Summary:
We reviewed the results of the Dutch paediatric bone marrow transplant (BMT) program for children receiving HLA-identical BMT for β-thalassaemia major over an 18-year period. In all, 19 patients underwent a total of 21 transplants in our treatment centre between July 1984 and February 2002. Eight females (age 0.3–12 years; median 5 years) and 11 males (age 0.8–18 years; median 6 years) were included. Information, prospectively collected, included molecular defects, donor genotype, β/α-globin expression rates, serum ferritin levels, hepato-splenomegaly, chelation history, virology screening, liver pathology together with post-transplant outcome inclusive of leucocyte chimerism. In total, 11 patients received standard busulphan/cyclophosphamide (Bu/Cy) conditioning, with or without ATG. Stable engraftment was seen in 5/11 with late rejection occurring in six patients. Of these, two children underwent a second successful SCT. For this group, overall event-free survival (EFS) and disease-free survival (DFS) were 90 (10/11) and 64% (7/11), respectively. The probability of rejection was 55%. Subsequent addition of melphalan to the conditioning regimen resulted in long-term stable engraftment in all patients with an EFS/DFS for this group of 90% (9/10). Treatment-related mortality, irrespective of conditioning, was low at 5% (1/19 patients). Veno-occlusive disease (VOD) occurred in 19% (4/21 transplants) and acute GvHD in 19% (4/21 transplants). Post-BMT β/α synthetic ratio measurement monitored donor erythroid engraftment and predicted rejection with a return to transfusion dependency. Maintained full donor chimerism is indicative of stable engraftment both for leucocyte and erythroid lineages, whereas mixed donor chimerism is not. Our results emphasise the importance of the conditioning regimen and post-transplant chimerism surveillance predictive of rejection or long-term stable engraftment.
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References
Apperley JF . Bone marrow transplant for the hemoglobinopathies: past, present and future. Clin Haematol 1993; 6: 299–325.
Weatherall D . The treatment of thalassaemia, slow progress and new dilemmas. N Engl J Med 1993; 329: 877–879.
Mentzer WC . Bone marrow transplantation for hemoglobinopathies. Curr Opin Hematology 2000; 7: 9–17.
Piga A, Longo F, Voi V et al. Late effects of bone marrow transplantation for thalassemia. Ann NY Acad Sci 1998; 850: 294–299.
Lucarelli G, Galimberti M, Polchi P et al. Bone marrow transplantation in patients with thalassemia. N Engl J Med 1990; 322: 417–421.
Clift RA, Johnson FL . Marrow transplants for thalassemia: the USA experience. Bone Marrow Transplant 1997; 19S2: 57–59.
Lucarelli G, Galimberti M, Giardani C et al. Bone marrow transplantation in thalassemia: the experience of Pesaro. Ann NY Acad Sci 1998; 850: 270–275.
Borgna-Pignatti C, Rugolotto S, De Stafano P et al. Survival and disease complications in thalassemia major. Ann NY Acad Sci 1998; 850: 227–231.
Lucarelli G, Galimberti M, Polchi P et al. Bone marrow transplantation in adult thalassemia. Blood 1992; 80: 1603–1609.
Lucarelli G, Clift RA, Galimberti M et al. Marrow transplantation for patients with thalassemia: results in class 3 patients. Blood 1996; 87: 2082–2088.
Lucarelli G, Clift RA, Galimberti M et al. Bone marrow transplantation in adult thalassemic patients. Blood 1999; 93: 1164–1167.
Angelucci E, Baronciani D, Lucarelli G et al. Needle liver biopsy in thalassemia: analyses of diagnostic accuracy and safety in 1184 consecutive biopsies. Br J Haematol 1995; 89: 757–761.
Cremers S, Schoemaker R, Bredius R et al. Pharmacokinetics of intravenous busulfan in children prior to stem cell transplantation. Br J Clin Pharmacol 2002; 53: 386–389.
Vossen JM, Heidt PJ, van den Berg H et al. Prevention of infection and graft-versus-host disease by suppression of intestinal microflora in children treated with allogeneic bone marrow transplantation. Eur J Clin Microbiol Infect Dis. 1990; 9: 14–23.
Martin PJ, Schoch G, Fischer L et al. A retrospective analysis of therapy for acute graft-versus-host disease: Initial treatment. Blood 1990; 76: 1464–1470.
Sullivan K . Prevention and treatment of chronic graft-versus-host disease. Marrow Transplant Rev 1992; 76: 1464–1468.
Bernini LF . Rapid estimation of hemoglobin A2 by DEAE chromatography. Biochem Genet 1969; 2: 305–310.
Giordano PC, Harteveld CL, Heister JGAM et al. The molecular spectrum of β-thalassemia and abnormal hemoglobins in the allochthonous and autochthonous Dutch population. Commun Genet 1998; 1: 243–251.
Giordano PC, van Delft P, Batelaan D et al. Hemoglobinopathy analyses in the Netherlands: a report of an in vitro globin chain biosynthesis survey using a rapid, modified method. Clin Lab Haem 1999; 21: 247–255.
