Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background:HAX1-related congenital neutropenia (HAX1-CN; Kostmann syndrome), is an orphan autosomal recessive inborn disease caused by pathogenic mutations in the HAX1 gene. HAX1-CN contributes to 12.3% of genetically classified cases of CNs, being the third largest group after ELANE and SBDS associated neutropenias in the Severe Chronic Neutropenia International Registry (SCNIR) in Europe. Affected patients suffer from bone marrow failure, as assessed by a maturation arrest of the myelopoiesis, revealing persistent severe neutropenia in the peripheral blood (ANC less than 500/μl) from birth. The disorder is strongly associated with severe bacterial infections in untreated patients. Increase in ANC under G-CSF therapy has reduced infections significantly. Prolonged life expectancy has revealed a high risk for developing myelodysplastic syndrome or acute myeloid leukemia (MDS/AML). The SCNIR monitors the clinical course, treatment, and outcome of patients with severe chronic neutropenia subtypes since 1994, including the world’s largest collection of long-term data on HAX1-CN. Aims: The aim of this clinical observation study is to document the natural course of disease, response to treatment and long-term outcome of HAX1-CN patients. Methods: All HAX1-CN patients enrolled in the SCNIR in Europe were included in this report. Informed consents were obtained according to the Declaration of Helsinki. Standardized clinical parameters at diagnosis and during annual follow-up, as well as family history were collected by the registry. Results: Here we describe the course of HAX1-CN disease, response to treatment and long-term outcome in 72 patients with different types of HAX1 mutations enrolled in the SCNIR in Europe, which is the World’s largest cohort of pediatric and adult HAX1-CN patients reported. The patients cohort characteristics: 39 male, 33 female; 56 minor (below 18 years) and 16 adults (median age 10.4 years, range 1 to 40.8 years). All 72 patients received long-term treatment with hematopoietic growth factor G-CSF and responded well to individual G-CSF doses, (median dose 3.59 µg/kg/d). All studied patients benefit from G-CSF therapy, which results in significant reduction of infections and overall improvement of quality of life. MDS/AML has developed in 11% of the studied cohort in all ages. Acquired somatic mutations in CSF3R and other leukemia-associated genes play a role in leukemogenesis and may be detected prior to MDS/AML. Non-hematological manifestations frequently include CNS (seizures), musculoskeletal system (short statue), and reproductive system (various hypogonadism forms). Summary/Conclusion: Patients with all known types of HAX1 mutations present with severe congenital neutropenia, but respond well to long-term G-CSF treatment. Continuous G-CSF therapy significantly improves the quality of life and allows pediatric patients to reach adulthood. Secondary ovarian insufficiency is frequently observed in young HAX1-CN female patients early after puberty and should be closely monitored during the course of disease. Patients with MDS/AML require stem cell transplantation. Regular monitoring of somatic leukemia associated mutations is recommended. The SCNIR provides a long-term follow up and monitoring of severe neutropenic patients, including the collection of the CN patient´s samples in a centralized biobank, which enables bringing forward the understanding of the mechanisms and consequences of this orphan disease, as well as development of efficient diagnostic and treatment standards. Keywords: Neutropenia, Myelodysplastic syndrome, Bone marrow failure, Acute myeloid leukemia

Summary HAX1 ‐related congenital neutropenia ( HAX1 ‐CN) is a rare autosomal recessive disorder caused by pathogenic variants in the HAX1 gene. HAX1 ‐CN patients suffer from bone marrow failure as assessed by a maturation arrest of the myelopoiesis revealing persistent severe neutropenia from birth. The disorder is strongly associated with severe bacterial infections and a high risk of developing myelodysplastic syndrome or acute myeloid leukaemia. This study aimed to describe the long‐term course of the disease, the treatment, outcome and quality of life in patients with homozygous HAX1 mutations reported to the European branch of the Severe Chronic Neutropenia International Registry. We have analysed a total of 72 patients with different types of homozygous ( n = 68), compound heterozygous ( n = 3), and digenic ( n = 1) HAX1 mutations. The cohort includes 56 paediatric (<18 years) and 16 adult patients. All patients were initially treated with G‐CSF with a sufficient increase in absolute neutrophil counts. Twelve patients required haematopoietic stem cell transplantation for leukaemia ( n = 8) and non‐leukaemic indications ( n = 4). While previous genotype–phenotype reports documented a striking correlation between two main transcript variants and clinical neurological phenotypes, our current analysis reveals novel mutation subtypes and clinical overlaps between all genotypes including severe secondary manifestations, e.g., high incidence of secondary ovarian insufficiency.

