Publications by authors named "Denise Bonney"

33 Publications

Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease.

Orphanet J Rare Dis 2021 May 21;16(1):235. Epub 2021 May 21.

Department of Blood and Marrow Transplantation, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK.

Background: Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access.

Results: We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT-multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition.

Conclusion: We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.
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http://dx.doi.org/10.1186/s13023-021-01849-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139039PMC
May 2021

High penetrance of myeloid neoplasia with diverse clinical and cytogenetic features in three siblings with a familial GATA2 deficiency.

Cancer Genet 2021 Apr 23;256-257:77-80. Epub 2021 Apr 23.

Manchester Academic Health Science Centre; Department of Paediatric Haematology and Oncology, Royal Manchester Children's Hospital, Manchester NHS Foundation Trust Manchester, UK; Stem Cell and Leukaemia Proteomics Laboratory, Faculty of Medical and Human Sciences, Division of Cancer Studies, University of Manchester, UK; Department of Paediatric and Adolescent Oncology, The Christie NHS Foundation Trust, Manchester, UK. Electronic address:

Pathogenic germ-line variants in GATA2 (GATA2-deficiency) can cause childhood myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and can be associated with distinct clinical syndromic features. However, penetrance and genotype-phenotype correlations are incompletely understood. Here we report on the clinically diverse features of three siblings affected by GATA2c.1021_1031del over an 18-year period, all initially presenting in childhood and adolescence with MDS and AML with monosomy 7 (-7), and one also with trisomy 8 (+8). The siblings inherited a GATA2c.1021_1031del from their father who remains asymptomatic in his sixth decade. The two younger sisters are well after unrelated haematopoietic stem cell transplantation (HSCT), while the first boy died of severe chronic lung disease after sibling HSCT from his youngest sister, who subsequently also developed GATA2-deficiency associated MDS. This family illustrates high penetrance with variable genotype/phenotype correlation within one generation with GATA2-deficiency. We surmise that the lung disease post sibling HSCT was also caused by the GATA2-deficiency. The experience with this family underlines the necessity for GATA2 analysis in all apparently sporadic childhood and teenage MDS and AML with -7 also in the absence of a family history or other clinical features, and rigorous genetic testing in siblings. Moreover, our findings support the arguments for pre-emptive HSCT in variant-carrying siblings.
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http://dx.doi.org/10.1016/j.cancergen.2021.04.002DOI Listing
April 2021

Cord blood CD8+ T-cell expansion following granulocyte transfusions eradicates refractory leukemia.

Blood Adv 2020 09;4(17):4165-4174

Department of Bone Marrow Transplantation, Royal Manchester Children's Hospital, Manchester, United Kingdom.

The action of hematopoietic cell transplantation in controlling leukemia is principally mediated by donor T cells directed against residual recipient malignant cells. However, its utility is limited by graft-versus-host disease (GVHD), where alloreactivity is extended beyond leukemic and marrow cells. In a human/murine chimeric model, we previously showed that the preferential infiltration of cord blood (CB) CD8+ T cells eradicates an Epstein-Barr virus-driven lymphoblastoid tumor without causing xenogeneic GVHD. In the clinic, however, cord blood CD8+ T-cell reconstitution is significantly delayed, and the observation of such a robust antileukemia effect mediated by cord blood CD8+ T cells has not been reported. We describe an observation of very early T-cell expansion in 4 high-risk pediatric leukemia patients receiving third-party, pooled granulocytes after T cell-replete CB transplantation (CBT). The T-cell expansion was transient but robust, including expansion of CD8+ T cells, in contrast to the delayed CD8+ T-cell expansion ordinarily observed after T cell-replete CBT. The CD8+ T cells were polyclonal, rapidly switched to memory phenotype, and had the ability to mediate cytotoxicity. This phenomenon is reproducible, and each patient remains in long-term remission without GVHD. The results suggest that fetal-derived CB CD8+ T cells can be exploited to generate robust antileukemia effects without GVHD.
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http://dx.doi.org/10.1182/bloodadvances.2020001737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479944PMC
September 2020

Genomic profiling of acute myeloid leukaemia associated with ataxia telangiectasia identifies a complex karyotype with wild-type TP53 and mutant KRAS, G3BP1 and IL7R.

