Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes

Transcription

1 Bone Marrow Transplantation (2015), Macmillan Publishers Limited All rights reserved /15 SPECIAL REPORT Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes R Peffault de Latour 1, C Peters 2, B Gibson 3, B Strahm 4, A Lankester 5, CD de Heredia 6, D Longoni 7, F Fioredda 8, F Locatelli 9, I Yaniv 10, J Wachowiak 11, J Donadieu 12, A Lawitschka 2, M Bierings 13, M Wlodarski 14, S Corbacioglu 15, S Bonanomi 16, S Samarasinghe 17, T Leblanc 18, C Dufour 19 and J-H Dalle 18,20 on behalf of the Pediatric Working Party (PDWP) and the Severe Aplastic Anemia Working Party (SAAWP) of the European Group for Blood and Marrow Transplantation (EBMT) Allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential to cure patients with an inherited bone marrow failure syndrome (IBMFS). However, the procedure involves the risk of treatment-related mortality and may be associated with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks. IBMFS are rare, whereas case reports and small series in the literature illustrate highly heterogeneous practices in terms of indications for HSCT, timing, stem cell source and conditioning regimens. A consensus meeting was therefore held in Vienna in September 2012 on behalf of the European Group for Blood and Marrow Transplantation to discuss HSCT in the setting of IBMFS. This report summarizes the recommendations from this expert panel, including indications for HSCT, timing, stem cell source and conditioning regimen. Bone Marrow Transplantation advance online publication, 8 June 2015; doi: /bmt INTRODUCTION Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of rare hematological disorders characterized by ineffective hematopoiesis and a predisposition to cancer. IBMFS are classically associated with a range of congenital abnormalities. Most common are failure of DNA repair and telomere dysregulation, which characterize Fanconi anemia (FA) and dyskeratosis congenita (DC), respectively. Mutations affecting ribosome assembly or function are associated with Diamond Blackfan anemia (DBA) and Shwachman Diamond syndrome (SDS; for a review see ref. 1). In the absence of an acceptable donor, the treatment for patients with IBMFS remains supportive with blood products and antibiotics. In a number of specific situations, detailed in each of the disease sections below, hematopoietic stem cell transplantation (HSCT) is the treatment of choice. A consensus meeting was held in Vienna in September 2012 on behalf of the European Group for Blood and Marrow Transplantation (EBMT) to discuss HSCT in the setting of IBMFS. General as well as disease-based recommendations from this expert panel are presented in this report. METHODOLOGY In September 2012, 30 experts (9 countries) from the Pediatric Disease Working Parties (PDWP) and the Severe Aplastic Anemia Working Parties (SAAWP) of the EBMT met in Vienna to agree on evidence-based and expert opinion-based consensus recommendations for the management of IBMFS, which included emerging data on the biology of these disorders and information from recent publications. Prior to the conference, appropriate literature was identified from the Pubmed library using the terms transplantation', 'inherited/congenital', 'bone marrow failure' and 'anaemia/anemia. In addition, abstracts from recent international hematology and HSCT meetings were reviewed. During the conference, experts presented data on diagnosis and management of IBMFS. Recommendations based on firm reproducible data are presented in this report without further clarification, 1 Service d Hématologie Greffe, Hôpital Saint-Louis, AP-HP, Paris, France; 2 Stem Cell Transplantation Unit, St Anna Children s Hospital, Vienna, Austria; 3 Royal Hospital for Sick Children, Glasgow, Scotland; 4 Department of Pediatrics and Adolescent Medicine, Pediatric Hematology and Oncology, University Medical Centre, Freiburg, Germany; 5 Department of Pediatrics, Division of Immuno-Hematology and Stem Cell Transplantation, Leiden University Medical Centre, Leiden, The Netherlands; 6 Servicio de Oncología y Hematología Pediátricas, Hospital Vall d Hebron, Barcelona, Spain; 7 Bone Marrow Transplantation Unit, San Gerardo Hospital, Monza, Italy; 8 Dipartimento di Emato Oncologia Pediatrica, Ematologia