Congenital bone marrow failure syndromes (BMFSs) are relatively rare disorders characterized by aberrant development in one or more hematopoietic lineages. Genetic alterations have now been identified in most of these disorders although the exact role of the molecular defects has yet to be elucidated. Most of these diseases are successfully managed with supportive care, however, treatment refractoriness and disease progression—often involving malignant transformation—may necessitate curative treatment with hematopoietic stem cell transplantation. Due to the underlying molecular defects, the outcome of transplantation for BMFS may be dramatically different than those associated with transplantation for more common diseases, including leukemia. Given recent improvements in survival and molecular diagnosis of bone marrow failure syndrome patients presenting at adult ages without physical stigmata, it is important for both pediatric and adult hematologists to be aware of the possible diagnosis of BMF syndromes and the unique approaches required in treating such patients. 1. Introduction Bone marrow failure syndromes (BMFSs) are a constellation of disorders characterized by abnormal hematopoiesis and often accompanied by assorted physical findings and a strikingly increased risk for hematologic malignancy. Historically, patients presented with significant cytopenias and physical stigmata during childhood. However, it is now evident that BMFS posses a broad range of phenotype penetrance and an increasing number of patients are being identified in adulthood, occasionally presenting with leukemia or aplastic anemia. Some BMFS disorders are associated with defective DNA repair or maintenance pathways and possess increased sensitivity to DNA-damaging agents including chemotherapy and radiation. These sensitivities have been clearly demonstrated by the significantly increased chemotherapy-related and stem cell transplant-related morbidity and mortality in BMFS patients. It is therefore important for both pediatric and adult hematologists to be aware of the presentation, management, complications, and approaches to treat BMFS. We review here transplantation approaches and outcomes in patients with Fanconi Anemia, Diamond-Blackfan anemia, dyskeratosis congenita, severe congenital neutropenia, and Shwachman-Diamond syndrome to illustrate their relative risks for malignancy and reported utility of varying transplant regimens. The reporting of cumulative transplant outcomes will hopefully add clarity to the indications for transplantation in these disorders. 2. Fanconi
References
[1]
P. S. Rosenberg, Y. Huang, and B. P. Alter, “Individualized risks of first adverse events in patients with Fanconi anemia,” Blood, vol. 104, no. 2, pp. 350–355, 2004.
[2]
D. I. Kutler, A. D. Auerbach, J. Satagopan et al., “High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia,” Archives of Otolaryngology, vol. 129, no. 1, pp. 106–112, 2003.
[3]
P. S. Rosenberg, M. H. Greene, and B. P. Alter, “Cancer incidence in persons with Fanconi anemia,” Blood, vol. 101, no. 3, pp. 822–826, 2003.
[4]
E. Gluckman, A. Devergie, and G. Schaison, “Bone marrow transplantation in Fanconi anaemia,” British Journal of Haematology, vol. 45, no. 4, pp. 557–564, 1980.
[5]
R. Berger, A. Bernheim, E. Gluckman, and C. Gisselbrecht, “In vitro effect of cyclophosphamide metabolites on chromosomes of Fanconi anaemia patients,” British Journal of Haematology, vol. 45, no. 4, pp. 565–568, 1980.
[6]
E. Gluckman, A. Devergie, and J. Dutreix, “Radiosensitivity in Fanconi anaemia: application to the conditioning regimen for bone marrow transplantation,” British Journal of Haematology, vol. 54, no. 3, pp. 431–440, 1983.
[7]
A. Farzin, S. M. Davies, F. O. Smith et al., “Matched sibling donor haematopoietic stem cell transplantation in Fanconi anaemia: an update of the Cincinnati Children's experience,” British Journal of Haematology, vol. 136, no. 4, pp. 633–640, 2007.
[8]
J. E. Wagner, M. Eapen, M. L. MacMillan et al., “Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia,” Blood, vol. 109, no. 5, pp. 2256–2262, 2007.
[9]
E. Gluckman, V. Rocha, I. Ionescu et al., “Results of unrelated cord blood transplant in fanconi anemia patients: risk factor analysis for engraftment and survival,” Biology of Blood and Marrow Transplantation, vol. 13, no. 9, pp. 1073–1082, 2007.
[10]
R. Pasquini, J. Carreras, M. C. Pasquini et al., “HLA-matched sibling hematopoietic stem cell transplantation for fanconi anemia: comparison of irradiation and nonirradiation containing conditioning regimens,” Biology of Blood and Marrow Transplantation, vol. 14, no. 10, pp. 1141–1147, 2008.
