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Patients with an ABL-class fusion have a high risk of relapse on standard chemotherapy but are sensitive to tyrosine kinase inhibitors (TKI). In UKALL2011, we screened patients with post-induction MRD ≥1% and positive patients (12%) received adjuvant TKI. As the intervention started during UKALL2011, not all eligible patients were screened prospectively. Retrospective screening of eligible patients allowed the outcome of equivalent ABL-class patients who did and did not receive a TKI in first remission to be compared. ABL-class patients who received a TKI in first remission had a reduced risk of relapse/refractory disease: 0% vs. 63% at four years (P = 0·009).

Red cell transfusion has an important role in the management of sickle cell disease (SCD) in both emergency and elective settings. However, because of insufficient randomised data, it is not always clear when or how to use red cell transfusion. A companion guideline, Guidelines on red cell transfusion in sickle cell disease Part I: principles and laboratory aspects, addresses the general principles of transfusion practice in SCD (Davis et al, 2016, BJH in press). The present guideline examines current available evidence on indications for transfusion in SCD. This may not be appropriate for all clinical scenarios and clinical decisions must be based on individual patient considerations. In both guidelines, the term sickle cell disease refers to all genotypes of the disease, and sickle cell anaemia to the homozygous state (SS).

Leukaemia is the most common cancer in children. Leukaemia results from clonal proliferation of stem cells and leads to bone marrow failure. Symptoms at presentation include bruising, bleeding, pallor due to anaemia and infection. The incidence is approximately 5 in 100 000 children. The cause is largely unknown although there is a predisposition in certain congenital conditions such as Fanconi's Anaemia and Down's syndrome and there is some understanding of how genetic mutations may cause leukaemia, but this is not thought to be a single event. The treatment of acute lymphoblastic leukaemia in children older than 1 year is extremely successful and continues to improve. Treatment is tailored according to response (minimal residual disease directed). Multi-agent immunosuppressive chemotherapy, with central nervous system prophylaxis is given over 2–3 years. Acute myeloid leukaemia is five times less common than acute lymphoblastic leukaemia and is treated intensively for 4–5 months and cure rates have remained at 60–70% for two to three decades. Survival has improved due to better supportive care. Chronic myeloid leukaemia is rare and treated with tyrosine kinase inhibitors and as in preleukemic conditions (myelodyplasia) may require allogenic bone marrow transplant.

Background Sickle cell disease (SCD) is one of the most common causes of stroke in children worldwide. Based on the results of the Stroke Prevention Trial in Sickle Cell Anemia (STOP), annual transcranial Doppler ultrasound (TCD) screening for affected children is standard practice. However, the need for TCD surveillance programs could override the accuracy of the screening, affecting the correct stratification of stroke risk and subsequent clinical management of the target population. Aims To shed light on this issue, a systematic review of the literature on TCD screening for children and adolescents with SCD was carried out (CRD42016050549), according to a list of clinically relevant questions, with a particular focus on screening practices in European countries. Quality of the evidence was rated using the grading of recommendations assessment, development and evaluation. Summary of review Thirty-three studies published in English or French were included (5 randomized controlled trials, 8 experimental non-randomized, and 20 observational studies). The quality of the retrieved evidence ranged between low and high, but was rated as moderate or high most of the times. TCD is effective as a screening tool for the primary prevention of stroke in SCD children. There is no high-quality evidence on the effectiveness of alternative screening methods, such as imaging-TCD with or without angle correction or magnetic resonance angiography. No evidence was found on effectiveness of the screening on children on hydroxyurea and with genotypes other than HbSS and HbS/β0. No European data were found on screening rates or adherence of screening practices to the STOP protocol. Conclusions High-quality studies on alternative screening methods that are currently used in real-world practice, and on screening applicability to specific subgroups of patients are urgently needed. Considering the low awareness of the disease in European countries and the lack of data on screening practices and adherence, clinicians need up-to-date guidelines for more uniform and evidence-based surveillance of children with SCD.