Purpose The United Kingdom Childhood Cancer Study’s (UKCCS’s) matched cohort was established to examine the longer term morbidity and mortality of individuals previously diagnosed with cancer before 15 years of age, comparing future healthcare patterns in 5-year cancer survivors to baseline activity seen in age- and sex-matched individuals from the general population.Participants Predicated on a national childhood cancer case-control study conducted in the early 1990s (4430 cases, 9753 controls) in England, Scotland and Wales, the case population comprises 3125 cancer survivors (>5 years), and the control population 7156 age- and sex-matched individuals from the general population who did not have cancer as a child. Participants are now being followed up via linkage to national administrative healthcare databases (deaths, cancers and secondary care hospital activity).Findings to date Enabling the creation of cohorts with minimal selection bias and loss to follow-up, the original case-control study registered all newly diagnosed cases of childhood cancer and their corresponding controls, regardless of their family’s participation. Early findings based on the registered case population found marked survival variations with age and sex across subtypes and differences with deprivation among acute lymphoblastic leukaemia (ALL) survivors. More recently, comparing the health-activity patterns of the case and control populations revealed that survivors of childhood ALL experienced excess outpatient and inpatient activity across their teenage/young adult years. Adding to increased risks of cancer and death and involving most clinical specialties, excesses were not related to routine follow-up monitoring and showed no signs of diminishing over time.Future plans With annual linkage updates, the UKCCS’s maturing population-based matched cohorts provide the foundation for tracking the health of individuals through their lifetime. Comparing the experience of childhood cancer survivors to that of unaffected general-population counterparts, this will include examining subsequent morbidity and mortality, secondary care hospital activity and the impact of deprivation on longer term outcomes.

We analysed the spectrum of congenital hand differences in a cohort of patients with Fanconi anaemia (FA). Data of 48 FA patients at the National Cancer Institute were reviewed focusing on age at diagnosis, type and severity of limb difference and any potential association with other known clinical anomalies that are part of the FA phenotype, specifically VACTERL-H and PHENOS. Twenty-eight patients had an upper limb difference, which always included thumb hypoplasia. Twenty-three patients had bilateral upper limb differences, including varying combinations and severities of thumb hypoplasia, radial dysplasia and thumb duplication. Patients with a limb difference were diagnosed at a younger age (<2 years: 15/28 with limb anomaly versus 4/20 without a limb anomaly). However, 7/28 with limb anomalies, usually thumb hypoplasia, were not diagnosed until after 6 years of age. This study demonstrates the broad spectrum of radial ray anomalies within the FA phenotype along with the possibility of either unilateral or bilateral upper limb differences and adds further merit to consideration of screening for FA in all cases of radial ray anomaly.Level of evidence: II.