[11]
F. Locatelli, M. Zecca, A. Pession et al., “The outcome of children with Fanconi anemia given hematopoietic stem cell transplantation and the influence of fludarabine in the conditioning regimen: a report from the Italian Pediatric Group,” Haematologica, vol. 92, no. 10, pp. 1381–1388, 2007.
[12]
M. L. MacMillan, “Alternate donor Hct for Fanconi anemia (Fa): results of a total body irradiation (Tbi) dose de-escalation study,” Biology of Blood and Marrow Transplantation, vol. 15, no. 2, pp. 3–4, 2009.
[13]
A. J. Janov, T. Leong, D. G. Nathan, and E. C. Guinan, “Diamond-Blackfan anemia: natural history and sequelae of treatment,” Medicine, vol. 75, no. 2, pp. 77–87, 1996.
[14]
J. M. Lipton, N. Federman, Y. Khabbaze et al., “Osteogenic sarcoma associated with Diamond-Blackfan anemia: a report from the Diamond-Blackfan anemia registry,” Journal of Pediatric Hematology/Oncology, vol. 23, no. 1, pp. 39–44, 2001.
[15]
J. M. Lipton, M. Kudisch, R. Gross, and D. G. Nathan, “Defective erythroid progenitor differentiation system in congenital hypoplastic (Diamond-Blackfan) anemia,” Blood, vol. 67, no. 4, pp. 962–968, 1986.
[16]
B. E. Glader and K. Backer, “Elevated red cell adenosine deaminase activity: a marker of disordered erythropiesis in Diamond-Blackfan anaemia and other haematologic diseases,” British Journal of Haematology, vol. 68, no. 2, pp. 165–168, 1988.
[17]
A. Vlachos, S. Ball, N. Dahl et al., “Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference,” British Journal of Haematology, vol. 142, no. 6, pp. 859–876, 2008.
[18]
H. Mugishima, S. Ohga, A. Ohara, S. Kojima, K. Fujisawa, and I. Tsukimoto, “Hematopoietic stem cell transplantation for Diamond-Blackfan anemia: a report from the Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology,” Pediatric Transplantation, vol. 11, no. 6, pp. 601–607, 2007.
[19]
C. S. August, E. King, and J. H. Githens, “Establishment of erythropoiesis following bone marrow transplantation in a patient with congenital hypoplastic anemia (Diamond Blackfan syndrome),” Blood, vol. 48, no. 4, pp. 491–498, 1976.
[20]
A. Vlachos, N. Federman, C. Reyes-Haley, J. Abramson, and J. M. Lipton, “Hematopoietic stem cell transplantation for Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry,” Bone Marrow Transplantation, vol. 27, no. 4, pp. 381–386, 2001.
[21]
V. Roy, W. S. Pérez, M. Eapen et al., “Bone marrow transplantation for diamond-blackfan anemia,” Biology of Blood and Marrow Transplantation, vol. 11, no. 8, pp. 600–608, 2005.
[22]
A. Vlachos and E. Muir, “How I treat Diamond Blackfan anemia,” Blood. In press.
[23]
M. Kirwan and I. Dokal, “Dyskeratosis congenita, stem cells and telomeres,” Biochimica et Biophysica Acta, vol. 1792, no. 4, pp. 371–379, 2009.
[24]
B. P. Alter, N. Giri, S. A. Savage, and P. S. Rosenberg, “Cancer in dyskeratosis congenita,” Blood, vol. 113, no. 26, pp. 6549–6557, 2009.
[25]
B. P. Alter, N. Giri, S. A. Savage et al., “Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study,” British Journal of Haematology, vol. 150, no. 2, pp. 179–188, 2010.
[26]
M. Yabe, H. Yabe, K. Hattori et al., “Fatal interstitial pulmonary disease in a patient with dyskeratosis congenita after allogeneic bone marrow transplantation,” Bone Marrow Transplantation, vol. 19, no. 4, pp. 389–392, 1997.
[27]
B. Nobili, G. Rossi, P. De Stefano et al., “Successful umbilical cord blood transplantation in a child with dyskeratosis congenita after a fludarabine-based reduced-intensity conditioning regimen,” British Journal of Haematology, vol. 119, no. 2, pp. 573–574, 2002.
[28]
T. Güng？r, S. Corbacioglu, R. Storb, and R. A. Seger, “Nonmyeloablative allogeneic hematopoietic stem cell transplantation for treatment of Dyskeratosis congenita,” Bone Marrow Transplantation, vol. 31, no. 5, pp. 407–410, 2003.
