Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation ...in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.
•Identification of SRP54 mutations in congenital neutropenia.•SRP54 mutations induce ER stress and autophagy associated with apoptosis.
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Autoimmune hemolytic anemia is a rare condition in children. Little is known about its initial presentation and the subsequent progression of the disease.
Since 2004, a national observational study ...has been aiming to thoroughly describe cases and identify prognostic factors. Patients from all French hematologic pediatric units have been included if they had a hemoglobin concentration less than 11 g/dL, a positive direct antiglobulin test and hemolysis. Evans' syndrome was defined by the association of autoimmune hemolytic anemia and immunological thrombocytopenic purpura. Data from patients' medical records were registered from birth to last follow-up. Autoimmune hemolytic anemia was classified as primary or secondary. Remission criteria, qualifying the status of anemia at last follow-up, were used with the aim of identifying a subgroup with a favorable prognosis in continuous complete remission.
The first 265 patients had a median age of 3.8 years at diagnosis. In 74% of cases the direct antiglobulin test was IgG/IgG+C3d. Consanguinity was reported in 8% of cases and first degree familial immunological diseases in 15% of cases. Evans' syndrome was diagnosed in 37% of cases. Autoimmune hemolytic anemia was post-infectious in 10%, immunological in 53% and primary in 37% of cases. After a median follow-up of 3 years, 4% of children had died, 28% were still treatment-dependent and 39% were in continuous complete remission. In multivariate analysis, IgG and IgG+C3d direct antiglobulin tests were associated with a lower rate of survival with continuous complete remission (adjusted hazard ratio, 0.43; 95% confidence interval, 0.21-0.86).
This nationwide French cohort is the largest reported study of childhood autoimmune hemolytic anemia. The rarity of this condition is confirmed. Subgroups with genetic predisposition and underlying immune disorders were identified.
The large number of drugs administered simultaneously to neonates and children in hospital results in the formation of particles that are potentially infused. We have investigated the ability of IV ...in-line filters to eliminate particulate matter from multidrug infusion lines and so prevent contamination. The impact on particle occurrence of the internal volume of the IV line below the in-line filter was then evaluated. The multidrug therapy given to children was reproduced with and without in-line filtration. Three combinations with a filter were tested to vary the internal volume (V) between the filter and the catheter egress. The catheter was then connected to a dynamic particle count to evaluate the particulate matter potentially administered to children during infusion. The introduction of in-line filters led to a significant reduction in overall particulate matter, from 416,974 208,479-880,229 to 7,551 1,985-11,287 particles (p < 0.001). Larger particles of ≥10 and 25 µm were also significantly reduced. Adding an extension set to the egress of the in-line filter (V = 1.7 mL) caused a significant increase in particulate contamination for both. This study showed that in-line filtration is an effective tool in preventing particle administration to patients. Their position in the infusion in-line is therefore important because of its impact on internal volume and drug particle formation.
To evaluate the efficacy of vinblastine for relapsed/refractory anaplastic large-cell lymphoma (ALCL).
Data were reviewed on all 36 patients included prospectively in the French database for ...pediatric ALCL who were treated with vinblastine (6 mg/m(2)/wk) for resistant primary disease (one), a first relapse (15), or subsequent relapses (20). Fifteen patients had undergone hematopoietic stem-cell transplantation (HSCT) for a previous relapse.
Six patients were not evaluable for response, 25 (83%) of 30 evaluable patients achieved a complete remission (CR), and five experienced progressive disease. Among the 31 patients who achieved a CR with vinblastine or before its initiation, six patients were treated with HSCT and 25 with vinblastine alone (median duration, 14 months). Overall, nine of 25 patients treated with vinblastine alone have remained in CR (median, 7 years since the end of treatment), and 16 patients have relapsed. Vinblastine was still efficient for subsequent relapses. With a median follow-up of 9.2 years, 12 patients have died (four as a result of toxicity after HSCT and eight as a result of disease), and 24 patients are alive (15 following treatment with single-agent vinblastine for the last event). Five-year overall survival is 65% (95% CI, 48% to 79%), and 5-year event-free survival is 30% (95% CI, 17% to 47%).
Vinblastine is highly efficient in relapsed ALCL and may produce durable remissions. The optimal treatment duration still has to be assessed. These results should be borne in mind when designing future phase II studies with the targeted therapies directed against anaplastic lymphoma kinase.
