T(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: An international study of 62 patients

Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-American-British M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature

Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial

Purpose Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). Materials and Methods Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. Results One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). Conclusion The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era

Acute childhood leukaemia and environmental exposure to potential sources of benzene and other hydrocarbons; a case-control study

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

A cohort of French pediatric patients with primary immunodeficiencies: are patient preferences regarding replacement immunotherapy fulfilled in real-life conditions?

Marl&egrave;ne Pasquet,1 Isabelle Pellier,2 Nathalie Aladjidi,3 Anne Auvrignon,4 Patrick Cherin,5 Pierre Clerson,6 Gregoire Jacques No&euml;l Cozon,7 Roland Jaussaud,8 Boris Bienvenu,9 Cyrille Hoarau10 1Pediatric Hematology and Oncology Department, University Hospital Centre of Toulouse, Toulouse, 2University Hospital of Angers, Angers, 3Paediatric Hematology Unit, CEREVANCE, CIC 1401, Inserm CICP, Hospital Pellegrin, 4Trousseau Hospital, 5Internal Medicine Department, Paris, 6Soladis Clinical Studies, Roubaix, 7Clinical Immunology, Edouard Herriot Hospital, Lyon, 8Internal Medicine and Clinical Immunology Department, University Hospital Centre of Nancy, Nancy, 9Internal Medicine Department, University Hospital Centre of Caen, Caen, 10Renal Transplantation and Clinical immunology Department, University Hospital Centre of Tours, Tours, France Objective: To assess quality of life and satisfaction regarding immunoglobulin-replacement therapy (IgRT) treatment according to the route (intravenous Ig [IVIg] or subcutaneous Ig [SCIg]) and place of administration (home-based IgRT or hospital-based IgRT).Subjects and methods: Children 5&ndash;15 years old treated for primary immunodeficiency disease (PIDD) with IgRT for &ge;3 months were included in a prospective, noninterventional cohort study and followed over 12 months. Quality of life was assessed with the Child Health Questionnaire &ndash; parent form (CHQ-PF)-50 questionnaire. Satisfaction with IgRT was measured with a three-dimensional scale (Life Quality Index [LQI] with three components: factor I [FI], treatment interference; FII, therapy-related problems; FIII, therapy settings).Results: A total of 44 children (9.7&plusmn;3.2 years old) receiving IgRT for a mean of 5.6&plusmn;4.5 years (median 4.1 years) entered the study: 18 (40.9%) were receiving hospital-based IVIg, two (4.6%) were receiving home-based IVIg, and 24 (54.6%) were treated by home-based SCIg. LQI FIII was higher for home-based SCIg than for hospital-based IVIg (P=0.0003), but there was no difference for LQI FI or LQI FII. LQI FIII significantly improved in five patients who switched from IVIg to SCIg during the follow-up when compared to patients who pursued the same regimen (either IVIg or SCIg). No difference was found on CHQ-PF50 subscales, LQI FI, or LQI FII.Conclusion: Home-based SCIg gave higher satisfaction regarding therapy settings than hospital-based IVIg. No difference was found on other subscales of the LQI or CHQ-PF50 between hospital-based IVIG and home-based SCIG. Keywords: primary immunodeficiency, pediatric, immunotherapy, immunoglobulins, satisfaction, preferenc

Translocation t (6; 9)(p22; q34)/DEK-NUP214 rearranged Pediatric AML:: A Retrospective international Study