Clinica e di Laboratorio, IRCCS Istituto G. Gaslini, Genova, Italy; 9 Dipartimento di Onco-Ematologia Pediatrica e Medicina Trasfusionale, U.O. di Oncologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy; 10 Pediatric Hematology Oncology and Stem Cell Transplantation Division, Schneider Children's Medical Centre of Israel, Sackler Faculty of Medicine Tel Aviv University, Petah Tikva, Israel; 11 Department of Pediatric Oncology, Hematology and Transplantology, University of Medical Sciences, Poznan, Poland; 12 Service d'hémato-oncologie Pédiatrique, Hopital Trousseau AP-HP, Paris Registre des neutropénies, Centre de référence des déficits immunitaires héréditaires (neutropénies), Paris, France; 13 BMT-Unit, University Medical Centre Utrecht Pediatrics, Utrecht, The Netherlands; 14 Department of Pediatrics, Hematology and Oncology, University of Freiburg, Freiburg, Germany; 15 Pediatric Hematology, Oncology and Stem Cell Transplantation, Children's Hospital, University of Regensburg, Regensburg, Germany; 16 Pediatric Hematology Unit, San Gerardo Hospital, Monza, Italy; 17 Pediatric Hematology, Great Ormond Street Hospital, London, UK; 18 Service d hémato-immunologie pédiatrique, GH Robert-Debré, AP-HP, Paris, France; 19 Pediatric Hematology, G. Gaslini Institute, Genova, Italy and 20 Université Paris Diderot Paris 7, Pres Paris-Cité Sorbonne, Paris, France. Correspondence: Professor R Peffault de Latour, Department of Hematology and Transplantation, Service d Hématologie Greffe, Hôpital Saint-Louis, AP-HP, 1 avenue Claude Vellefaux, Paris 75010, France. regis.peffaultdelatour@aphp.fr Received 8 August 2014; revised 23 March 2015; accepted 18 April 2015

2 2 whereas recommendations based on expert opinion, following agreement among the panel of 30 experts, are indicated as such. DEFINITIONS AND GENERAL CONSIDERATIONS Donor type and HLA-typing A matched sibling donor is a family donor who shares the same parental haplotypes as the patient. It is important that all potential related donors are tested for the gene defect responsible for the disorder, identified in the index patient, so as to avoid the use of a donor who will in time eventually develop bone marrow failure (BMF). A matched unrelated donor (UD) is defined by a 10/10 allelic HLA-matched compatibility (HLA-A, -B, -C, -DQ and -DRB1 typing at the allele level). Cord blood is considered to be matched in cases where 6 out of 6 HLA Ags are similar, based on Ag-level HLA-A and -B typing and allele-level HLA-DRB1 typing. Matched related cord blood is a good option. Mismatched UDs (not 10/10 allelic HLA-matched), unrelated cord blood or haplo-identical HSCTs should only be performed in experienced centers. Recipient age at time of HSCT HSCT should be performed as early as possible. Evidently, age alone is not an indication for HSCT and should be considered in cases of hematological manifestations (cf. specific considerations below). Source of stem cells Bone marrow has been shown to be superior to peripheral blood as a stem cell source in patients with acquired aplastic anemia undergoing matched sibling or unrelated transplants. 2,3 PBSC should be avoided because of the associated higher risk of extensive chronic GvHD compared with bone marrow. Similar results have been published recently for patients with FA. 4 These results lead us to recommend bone marrow as the preferred choice of stem cells for all children with IBMFS. Cell dose The recommended cell dose is total nucleated cells/kg of recipient body weight for bone marrow stem cells, and total nucleated cells/kg of recipient body weight before freezing for cord stem cells. 5 Conditioning regimen International criteria exist defining reduced-intensity conditioning (RIC) and myeloablative conditioning (MAC) regimens. 