International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome.

BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). OBJECTIVES: This study sought to characterize HCT outcomes in APDS. METHODS: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT. RESULTS: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT. CONCLUSIONS: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.

Relapse of Aplastic Anemia with Majority Donor Chimerism (Donor-Type Aplasia) Occurring Late after Bone Marrow Transplantation.

There have been sporadic reports of the development of delayed disease recurrence after bone marrow transplantation for severe aplastic anemia despite sustained majority or full donor chimerism. This is termed "donor-type aplasia" (DTA). We describe the management and outcome of 11 pediatric patients from 8 institutions in Europe, the United States, and the Middle East who developed DTA at a mean of 35 months post-transplant. These patients were initially transplanted at a mean age of 10.0 years (range, 5.8 to 16.0 years), 9 from matched sibling donors and 2 from matched unrelated donors. Attempts to treat DTA with varying combinations of additional immunosuppression (including intravenous immunoglobulin, donor lymphocyte infusions, stem cell boosts, and other therapies) failed. Ten patients have received a conditioned second transplant, 9 from the same donor and 1 from a new matched unrelated donor. Aplasia has resolved in the remaining patient in response to ongoing eltrombopag therapy. All patients were alive at a mean of 92 months (range, 26 to 195) after a second transplant; 6 are in complete remission, but 4 suffered from second/recurrent DTA at 16 to 129 months after retransplant and required further transplant therapy.

Neutropenia in Barth syndrome: characteristics, risks, and management.

PURPOSE OF REVIEW: Barth syndrome (BTHS) is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems, and constitutional growth delay. We conducted this review of neutropenia in BTHS to aid in the diagnosis of this disease, and to improve understanding of both the consequences of neutropenia and the benefits of treatment with granulocyte colony-stimulating factor (G-CSF). RECENT FINDINGS: In 88 patients with BTHS, neutropenia, that is, at least one count below 1.5 × 10/l, was detected in 74 (84%) and 44% had severe chronic neutropenia, with multiple counts below 0.5 × 10/l. The pattern of neutropenia varied between intermittent and unpredictable, chronic and severe, or cyclical with mathematically regular oscillations. Monocytosis, that is, monocytes more than 1.0 × 10/l, was observed at least once in 64 of 85 (75%) patients. G-CSF was administered to 39 of 88 patients (44%). Weekly average G-CSF doses ranged from 0.12 to 10.92 µg/kg/day (mean 1.16 µg/kg/day, median 1.16 µg/kg/day). Antibiotic prophylaxis was additionally employed in 21 of 26 neutropenic patients. Pretreatment bone marrow evaluations predominantly showed reduced myeloid maturation which normalized on G-CSF therapy in seven of 13 examined. Consistent clinical improvement, with reduced signs and symptoms of infections, was observed in response to prophylactic G-CSF ±â€Šprophylactic antibiotics. However, despite G-CSF and antibiotics, one adult patient died with multiple infections related to indwelling medical devices and gastrostomy site infection after 15.5 years on G-CSF and a pediatric patient required gastrostomy removal for recurrent abdominal wall cellulitis. SUMMARY: BTHS should be considered in any men with neutropenia accompanied by any of the characteristic features of this syndrome. Prophylaxis with G-CSF ±â€Šantibiotics prevents serious bacterial infections in the more severe neutropenic patients although infections remain a threat even in patients who are very compliant with therapy, especially in those with indwelling devices.

Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant.

