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Conditioning Regimens

Allogeneic hematopoietic SCT in patients with AML following treosulfan/fludarabine conditioning

Abstract

An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The safety and efficacy of this new conditioning regimen has been investigated prospectively in patients with AML. A total number of 75 patients with AML in CR were treated with 3 × 14 g/m2 treosulfan and 5 × 30 mg/m2 fludarabine, followed by matched sibling or unrelated SCT. Patients were evaluated for engraftment, adverse events, GVHD, and for non-relapse mortality, relapse incidence, overall and disease-free survival (DFS). All patients showed primary engraftment of neutrophils after a median of 20 days. Non-hematological adverse events grade III–IV in severity included mainly infections (59%) and gastrointestinal symptoms (7%). Acute GVHD grade II–IV occurred in 21% and extensive chronic GVHD occurred in 16% of the patients. After a median follow-up of 715 days, the 2-year overall and DFS estimates were 61% and 55%, respectively. The 2-year incidences of relapse and non-relapse mortality reached 34% and 11%, respectively. In summary, our data confirm promising safety and efficacy of the treosulfan-based conditioning therapy in AML patients, ClinicalTrials.gov Identifier: NCT01063660.

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References

  1. Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 2009; 301: 2349–2361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hegenbart U, Niederwieser D, Sandmaier BMH, Maris MB, Shizuru JA, Greinix H et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol 2006; 24: 444–453.

    Article  CAS  PubMed  Google Scholar 

  3. Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol 2010; 28: 2859–2867.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Gupta V, Tallman MS, Weisdorf DJ . Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood 2011; 117: 2307–2318.

    Article  CAS  PubMed  Google Scholar 

  5. De Lima M, Anagnostopoulos A, Munsell M, Shahjahan M, Ueno N, Ippoliti C et al. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood 2004; 104: 865–872.

    Article  CAS  PubMed  Google Scholar 

  6. Alyea EP, Kim HT, Ho V, Cutler C, Gribben J, DeAngelo DJ et al. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood 2005; 105: 1810–1814.

    Article  CAS  PubMed  Google Scholar 

  7. Graef T, Vaupel M, Fenk R, Ruf L, Zohren F, Germing U et al. Prognostic factors for patients with acute myeloid leukaemia or high-risk myelodysplastic syndromes undergoing myeloablative or non-myeloablative allogeneic blood stem cell transplantation. Hematol Oncol 2007; 25: 170–177.

    Article  PubMed  Google Scholar 

  8. Sjoo F, Hassan Z, Abedi-Valugerdi M, Griskevicius L, Nilsson C, Remberger M et al. Myeloablative and immunosuppressive properties of treosulfan in mice. Exp Hematol 2006; 34: 115–121.

    Article  PubMed  Google Scholar 

  9. Munkelt D, Koehl U, Kloess S, Zimmermann SY, Kalaäoui RE, Wehner S et al. Cytotoxic effects of treosulfan and busulfan against leukemic cells of pediatric patients. Cancer Chemother Pharmacol 2008; 62: 821–830.

    Article  CAS  PubMed  Google Scholar 

  10. Ploemacher RE, Johnson KW, Rombouts EJC, Etienne K, Westerhof GR, Baumgart J et al. Addition of treosulfan to a nonmyeloablative conditioning regimen results in enhanced chimerism and immunologic tolerance in an experimental allogeneic bone marrow transplant model. Biol Blood Marrow Transplant 2004; 10: 236–245.

    Article  CAS  PubMed  Google Scholar 

  11. Schmidmaier R, Oellerich M, Baumgart J, Emmerich B, Meinhardt G . Treosulfan-induced apoptosis in acute myeloid leukemia cells is accompanied by translocation of protein kinase C delta and enhanced by bryostatin-1. Exp Hematol 2004; 32: 76–86.

    Article  CAS  PubMed  Google Scholar 

  12. Bosanquet AG, Burlton AR . Airborne cytotoxicity in the DiSC assay caused by solutions of treosulfan but not busulphan. Cytotechnology 1994; 16: 131–136.

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. Kroger 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 acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS). Bone Marrow Transplant 2006; 37: 339–344.

