Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only definitive treatment for severe bone marrow dysfunction and clonal disorders in patients diagnosed with Shwachman–Diamond syndrome (SDS). In an attempt to minimize regimen-related toxicity (RRT), we have initiated a fludarabine/treosulfan/melphalan-based pilot protocol avoiding the combination of busulfan and cyclophosphamide. Median age at transplantation was 9.6 years (range 1.5–17 years). All three patients received conditioning with fludarabine (30 mg/m2/day × 6), treosulfan (12 g/m2/day × 3) and melphalan (140 mg/m2/day × 1). CAMPATH-1H (0.1 mg/kg × 2) was added in two cases, while rabbit ATG (Genzyme; 3 × 2.5 mg/kg) was given to the cord blood recipient. One patient was transplanted with a non-manipulated marrow graft from an HLA-identical sibling, one with a marrow graft from a 10/10 matched unrelated donor, and one with a 9/10 matched unrelated umbilical cord blood (UCB) unit. Mean cell doses given were 3.6 × 108 nucleated cells/kg BW for the bone marrow recipients and 4.2 × 107 nucleated cells/kg BW for UCB recipient. Overall, two of three patients are alive and display 100% donor chimerism. Acute graft-versus-host disease grade II was seen in one patient, while no GVHD exceeding grade I occurred in the remaining two.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Shwachman H, Diamond LK, Oski FA, Khaw KT . The syndrome of pancreatic insufficiency and bone marrow dysfunction. J Pediatr 1964; 65: 645–663.
Smith OP, Hann IM, Chessells JM, Reeves BR, Milla P . Haematological abnormalities in Shwachman–Diamond syndrome. Br J Haematol 1996; 94: 279–284.
Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR et al. Mutations in SBDS are associated with Shwachman–Diamond syndrome. Nat Genet 2003; 33: 97–101.
Rothbaum R, Perrault J, Vlachos A, Cipolli M, Alter BP, Burroughs S et al. Shwachman–Diamond syndrome: report from an international conference. J Pediatr 2002; 141: 266–270.
Ginzberg H, Shin J, Ellis L, Morrison J, Ip W, Dror Y et al. Shwachman syndrome: phenotypic manifestations of sibling sets and isolated cases in a large patient cohort are similar. J Pediatr 1999; 135: 81–88.
Lesesve JF, Dugue F, Gregoire MJ, Witz F, Dror Y . Shwachman–Diamond syndrome with late-onset neutropenia and fatal acute myeloid leukaemia without maturation: a case report. Eur J Haematol 2003; 71: 393–395.
Donadieu J, Michel G, Merlin E, Bordigoni P, Monteux B, Beaupain B et al. Hematopoietic stem cell transplantation for Shwachman–Diamond syndrome: experience of the French neutropenia registry. Bone Marrow Transplant 2005; 36: 787–792.
Fleitz J, Rumelhart S, Goldman F, Ambruso D, Sokol RJ, Pacini D et al. Successful allogeneic hematopoietic stem cell transplantation (HSCT) for Shwachman–Diamond syndrome. Bone Marrow Transplant 2002; 29: 75–79.
Slattery JT, Kalhorn TF, McDonald GB, Lambert K, Buckner CD, Bensinger WI et al. Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients. J Clin Oncol 1996; 14: 1484–1494.
Savilahti E, Rapola J . Frequent myocardial lesions in Shwachman's syndrome. Eight fatal cases among 16 Finnish patients. Acta Paediatr Scand 1984; 73: 642–651.
Browne RK, Scheltinga DM, Pomering M, Mahony M . Testicular myxosporidiasis in anurans, with a description of Myxobolus fallax n.sp. Syst Parasitol 2002; 52: 97–110.
Voorter CE, Rozemuller EH, de Bruyn-Geraets D, van der Zwan AW, Tilanus MG, van den Berg-Loonen EM . Comparison of DRB sequence-based typing using different strategies. Tissue Antigens 1997; 49: 471–476.
Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986; 314: 729–735.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.
Vibhakar R, Radhi M, Rumelhart S, Tatman D, Goldman F . Successful unrelated umbilical cord blood transplantation in children with Shwachman–Diamond syndrome. Bone Marrow Transplant 2005; 36: 855–861.