Cidofovir is preemptively used for controlling adenoviremia and preventing disseminated viral disease in hematopoietic cell transplant (HCT) recipients but does not lead to resolution of viremia without T-cell immune-reconstitution. The lipid-conjugated prodrug of cidofovir, brincidofovir, has improved oral bioavailability and achieves higher intracellular concentrations of active drug. We present retrospective multicenter data comparing the kinetics of viremia and toxicities following preemptive treatment with and brincidofovir in children and adolescents diagnosed with HCT-related adenoviremia. Forty-one episodes (18 = brincidofovir; 23 = cidofovir) of antiviral therapy were observed in 27 patients. The 2 groups had comparable immune-reconstitution and viral burden. Major (≥2 log-reduction in 2 weeks; n = 13) and minor (≥1 to ≤2 log-reduction in 2 weeks; n = 2) virological responses were observed in 15 (83%) brincidofovir episodes compared to only 2 (9%) major virological responses with cidofovir (P < .0001). Brincidofovir mediated major responses in 9 of 11 cidofovir-unresponsive patients and resulted in complete responses (CR) despite significant lymphopenia (Brincidofovir vs cidofovir; CR = 13 (80%) vs 8 (35%); median lymphocyte count = 320/µl vs 910/µl; P < .05). One patient experienced abdominal cramps and diarrhea necessitating interruption of brincidofovir and none developed nephrotoxicity with brincidofovir. Thus, brincidofovir is well-tolerated and highly efficacious in controlling adenoviremia during the lymphopenic phase of HCT.

A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.

Recently, CLPB deficiency has been shown to cause a genetic syndrome with cataracts, neutropenia, and 3-methylglutaconic aciduria. Surprisingly, the neurological presentation ranges from completely unaffected to patients with virtual absence of development. Muscular hypo- and hypertonia, movement disorder and progressive brain atrophy are frequently reported. We present the foetal, peri- and neonatal features of 31 patients, of which five are previously unreported, using a newly developed clinical severity scoring system rating the clinical, metabolic, imaging and other findings weighted by the age of onset. Our data are illustrated by foetal and neonatal videos. The patients were classified as having a mild (n = 4), moderate (n = 13) or severe (n = 14) disease phenotype. The most striking feature of the severe subtype was the neonatal absence of voluntary movements in combination with ventilator dependency and hyperexcitability. The foetal and neonatal presentation mirrored the course of disease with respect to survival (current median age 17.5 years in the mild group, median age of death 35 days in the severe group), severity and age of onset of all findings evaluated. CLPB deficiency should be considered in neonates with absence of voluntary movements, respiratory insufficiency and swallowing problems, especially if associated with 3-methylglutaconic aciduria, neutropenia and cataracts. Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients. The neonatal presentation of CLPB deficiency predicts the course of disease in later life, which is extremely important for counselling.

Clinical Characteristics and Outcomes of Cardiomyopathy in Barth Syndrome: The UK Experience.

Barth syndrome (BTHS) is an X-linked disorder characterised by cardiomyopathy, neutropenia, skeletal myopathy and growth delay. This study describes the UK national clinical experience and outcome of cardiomyopathy in BTHS. The clinical course and echocardiographic changes of all patients with BTHS in the UK were reviewed from 2004 to 2014. In addition, strain analysis using 2D speckle tracking echocardiography was performed to further assess left ventricular function in the most recent follow-up. At last follow-up, 22 of 27 patients were alive with a median age of 12.6 (2.0-23.8) years; seven underwent cardiac transplantation at a median age of 2 (0.33-3.6) years, and five died (18.5%) at a median age of 1.8 (0.02-4.22) years. All deaths were related to cardiomyopathy or its management. Left ventricular diastolic dimension and systolic function measured by fractional shortening tended to normalise and stabilise after the first 3 years of life in the majority of patients. However, patients with BTHS (n = 16) had statistically significant reduction in global longitudinal and circumferential strain compared to controls (n = 18), (p < 0.001), despite apparent normal conventional measures of function. There was also reduced or reversed apical rotation and reduced left ventricular twist. Sustained ventricular arrhythmia was not seen at follow-up. Cardiac phenotype in BTHS is variable; however, longer-term outcome in our cohort suggests good prognosis after the first 5 years of life. Most patients appeared to have recovered near normal cardiac function by conventional echocardiographic measures, but strain analysis showed abnormal myocardial deformation and rotational mechanics.