OBJECTIVES:To examine morbidity and mortality among teenagers and young adults (TYAs) previously diagnosed with acute lymphoblastic leukaemia (ALL) in childhood, and compare to the general TYA population. DESIGN:National population-based sex-matched and age-matched case-control study converted into a matched cohort, with follow-up linkage to administrative healthcare databases. SETTING:The study population comprised all children (0-14 years) registered for primary care with the National Health Service (NHS) in England 1992-1996. PARTICIPANTS:1082 5-year survivors of ALL diagnosed<15 years of age (1992-1996) and 2018 unaffected individuals; followed up to 15 March 2020. MAIN OUTCOME MEASURES:Associations with hospital activity, cancer and mortality were assessed using incidence rate ratios (IRR) and differences. RESULTS:Mortality in the 5-year ALL survivor cohort was 20 times higher than in the comparison cohort (rate ratio 21.3, 95% CI 11.2 to 45.6), and cancer incidence 10 times higher (IRR 9.9 95% CI 4.1 to 29.1). Hospital activity was increased for many clinical specialties, the strongest associations being for endocrinology; outpatient IRR 36.7, 95% CI 17.3 to 93.4 and inpatient 19.7, 95% CI 7.9 to 63.2 for males, and 11.0, 95% CI 6.2 to 21.1 and 6.2 95% CI 3.1 to 13.5, respectively, for females. Notable excesses were also evident for cardiology, neurology, ophthalmology, respiratory medicine and general medicine. Males were also more likely to attend gastroenterology; ear, nose and throat; urology; and dermatology, while females were more likely to be seen in plastic surgery and less likely in midwifery. CONCLUSIONS:Adding to excess risks of death and cancer, survivors of childhood ALL experience excess outpatient and inpatient activity across their TYA years, which is not related to routine follow-up monitoring. Involving most clinical specialties, associations are striking, showing no signs of diminishing over time. Recognising that all survivors are potentially at risk of late treatment-associated effects, our findings underscore the need to take prior ALL diagnosis into account when interpreting seemingly unrelated symptoms later in life.

Treatment of childhood cancer in High income countries (HIC) has been a success story of the 20th century with data demonstrating ever increasing survival. Some countries (for example, the UK) have national and regional registries providing high quality data, whilst in other countries the lack of population based data makes comparison impossible. In middle and low income countries (MIC and LIC) the incidence of childhood cancer appears to be lower than in HIC, almost certainly due to the lack of diagnosing and reporting of cases. There may be poor understanding and recognition of symptoms, presentation to traditional healers, poor access to healthcare facilities in rural areas and lack of diagnostic testing. Once on treatment, abandonment of further care can be multifactorial in underlying cause but subsequent relapse and death may add to suspicion of "western" medicine. Additionally, the presenting symptoms of childhood cancer can mimic common infectious diseases such as malaria so that cases remain undiagnosed. By reflecting on some common examples of childhood cancer it can be helpful to identify the points on the pathway to diagnosis and treatment which demonstrate the differences between HIC and MIC/LIC. Some interventions, such as funding for travel to treatment centres, accommodation and treatment, can make the difference between some treatment and no treatment. Highlighting these opportunities for change will improve outcomes in childhood cancer and raise standards of care for paediatrics in general. We have described the pathway to diagnosis and management of childhood cancers in HIC and presented the pathways for common malignancies in HIC and comparators for MIC/LIC to encourage supportive dialogue to improve measures to widen global access to diagnosis and management for children with these conditions. A longer term goal would be to support registries for population-based data collection as part of wider understanding of cancer on a global scale.

India has made significant improvement in childhood cancer services in last few decades. However, the outcome still remains modest as compared to global standards due to significant barriers in recognition, diagnosis and cure. Data regarding comprehensive childhood cancer burden in country is lacking due to low and urban predominant coverage of population-based cancer registry programs. The available data shows lower incidence of childhood cancer incidence especially in leukaemia and CNS tumours which may suggest poor awareness of caregivers and delayed diagnosis with many "missed cases". Incidence data are also skewed towards male preponderance which suggests gender bias in seeking healthcare. The childhood cancer services in India are predominantly restricted to few tertiary care centres in major cities. The outcome in major groups of cancer is complicated by delayed and more advanced stage of presentation and poor supportive care during intensive treatment. Treatment refusal and abandonment remains major hurdles. Last few decades saw development of dedicated paediatric oncology services and training programs in the country. The development of InPOG (Indian Paediatric Oncology group) for conducting collaborative trials will lead to adoption of uniform treatment protocols suited for the country. Financial support through the government promoted health insurance and holistic support through philanthropic organizations have improved treatment adherence and outcome. Moving forward, the focus should be on strengthening the cancer registries for capturing nationwide data, improving awareness of childhood cancer among caregivers and healthcare workers for early recognition and improving accessibility of childhood cancer care services beyond major cities.