Pediatr Blood Cancer 2020 09 8;67(9):e28354. Epub 2020 May 8.

Department of Paediatric Hematology and Oncology, Royal Manchester Children's Hospital, Central Manchester Foundation Trust, Manchester, UK.

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http://dx.doi.org/10.1002/pbc.28354DOI Listing
September 2020

Burden of adenoviraemia predicts survival in paediatric recipients of allogeneic haematopoietic stem cell transplant.

J Clin Virol 2020 06 19;127:104373. Epub 2020 Apr 19.

Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Oxford Road, Manchester, M13 9WL, United Kingdom.

Background: Adenoviraemia occurs in 15 to 30% of paediatric allogeneic haematopoietic stem cell transplant (HSCT) recipients, and is a significant cause of morbidity and mortality which lacks satisfactory therapeutic options. The relationship between burden of adenovirus and mortality is poorly defined in this patient group.

Objectives: To determine the relationship between adenoviraemia and mortality in paediatric HSCT recipients.

Study Design: A retrospective review of blood adenovirus PCR results in paediatric HSCT recipients spanning February 2003 to September 2016 was conducted. Three measures of adenovirus burden were defined; number of days with significant viraemia, peak adenovirus load and Area under the Curve and related to outcome post-HSCT.

Results: A total of 62 patients with episodes of positive blood adenovirus PCR were identified for analysis. Adenoviraemia of more than 7 days, peak viral load of >8000 copies/ml and higher 16 week Area under the Curve were all significantly associated with higher non-relapse mortality in paediatric HSCT recipients.

Conclusions: This retrospective analysis highlights the important predictive value of adenoviral load for non-relapse mortality in young allogeneic HSCT recipients. These data also suggest a possible role for use of these measures as end points in trials of novel adenoviral therapies.
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http://dx.doi.org/10.1016/j.jcv.2020.104373DOI Listing
June 2020

Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR.

Nat Med 2019 09 2;25(9):1408-1414. Epub 2019 Sep 2.

University College London Genomics, London, UK.

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL), but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19 clones. Some factors, including the choice of single-chain spacer and extracellular and costimulatory domains, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.
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http://dx.doi.org/10.1038/s41591-019-0549-5DOI Listing
September 2019

Immune cytopenia post-cord transplant in Hurler syndrome is a forme fruste of graft rejection.

Blood Adv 2019 02;3(4):570-574

Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, United Kingdom.

Umbilical cord blood (UCB) is the preferred donor cell source for children with Hurler syndrome undergoing transplant, and its use has been associated with improved "engrafted survival" rates. However, as in other pediatric recipients of UCB transplants for nonmalignant disease, immune-mediated cytopenia (IMC) is a significant complication. This article describes 8 episodes of IMC in 36 patients with Hurler syndrome undergoing UCB transplant. The incidence of IMC was increased in those with a higher preconditioning absolute lymphocyte count and in those conditioned with fludarabine-containing regimens rather than cyclophosphamide, and it included red cell alloantibodies directed at cord blood group antigens that are novel to the recipient. In several cases, IMC was a precursor to immune-mediated complete graft rejection. We describe IMC as part of a spectrum of graft rejection by a residual competent host immune system and a forme fruste of complete graft rejection.
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http://dx.doi.org/10.1182/bloodadvances.2018026963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391675PMC
February 2019

Molecular monitoring of adenovirus reactivation in faeces after haematopoietic stem-cell transplantation to predict systemic infection: a retrospective cohort study.

Lancet Haematol 2018 Sep;5(9):e422-e429

Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, UK. Electronic address:

Background: Faecal shedding of adenovirus following allogeneic haematopoietic stem-cell transplantation (HSCT) is an early sign of loss of immune control over adenovirus, but there is no consensus on the role of monitoring of faecal adenoviral load by serial testing. We investigated whether serial faecal PCR monitoring could predict the risk of adenoviraemia and survival outcomes after HSCT.