Summary Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next‐generation‐sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical‐grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically‐reliable diagnostic test and minimize false‐negative results we developed an open‐source tool (CoverMi) to accurately determine base‐coverage and the ‘discoverability’ of known mutations for every sample. We validated our 33‐gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS‐based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.

Background Anthracycline cardiomyopathy is of concern in children treated for acute myeloid leukaemia (AML), but there are few data on the incidence and natural history of cardiotoxicity after AML treatment in the United Kingdom, where regimens have included high anthracycline exposure. Procedure Prevalence and predictors of cardiotoxicity were retrospectively reviewed in 124 children treated on the MRC AML 10 and AML 12 trials in a single, large centre from November 1987 to September 2004. Subclinical cardiotoxicity was defined as a shortening fraction of less than 28% and clinical cardiomyopathy as evidence of heart failure, and both were classified as late cardiotoxicity 1 year after completing first line therapy. Results Cumulative survival was 61% at 10 years. The prevalence of early and late cardiotoxicity was 13.7% (95%-CI: 8.2–22.0%) and 17.4% (95%-CI: 10.9–26.8%), respectively. Early cardiotoxicity was a strong predictor (OR = 9.18; 95%-CI: 2.10–40.11; P

We report the incidence and outcome of venous thrombosis (VT) in the UK acute lymphoblastic leukaemia (ALL) 2003 trial. VT occurred in 59/1824 (3.2%) patients recruited over 5 years with 90% occurring during a period of Asparagine depletion. Pegylated Escherichia Coli Asparaginase (Peg-ASP) 1000 units/m(2) was used throughout. Thirty-four children received further Peg-ASP, most with concurrent heparin prophylaxis. There were no episodes of bleeding or recurrent thrombosis. Optimal Asparagine depletion is central to success of modern regimes for treatment of ALL. This report confirms a significant risk of thrombosis with such therapy, but demonstrates that re-exposure to Asparaginase is feasible and safe.

Background and aims Children receiving chemotherapy are at an increased risk of typhlitis, also known as neutropenic enterocolitis. It is characterised by fever and abdominal pain in a neutropenic patient receiving chemotherapy. It is a significant cause of mortality and morbidity in paediatric haemato-oncology patients. We review our experience with typhlitis in children with cancer over the past 5 years. Most cases can be managed conservatively but one case importantly highlights the rare need for surgical intervention. Methods A retrospective analysis of case notes was performed of all paediatric haemato-oncology patients with typhlitis at a tertiary paediatric hospital from January 2011 till present. Results We report 6 cases of typhlitis at our institution over the last 5 years. 3 patients had acute lymphoblastic leukaemia (ALL), one had haemophagocytic lymphohistiocytosis (HLH), one had relapsed Wilm’s tumour and one had neuroblastoma. 3 were male; 3 were female. Median age at diagnosis was 12 years (range 5–16 years). All 6 cases had presented with abdominal pain, neutropenia and fever. Neutrophil count ranged from zero to 0.67 × 10 9 /l. Radiological investigation by US/CT showed bowel wall thickening in all 6 cases in keeping with typhlitis. All patients initially received conservative medical management with bowel rest, intravenous nutritional support, broad spectrum intravenous antibiotics and sometimes G-CSF support. PICU support was needed for some these patients (both inotropic support and ventilation). All patients improved with neutrophil recovery but one patient had prolonged neutropenia and required definitive surgical management and hemicolectomy. Conclusion Typhlitis is a life-threatening complication in paediatric haemato-oncology patients particularly those receiving intensive chemotherapy with corticosteroid exposure and prolonged periods of neutropenia. Most cases can be managed conservatively however surgical intervention may be required in few cases that fail aggressive medical management or develop complications such as perforation. Increased clinical awareness of typhlitis is necessary to establish an early diagnosis. Radiological investigation with US/CT is essential to make a definitive diagnosis. Early surgical opinion is required for appropriate management.

Summary 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.