Background A recent systematic review and meta-analysis identified a paucity of randomised-controlled trials (RCTs) investigating the use of probiotics to reduce or prevent mucositis and infection in children with cancer. Objective This study evaluated the feasibility of undertaking an RCT and investigated the efficacy of probiotics for reducing or preventing mucositis and infection in children with cancers. Setting The Paediatric Oncology and Haematology department at Leeds Teaching Hospital, UK. Patients Children aged 1 year or older, receiving chemotherapies likely to cause mucositis. Interventions Participants were randomised to receive the probiotic or placebo on day 1-14 of a chemotherapy cycle. Participants were also required to complete a patient diary for 21 days. Main outcome measures To assess whether it is feasible to recruit children diagnosed with cancer who are at risk of developing mucositis to an adequately powered RCT. Results Between May and November 2019, 34 out of 39 eligible participants were approached. Ten patients were recruited (4 probiotic and 6 placebo) of which 2 participants withdrew. Seven participants partially completed the diary but only two participants completed 80% or more. Eligible participants appeared to prefer giving informal verbal feedback when in direct contact with research and healthcare professionals. Conclusion This study demonstrated that recruitment needs to be improved prior to undertaking an adequately powered RCT.

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

Adenovirus infection is a well-known complication in patients receiving hematopoietic stem cell transplantation (HSCT). Brincidofovir (BCV) is an orally bioavailable lipid conjugate of cidofovir, which has activity against adenoviruses. We present a review of adenovirus infections treated with BCV which were unresponsive to cidofovir initially in 4 patients and it was used upfront in one patient. Children with adenovirus infection following HSCT treated with BCV, between July 2014 and February 2018 were recognized. Five patients including 3 male and 2 female with a median age of 10 years (range, 2.2 to 10 y) were identified. The median days of adenoviremia detection was 18 days (range, 7 to 303 d) posttransplant. The median peak viral load by quantitative polymerase chain reaction was 21,38,000 copies/mL (range, 1,77,200 to 31,97,000 copies/mL). The median time from first detection of adenoviremia to become negative was 30 days (range, 15 to 113 d). The sites involved were gastrointestinal tract in all patients and 2 patients had additional respiratory tract involvement. Two patients survived and 3 patients died of sepsis. All patients responded well to BCV and no adverse effect was noticed. We saw the good safety profile and excellent antiadenoviral activity of BCV in pediatric patients receiving HSCT without the nephrotoxicity and it may have a role in preemptive therapy.

Introduction Osteonecrosis is a well-recognised treatment-related morbidity risk in patients diagnosed with acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma (LBL), with a high rate of affected patients requiring surgical intervention. Patients may have asymptomatic changes on imaging studies that spontaneously regress, and little is known about the natural history of osteonecrotic changes seen. The main aim of the British OsteoNEcrosis Study (BONES) is to determine the incidence of symptomatic and asymptomatic osteonecrosis in the lower extremities of survivors of ALL or LBL diagnosed aged 10–24 years in the UK at different time points in their treatment. This study also aims to identify risk factors for progression and the development of symptomatic osteonecrosis in this population, as well as specific radiological features that predict for progression or regression in those with asymptomatic osteonecrosis Methods and analysis BONES is a prospective, longitudinal cohort study based at principal treatment centres around the UK. Participants are patients aged 10–24 years diagnosed with ALL or LBL under standard criteria. Assessment for osteonecrosis will be within 4 weeks of diagnosis, at the end of delayed intensification and 1, 2 and 3 years after the start of maintenance therapy. Assessment will consist of MRI scans of the lower limbs and physiotherapy assessment. Clinical and biochemical data will be collected at each of the time points. Bone mineral density data and vertebral fracture assessment using dual-energy X-ray absorptiometry will be collected at diagnosis and annually for 3 years after diagnosis of malignancy. Ethics and dissemination Ethical approval has been obtained through the Yorkshire and Humber Sheffield Research Ethics Committee (reference number: 16/YH/0206). Study results will be published on the study website, in peer-reviewed journals and presented at relevant conferences and via social media. Trial registration number NCT02598401; Pre-results.