The cytogenetic subgroup t(6;9)(p22;q34), previously often reported as a breakpoint in 6p23, is defined as a distinct entity in the 2008 WHO classification of acute myeloid leukemia (AML). The translocation results in a chimeric fusion between DEK at 6p22.3 and NUP214 at 9q34.13 generating the DEK-NUP214 fusion gene. In adults, t(6;9) is associated with young age, very poor outcome, and a higher prevalence of FLT3-ITD than in any other type of AML. To date, the clinical impact of t(6;9) has not been independently described in a pediatric cohort. In this retrospective study, we aimed to characterize the clinical, genetic and morphological features of t(6;9) in childhood AML and to evaluate outcome. Children aged 0\u201318 years and diagnosed with t(6;9)-positive AML or MDS within the period January 1, 1993 to December 31, 2011 were included. The presence of the translocation was determined by conventional karyotyping, FISH, or RT-PCR. Patients with Down syndrome and therapy-related AML were excluded. All major pediatric AML study groups were invited to submit clinical data. In addition, diagnostic smears and biopsies were requested for central reviewing and viable cells or RNA for gene expression profiling (GEP). All karyotypes were centrally reviewed and described according to the International System for Human Cytogenetic Nomenclature. GEP was performed on available frozen diagnostic samples from 297 pediatric AML patients including 6 patients with t(6;9). Based on p-value, log-fold change and biological relevance, the following 4 genes were selected for validation by quantitative real-time PCR (RT-qPCR); eyes absent homolog 3 at 1p35.3 (EYA3), sestrin 1 at 6q21(SESN1), PR domain containing 2, with ZNF domain at 1p36.21 (PRDM2, also known as RIZ1), and histone cluster 2, H4a at 1q21.2 (HIST2H4). Validation was performed on 48 patient samples: t(6;9) (n=17), other pediatric AML (n=31) and 14 cell lines including one with t(6;9)(p22;q34). A total of 58 pediatric patients with a DEK-NUP214 t(6;9) myeloid malignancy from 24 study groups were included in the study: 50 were diagnosed as de novo AML (0.5% of all AML during the study period) and 8 as MDS. Patients with t(6;9) were characterized by a late onset as well as male preponderance; median age was 11 years (range 3\u201318 years) and the male:female ratio 39:19 (p<0.01). The median white blood cell count (WBC) was 15.6x109/L (range 0.2\u2013191). Bilinear dysplasia with pseudo-Pelger-Hu\uebt cells was commonly seen (92% of reviewed evaluable material), and Auer rods were reported in 10 patients, whereas basophilia, in contrast to adults, was absent in this pediatric cohort. FAB-M2 dominated (45%), followed by M4 in 24%. The t(6;9) was the sole cytogenetic abnormality in 81%. Trisomies 8 and 13 constituted 40% of the additional aberrations, either alone or together. FLT3-ITD was present in 44% (n=11) of the cohort with known FLT3 status. The 5-year OS for AML and MDS was 55% and 86%, 5-year EFS was 33% and 56%, respectively. Presence of FLT3-ITD had a non-significant negative effect on OS: 32% for FLT3-ITD-positive cases vs. 67% for FLT3-ITD-negative cases, (p=0.15). The 5-year OS for patients treated with stem cell transplant (SCT) in 1st complete remission (CR) or with refractory disease (RD) was 82% (n=20) vs. 56% with chemotherapy (n=30), (p=0.10). Children who died within 3 months from diagnosis were excluded from the analysis of SCT vs. chemotherapy. The GEP performed on 6 pediatric t(6;9) positive patients showed a unique signature with 180 significantly differentially expressed genes. High expression of EYA3, SESN1, PRDM2/RIZ1 and HIST2H4, was confirmed by RT q-PCR. The levels of expression were significantly elevated for all 4 genes in the t(6;9)-positive cases compared with other AML subtypes. In conclusion, we present a large international series of 58 children with DEK-NUP214/ t(6;9)(p22;q34)-positive myeloid leukemia, representing 0.5% of all childhood AML. The cases were characterized by late onset, male predominance, myelodysplasia, and a unique gene expression signature. The 5-year OS was intermediate and substantially better than reported in adults. SCT in 1st CR or in RD did non-significantly improve the OS compared with conventional chemotherapy alone

From the original SARS-CoV-2 strain to the Omicron variant: Predictors of COVID-19 in ambulatory symptomatic children

International audienceObjectives: To determine the predictors of a positive SARS-CoV-2 test in a pediatric ambulatory setting.Patients and methods: We performed a cross-sectional prospective study (November 2020-February 2022) of 93 ambulatory settings in France. We included symptomatic children < 15 years old tested for SARS-CoV-2. For each period corresponding to the spread of the original strain and its variants (period 1: original strain; period 2: Alpha, period 3: Delta; period 4: Omicron), we used a multivariate analysis to estimate adjusted odds ratios (aORs) associated with COVID-19 among age, signs, symptoms or contact, and 95 % confidence intervals (95CIs).Results: Of 5,336 children, 13.9 % (95CI 13.0-14.8) had a positive test. During the first three periods, the positivity rate ranged from 5.6 % (95CI 4.6-6.7) to 12.6 % (95CI 10.8-14.6). The main factors associated with a positive test were contact with an infected adult at home or outside the home (aOR 11.5 [95CI 4.9-26.9] to 38.9 [95CI 19.3-78.7]) or an infected household child (aOR 15.0 [95CI 4.8-47.1] to 28.4 [95CI 8.7-92.6]). By contrast, during period 4, aORs for these predictors were substantially lower (2.3 [95CI 1.1-4.5] to 5.5 [95CI 3.2-7.7]), but the positivity rate was 45.7 % (95CI 42.3-49.2).Conclusions: In pediatric ambulatory settings, before the Omicron period, the main predictor of a positive test was contact with an infected person. During the Omicron period, the odds of these predictors were substantially lower while the positivity rate was higher. An accurate diagnostic strategy should only rely on testing and not on age, signs, symptoms or contact