Methods: We did a retrospective cohort study at the Royal Manchester Children's Hospital, Manchester, UK, of patients who had received their first allogeneic HSCT between Feb 1, 2003, and Sept 1, 2016, and adenovirus infection recorded in their medical records. We excluded patients who had received second or third transplants or autologous HSCT transplants. We obtained characteristics of patients and transplants, including mortality and adenoviral reactivation, from medical records and the hospital database. All patients had blood samples tested weekly for adenovirus by PCR until immunosuppression was stopped and CD3 T-cell count recovered to greater than 0·3 × 10/L. Faecal PCR was done before transplantation in all patients, and after transplantation in patients who had diarrhoea, at the onset of symptoms and weekly thereafter until diarrhoea resolved. We analysed all samples available before and after HSCT. We did subgroup analyses for patients undergoing HSCT for cancer versus non-malignant conditions. We also assessed whether 5 log copies per g faeces was a suitable predictive threshold for adenoviraemia.

Findings: We included 341 patients who had undergone a first allogeneic HSCT (median age 4·6 years, IQR 1·5-8·0, range 0-20·0). After HSCT, PCR was done in 4116 faecal samples from 293 (86%) patients who had diarrhoea and in 10 649 blood samples from 341 patients. Follow-up ended on July 14, 2017. 173 (59%) of 293 patients had adenovirus in faecal samples and 63 (18%) of 341 had adenovirus in blood samples. Maximum faecal viral load before adenoviraemia correlated significantly with maximum blood viral load (r=0·51, 95% CI 0·38-0·61, p<0·0001). Faecal adenoviral viral load greater than 5 log copies per g faeces was predictive of adenoviraemia (odds ratio 10·2, 95% CI 4·9-21·6, p<0·0001) with sensitivity 75·9% and specificity 74·8%. These values were increased further in patients with cancer, to 86·4% and 87·5%, respectively. Among the 28 patients who had positive faecal and blood samples and who had undergone serial faecal PCR monitoring after HSCT, the median time between reaching the faecal viral load threshold and onset of adenoviraemia was 8·0 days (IQR 2·3-21·8, 95% CI 4·0-16·0). Non-relapse mortality was not associated with adenovirus reactivation in faeces alone (9·2%, 95% CI 5·4-14·3 in patients without reactivation vs 7·8%, 3·8-13·7 in those with positive faeces only), but was significantly increased in patients who developed adenoviraemia (27·0%, 95% CI 16·7-38·4, p<0·0001).

Interpretation: We identified a threshold faecal viral load that can predict the risk of adenoviraemia. Our findings support proliferation of adenovirus in the gastrointestinal tract before viraemia develops. Faecal PCR is suitable for early detection of children and young adults at risk of adenoviraemia, and its use might help reduce non-relapse mortality in allogeneic HSCT recipients.

Funding: None.
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http://dx.doi.org/10.1016/S2352-3026(18)30130-3DOI Listing
September 2018

Patterns and frequency of renal abnormalities in Fanconi anaemia: implications for long-term management.

Pediatr Nephrol 2018 09 12;33(9):1547-1551. Epub 2018 Apr 12.

Manchester Academic Health Science Centre, Manchester, UK.

Background: Fanconi anaemia (FA) is an inherited disease with bone marrow failure, variable congenital and developmental abnormalities, and cancer predisposition. With improved survival, non-haematological manifestations of FA become increasingly important for long-term management. While renal abnormalities are recognized, detailed data on patterns and frequency and implications for long-term management are sparse.

Methods: We reviewed clinical course and imaging findings of FA patients with respect to renal complications in our centre over a 25-year period to formulate some practical suggestions for guidelines for management of renal problems associated with FA.

Results: Thirty patients including four sibling sets were reviewed. On imaging, 14 had evidence of anatomical abnormalities of the kidneys. Two cases with severe phenotype, including renal abnormalities, had chronic kidney disease (CKD) at diagnosis. Haematopoietic stem cell transplantation was complicated by significant acute kidney injury (AKI) in three cases. In three patients, there was CKD at long-term follow-up. All patients had normal blood pressure.