6 Detailed specific recommendations for each disorder are described herein. TBI should be avoided to limit long-term complications. GvHD prophylaxis GvHD is one of the most significant complications in nonmalignant diseases and must be avoided. GvHD prophylaxis should include cyclosporin A plus methotrexate. Cyclosporin A should be gradually reduced until it can be discontinued, in the absence of chronic GvHD, 6 12 months after HSCT. These later recommendations are derived from what has been published in acquired severe aplastic anemia from sibling donors 7 and unrelated transplantation, 8 using bone marrow as a stem cell source. Pre-transplantation serotherapy (either anti-thymoglobuline or alemtuzumab) is recommended for UD-HSCT, but not for matched sibling donor HSCT because of the associated immunosuppression in the early months post HSCT, which has the potential for higher transplantation-related morbidity and mortality owing to opportunistic infections. SPECIFIC CONSIDERATIONS REGARDING IBMFS WITH PANCYTOPENIA AT PRESENTATION FA State of the art. FA is characterized by congenital organ and skeletal abnormalities, progressive BMF and a predisposition for malignancy. HSCT is the only curative option for BMF, 9 11 but increases the risk of secondary cancers in a population already at increased risk. 4,12 Conditioning regimens employing reduced doses of cyclophosphamide (with or without limited field radiotherapy), have cured FA-related BMF in patients transplanted from a matched related family donor. Published results on UD-HSCT have historically been less encouraging, mainly because of an increased risk of graft failure and higher incidences of both acute and chronic GvHD; however, more encouraging results have recently been reported for UD-HSCT in FA, using fludarabinebased RIC regimens with or without T-cell depletion. 4,9 11 Clonal evolution to myelodysplastic syndrome (MDS) and AML is part of the natural evolution of FA and successful HSCT has recently been reported in this setting by the Center for International Blood and Marrow Transplant Research. 13 Indications for HSCT. The optimal timing of HSCT is difficult to define, but the panel of experts agrees that an ideal time is before the patient has received 20 red cell and/or single platelet transfusions, androgen therapy and has developed clonal evolution (MDS or leukemia). These recommendations have already been published elsewhere. 14 To avoid receiving this level of blood-product support, standard-risk patients ( o18 years of age, good organ function, absence of advanced MDS or leukemia) should undergo HSCT when persistent or moderately severe cytopenia develops (that is, hemoglobino8 g/dl; absolute neutrophil counto per liter and/or platelet counto per liter). Any patients who have not been transplanted should undergo an annual bone marrow aspirate with cytogenetic evaluation to detect early dysplastic changes which are an indication for HSCT. Isolated cytogenetic abnormalities should not be considered per se to be an indication of HSCT, as persistent/recurrent chromosome abnormalities without evolution to aplasia or leukemia have been reported. 15 This latter situation is the subject of intense research worldwide. Contraindication. HSCT is contraindicated in FA patients demonstrating somatic mosaicism without clonal evolution, as these patients usually present normal or subnormal hematologic counts without transfusion support or susceptibility to infection. Recommendations. Preparative regimens for HSCT in patients with FA should be modified compared with standard conditioning to limit tissue damage, which cannot be repaired because of the chromosomal instability present in all FA cells, including nonhematopoietic tissues. A RIC regimen should therefore be used with reduced doses of cyclophosphamide (20 40 mg/kg) to limit toxicity. The use of fludarabine with or without T-cell depletion 4,9,10 has led to significant improvement in outcomes in recent years and should be included in the conditioning regimen. Irradiation should not be routinely used to avoid further impairment of DNA repair. The exception is low-dose TBI (that is, TBI 2 gray) when the risk of rejection is high (high-burden transfusion history and unrelated cord blood as the source of stem cells). In the most recent period, a fludarabine-based conditioning regimen led to 2-year overall survival of 80 90% after sibling transplantation 16 and 70 80% after matched unrelated HSCT. 9,10 The prognosis is poor for patients with clonal evolution (that is, MDS, AML) at the time of transplantation and the management of such patients remains challenging. 13,17 However, a recent study suggested that a sequential approach with chemotherapy Bone Marrow Transplantation (2015), Macmillan Publishers Limited