Hepatic veno-occlusive disease NOD) is a common (10-50%) and serious complication of haematological stein cell transplantation (HSCT), with up to 90% mortality rates. We carried out a study to assess whether the use of prophylactic defibrotide in paediatric patients undergoing HSCT results in a lower frequency or severity of hepatic VOD. Procedure. Forty-seven Successive patients who underwent transplantation between April 2004 and December 2005 were given defibrotide prophylaxis and were compared with 56 historical controls transplanted between November 2001 and April 2004. No serious side effects were reported. High risk patients in the control group received Ursodeoxycholic acid and tinzaparin as VOD prophylaxis. The groups were matched for sex, age, type of transplant and risk. Results. in the defibrotide group, four patients developed clinical VOD (Seattle criteria) although two had liver biopsies which showed graft versus host disease (CvHD). Defibrotide dose was increased and symptoms resolved within 14 days. Of the control group four patients had VOD. Two of these patients had reversed hepatic vein flow and died 30 days post-transplant, partly clue to VOID. VOD was associated with busulfan conditioning (P=0.001) and not with age, sex, type of transplant, GvHD, abnormal liver function prior to transplant or type of antifungal prophylaxis. Conclusions. VOD incidence and severity was reduced in the defibrotide group Which Suggests that defibrotide might be effective in preventing and treating VOD. Sufficiently powered randomised trials are now required to definitively test the role of defibrotide in this setting.

Myelodysplastic syndrome is a heterogenous clonal disorder stemming from an insult at the progenitor cell level. The development of an International Prognostic Scoring System (IPSS) based on bone marrow blast percentage, degree of cytopenia and karyotype has allowed the widespread application of the IPSS to guide therapy in patients with MDS. To date, there are no reports distinguishing primary MDS from therapy related MDS (t-MDS) in terms of outcomes within a treatment algorithm. We performed a comparative analysis of patients with primary MDS and t-MDS, to ascertain whether both groups have similar risk profiles and outcomes within a defined treatment protocol. Between 1995 and 2005, 95 patients were diagnosed with MDS at our centre with an average follow-up of 6 years. In total, 50 patients presented in a de novo setting of which 41 received intensive therapy and 9 patients received non-intensive treatment. Of the 45 patients diagnosed with t-MDS, 25 received intensive treatment and 20 patients were managed non-intensively. Therapeutic decisions were based on ECOG performance status and cytogenetic risk group. Demographic analysis of primary and t-MDS patients showed no significant differences when comparing age, sex, degree of presentation cytopenia, or median IPSS score (IPSS 2.0 for primary MDS and 1.5 for t-MDS, p=0.4). In the primary MDS group, 32 patients had an IPSS of ≥1.5 (INT-2/high risk MDS) compared to 27 patients in the t-MDS group. There were 18 patients with primary MDS and 18 patients with t-MDS in the INT-1/low risk category (IPSS ≤1.0). Cytogenetic analysis of primary MDS and t-MDS patients showed a greater frequency of complex karyotypes and chromosome 7 abnormalities in t-MDS patients. A normal karyotype was commoner in the primary group (19:6 patients respectively). The median overall survival (OS) was 25 months for primary MDS patients and 16 months for the t-MDS group (p=0.1). On multivariate analysis, WBC and blast percentage were independent predictors of OS in primary MDS patients (p1.0, p=0.02). Remission rates were higher in primary MDS (86%) compared to t-MDS patients (68%) within the intensively treated arm (81% versus 39% for whole group, respectively). However, this did not translate into a better relapse free survival for primary MDS patients (p=0.9). Univariate analysis using binary logistic regression did not identify any factors that predicted response in the primary group. Age was a significant predictive factor for likelihood of response in the t-MDS group (p=0.008). These findings suggest that prognostic systems may need to be refined in MDS for patients presenting with de novo or therapy related disease. Adjustment for performance status may additionally contribute to risk based therapeutic protocols. According to our results, primary MDS may be more chemosensitive than t-MDS but if responses are obtained in t-MDS patients, they are maintained at a similar rate to primary MDS.