Conclusions: Evaluation of renal anatomy with ultrasound imaging is important at diagnostic workup of FA. While CKD is uncommon at diagnosis, our data suggests that the incidence of CKD increases with age, in particular after haematopoietic stem cell transplantation. Monitoring of renal function is essential for management of FA. Based on these long-term clinical observations, we formulate some practical guidelines for assessment and management of renal abnormalities in FA.
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http://dx.doi.org/10.1007/s00467-018-3952-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061664PMC
September 2018

Ascitic fluid drainage using a peritoneal dialysis catheter to prevent and treat multi-organ dysfunction in veno-occlusive disease in children undergoing hematopoietic stem cell transplantation.

Pediatr Blood Cancer 2017 Sep 28;64(9). Epub 2017 Feb 28.

Blood and Marrow Transplantation Unit, Royal Manchester Children's Hospital, Manchester, UK.

Veno-occlusive disease (VOD), or sinusoidal obstruction syndrome, is a well-recognised, serious complication associated with the chemotherapy conditioning therapy used in hematopoietic stem cell transplantation (HSCT). Fluid management is typically challenging in children with this condition. We describe effective early use of peritoneal dialysis catheters to drain extravascular, intra-abdominal fluid in children with VOD, allowing intravascular fluid administration to preserve renal perfusion and function, preventing multi-organ dysfunction. All but one of the children are long-term survivors, both of their significant VOD and their HSCT. The child that did not survive died from their underlying metabolic illness, not VOD.
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http://dx.doi.org/10.1002/pbc.26469DOI Listing
September 2017

The role of extracorporeal photopheresis in the management of cutaneous T-cell lymphoma, graft-versus-host disease and organ transplant rejection: a consensus statement update from the UK Photopheresis Society.

Br J Haematol 2017 04 21;177(2):287-310. Epub 2017 Feb 21.

University Hospitals Birmingham NHS Trust, Birmingham, UK.

Extracorporeal photopheresis (ECP) has been used for over 35 years in the treatment of erythrodermic cutaneous T-cell lymphoma (CTCL) and over 20 years for chronic and acute graft-versus-host disease (GvHD) and solid organ transplant rejection. ECP for CTCL and GvHD is available at specialised centres across the UK. The lack of prospective randomised trials in ECP led to the development of UK Consensus Statements for patient selection, treatment schedules, monitoring protocols and patient assessment criteria for ECP. The recent literature has been reviewed and considered when writing this update. Most notably, the national transition from the UVAR XTS machine to the new CELLEX machine for ECP with dual access and a shorter treatment time has led to relevant changes in these schedules. This consensus statement updates the previous statement from 2007 on the treatment of CTCL and GvHD with ECP using evidence based medicine and best medical practise and includes guidelines for both children and adults.
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http://dx.doi.org/10.1111/bjh.14537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412836PMC
April 2017

An emerging opportunistic infection: fatal astrovirus (VA1/HMO-C) encephalitis in a pediatric stem cell transplant recipient.

Transpl Infect Dis 2016 Dec 27;18(6):960-964. Epub 2016 Oct 27.

Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, UK.

Neuroinvasive astrovirus (VA1-HMO-C) is an emerging life-threatening infection in immunocompromised hosts. We describe an 8-month-old child who died of VA1/HMO-C encephalitis following bone marrow transplantation. The diagnosis was only made post-mortem using RNA deep sequencing of the brain. Repeat analysis of the post-mortem brain tissue using polymerase chain reaction specific primers for VA1/HMO-C was positive. Astrovirus VA1/HMO-C should be included in the evaluation of patients with similar encephalitis.
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http://dx.doi.org/10.1111/tid.12607DOI Listing
December 2016

Successful Curative Therapy With Rituximab and Allogeneic Haematopoietic Stem Cell Transplantation for MALT Lymphoma Associated With STK4-Mutated CD4+ Lymphocytopenia.

Pediatr Blood Cancer 2016 09 10;63(9):1657-9. Epub 2016 May 10.

Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, UK.

Idiopathic CD4+ lymphocytopenia and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) are rare diseases in children. We report the first case of a child with STK4-mutated CD4+ lymphocytopenia who developed Epstein-Barr virus associated MALT lymphoma arising in the salivary gland. The child achieved complete remission with rituximab, and her immunodeficiency was cured by haematopoietic stem cell transplantation. The child remained well 24 months post transplantation.
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http://dx.doi.org/10.1002/pbc.26048DOI Listing
September 2016

Rituximab-induced Cytokine Storm in the Absence of Overt Lymphoproliferative Disease.

J Pediatr Hematol Oncol 2016 Jan;38(1):e29-31

Departments of *Paediatric Haematology †Paediatric Immunology, Royal Manchester Children's Hospital, Manchester, UK.

Rituximab is a monoclonal antibody that first demonstrated efficacy in the treatment of lymphoma but has since seen a dramatic growth in its use for other conditions. Cytokine release syndrome (CRS) is a rare but potentially fatal complication of rituximab infusion that has been described in patients with bulky lymphoproliferative disease. Here we report a convincing case of CRS occurring in a patient with no demonstrable lymphoproliferation. This case has implications for our understanding of the pathogenesis of CRS, our attempts to define an at-risk population and the design of future monoclonal antibodies.
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http://dx.doi.org/10.1097/MPH.0000000000000485DOI Listing
January 2016

Central nervous system abnormalities in Fanconi anaemia: patterns and frequency on magnetic resonance imaging.

Br J Radiol 2015 15;88(1056):20150088. Epub 2015 Sep 15.

3 Children's Brain Tumour Research Network, University of Manchester, Royal Manchester Children's Hospital, Manchester, UK.

Objective: Fanconi anaemia (FA) is an inherited disease associated with congenital and developmental abnormalities resulting from the disruption of a multigenic DNA damage response pathway. This study aimed to define the MRI appearances of the brain in patients with FA in correlation with their genetic and clinical features.

Methods: A review of the brain MRI in 20 patients with FA was performed. Pituitary size and frequencies of the radiological findings of individuals with FA and age-matched controls were determined.

Results: Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males). In five cases (25%, p = 0.02), the pituitary morphology was also abnormal. Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy-Walker variant (n = 2) and cerebellar atrophy (n = 2). Six patients (30%, p = 0.01) had morphological structural variation of the corpus callosum (CC).

Conclusion: The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development. MRI brain imaging is important for endocrine assessment and pre-transplant evaluation and can make an important contribution to clinical decision-making.

Advances In Knowledge: The incidence of brain structural abnormalities in FA is higher than previously reported, with abnormalities of the posterior fossa, CC and pituitary being common. There is an association with gender and reduction in pituitary size which does not strongly correlate with biochemically evident endocrine abnormality.
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http://dx.doi.org/10.1259/bjr.20150088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984929PMC
March 2016

Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines.

Biol Blood Marrow Transplant 2015 Jun 20;21(6):1106-9. Epub 2015 Feb 20.

Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

Allogeneic hematopoietic cell transplantation (HCT) is the only treatment able to prevent progressive neurodegenerative disease in a selected group of mucopolysaccharidosis (MPS) disorders. However, its use was historically limited by the high risk of graft failure and transplantation-related morbidity and mortality. Therefore, since 2005 new international HCT guidelines for MPS disorders were proposed. The survival and graft outcomes of MPS patients receiving HCT according to these guidelines in 2 European centers of expertise were evaluated. Two consecutive conditioning regimens were used, busulfan/cyclophosphamide or fludarabine/busulfan-based, both with exposure-targeted i.v. busulfan. A noncarrier matched sibling donor (MSD), matched unrelated cord blood (UCB), or matched unrelated donor (MUD) were considered to be preferred donors. If not available, a mismatched UCB donor was used. Participants were 62 MPS patients (56 MPS type I-Hurler, 2 MPS type II, 2 MPS type III, and 2 MPS type VI) receiving HCT at median age 13.5 months (range, 3 to 44). Forty-one patients received a UCB donor, 17 MSD, and 4 MUD. High overall survival (95.2%) and event-free survival (90.3%) were achieved with only low toxicity: 13.3% acute graft-versus-host disease aGVHD) grades II to IV and 14.8% chronic GVHD (1.9% extensive). A mismatched donor predicted for lower event-free survival (P = .04). A higher age at HCT was a predictor for both aGVHD (P = .001) and chronic GVHD (P = .01). The use of a mismatched donor was a predictor for aGVHD (P = .01). Higher rates of full-donor chimerism were achieved in successfully transplanted UCB recipients compared with MSD/MUD (P = .002). If complying with the international HCT guidelines, HCT in MPS patients results in high safety and efficacy. This allows extension of HCT to more attenuated MPS types. Because a younger age at HCT is associated with reduction of HCT-related toxicity, newborn screening may further increase safety.
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http://dx.doi.org/10.1016/j.bbmt.2015.02.011DOI Listing
June 2015

Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD).

Blood 2014 Oct 5;124(18):2867-71. Epub 2014 Sep 5.

Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada;

Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.
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http://dx.doi.org/10.1182/blood-2014-08-591370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215314PMC
October 2014

Complications of Reduced Intensity Conditioning HSCT for XIAP Deficiency (Alloimmune Cytopenias and HLH) Successfully Managed With Donor Lymphocyte Infusion.

J Pediatr Hematol Oncol 2015 Apr;37(3):e198-9

Departments of *Paediatric Immunology †Transplantation Laboratory ‡Paediatric Haematology, Royal Manchester Children's Hospital, Central Manchester Foundation Trust NHS Hospitals, Manchester, UK.

X-linked inhibitor of apoptosis protein deficiency is a rare illness and although stem cell transplant is curative, full intensity conditioning is associated with high mortality rates. We describe a child with unusual complications associated with residual host lymphocytes following reduced intensity stem cell transplant. Recipient derived, donor directed, antigranulocyte antibodies led to life-threatening and prolonged neutropenia and residual recipient lymphocytes reestablished hemophagocytic lymphohistiocytosis after withdrawal of immune suppression despite high levels of whole blood chimerism. Hemophagocytic lymphohistiocytosis was abolished following specific improvement in donor T-cell chimerism after donor lymphocyte infusions, and alloimmune cytopenias were no longer evident.
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http://dx.doi.org/10.1097/MPH.0000000000000191DOI Listing
April 2015

A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD).

Blood 2013 Jul 3;122(1):112-23. Epub 2013 Apr 3.

Department of Haematology, Royal Manchester Children's Hospital, Manchester, United Kingdom.

Congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders identified by pathological erythroid precursors with perinuclear mitochondrial iron deposition in bone marrow. An international collaborative group of physicians and laboratory scientists collated clinical information on cases of CSA lacking known causative mutations, identifying a clinical subgroup of CSA associated with B immunodeficiency, periodic fevers, and development delay. Twelve cases from 10 families were identified. Median age at presentation was 2 months. Anemia at diagnosis was sideroblastic, typically severe (median hemoglobin, 7.1 g/dL) and markedly microcytic (median mean corpuscular volume, 62.0 fL). Clinical course involved recurrent febrile illness and gastrointestinal disturbance, lacking an infective cause. Investigation revealed B-cell lymphopenia (CD19⁺ range, 0.016-0.22 × 10⁹/L) and panhypogammaglobulinemia in most cases. Children displayed developmental delay alongside variable neurodegeneration, seizures, cerebellar abnormalities, sensorineural deafness, and other multisystem features. Most required regular blood transfusion, iron chelation, and intravenous immunoglobulin replacement. Median survival was 48 months, with 7 deaths caused by cardiac or multiorgan failure. One child underwent bone marrow transplantation aged 9 months, with apparent cure of the hematologic and immunologic manifestations. We describe and define a novel CSA and B-cell immunodeficiency syndrome with additional features resembling a mitochondrial cytopathy. The molecular etiology is under investigation.
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http://dx.doi.org/10.1182/blood-2012-08-439083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761334PMC
July 2013

Heterozygote FANCD2 mutations associated with childhood T Cell ALL and testicular seminoma.