3 combined with RIC for clonal evolution achieved good results in a limited number of patients. 18 The panel of experts agrees that the latter approach is appropriate for patients with a blast count 10%, but that patients with a blast count below this threshold should be treated according to previous recommendations, with no additional chemotherapy preceding HSCT, owing to a predictable higher rate of toxicity. DC State of the art. DC is characterized by the triad of reticulated skin hyperpigmentation, nail dystrophy and oral leukoplakia. The phenotype is in fact much more heterogeneous than previously reported; and in some cases may include pulmonary and/or hepatic fibrosis. Telomerase dysfunction and ribosome deficiency characterize this disorder, whereas mutations in eight genes (DKC1, TERT, TERC, TINF1, NOP10, NPH2, TCAB1 and RTEL1) involved in the telomerase complex have been identified in recent years. 19,20 Until recently, HSCT has shown disappointing results, mainly owing to severe late effects, which have included graft failure, GvHD, sepsis and, more importantly, the propensity to develop organ toxicity, including pulmonary fibrosis, hepatic cirrhosis and veno-occlusive disease, among others. 21 Indication for HSCT. BMF occurs in 80% of patients and is the main indication for HSCT. Clonal evolution (MDS or AML) is also common, owing to the cancer predisposition which characterizes this disorder. 22 Recommendations. Matched sibling donors remain the donors of choice, as mismatched related or UDs are associated with an inferior outcome. 23 The hypersensitivity to irradiation and chemotherapy, and possible pre-existing organ dysfunction result in a poor survival rate following conventional MAC. 24 Fludarabinecontaining non-mac regimens are being increasingly used and will hopefully lead to better outcomes. The expert panel found the literature too scarce to issue any valid recommendations. Many patients with DC will succumb at an early age to nonhematological complications associated with their disease, and this issue should be explored in families of potential transplant recipients. SPECIFIC CONSIDERATIONS REGARDING IBMFS WITH SINGLE-CELL DEFECTS AT PRESENTATION Severe congenital neutropenia (SCN) State of the art. SCN is characterized by profound neutropenia diagnosed early in life and complicated by recurrent severe and life-threatening bacterial infections. 25 SCN is caused by mutations of several genes: ELANE gene and SBDS are the most frequent, whereas HAX1, G6PC3, WASP, VPS45, GATA2 and GFi1 may also be found. In addition to life-threatening infections, another major complication is clonal evolution (AML and MDS), affecting ~ 10% of patients. The use of G-CSF therapy has radically changed patient outcomes. 26 HSCT is still the only curative treatment for patients refractory to G-CSF and in cases of clonal evolution (AML and MDS). Indications for HSCT. Established indications for transplantation in SCN include G-CSF resistance (420 μg/kg/day for more than 1 month without neutrophil normalization) even in the absence of infections and clonal evolution (AML and MDS). 27,28 Furthermore, indications for HSCT appear appropriate in patients with neutropenia dependent on chronically high doses of G-CSF (at least 10 μg/kg/day for at least 3 months per year), regarding the potential but not yet proven higher risk of clonal evolution, 29 and for patients with recurrent bacterial infections from a matched family donor. 29 Moreover, GATA2 mutations have been recently identified as a cause of mild congenital neutropenia associated with a high risk of leukemic transformation usually refractory to chemotherapy; 30 as such, the panel of experts agrees that HSCT might be considered if a matched donor is identified. Recommendations. The majority of published cases of patients with SCN undergoing HSCT received MAC prior to HSCT, usually with busulfan and cyclophosphamide. This regimen was effective, with rare graft failure and full chimerism achieved in almost all patients. 27 Less toxic, non-myeloablative, fludarabine-based conditioning regimens might reduce transplant-related mortality, but experience is still very limited. The combined overall and event-free survival for patients transplanted without malignant transformation is excellent at 89% and 75%, respectively. 