Cardiolipin fingerprinting of leukocytes by MALDI-TOF/MS as a screening tool for Barth syndrome.

Barth syndrome (BTHS), an X-linked disease associated with cardioskeletal myopathy, neutropenia, and organic aciduria, is characterized by abnormalities of card-iolipin (CL) species in mitochondria. Diagnosis of the disease is often compromised by lack of rapid and widely available diagnostic laboratory tests. The present study describes a new method for BTHS screening based on MALDI-TOF/MS analysis of leukocyte lipids. This generates a "CL fingerprint" and allows quick and simple assay of the relative levels of CL and monolysocardiolipin species in leukocyte total lipid profiles. To validate the method, we used vector algebra to analyze the difference in lipid composition between controls (24 healthy donors) and patients (8 boys affected by BTHS) in the high-mass phospholipid range. The method of lipid analysis described represents an important additional tool for the diagnosis of BTHS and potentially enables therapeutic monitoring of drug targets, which have been shown to ameliorate abnormal CL profiles in cells.

Similar outcome of upfront-unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party, Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT.

We explored the feasibility of unrelated donor haematopoietic stem cell transplant (HSCT) upfront without prior immunosuppressive therapy (IST) in paediatric idiopathic severe aplastic anaemia (SAA). This cohort was then compared to matched historical controls who had undergone first-line therapy with a matched sibling/family donor (MSD) HSCT (n = 87) or IST with horse antithymocyte globulin and ciclosporin (n = 58) or second-line therapy with unrelated donor HSCT post-failed IST (n = 24). The 2-year overall survival in the upfront cohort was 96 ± 4% compared to 91 ± 3% in the MSD controls (P = 0·30) and 94 ± 3% in the IST controls (P = 0·68) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (P = 0·02).The 2-year event-free survival in the upfront cohort was 92 ± 5% compared to 87 ± 4% in MSD controls (P = 0·37), 40 ± 7% in IST controls (P = 0·0001) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (n = 24) (P = 0·02). Outcomes for upfront-unrelated donor HSCT in paediatric idiopathic SAA were similar to MSD HSCT and superior to IST and unrelated donor HSCT post-IST failure. Front-line therapy with matched unrelated donor HSCT is a novel treatment approach and could be considered as first-line therapy in selected paediatric patients who lack a MSD.

Barth syndrome without tetralinoleoyl cardiolipin deficiency: a possible ameliorated phenotype.

Barth syndrome (BTHS) is an X-linked disorder characterised by cardiac and skeletal myopathy, growth delay, neutropenia and 3-methylglutaconic aciduria (3-MGCA). Patients have TAZ gene mutations which affect metabolism of cardiolipin, resulting in low tetralinoleoyl cardiolipin (CL(4)), an increase in its precursor, monolysocardiolipin (MLCL), and an increased MLCL/CL(4) ratio. During development of a diagnostic service for BTHS, leukocyte CL(4) was measured in 156 controls and 34 patients with genetically confirmed BTHS. A sub-group of seven subjects from three unrelated families was identified with leukocyte CL(4) concentrations within the control range. This had led to initial false negative disease detection in two of these patients. MLCL/CL(4) in this subgroup was lower than in other BTHS patients but higher than controls, with no overlap between the groups. TAZ gene mutations in these families are all predicted to be pathological. This report describes the clinical histories of these seven individuals with an atypical phenotype: some features were typical of BTHS (five have had cardiomyopathy, one family has a history of male infant deaths, three have growth delay and five have 3-MGCA) but none has persistent neutropenia, five have excellent exercise tolerance and two adults are asymptomatic. This report also emphasises the importance of measurement of MLCL/CL(4) ratio rather than CL(4) alone in the biochemical diagnosis of the BTHS.

Impact of immune modulation with in vivo T-cell depletion and myleoablative total body irradiation conditioning on outcomes after unrelated donor transplantation for childhood acute lymphoblastic leukemia.

