International audiencePurpose Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAFV600E mutation occurs frequently, but clinical significance remains to be determined. Patients and Methods BRAFV600E mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. Results Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAFV600E mutation. Patients with BRAFV600E manifested more severe disease than did those with wild-type BRAF. Patients with BRAFV600E comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P , .001). BRAFV600E mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAFV600E more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). Conclusion In children with LCH, BRAFV600E mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy. © 2016 by American Society of Clinical Oncology

This study investigated the role of factors considered related to early stimulation of the immune system in the etiology of childhood acute leukemia. The national registry-based case-control study ESCALE was carried out in France in 2003-2004. Population controls were frequency matched to cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios were estimated using unconditional regression models adjusted for potential confounders. Included were 634 acute lymphoblastic leukemia cases, 86 acute myeloblastic leukemia cases, and 1,494 controls aged ≥1 year. Negative associations were observed between acute lymphoblastic leukemia and birth order (P for trend < 0.0001), attendance at a day-care center before age 1 year (odds ratio (OR) = 0.8, 95% confidence interval (CI): 0.6, 1.1), prolonged breastfeeding (OR = 0.7, 95% CI: 0.5, 1.0), repeated early common infections (OR = 0.7, 95% CI: 0.6, 0.9), regular contact with farm animals (OR = 0.6, 95% CI: 0.5, 0.8), frequent farm visits in early life (OR = 0.4, 95% CI: 0.3, 0.6), and history of asthma (OR = 0.7, 95% CI: 0.4, 1.0) or eczema (OR = 0.7, 95% CI: 0.6, 0.9). Results support the hypothesis that repeated early infections and asthma may play a role against childhood acute leukemia.

The online version of this article has a Supplementary Appendix. BackgroundPatients with the Shwachman-Diamond syndrome often develop hematologic complications. No risk factors for these complications have so far been identified. The aim of this study was to classify the hematologic complications occurring in patients with Shwachman-Diamond syndrome and to investigate the risk factors for these complications. Design and MethodsOne hundred and two patients with Shwachman-Diamond syndrome, with a median followup of 11.6 years, were studied. Major hematologic complications were considered in the case of definitive severe cytopenia (i.e. anemia <7 g/dL or thrombocytopenia <20×10 9 /L), classified as malignant (myelodysplasia/leukemia) according to the 2008 World Health Organization classification or as non-malignant. ResultsSevere cytopenia was observed in 21 patients and classified as malignant severe cytopenia (n=9), non-malignant severe cytopenia (n=9) and malignant severe cytopenia preceded by nonmalignant severe cytopenia (n=3). The 20-year cumulative risk of severe cytopenia was 24.3% (95% confidence interval: 15.3%-38.5%). Young age at first symptoms (<3 months) and low hematologic parameters both at diagnosis of the disease and during the follow-up were associated with severe hematologic complications (P<0.001). Fifteen novel SBDS mutations were identified. Genotype analysis showed no discernible prognostic value. ConclusionsPatients with Shwachman-Diamond syndrome with very early symptoms or cytopenia at diagnosis (even mild anemia or thrombocytopenia) should be considered at a high risk of severe hematologic complications, malignant or non-malignant. Transient severe cytopenia or an indolent cytogenetic clone had no deleterious value.Key words: Shwachman-Diamond syndrome, genotype, aplastic anemia, secondary leukemia, cytopenia, myelodysplasia, monosomy 7.Citation: Donadieu J, Fenneteau O, Beaupain B, Beaufils S, Bellanger F, Mahlaoui N, Lambilliotte A, Aladjidi N, Bertrand Y, Mialou V, Perot C, Michel G, Fouyssac F, Paillard C, Gandemer V, Boutard P, Schmitz J, Morali A, Leblanc T, Bellanné-Chantelot C, and Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome

Aim: To analyse the association between potential environmental exposure to hydrocarbons and the risk of acute childhood leukaemia. Methods: A hospital based multicentre case control study, stratified on centre, age, and sex, with 280 leukaemia cases and 285 controls was carried out. Data were collected by a standardised interview of the mothers. Results: No clear association was seen between maternal occupational exposure to hydrocarbons during pregnancy and leukaemia, or between residential traffic density and leukaemia. There was an association between dwellings neighbouring a petrol station or a repair garage during childhood and the risk of childhood leukaemia (OR 4.0, 95% CI 1.5 to 10.3), with a duration trend. The association, which appeared particularly strong for acute non-lymphocytic leukaemia (OR 7.7, 95% CI 1.7 to 34.3), was not altered by adjustment for potential confounding factors. Conclusions: Results showed an association between acute childhood leukaemia and dwellings neighbouring auto repair garages and petrol stations, which are benzene emitting sources. These findings could be due to chance, although the strength of the association and the duration trend are arguments for a causal association.

The French national cohort of children with Langerhans cell histiocytosis (LCH) has included 1478 patients since it was established in 1983. LCH therapeutic strategies substantially changed in 1998, so we have divided the cohort into two 15-year periods. Starting in 1998, therapy duration increased from 6 to 12 months, repeated induction therapy was performed in cases showing a poor response to the first induction with vinblastine and steroids, and refractory disease in a risk organ (RO+) was treated with cladribine and cytarabine. A total of 483 (33%) patients were enrolled before 1998, and 995 (67%) after 1998. Five-year survival was 96·6% (95% confidence interval: 95·4-97·5%) overall, improving from 92% pre-1998 to 99% post-1998 (P < 0·001 adjusted to disease extent). This change was supported by an increase in 5-year survival from 60% to 92% in the RO+ group. Survival was particularly associated with cladribine and cytarabine among refractory RO+ patients. Disease reactivation was slightly less frequent after 1998, due to better enrolment of single-system patients, extended therapy duration, and more efficient second-line therapy. The crude rates of endocrine and neurological sequelae (the most frequent sequelae) appeared to improve over time, but this difference was not observed when the analysis was stratified by disease extent.