31 As expected, HSCT outcomes for patients with malignant transformation are inferior. The need for chemotherapy prior to HSCT for patients who have undergone clonal evolution is controversial. Overall, this approach should be reserved for patients with overt leukemia, 27,32 and can be deleterious in other patients (that is, MDS) as it may contribute to an increased risk of infection. 27 SDS State of the art. SDS is part of the congenital neutropenia family. It is a recessive disorder characterized by exocrine pancreatic insufficiency, skeletal abnormalities (metaphyseal dysostosis), mild intellectual retardation and bone marrow dysfunction manifested by cytopenia. 33 Patients with SDS are at an increased risk of developing aplastic anemia, MDS and AML where HSCT is the only curative option. Indications for HSCT. HSCT is indicated in cases involving worsening cytopenias with increased transfusion dependence and/or MDS or leukemia transformation. Recommendations. No firm recommendations can be made. The literature is still limited and mainly comprises case reports. In exceptional cases, mismatched donors have been reported. Though the mechanism is unclear, patients with SDS tend to have increased toxicity with intensive conditioning regimen with 30 40% treatment-related mortality. 34 A reduced-intensity approach might be useful in this situation but again experiences are limited. 35 The survival rates of patients with leukemia or MDS transformation remain poor, with high transplant toxicity-related death and relapse. 36 DBA State of the art. DBA is an autosomal dominant IBMFS characterized by an aregenerative and often macrocytic anemia with erythroblastopenia, which may be associated with mild leuconeutropenia and thrombocytopenia. Approximately 60% of patients may not require any transfusions with small doses of steroids. HSCT is the only curative option in transfusiondependent patients. In other cases, red blood cell transfusions remain a therapeutic option because of the improved chelation available today. DBA patients are at increased risk of leukemia or MDS, but this is mainly a concern for adult patients. Some patients also respond to non-steroid drug treatment, 37 along with cases of spontaneous remission. Indications for HSCT. Non-response to steroids (no increase in reticulocyte counts after two trials of steroid therapy at 1 mg/kg/day), clonal evolution and aplastic anemia (a very rare event in DBA patients) are indications for HSCT. HSCT may also be considered for certain patients who respond to steroids but require more than 0.3 mg/kg/day Macmillan Publishers Limited Bone Marrow Transplantation (2015), 1 5

4 4 Recommendations. An international consensus conference agrees with an indication of HSCT in children with an available matched family donor; 38 in this case the donor must be carefully evaluated in order to exclude a DBA silent phenotype. Only matched sibling donors may be recommended based on data from the literature leading to a 5-year overall survival of 80%. The panel of experts agrees that the strongest evidence is for standard MAC with fludarabine and busulfan or treosulfan. Thiotepa is also a reasonable option. Congenital amegakaryocytic thrombocytopenia State of the art. Congenital amegakaryocytic thrombocytopenia is characterized by the absence of megakaryocytes in the bone marrow secondary to a mutation in c-mpl. This gene codes for the thrombopoietin receptor. The inheritance is autosomal recessive. Patients with a severe form of the disease experience early pancytopenia (before the age of 2 5 years), aplastic anemia and leukemia 39 HSCT is the only curative option. The literature on HSCT for congenital amegakaryocytic thrombocytopenia is sparse and consists mainly of case reports and small series. An ongoing EBMT study on behalf of the PDWP involves 63 transplanted patients. 