[29]
A. C. Dietz, “Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita,” Bone Marrow Transplant. In press.
[30]
K. Devriendt, A. S. Kim, G. Mathijs et al., “Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia,” Nature Genetics, vol. 27, no. 3, pp. 313–317, 2001.
[31]
P. S. Rosenberg, B. P. Alter, A. A. Bolyard et al., “The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy,” Blood, vol. 107, no. 12, pp. 4628–4635, 2006.
[32]
P. S. Rosenberg, C. Zeidler, A. A. Bolyard et al., “Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy: short report,” British Journal of Haematology, vol. 150, no. 2, pp. 196–199, 2010.
[33]
M. H. Freedman, M. A. Bonilla, C. Fier et al., “Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy,” Blood, vol. 96, no. 2, pp. 429–436, 2000.
[34]
C. Zeidler, K. Welte, Y. Barak et al., “Stem cell transplantation in patients with severe congenital neutropenia without evidence of leukemic transformation,” Blood, vol. 95, no. 4, pp. 1195–1198, 2000.
[35]
C. Ferry, M. Ouachée, T. Leblanc et al., “Hematopoietic stem cell transplantation in severe congenital neutropenia: experience of the French SCN register,” Bone Marrow Transplantation, vol. 35, no. 1, pp. 45–50, 2005.
[36]
K. Oshima, R. Hanada, R. Kobayashi et al., “Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: an analysis of 18 Japanese cases,” Pediatric Transplantation, vol. 14, no. 5, pp. 657–663, 2010.
[37]
S. W. Choi, L. A. Boxer, M. A. Pulsipher et al., “Stem cell transplantation in patients with severe congenital neutropenia with evidence of leukemic transformation,” Bone Marrow Transplantation, vol. 35, no. 5, pp. 473–477, 2005.
[38]
L. Burroughs, A. Woolfrey, and A. Shimamura, “Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis,” Hematology/Oncology Clinics of North America, vol. 23, no. 2, pp. 233–248, 2009.
[39]
Y. Dror and M. H. Freedman, “Shwachman-Diamond syndrome: an inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment,” Blood, vol. 94, no. 9, pp. 3048–3054, 1999.
[40]
J. Donadieu, T. Leblanc, B. B. Meunier et al., “Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group,” Haematologica, vol. 90, no. 1, pp. 45–53, 2005.
[41]
J. Donadieu, G. Michel, E. Merlin et al., “Hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: experience of the French neutropenia registry,” Bone Marrow Transplantation, vol. 36, no. 9, pp. 787–792, 2005.
[42]
J. Fleitz, S. Rumelhart, F. Goldman et al., “Successful allogeneic hematopoietic stem cell transplantation (HSCT) for Shwachman-Diamond syndrome,” Bone Marrow Transplantation, vol. 29, no. 1, pp. 75–79, 2002.
[43]
R. Vibhakar, M. Radhi, S. Rumelhart, D. Tatman, and F. Goldman, “Successful unrelated umbilical cord blood transplantation in children with Shwachman-Diamond syndrome,” Bone Marrow Transplantation, vol. 36, no. 10, pp. 855–861, 2005.
[44]
M. Sauer, C. Zeidler, B. Meissner 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 Transplantation, vol. 39, no. 3, pp. 143–147, 2007.
[45]
D. Bhatla, S. M. Davies, S. Shenoy et al., “Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome,” Bone Marrow Transplantation, vol. 42, no. 3, pp. 159–165, 2008.
[46]
A. Tichelli, A. Rovó, and A. Gratwohl, “Late pulmonary, cardiovascular, and renal complications after hematopoietic stem cell transplantation and recommended screening practices,” Hematology, pp. 125–133, 2008.
[47]
Y. R. Abou-Mourad, B. C. Lau, M. J. Barnett et al., “Long-term outcome after allo-SCT: close follow-up on a large cohort treated with myeloablative regimens,” Bone Marrow Transplantation, vol. 45, no. 2, pp. 295–302, 2010.
[48]
U. Forinder, C. L？f, and J. Winiarski, “Quality of life and health in children following allogeneic SCT,” Bone Marrow Transplantation, vol. 36, no. 2, pp. 171–176, 2005.
[49]
C. M. L？f, U. Forinder, and J. Winiarski, “Risk factors for lower health-related QoL after allogeneic stem cell transplantation in children,” Pediatric Transplantation, vol. 11, no. 2, pp. 145–151, 2007.