To determine whether in vivo T-cell depletion, which lowers GVHD, abrogates the antileukemic benefits of myeloablative total body irradiation-based conditioning and unrelated donor transplantation, in the present study, we analyzed 715 children with acute lymphoblastic leukemia. Patients were grouped for analysis according to whether conditioning included antithymocyte globulin (ATG; n = 191) or alemtuzumab (n = 132) and no in vivo T-cell depletion (n = 392). The median follow-up time was 3.5 years for the ATG group and 5 years for the alemtuzumab and T cell-replete groups. Using Cox regression analysis, we compared transplantation outcomes between groups. Compared with no T-cell depletion, grade 2-4 acute and chronic GVHD rates were significantly lower after in vivo T-cell depletion with ATG (relative risk [RR] = 0.66; P = .005 and RR = 0.55; P < .0001, respectively) or alemtuzumab (RR = 0.09; P < .003 and RR = 0.21; P < .0001, respectively). Despite lower GVHD rates after in vivo T-cell depletion, nonrelapse mortality, relapse, overall survival, and leukemia-free survival (LFS) did not differ significantly among the treatment groups. The 3-year probabilities of LFS after ATG-containing, alemtuzumab-containing, and T cell-replete transplantations were 43%, 49%, and 46%, respectively. These data suggest that in vivo T-cell depletion lowers GVHD without compromising LFS among children with acute lymphoblastic leukemia who are undergoing unrelated donor transplantation with myeloablative total body irradiation-based regimens.

Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency.

Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed outcome of HCT in 106 patients with ADA-SCID who received a total of 119 transplants. HCT from matched sibling and family donors (MSDs, MFDs) had significantly better overall survival (86% and 81%) in comparison with HCT from matched unrelated (66%; P < .05) and haploidentical donors (43%; P < .001). Superior overall survival was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; P < .003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T-cell numbers were similar, although a faster rate of T-cell recovery was observed after MSD/MFD HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT. These data detail for the first time the outcomes of HCT for ADA-SCID and show that, if patients survive HCT, long-term cellular and humoral immune recovery is achieved.

Odontoid infiltration and spinal compression in Farber Disease: reversal by haematopoietic stem cell transplantation.

Farber disease (FD) is a lysosomal storage disorder caused by accumulation of ceramide in various organs and tissues, most notably the central nervous system, subcutaneous tissues and respiratory tract. We report a girl who developed major destructive bone involvement, which affected the odontoid process and produced spinal compression at 9 years of age. Bone involvement was proven histologically but resolved, as assessed by serial MRI scanning, following matched unrelated donor haematopoietic stem cell transplantation. This transplant resulted in only partial donor chimerism (less than 10 % donor cells in peripheral blood), yet this was sufficient to almost normalize acid ceramidase levels in leukocytes and to produce dramatic improvements in subcutaneous nodules and joint mobility as well as the beneficial effect on the involved bone. Unfortunately, the transplant was rejected after 2 years but the patient was rescued from an aplastic state by successful haploidentical peripheral blood stem cell transplantation and remained a full donor chimera without recurrence of the bone involvement and with steadily improving mobility at the age of 17 years. We describe an FD patient who presented with severe destruction of the odontoid by inflammatory tissue which was reversed after long-term control achieved by allogeneic hematopoietic stem cell transplantation. After extensive literature search, we believe that this is the first report of bony involvement in Farber disease.

Long-term outcomes of hematopoietic stem cell transplantation for severe treatment-resistant autoimmune cytopenia in children.

We analyzed the long-term outcomes of pediatric patients registered in the European Group for Blood and Marrow Transplantation database who underwent hematopoietic stem cell transplantation (HSCT) for severe treatment refractory autoimmune cytopenia. With a median follow-up of 100 months, event-free survival was 54% overall, with no significant difference between allogeneic HSCT (n = 15) and autologous HSCT (n = 7) recipients (58% versus 42%; P = .50). Despite a trend toward failure of response or relapse after autologous HSCT compared with allogeneic HSCT, the difference was not significant (43% versus 13%; P = .30). Treatment-related mortality was high in both HSCT groups (29% and 16%; P = .09). Based on the limited numbers of subjects in this retrospective analysis, both allogeneic and autologous HSCT may induce complete and persistent responses in approximately one-half of pediatric patients with severe refractory autoimmune cytopenia, although treatment-related toxicity is high.

