Cornelia de Lange Syndrome (CdLS) is a rare autosomal dominant developmental disorder characterized by a distinctive facial dysmorphism and variable developmental anomalies including prenatal and postnatal growth delay, microcephaly, intellectual disability, upper limb anomalies and hirsutism. CdLS
Background Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse. Methods A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel. Results Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion. Conclusions This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.
Thiamine responsive megaloblastic anemia (TRMA) is an autosomal recessive disorder with a triad of symptoms: megaloblastic anemia, deafness, and non-type 1 diabetes mellitus. Occasionally, cardiac abnormalities and abnormalities of the optic nerve and retina occur as well. Patients with TRMA often respond to treatment with pharmacological doses of thiamine. Recently, mutations were found in patients with TRMA in a thiamine transporter gene (SLC19A2). We here describe the mutations found in eight additional families. We found four novel mutations and three that were previously described. Of the novel ones, one is a nonsense mutation in exon 1 (E65X), two are missense mutations in exon 2 (S142F, D93H), and another is a mutation in the splicing donor site at the 5' end of intron 4 (C1223+1G>A). We also summarize the state of knowledge on all mutations found to date in TRMA patients. SLC19A2 is the first thiamine transporter gene to be described in humans. Reviewing the location and effect of the disease causing mutations can shed light on the way the protein functions and suggest ways to continue its investigation.
BACKGROUND Chronic exchange transfusion is effective for primary and secondary prevention of stroke in children with sickle cell anemia (SCA). Erythrocytapheresis is recognized to be the most efficient approach; however, it is not widely implemented and is not suitable for all patients. The aim of our study was to compare automated exchange transfusion (AET) with our manual method of exchange transfusion and, in particular, to evaluate the efficacy, safety, and cost of our manual method. STUDY DESIGN AND METHODS Thirty‐nine SCA children with stroke and/or abnormal findings on transcranial Doppler were included in the study. We retrospectively analyzed 1353 exchange sessions, including 333 sessions of AET and 1020 sessions of manual exchange transfusion (MET). RESULTS Both methods were well tolerated. The median decrease in hemoglobin (Hb)S per session was 21.5% with AET and 18.8% with our manual method ( p < 0.0001) with no major increase in red blood cell consumption. Iron overload was well controlled, even with the manual method, with a median (interquartile range) ferritin level of 312 (152‐994) µg/L after 24 months of transfusions. The main differences in annual cost relate to equipment costs, which were 74 times higher with the automated method. CONCLUSION Our study shows that continuous MET has comparable efficacy to the automated method in terms of stroke prevention, decrease in HbS, and iron overload prevention. It is feasible in all hospital settings and is often combined with AET successively over time.
This trial explored the efficacy of re-induction chemotherapy including bortezomib in paediatric relapsed/refractory acute lymphoblastic leukaemia. Patients were randomized 1:1 to bortezomib (1.3 mg/m2 /dose) administered early or late to a dexamethasone and vincristine backbone. Both groups did not differ regarding peripheral blast count on day 8, the primary endpoint. After cycle 1, 8 of 25 (32%) patients achieved complete remission with incomplete blood count recovery, 7 (28%) a partial remission and 10 had treatment failure. Most common grade 3-4 toxicities were febrile neutropenia (31%) and pain (17%). Bortezomib was safely combined with vincristine. Bortezomib rarely penetrated the cerebrospinal fluid.