    Article  CAS  PubMed  Google Scholar 

  15. Schmidt-Hieber M, Blau IW, Trenschel R, Andreesen R, Stuhler G, Einsele H et al. Reduced-toxicity conditioning with fludarabine and treosulfan prior to allogeneic stem cell transplantation in multiple myeloma. Bone Marrow Transplant 2007; 39: 389–396.

    Article  CAS  PubMed  Google Scholar 

  16. Shimoni A, Hardan I, Shem-Tov N, Rand A, Yerushalmi R, Nagler A . Fludarabine and treosulfan: a novel modified myeloablative regimen for allogeneic hematopoietic stem-cell transplantation with effective antileukemia activity in patients with acute myeloid leukemia and myelodysplastic syndromes. Leuk Lymphoma 2007; 48: 2352–2359.

    Article  CAS  PubMed  Google Scholar 

  17. Holowiecki J, Giebel S, Wojnar J, Krawczyk-Kulis M, Markiewicz M, Holowiecka-Goral A et al. Treosulfan and fludarabine low-toxicity conditioning for allogeneic haematopoietic stem cell transplantation in chronic myeloid leukaemia. Br J Haematol 2008; 142: 284–292.

    Article  CAS  PubMed  Google Scholar 

  18. Ruutu T, Beelen D, Finke J, Trenschel R, Finke J, Schnitzler M et al. Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplasic syndromes: final results of an international prospective phase II trial. Haematologica 2011; 96: 1344–1350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nemecek ER, Guthrie KA, Sorror ML, Wood BL, Doney KC, Hilger RA et al. Conditioning with treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. Biol Blood Marrow Transplant 2011; 17: 341–350.

    Article  CAS  PubMed  Google Scholar 

  20. Casper J, Wolff D, Knauf W, Blau IW, Ruutu T, Volin L et al. Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning. J Clin Oncol 2010; 28: 3344–3351.

    Article  CAS  PubMed  Google Scholar 

  21. Bernardo ME, Zecca M, Piras E, Vacca A, Giorgiani G, Cugno C et al. Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in patients with thalassaemia major. Br J Haematol 2008; 143: 548–551.

    PubMed  Google Scholar 

  22. Cutting R, Mirelman A, Vora A . Treosulphan as an alternative to busulphan for myeloablative conditioning in paediatric allogeneic transplantation. Br J Haematol 2008; 143: 748–751.

    Article  CAS  PubMed  Google Scholar 

  23. Greystoke B, Bonanomi S, Carr TF, Gharib M, Khalid T, Coussons M et al. Treosulfan-containing regimens achieve high rates of engraftment associated with low transplant morbidity and mortality in children with non-malignant disease and significant co-morbidities. Br J Haematol 2008; 142: 257–262.

    Article  CAS  PubMed  Google Scholar 

  24. Wachowiak J, Sykora KW, Cornish J, Chybicka A, Kowalczyk JR, Gorczyñska E 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 2011 (e-pub ahead of print 7 February 2011; doi:10.1038/bmt.2010.343).

  25. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M et al. Veno-occlusive 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  PubMed  Google Scholar 

  26. Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987; 44: 778–783.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Frassoni F, Labopin M, Powles R, Mary JY, Arcese W, Bacigalupo A et al. Effect of centre on outcome of bone-marrow transplantation for acute myeloid leukaemia. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet 2000; 355: 1393–1398.

    Article  CAS  PubMed  Google Scholar 

  29. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.

    Article  CAS  PubMed  Google Scholar 

  30. Stelljes M, Bornhauser M, Kroger M, Beyer J, Sauerland MC, Heinecke A et al. Conditioning with 8 Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Blood 2005; 106: 33141–33321.

    Article  Google Scholar 

  31. Ringden O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 2009; 27: 4570–4577.

    Article  PubMed  Google Scholar 

  32. Tauro S, Craddock C, Peggs K, Begum G, Mahendra P, Cook G et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005; 23: 9387–9393.

    Article  CAS  PubMed  Google Scholar 

  33. Sayer HG, Kroger M, Beyer J, Kiehl M, Klein SA, Schaefer-Eckart K et al. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor. Bone Marrow Transplant 2003; 31: 1089–1095.

    Article  CAS  PubMed  Google Scholar 

  34. van Besien K, Artz A, Smith S, Cao D, Rich S, Godley L et al. Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005; 23: 5728–5738.