X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease.

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.

Diagnosis of Barth syndrome using a novel LC-MS/MS method for leukocyte cardiolipin analysis.

Barth syndrome (BTHS) is an X-linked disorder characterised by cardiomyopathy, skeletal myopathy, growth retardation, neutropenia and 3-methylglutaconic aciduria. It is caused by mutations in the TAZ gene which codes for tafazzin, a protein with acyl transferase activity involved in synthesis of cardiolipin. Monolysocardiolipin (MLCL) is an intermediate in this process. Diagnosis of BTHS is difficult, as clinical and biochemical features are variable and numerous TAZ mutations have been described. These factors, together with lack of a straightforward diagnostic test are thought to have contributed to under-diagnosis of the condition. A novel method for cardiolipin analysis by reversed-phase ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is reported which is less complicated and faster than previously described methods and uses a readily available sample type. The equipment, reagents and expertise required are found in most clinical laboratories performing metabolic investigations. Leukocytes were prepared from whole blood, phospholipids extracted and tetralinoleyl cardiolipin (CL4) and MLCL analysed by UPLC-MS/MS. Reference values were derived from analysis of 76 control and 23 BTHS samples as follows: CL4 in controls >132 (95 % CI 100-169), BTHS <30.2 (21.3-40.4) pmol/mg protein; MLCL/CL4 ratio in controls <0.006 (0.004-0.009) and >2.52 (1.51-4.22) in BTHS patients. We describe an improved method for CL4 and MLCL/CL4 analysis which can be incorporated into the routine work of a clinical biochemistry laboratory. It shows 100 % sensitivity and specificity for BTHS, making it a suitable diagnostic test.

Congenital amegakaryocytic thrombocytopenia (CAMT) presenting as severe pancytopenia in the first month of life.

Congenital amegakaryocytic thrombocytopenia (CAMT) is characterised by neonatal thrombocytopenia, with reduced or absent bone marrow megakaryocytes, leading eventually to pancytopenia. The mean age for progression to bone marrow failure is four years, with the earliest reported being six months. We describe a CAMT patient with compound heterozygous mutations of the causative MPL gene (one being a previously unreported splice site mutation in intron 11) who developed pancytopenia within the first month of life. This report emphasises the importance of considering CAMT in the differential diagnosis of congenital aplastic anaemia or idiopathic aplastic anaemia in babies.

Successful mechanical circulatory support for 251 days in a child with intermittent severe neutropenia due to Barth syndrome.

Barth syndrome is an X-linked recessive disorder that is characterized by cardiomyopathy, variable neutropenia, skeletal myopathy, growth delay, and organic aciduria. The cardiac involvement typically results in a high risk of severe heart failure in infancy or early childhood. While Berlin Heart EXCOR is widely accepted as ventricular assistance in pediatric patients with end-stage cardiac failure, infections remain a frequent and potentially severe complication. Therefore, the extended use of the device in the setting of intermittent or severe neutropenia is challenging. We present the case of a three-yr child with Barth syndrome who was bridged successfully to transplant with a Berlin Heart EXCOR assist device for eight months (251 days) without major infectious complication, despite several episodes of severe neutropenia. This case demonstrates that prolonged mechanical circulatory support for a patient with neutropenia is feasible without important morbidity, with careful monitoring and a multidisciplinary approach. G-CSF provides an excellent support in managing neutropenia.

Successful cord blood transplantation in a patient with malignant infantile osteopetrosis and hemophilia.