Stary J, Locatelli F, Niemeyer CM . Stem cell transplantation for aplastic anemia and myelodysplastic syndrome. Bone Marrow Transplant 2005; 35 (Suppl 1): S13–S16.
Tsai PH, Sahdev I, Herry A, Lipton JM . Fatal cyclophosphamide-induced congestive heart failure in a 10-year-old boy with Shwachman–Diamond syndrome and severe bone marrow failure treated with allogeneic bone marrow transplantation. Am J Pediatr Hematol Oncol 1990; 12: 472–476.
Sensenbrenner LL, Owens Jr AH, Heiby JR, Jeejeebhoy HF . Comparative effects of cytotoxic agents on transplanted hematopoietic and antibody-producing cells. J Natl Cancer Inst 1973; 50: 1027–1033.
Fried W, Kedo A, Barone J . Effects of cyclophosphamide and of busulfan on spleen colony-forming units and on hematopoietic stroma. Cancer Res 1977; 37: 1205–1209.
Thomas ED, Buckner CD, Rudolph RH, Fefer A, Storb R, Neiman PE et al. Allogeneic marrow grafting for hematologic malignancy using HL-A matched donor-recipient sibling pairs. Blood 1971; 38: 267–287.
Keating MJ, O'Brien S, Lerner S, Koller C, Beran M, Robertson LE et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 1998; 92: 1165–1171.
Chun HG, Leyland-Jones B, Cheson BD . Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. J Clin Oncol 1991; 9: 175–188.
McDonald GB, Slattery JT, Bouvier ME, Ren S, Batchelder AL, Kalhorn TF et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 2003; 101: 2043–2048.
Kashyap A, Wingard J, Cagnoni P, Roy J, Tarantolo S, Hu W et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biol Blood Marrow Transplant 2002; 8: 493–500.
Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 1983; 309: 1347–1353.
Bearman SI . Veno-occlusive disease of the liver. Curr Opin Oncol 2000; 12: 103–109.
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.
van Pel M, van Breugel DW, Vos W, Ploemacher RE, Boog CJ . Towards a myeloablative regimen with clinical potential: I. Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers. Bone Marrow Transplant 2003; 32: 15–22.
Fichtner I, Becker M, Baumgart J . Antileukaemic activity of treosulfan in xenografted human acute lymphoblastic leukaemias (ALL). Eur J Cancer 2003; 39: 801–807.
Locatelli F, Pession A, Comoli P, Bonetti F, Giorgiani G, Zecca M et al. Role of allogeneic bone marrow transplantation from an HLA-identical sibling or a matched unrelated donor in the treatment of children with juvenile chronic myeloid leukaemia. Br J Haematol 1996; 92: 49–54.
Locatelli F, Niemeyer C, Angelucci E, Bender-Gotze C, Burdach S, Ebell W et al. Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood. J Clin Oncol 1997; 15: 566–573.
Acknowledgements
This work was supported in part by the ‘Elternverein zur Unterstützung der Behandlung krebskranker Kinder Hannover e.V.’ and by the BMBF Network Congenital Bone Marrow Failure Syndromes (01GM0307).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sauer, M., Zeidler, C., Meissner, B. et al. Substitution of cyclophosphamide and busulfan by fludarabine, treosulfan and melphalan in a preparative regimen for children and adolescents with Shwachman–Diamond syndrome. Bone Marrow Transplant 39, 143–147 (2007). https://doi.org/10.1038/sj.bmt.1705553
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bmt.1705553
Keywords
This article is cited by
-
Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman–Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT)
Bone Marrow Transplantation (2020)
-
In Vitro Study of the Enzymatic and Nonenzymatic Conjugation of Treosulfan with Glutathione
European Journal of Drug Metabolism and Pharmacokinetics (2019)
-
Allogeneic hematopoietic stem cell transplantation for inherited bone marrow failure syndromes
International Journal of Hematology (2016)
-
Long-term follow-up of children conditioned with Treosulfan: German and Austrian experience
Bone Marrow Transplantation (2013)
-
Congenital neutropenia: diagnosis, molecular bases and patient management
Orphanet Journal of Rare Diseases (2011)