Within the International Registry of Childhood Chronic Myeloid Leukemia (CML), we identified 18 patients less than 18 years old at diagnosis of CML who were in the chronic phase and exhibiting a ...sustained deep molecular response (DMR) to imatinib defined as BCR-ABL1/ABL1 < 0.01% (MR
) for at least two years followed by discontinuation of imatinib. Before discontinuation, the median duration of imatinib was 73.2 months (range, 32-109) and the median duration of MR
was 46.2 months (range, 23.9-98.6). Seven patients experienced loss of major molecular response (MMR) 4.1 months (range, 1.9-6.4) after stopping and so restarted imatinib. The median molecular follow-up after discontinuation was 51 months (range, 6-100) for the nine patients without molecular relapse. The molecular free remission rate was 61% (95% CI, 38-83%), 56% (95% CI, 33-79%) and 56% (95% CI, 33-79%) at 6, 12 and 36 months, respectively. Six of the seven children who experienced molecular relapse after discontinuation regained DMR (median, 4.7 months; range, 2.5-18) after restarting imatinib. No withdrawal syndrome was observed. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment and DMR durations before discontinuation had no influence on treatment free remission. These data suggest that imatinib can be safely discontinued in children with sustained MR
for at least two years.
Genome-wide association studies (GWAS) have identified that frequent polymorphisms in ARID5B and IKZF1, two genes involved in lymphoid differentiation, increase the risk of childhood acute ...lymphoblastic leukemia (ALL). These findings markedly modified the current field of research on the etiology of ALL. In this new context, the present exploratory study investigated the possible interactions between these at-risk alleles and the non-genetic suspected ALL risk factors that were of sufficient prevalence in the French ESCALE study: maternal use of home insecticides during pregnancy, preconception paternal smoking, and some proxies for early immune modulation, i.e. breastfeeding, history of common infections before age one year, and birth order. The analyses were based on 434 ALL cases and 442 controls of European origin, drawn from the nationwide population-based case-control study ESCALE. Information on non-genetic factors was obtained by standardized telephone interview. Interactions between rs10740055 in ARID5B or rs4132601 in IKZF1 and each of the suspected non-genetic factors were tested, with the SNPs coded as counts of minor alleles (trend variable). Statistical interactions were observed between rs4132601 and maternal insecticide use (p = 0.012), breastfeeding p = 0.017) and repeated early common infections (p = 0.0070), with allelic odds ratios (OR) which were only increased among the children not exposed to insecticides (OR = 1.8, 95%CI: 1.3, 2.4), those who had been breastfed (OR = 1.8, 95%CI: 1.3, 2.5) and those who had had repeated early common infections (OR = 2.4, 95%CI: 1.5, 3.8). The allelic ORs were close to one among children exposed to insecticides, who had not been breastfed and who had had no or few common infections. Repeated early common infections interacted with rs10740055 (p = 0.018) in the case-only design. Further studies are needed to evaluate whether these observations of a modification of the effect of the at-risk alleles by non-genetic factors are chance findings or reflect true underlying mechanisms.
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Despite major treatment improvements over the past decades, pediatric acute myeloid leukemia (AML) is still a life‐threatening malignancy with ...relapse rates up to 30% and survival rates below 75%. A better description of the pattern of molecular aberrations in childhood AML is needed to refine prognostication in such patients. We report here the comprehensive molecular landscape using both high‐throughput sequencing focused on 36 genes and ligation‐dependent RT‐PCR in 385 children with de novo AML enrolled in the prospective ELAM02 trial and we evaluated their prognostic significance. Seventy‐six percent of patients had at least 1 mutation among the genes we screened. The most common class of mutations involved genes that control kinase signaling (61%) followed by transcription factors (16%), tumor suppressors (14%), chromatin modifiers (9%), DNA methylation controllers (8%), cohesin genes (5%), and spliceosome (3%). Moreover, a recurrent transcript fusion was detected in about a half of pediatric patients. Overall, CBF rearrangements, NPM1 and double CEBPA mutations represented 37% of the cohort and defined a favorable molecular subgroup (3 years OS: 92.1%) while NUP98 fusions, WT1, RUNX1, and PHF6 mutations (15% of the cohort) segregated into a poor molecular subgroup (3 years OS: 46.1%). KMT2A‐rearrangements (21% of the cohort) were associated with an intermediate risk. Despite some overlaps, the spectrum of molecular aberrations and their prognostic significance differ between childhood and adult AML. These data have important implications to contribute in refining risk stratification of pediatric AML and show the need for further validations in independent pediatric cohorts.
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