    Article  CAS  PubMed  Google Scholar 

  35. Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ . Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005; 23: 5675–5687.

    Article  PubMed  Google Scholar 

  36. Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia 2006; 20: 322–328.

    Article  CAS  PubMed  Google Scholar 

  37. Martino R, Valcarcel D, Brunet S, Sureda A, Sierra J . Comparable non-relapse mortality and survival after HLA-identical sibling blood stem cell transplantation with reduced or conventional-intensity preparative regimens for high-risk myelodysplasia or acute myeloid leukemia in first remission. Bone Marrow Transplant 2008; 41: 33–38.

    Article  CAS  PubMed  Google Scholar 

  38. Pidala J, Kim J, Anasetti C, Kharfan-Dabaja MA, Field T, Perkins J et al. Targeted i.v. BU and fludarabine (t-i.v. BU/Flu) provides effective control of AML in adults with reduced toxicity. Bone Marrow Transplant 2011; 46: 641–649.

    Article  CAS  PubMed  Google Scholar 

  39. Blaise D, Maraninchi D, Archimbaud E, Reiffers J, Devergie A, Jouet JP et al. Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-Cytoxan versus Cytoxan-total body irradiation as preparative regimen: a report from the Group d’Etudes de la Greffe de Moelle Osseuse. Blood 1992; 79: 2578–2582.

    CAS  PubMed  Google Scholar 

  40. Ferry C, Socie G . Busulfan-cyclophosphamide versus total body irradiation-cyclophosphamide as preparative regimen before allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia: what have we learned? Exp Hematol 2003; 31: 1182–1186.

    Article  CAS  PubMed  Google Scholar 

  41. Grigg AP, Gibson J, Bardy PG, Reynolds J, Shuttleworth P, Koelmeyer RL et al. A prospective multicenter trial of peripheral blood stem cell sibling allografts for acute myeloid leukemia in first complete remission using fludarabine-cyclophosphamide reduced intensity conditioning. Biol Blood Marrow Transplant 2007; 13: 560–567.

    Article  CAS  PubMed  Google Scholar 

  42. Blaise D, Vey N, Faucher C, Mohty M . Current status of reduced-intensity-conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica 2007; 92: 533–541.

    Article  PubMed  Google Scholar 

  43. Blaise DP, Michel Boiron J, Faucher C, Mohty M, Bay JO, Bardoux VJ et al. Reduced intensity conditioning prior to allogeneic stem cell transplantation for patients with acute myeloblastic leukemia as a first-line treatment. Cancer 2005; 104: 1931–1938.

    Article  CAS  PubMed  Google Scholar 

  44. Valcarcel D, Martino R, Caballero D, Martin J, Ferra C, Nieto JB et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008; 26: 577–584.

    Article  CAS  PubMed  Google Scholar 

  45. Marks R, Potthoff K, Hahn J, Ihorst G, Bertz H, Spyridonidis A et al. Reduced-toxicity conditioning with fludarabine, BCNU, and melphalan in allogeneic hematopoietic cell transplantation: particular activity against advanced hematologic malignancies. Blood 2008; 112: 415–425.

    Article  CAS  PubMed  Google Scholar 

  46. Russell JA, Savoie ML, Balogh A, Turner AR, Larratt L, Chaudhry MA et al. Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 CGY total-body irradiation, and thymoglobulin. Biol Blood Marrow Transplant 2007; 13: 814–821.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all patients who participated in this trial as well as the nursing staff.

This work was supported by an unrestricted grant of medac GmbH (Hamburg, Germany).

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Correspondence to J Casper.

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Professor Dr DW Beelen, Professor Dr J Casper and Professor Dr M Freund have received research funding by medac GmbH and they have received honoraria for speeches and presentations. Professor Dr J Casper has consulted for medac GmbH and received compensation. Dr J Baumgart, Dr HA Mylius and Dr U Pichlmeier are compensated employees of medac GmbH. All other authors declare no conflict of interest.

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Casper, J., Holowiecki, J., Trenschel, R. et al. Allogeneic hematopoietic SCT in patients with AML following treosulfan/fludarabine conditioning. Bone Marrow Transplant 47, 1171–1177 (2012). https://doi.org/10.1038/bmt.2011.242

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