Fam Cancer 2012 Dec;11(4):661-5

Department of Clinical Genetics and Human Genetics, University Medical Centre, Free University of Amsterdam, Amsterdam, The Netherlands.

Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities characterised by cellular cross linker hypersensitivity. FA is caused by mutations in any of so far 15 identified FANC genes, which encode proteins that interact in a common DNA damage response (DDR) pathway. Individuals with FA have a high risk of developing acute myeloid leukaemia (AML) and squamous cell carcinoma. An increased cancer risk has been firmly established for carriers of mutations in FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, RAD51C/FANCO and link the FA pathway to inherited breast and ovarian cancer. We describe a pedigree with FANCD2 mutations c.458T > C (p.Leu153Ser) and c.2715 + 1G > A (p.Glu906LeufsX4) with mild phenotype FA in the index case, T cell ALL in the Leu153Ser heterozygous brother and testicular seminoma in the p.Glu906LeufsX4 heterozygous father. Both FANCD2 alleles were present in the T Cell ALL and the seminoma. This links specific FANCD2 mutations to T cell ALL and seminoma without evidence of allelic loss in the tumour tissue.
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http://dx.doi.org/10.1007/s10689-012-9553-3DOI Listing
December 2012

Management of mucopolysaccharidosis type IH (Hurler's syndrome) presenting in infancy with severe dilated cardiomyopathy: a single institution's experience.

J Inherit Metab Dis 2013 Mar 21;36(2):263-70. Epub 2012 Jun 21.

Department of Paediatric Haematology, Royal Manchester Children's Hospital, Manchester, UK.

Mucopolysaccharidosis type IH (MPSIH) is a lysosomal storage disorder whose untreated course involves progressive multisystem deterioration and death within the first decade of life. Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment modality that improves functional outcome and long-term survival. Optimal outcome requires transplantation early in life and with myeloablative conditioning. Severe cardiomyopathy can be present at diagnosis and may seemingly preclude this approach. We performed a retrospective review of those cases transplanted in Manchester since 2000 that initially presented with established cardiomyopathy, with a view to identifying general management principles. Of 44 MPSIH children transplanted in this period, 6 had displayed moderate or severe cardiomyopathy at presentation; symptomatic cardiac failure was the predominant presenting feature in five of these. Echocardiographic and clinical improvement in cardiac function was observed with extended enzyme replacement therapy (ERT) in all cases, with recovery of fractional shortening to ≥25 % achieved in all patients before coming to transplant (after median 19 weeks ERT). All were transplanted successfully, with good functional and cardiologic outcomes. However, cyclophosphamide conditioning was implicated in acute post-transplant cardiac decompensation in several cases. Our experiences highlight three important messages: (1) A diagnosis of MPSIH should be considered in any infant presenting with unexplained severe cardiac failure; (2) ERT pre-transplant can improve cardiac function sufficiently to permit safe HSCT using myeloablative conditioning; and (3) High dose cyclophosphamide should be avoided in conditioning these patients.
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http://dx.doi.org/10.1007/s10545-012-9500-3DOI Listing
March 2013

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.

Blood 2012 Jun 9;119(25):6155-61. Epub 2012 May 9.

Great Ormond Street Hospital for Children National Health Service Trust, London, United Kingdom.

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.
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http://dx.doi.org/10.1182/blood-2012-01-405795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383023PMC
June 2012

Hemophagocytosis by leukemic megakaryoblasts in acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13;q13);RBM15-MKL1.

J Pediatr Hematol Oncol 2012 Oct;34(7):576-80

Department of Haematology & Oncology, Royal Manchester Children's Hospital, Manchester, UK.