BACKGROUND:Diagnostic challenges combined with the vulnerability of neonates to develop invasive candidiasis (IC) may lead to antifungal administration in the absence of IC. A modified point-prevalence study was performed to obtain an improved insight and understanding of antifungal prescribing in this specific patient population.METHODS:Neonates and infants ≤90 days of age receiving systemic antifungals from 12 centers in England were included. Data were collected prospectively during 26 consecutive weeks and entered into an online REDCap database.RESULTS:Two hundred eighty neonates and infants were included, the majority ≤1 month of age (68.2%). Prematurity was the commonest underlying condition (68.9%). Antifungals were prescribed for prophylactic reason in 79.6%; of those, 64.6% and 76.3% were extreme low birth weight infants and prematurely born neonates, respectively. Additional risk factors were present in almost all patients, but only 44.7% had ≥3 risk factors rendering them more susceptible to develop IC. Nonpremature and non extremely low birth weight premature infants only scored ≥3 risk factors in 32.6% and 15%, respectively. Fluconazole was the most common antifungal used (76.7% of all prescriptions), and commonly underdosed as treatment. The number of microbiologic proven IC was low, 5.4%.CONCLUSIONS:Neonatal antifungal prophylaxis is commonly prescribed outside the recommendations based on known risk profiles. Fluconazole is the main antifungal prescribed in neonates and infants, with underdosing frequently observed when prescribed for treatment. Number of proven IC was very low. These observations should be taken into consideration to develop a national pediatric Antifungal Stewardship program aiming to guide rational prescribing.

Probiotics are living microorganisms that confer a health benefit on the host when administered. This systematic review and meta-analysis investigates the efficacy and safety of probiotics in adult and paediatric patients diagnosed with cancer.

Summary‘Cure models’ offer additional information to traditional epidemiological approaches to assess survival for cancer patients by simultaneously estimating the proportion cured and the survival of those ‘uncured’. The proportion cured is a summary of long‐term survival while the median survival time of the uncured provides important information on those who are not long‐term survivors. Population‐based trends in the cure proportion and survival of the uncured for childhood acute lymphoblastic leukaemia (ALL) by clinical prognostic risk factors were estimated using flexible parametric cure models, based on overall survival and event‐free survival. Children aged 1–17 years diagnosed between 1990 and 2011 in Yorkshire, UK, were included (n = 492). The percentage cured increased from 77% (95% confidence interval 70–84%) in 1990–1997 to 89% (84–93%) in 2003–2011, while the median survival time of the uncured decreased from 3·2 years (2·2–4·1 years) to 0·7 years (0–1·5 years). Models based on event‐free survival showed a similar trend. The 5‐year cumulative incidence of relapse substantially decreased from 35% in 1990–97 to 9% in 2003–2011. These results show selective improvement in survival between 1990 and 2011 with a significant reduction in the risk of relapse alongside a reduced absolute duration of survival for those destined to be uncured.

Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10 −9 , odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10 −8 , OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.

OBJECTIVES:To establish prevalence, management and long-term outcomes of osteonecrosis (ON) in young people diagnosed with acute lymphoblastic leukaemia (ALL) between 2003 and 2011. DESIGN SETTING PARTICIPANTS:This study assessed ON in 3113 patients aged 1-24 years who participated in the UK national leukaemia study UKALL 2003. UKALL 2003 recruited patients in 40 UK hospitals between 2003 and 2011 and included patients between ages 1 and 25 diagnosed with ALL. RESULTS:170 patients were diagnosed with ON, giving a prevalence of 5.5%. The multivariable analysis showed that the risk of ON was highest for children aged between 10 and 20 years (ages 10-15 years, OR 23.7, 95% CI 14.8 to 38.0; ages 16-20 years, OR 22.5, 95% CI 12.7 to 39.8, compared with age <10 years). Among ethnic groups, Asian patients had the highest risk of ON (OR 1.92, 95% CI 1.1 to 3.6, compared with White patients). Eighty-five per cent of patients with ON had multifocal ON. Thirty-eight per cent of patients with ON required surgery and 19% of patients with ON required a hip replacement. Fifteen per cent of patients who had surgery still describe significant disability or use of a wheelchair. CONCLUSIONS:ON has considerable morbidity for patients being treated for ALL, with a high burden of surgery. Age and ethnicity were found to be the most significant risk factors for development of ON, with Asian patients and patients aged 10-20 years at diagnosis of ALL at greatest risk. These results will help risk stratify patients at diagnosis of ALL, and help tailor future prospective studies in this area.