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.
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.
We report the incidence and outcome of thrombosis in UKALL 2003. In this study NCI low risk patients receive 3 drug induction (Vincristine, Dexamethasone and Asparaginase), NCI high risk (upper age ...limit 20) receive additional Doxorubicin. Morphologic slow early responders (SER) are assigned “augmented BFM” therapy. In non SER, post induction treatment is randomly allocated by day 28 MRD; all patients receive at least one standard CCG modified BFM delayed intensification (DI) and monthly pulsed Vincristine and Dexamethasone during two (girls) or three (boys) years of maintenance. Pegylated E. Coli Asparaginase (Peg-ASP) (Oncospar, Medac UK) 1000 units/m2 is used throughout the protocol. Standard and Intermediate risk patients receive two doses Peg-ASP in induction at days 4 and 18 and a single dose on day 4 of each of two delayed intensifications. High risk patients receive an additional 8 doses during consolidation, interim maintenance and 2 delayed intensification courses. Thrombotic events were reported in 60 or 3.3% (37 male, median age 7 years) of the 1824 patients enrolled in ALL 2003 between October 2003 and June 2008. Of these, 52 or 87% occurred during a period of Asparagine depletion (38 induction, 12 in Delayed Intensification and 2 in Capizzi). Thrombosis was rare during maintenance although many patients retain central venous access throughout their therapy. A higher incidence of thrombus was seen during 4 rather than 3 drug induction 21/744 (2.8%) v 17/1082 (1.6%). This likely reflects increased age and greater use of central venous lines (CVL) in induction in this regime. The site of thrombus was reported in 51 patients: 25 were CVL related, 4 limb DVT independent of CVL, 18, involved cerebral venous sinuses (CerVS), 2 cerebral arteries (CerA), 1 portal vein,1 renal vein Outcome data is available for 38 patients with a minimum of 6 months follow up. No patient died due to thrombosis. 2 children were treated with aspirin after a cerebral arterial thrombus; both have on going mild hemiplegia. 2 children with active bleeding at the time of CVL associated venous clot were not anticoagulated. The remaining 34 who suffered venous thrombosis were anticoagulated (34 LMWH, 1 UFH & Warfarin, I Danaparoid) for a median of 3 months (range 1–17). None experienced significant bleeding or protocol delay. All patients (including 10 with CerVS) who suffered venous thrombus recovered fully. To date, 25 children (including 5 CervS thrombosis) received further therapy with Peg-ASP following a thrombotic episode. 13 received prophylactic heparin during Asparagine depleteion. No recurrence of thrombus was seen.
Modern paediatric ALL protocols rely heavily on profound Asparagine depletion, high dose steroids and the presence of central venous catheters. Consequently strategies for effective management of thrombosis are integral to such regimes. In ALL 2003 thrombosis occurred in 3% of patients over 95% of whom tolerated anticoagulation without bleeding or delay in therapy. All those suffering venous thrombosis made a full recovery. Importantly, re exposure to Asparaginase was feasible and safe even after CerVS thrombus.