MIOP is a congenital disorder of osteoclast differentiation or dysfunction. Inadequate bone resorption by osteoclasts results in a spectrum of complications including hypocalcemia, osteosclerosis, marrow failure, extramedullary hematopoiesis, hydrocephalus, visual deficits, and eventual mortality. Early diagnosis and timely HCT is a recommended treatment approach for select patients prior to the development of end-organ damage. A comorbid bleeding disorder presents a unique challenge in the setting of MIOP and cord blood HCT given the additional risk factors for bleeding including delayed engraftment, a high risk of developing sinusoidal obstruction syndrome, and potential need for emergent invasive procedures. To our knowledge, this is the first report of a patient with an autosomal recessive form of MIOP who successfully underwent a cord blood HCT complicated by the presence of mild hemophilia A and HCT-related complications including delayed engraftment, sinusoidal obstruction syndrome, and need for multiple invasive procedures (e.g., ventriculostomy, tracheostomy) without clinically significant bleeding. Given the underlying diagnosis of MIOP and need for HCT, the challenge of mitigating the significant risk of bleeding in a patient with a comorbid bleeding disorder is discussed.

Excellent outcome of matched unrelated donor transplantation in paediatric aplastic anaemia following failure with immunosuppressive therapy: a United Kingdom multicentre retrospective experience.

We retrospectively analysed the outcome of consecutive children with idiopathic severe aplastic anaemia in the United Kingdom who received immunosuppressive therapy (IST) or matched unrelated donor (MUD) haematopoietic stem cell transplantation (HSCT). The 6-month cumulative response rate following rabbit antithymocyte globulin (ATG)/ciclosporin (IST) was 32·5% (95% CI 19·3-46·6) (n = 43). The 5-year estimated failure-free survival (FFS) following IST was 13·3% (95% confidence interval [CI] 4·0-27·8). In contrast, in 44 successive children who received a 10-antigen (HLA-A, -B, -C, -DRB1, -DQB1) MUD HSCT there was an excellent estimated 5-year FFS of 95·01% (95% CI 81·38-98·74). Forty of these children had failed IST previously. HSCT conditioning was a fludarabine, cyclophosphamide and alemtuzumab (FCC) regimen and did not include radiotherapy. There were no cases of graft failure. Median donor chimerism was 100% (range 88-100%). A conditioning regimen, such as FCC that avoids total body irradiation is ideally suited in children. Our data suggest that MUD HSCT following IST failure offers an excellent outcome and furthermore, if a suitable MUD can be found quickly, MUD HSCT may be a reasonable alternative to IST.

The Barth Syndrome Registry: distinguishing disease characteristics and growth data from a longitudinal study.

Barth syndrome (BTHS); MIM accession # 302060) is a rare X-linked recessive cardioskeletal mitochondrial myopathy with features of cardiomyopathy, neutropenia, and growth abnormalities. The objectives of this study were to further elucidate the natural history, clinical disease presentation, and course, and describe growth characteristics for males with BTHS. Patients with a confirmed genetic diagnosis of BTHS are referred to the BTHS Registry through the Barth Syndrome Foundation, self-referral, or physician referral. This study is based on data obtained from 73 subjects alive at the time of enrollment that provided self-reported and/or medical record abstracted data. The mean age at diagnosis of BTHS was 4.04 ± 5.45 years. While the vast majority of subjects reported a history of cardiac dysfunction, nearly 6% denied any history of cardiomyopathy. Although most subjects had only mildly abnormal cardiac function by echocardiography reports, 70% were recognized as having cardiomyopathy in the first year of life and 12% have required cardiac transplantation. Of the 73 enrolled subjects, there have been five deaths. Growth curves were generated demonstrating a shift down for weight, length, and height versus the normative population with late catch up in height for a significant percentage of cases. This data also confirms a significant number of patients with low birth weight, complications in the newborn period, failure to thrive, neutropenia, developmental delay of motor milestones, and mild learning difficulties. However, it is apparent that the disease manifestations are variable, both over time for an individual patient and across the BTHS population.