40 Graft failure is the major problem (11/63 patients had a second HSCT, and 6 even had a third HSCT for primary graft failure). Indication for HSCT. Severe isolated thrombocytopenia or pancytopenia or clonal evolution (MDS or AML) are indications for HSCT. Recommendations. The panel of experts agrees that standard MAC based on fludarabine and either busulfan or treosulfan is recommended for clonal evolution, isolated thrombocytopenia and allo-immunization. RIC may be considered for patients with pancytopenia. CONCLUSION IBMFS are a heterogeneous group of rare hematological disorders. HSCT remains the only curative treatment option for disturbances of hematopoiesis in IBMFS. The literature is limited to case reports and small series, which makes evidence-based recommendation for HSCT difficult. Given that IBMFS are often characterized by non-hematological disease manifestations and increased intrinsic susceptibility to both acute and late treatment-related toxicity, the EBMT-PDWP and SAAWP recommendations are directed at avoiding HSCT-related toxicity. These patients are therefore at risk of both early and late complications, which may be severe and even fatal. Furthermore, patients who are exposed to secondary cancers post HSCT justify being followed-up closely in experienced centers even in the long-term following transplantation. It is important that all potential related donors are tested for the gene defect responsible for the disorder, identified in the index patient, so as to avoid the use of a donor who will eventually develop BMF. Prospective international clinical trials are urgently required in order to enhance the management of these rare disorders, and in time, lead to improved outcomes. CONFLICT OF INTEREST The authors declare no conflict of interest. AUTHOR CONTRIBUTIONS Conception and design: CP, J-HD; provision of study materials and patients: RPL, CP, BG, BS, AL, CDH, DL, FF, FL, IY, JW, JD, AL, MB, MW, SC, SB, SS, TL, CD, J-HD; data collection and assembly: RPL, J-HD; data analysis and interpretation: RPL, CP, BG, BS, AL, CDH, DL, FF, FL, IY, JW, JD, AL, MB, MW, SC, SB, SS, TL, CD, J-HD; manuscript: RPL, CP, J-HD; final approval of manuscript: RPL, CP, BG, BS, AL, CDH, DL, FF, FL, IY, JW, JD, AL, MB, MW, SC, SB, TL, CD, J-HD. REFERENCES 1 Shimamura A. Inherited bone marrow failure syndromes: molecular features. Hematology Am Soc Hematol Educ Program 2006, 1: Eapen M, Le Rademacher J, Antin JH, Champlin RE, Carreras J, Fay J et al. Effect of stem cell source on outcomes after unrelated donor transplantation in severe aplastic anemia. Blood 2011; 118: Bacigalupo A, Socie G, Schrezenmeier H, Tichelli A, Locasciulli A, Fuehrer M et al. Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia: survival advantage for bone marrow in all age groups. Haematologica 2012; 97: Peffault de Latour R, Porcher R, Dalle JH, Aljurf M, Korthof ET, Svahn J et al. Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European group for blood and marrow transplantation experience. Blood 2013; 122: Gluckman E, Ruggeri A, Volt F, Cunha R, Boudjedir K, Rocha V. Milestones in umbilical cord blood transplantation. Br J Haematol 2011; 154: Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009; 15: Locatelli F, Bruno B, Zecca M, Van-Lint MT, McCann S, Arcese W et al. Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial. Blood 2000; 96: Bacigalupo A, Socie G, Lanino E, Prete A, Locatelli F, Cesaro F et al. Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA Working Party. Haematologica 2010; 95: Wagner JE, Eapen M, MacMillan ML, Harris RE, Pasquini R, Boulad F et al. Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood 2007; 109: Locatelli F, Zecca M, Pession A, Morreale G, Longoni D, Di Bartolomeo P 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 2007; 92: Guardiola P, Pasquini R, Dokal I, Ortega JJ, van Weel-Sipman M, Marsh JC et al. Outcome of 69 allogeneic stem cell transplantations for Fanconi anemia using HLA-matched unrelated donors: a study on behalf of the European group for blood and marrow transplantation. Blood 2000; 95: Deeg HJ, Socie G, Schoch G, Henry-Amar M, Witherspoon RP, Devergie A et al. Malignancies after marrow transplantation for aplastic anemia and fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood 1996; 87: Ayas M, Saber W, Davies SM, Harris RE, Hale GA, Socie G et al. Allogeneic hematopoietic cell transplantation for fanconi anemia in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome, or acute leukemia. J Clin Oncol 2013; 31: MacMillan ML, Wagner JE. Haematopoeitic cell transplantation for Fanconi anaemia when and how? Br J Haematol 2010; 149: Alter BP, Caruso JP, Drachtman RA, Uchida T, Velagaleti GV, Elghetany MT et al. Fanconi anemia: myelodysplasia as a predictor of outcome. Cancer Genet Cytogenet 2000; 117: Benajiba L, Salvado C, Dalle JH, Jubert C, Galambrun C, Soulier J et al. HLA-matched related-donor HSCT in Fanconi anemia patients conditioned with cyclophosphamide and fludarabine. Blood 2015; 125: Mitchell R, Wagner JE, Hirsch B, DeFor TE, Zierhut H, MacMillan ML et al. Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia. Br J Haematol 2014; 164: Talbot A, Peffault de Latour R, Raffoux E, Buchbinder N, Vigouroux S, Milpied N et al. Sequential treatment for allogeneic hematopoietic stem cell transplantation in Fanconi anemia with acute myeloid leukemia. Haematologica 2014; 99: e199 e Mason PJ, Bessler M. The genetics of dyskeratosis congenita. Cancer Genet 2011; 204: Walne AJ, Vulliamy T, Kirwan M, Plagnol V, Dokal I. Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. Am J Hum Genet 2013; 92: Rocha V, Devergie A, Socie G, Ribaud P, Espérou H, Parquet N et al. Unusual complications after bone marrow transplantation for dyskeratosis congenita. Br J Haematol 1998; 103: Bone Marrow Transplantation (2015), Macmillan Publishers Limited

5 22 Savage SA, Alter BP. Dyskeratosis congenita. Hematol Oncol Clin North Am 2009; 23: Gadalla SM, Sales-Bonfim C, Carreras J, Alter BP, Antin JH, Ayas M et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita. Biol Blood Marrow Transplant 2013; 19: Amarasinghe K, Dalley C, Dokal I, Laurie A, Gupta V, Marsh J. Late death after unrelated-bmt for dyskeratosis congenita following conditioning with alemtuzumab, fludarabine and melphalan. Bone Marrow Transplant 2007; 40: Kostmann R. Infantile genetic agranulocytosis; agranulocytosis infantilis hereditaria. Acta Paediatr Suppl 1956; 45: Bonilla MA, Gillio AP, Ruggeiro M, Kernan NA, Brochstein JA, Abboud M et al. Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis. N Engl J Med 1989; 320: Ferry C, Ouachee M, Leblanc T, Michel G, Notz-Carrére A, Tabrizi R et al. Hematopoietic stem cell transplantation in severe congenital neutropenia: experience of the French SCN register. Bone Marrow Transplant 2005; 35: Zeidler C, Welte K, Barak Y, Barriga F, Bolyard AA, Boxer L et al. Stem cell transplantation in patients with severe congenital neutropenia without evidence of leukemic transformation. Blood 2000; 95: Donadieu J, Leblanc T, Bader Meunier B, Barkaoui M, Fenneteau O, Bertrand Y 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 2005; 90: Pasquet M, Bellanne-Chantelot C, Tavitian S, Prade N, Beaupain B, Larochelle O et al. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood 2013; 121: Connelly JA, Choi SW, Levine JE. Hematopoietic stem cell transplantation for severe congenital neutropenia. Curr Opin Hematol 2012; 19: Germeshausen M, Ballmaier M, Schulze H, Welte K, Flohr T, Beiske K et al. Granulocyte colony-stimulating factor receptor mutations in a patient with acute lymphoblastic leukemia secondary to severe congenital neutropenia. Blood 2001; 97: Dror Y, Donadieu J, Koglmeier J, Dodge J, Toiviainen-Salo S, Makitie O et al. Draft consensus guidelines for diagnosis and treatment of Shwachman Diamond syndrome. Ann NY Acad Sci 2011; 1242: Cesaro S, Oneto R, Messina C, Gibson BE, Buzyn A, Steward C et al. Haematopoietic stem cell transplantation for Shwachman Diamond disease: a study from the European Group for blood and marrow transplantation. Br J Haematol 2005; 131: Bhatla D, Davies SM, Shenoy S, Harris RE, Crockett M, Shoultz L et al. Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman Diamond syndrome. Bone Marrow Transplant 2008; 42: 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: Abkowitz JL, Schaison G, Boulad F, Brown DL, Buchanan GR, Johnson CA et al. Response of Diamond Blackfan anemia to metoclopramide: evidence for a role for prolactin in erythropoiesis. Blood 2002; 100: Vlachos A, Muir E. How I treat Diamond Blackfan anemia. Blood 116: Ballmaier M, Germeshausen M. Congenital amegakaryocytic thrombocytopenia: clinical presentation, diagnosis, and treatment. Semin Thromb Hemost 2011; 37: Fahd M, Dalissier A, Alahmari AA, Cornish J, Sedlaçek P, Yaniv I et al. Allogeneic stem cell transplantation in amegacaryocytosis: results of a retrospective study in EBMT centers.40th Annual Meeting of the European Society for Blood and Marrow Transplantation 30 March 2 April 2014, Milan, Italy. Oral presentation Macmillan Publishers Limited Bone Marrow Transplantation (2015), 1 5