Van Tol MJD, Langlois van den Bergh R, Mesker W et al. Simultaneous detection of X and Y chromosomes by two colour fluorescence in situ hybridisation in combination with immunophenotyping of single cells to document chimerism after sex-mismatched bone marrow transplantation. Bone Marrow Transplant 1998; 21: 497–503.
Van Leeuwen JEM, van Tol MJD, Bodzinga BG et al. Detection of mixed chimerism in flow-sorted cell subpopulations by PCR-amplified VNTR markers after allogeneic bone marrow transplantation. Br J Haematol 1991; 79: 218–225.
Yavarian M, Harteveld CL, Batelaan D et al. Molecular spectrum of β-thalassemia in the Iranian province of Hormozgan. Hemoglobin 2001; 25: 35–43.
van Rossum MAJ, Kahkonen M, van Weel MH et al. High rejection rates after bone marrow transplantation for pediatric thalassemia major patients. Bone Marrow Transplant 1995; 12: 100.
Lin KH, Lin KS . Allogeneic bone marrow transplantation for thalassemia in Taiwain: factors associated with graft failure. Am J Pediatr Hematol Oncol 1989; 11: 417–423.
Frappaz D, Gluckman E, Souillet G et al. Allogeneic bone marrow graft for thalassemia major. The French experience. Arch Fr Pediatr 1990; 47: 97–102.
Saunders EF, Oliveri N, Freedman MH . Unexpected complications after bone marrow transplant in transfusion-dependent children. Bone Marrow Transplant 1993; 12: 88–90.
Solh H, Rao K, Martins da Cunha A et al. Engraftment failure following bone marrow transplantation in children with thalassemia major using busulfan and cyclophosphamide conditioning. Pediatr Hematol Oncol 1997; 14: 73–77.
Ball LM, Bredius RGM, Lankester AC et al. Oral complications associated with melphalan in pediatric stem cell transplantation (SCT). Bone Marrow Transplant 2002; 29: S209.
Storb R, Yu C, Deeg HJ et al. Current and future preparative regimens for bone marrow transplantation in thalassemia. Ann NY Acad Sci 1998; 850: 276–287.
Hill RS, Petersen FB, Storb R et al. Mixed hematological chimerism after allogeneic marrow transplantation for severe aplastic anemia is associated with a higher risk for graft rejection and a lessened incidence of acute graft versus host disease. Blood 1986; 67: 811–816.
Nesci C, Manna M, Andreani M et al. Mixed chimerism in thalassemic patients after bone marrow transplantation. Bone Marrow Transplant 1992; 10: 143–146.
Kapelushnik J, Or R, Filon D et al. Analysis of beta-globin mutations shows stable mixed chimerism in patients with thalassemia after bone marrow transplantation. Blood 1995; 86: 3241–3246.
Andreani M, Manna M, Lucarelli G et al. Persistence of mixed chimerism in patients transplanted for the treatment of thalassemia. Blood 1996; 87: 3494–3499.
Andreani M, Nesci C, Lucarelli G et al. Long-term survival of ex-thalassemic patients with persistent mixed chimerism after bone marrow transplantation. Bone Marrow Transplant 2000; 25: 401–404.
Amrolia PJ, Vulliamy T, Vassiliou G et al. Analysis of chimerism in thalassaemic children undergoing stem cell transplantation. Br J Haematol 2001; 114: 219–225.
Weinberg RS, Vlachos A, Najfeld V et al. Disparate lympho-erythroid donor to recipient chimerism in a beta (0)-thalassaemia bone marrow transplant recipient with red cell indices indicative of apparent full engraftment. Br J Haematol 1997; 99: 61–63.
Locasciulli A, Bacigalupo A, van Lint MT et al. Hepatitis-C virus infection in patients undergoing allogeneic bone marrow transplantation. Transplantation 1991; 52: 315–318.
Erer B, Angelucci E, Lucarelli G et al. Hepatitis-C virus infections in thalassemia patients undergoing allogeneic bone marrow transplantation . Bone Marrow Transplant 1994; 14: 369–372.
Strasser SI, Myerson D, Spurgeon CL et al. Hepatis-C virus infection and bone marrow transplantation: a cohort study with ten year follow-up. Hepatology 1999; 29: 1893–1899.
Finch CA, Bellotti B, Stray S et al. Plasma ferritin determination as a diagnostic tool. West J Med 1986; 145: 657–664.
Brittenham GM, Cohen AR, McLaren C et al. Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am J Hematol 1993; 42: 81–87.
Acknowledgements
We thank the medical, nursing and ancillary staff of the IHOBA unit together with Mrs H. Bakker, data manager, Department of Paediatrics, LUMC and the staff of the Europdonor, Leiden, The Netherlands, for their help in the management of patients undergoing bone marrow transplantation. We thank Dr M.J.D van Tol of the Paediatric Immunology Laboratory, LUMC and Dr J Wijnen of the Sylvius Laboratory, Leiden for XY FISH and VNTR analysis, respectively.
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Ball, L., Lankester, A., Giordano, P. et al. Paediatric allogeneic bone marrow transplantation for homozygous β-thalassaemia, the Dutch experience. Bone Marrow Transplant 31, 1081–1087 (2003). https://doi.org/10.1038/sj.bmt.1704066
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DOI: https://doi.org/10.1038/sj.bmt.1704066
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