyk, Dr Gorczynska, Dr Choma, Dr Grund and Dr Peters declare no potential conflict of interest.

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Wachowiak, J., Sykora, KW., Cornish, J. et al. Treosulfan-based preparative regimens for allo-HSCT in childhood hematological malignancies: a retrospective study on behalf of the EBMT pediatric diseases working party. Bone Marrow Transplant 46, 1510–1518 (2011). https://doi.org/10.1038/bmt.2010.343

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