Acute megakaryoblastic leukemia is a rare variant of acute myeloid leukemia, whereby leukemic blasts display characteristic morphologic and phenotypic features indicating megakaryocytoid differentiation. A distinct entity characterized by the t(1;22)(p13;q13) translocation, resulting in the RBM15-MKL1 fusion oncogene, has been recently recognized. This is predominantly a disease afflicting infants and displays characteristic clinical features. We present a case of acute megakaryoblastic leukemia with t(1;22)(p13;q13) along with a discussion of the current understanding of the molecular biology of RBM15-MKL1. This case also displayed striking and unusual morphologic appearances including extensive hemophagocytosis by leukemic blasts, which has not been previously reported for this particular type of leukemia.
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http://dx.doi.org/10.1097/MPH.0b013e318245a027DOI Listing
October 2012

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

Br J Haematol 2012 May 29;157(3):339-46. Epub 2012 Feb 29.

Department of Paediatric & Adolescent Haematology, Great North Children's Hospital, Newcastle upon Tyne, UK.

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.
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http://dx.doi.org/10.1111/j.1365-2141.2012.09066.xDOI Listing
May 2012

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy.

Haematologica 2012 Sep 27;97(9):1320-8. Epub 2012 Feb 27.

Stem Cell & Neurotherapies, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.

Background: Mucopolysaccharidosis type I is caused by deficiency of α-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme. The incidence and impact of alloimmune responses in these patients remain unknown.

Design And Methods: We developed an immunoglobulin G enzyme-linked immunosorbent assay as well as in vitro catalytic enzyme inhibition and cellular uptake inhibition assays and quantified enzyme inhibition by allo-antibodies. We determined the impact of these antibodies in eight patients who received enzyme therapy before and during hematopoietic stem cell transplantation. In addition, 20 patients who had previously received an allogeneic stem cell transplant were tested to evaluate this treatment as an immune tolerance induction mechanism.

Results: High titer immune responses were seen in 87.5% (7/8) patients following exposure to α-L-iduronidase. These patients exhibited catalytic enzyme inhibition (5/8), uptake inhibition of catalytically active enzyme (6/8) or both (4/8). High antibody titers generally preceded elevation of previously described biomarkers of disease progression. The median time to development of immune tolerance was 101 days (range, 26-137) after transplantation. All 20 patients, including those with mixed chimerism (22%), tested 1 year after transplantation were tolerized despite normal enzyme levels.

Conclusions: We found a high incidence of neutralizing antibodies in patients with mucopolysaccharidosis type I treated with enzyme replacement therapy. We also found that allogeneic hematopoietic stem cell transplantation was an effective and rapid immune tolerance induction strategy.
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http://dx.doi.org/10.3324/haematol.2011.058644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436232PMC
September 2012

Pseudohyperkalaemia associated with leukaemic cell lysis during pneumatic tube transport of blood samples.

Pediatr Nephrol 2012 Jun 26;27(6):1029-31. Epub 2012 Feb 26.

Department of Haematology, Royal Manchester Children's Hospital, Manchester, UK.

Background: Pseudohyperkalaemia is relatively uncommon in children, but needs to be considered in cases where extreme hyperkalaemia is associated with normal renal function.

Case: A previously well 12 year-old boy presented with new onset T cell acute lymphoblastic leukaemia associated with a high peripheral blood white cell count. Plasma biochemistry tests on a blood sample sent to the laboratory using a pneumatic tube system showed a high plasma potassium level of 16.6 mmol/l, with otherwise normal electrolytes and renal function. A 12-lead electrocardiogram was normal, with no changes suggestive of hyperkalaemia. Pseudohyperkalaemia was suspected, and further samples transported to the laboratory by foot showed normal plasma potassium levels. It was subsequently demonstrated that the pseudohyperkalemia was due to the lysis of leukaemic white cells during the transport of blood samples from the ward to the laboratory within the pneumatic tube system.

Conclusions: Paediatricians caring for children with haematological malignancies need to be aware of this cause of pseudohyperkalaemia so that unnecessary treatment, including the commencement of acute dialysis, is avoided. We recommend that blood samples collected from children with high white cell count malignancies are transported to the laboratory by foot rather than in pneumatic tube systems.
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http://dx.doi.org/10.1007/s00467-012-2102-3DOI Listing
June 2012