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Noninfectious manifestations-allergy, autoimmunity/inflammation, lymphoproliferation, and malignancies-are known to exist in many primary immunodeficiency diseases (PID) and to participate in prognosis.To obtain a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French National Reference Center for Primary Immune Deficiencies (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry.These patients were followed for 10 years (2009-2018) by specialized centers in university hospitals. This study showed that 20.1% of patients without prior curative therapy (n = 1163) developed at least 1 manifestation (event) encompassing 277 events.Autoimmune/inflammatory events (n = 138) and malignancies (n = 85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 195 patients (14.2%) and were found to be causal in 43% of cases. Malignancies (odds ratio, 5.62; 95% confidence interval, 3.66-8.62) and autoimmunity (odds ratio, 1.9; 95% confidence interval, 1.27-2.84) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (mostly allogeneic hematopoietic stem cell transplantation, with a few cases of gene therapy or thymus transplantation) before the 10-year study period (n = 212) had comparatively reduced but still detectable clinical manifestations (n = 16) leading to death in 9.4% of them.This study points to the frequency and severity of noninfectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.

Background Safety of HPV vaccines is still in question due to reports of autoimmune diseases (ADs) following HPV immunization. Objectives To assess the risk of ADs associated with HPV vaccination of female adolescents/young adults in France. Methods Systematic prospective case-referent study conducted to assess the risks associated with real-life use of HPV vaccines. Cases were female 11–25 years old with incident ADs [central demyelination/multiple sclerosis (CD/MS), connective tissue disease (CTD), Guillain-Barre syndrome (GBS), type-1 diabetes (T1D), autoimmune thyroiditis (AT), and idiopathic thrombocytopenic purpura (ITP)]. Cases were consecutively and prospectively identified at specialized centers across France (2008–2014) and individually matched by age and place of residence to referents recruited in general practice. Risk was computed using multivariate conditional logistic regression models adjusted for family history of ADs, living in France (north/south), co-medications and co-vaccinations. Results With a total of 478 definite cases matched to 1869 referents, all ADs combined were negatively associated to HPV vaccination with an adjusted odds ratio of 0.58 (95% confidence interval: 0.41–0.83). Similar results were obtained for CD/MS, AT, CT, and T1D, the last two not reaching statistical significance. No association was found for ITP and GBS. Sensitivity analyses combining definite and possible cases with secondary time window showed similar results. Conclusion Exposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs.

Background: Castleman disease (CD) is a very rare non-malignant lymphoproliferation of undetermined origin. CD diagnosis is difficult and often delayed because of insidious onset, low awareness and clinical heterogeneity. Two major disease phenotypes can be distinguished: unicentric CD (UCD) and multicentric CD (MCD). Diagnosis confirmation is based on histopathological findings on an involved lymph node. Objectives: We attempted to survey all cases of paediatric CD identified in France so far, in order to set up a national registry aimed to improve CD early recognition, treatment and follow-up, within the context of a new reference centre (http://www.castleman.fr). Methods: In 2016, we e-mailed a questionnaire to members of the French paediatric immunohaematology society, the French paediatric rheumatology society and the French Reference Centre for Castleman Disease to retrospectively collect cases of paediatric CD (first symptoms before age 18 years). Anatomopathological confirmation was mandatory. Results: We identified 23 patients (12 girls and 11 boys) diagnosed with UCD (n=17) and MCD (n=6) between 1994 and 2018 in 14 centres. The average age at first symptoms was 11.5 years for UCD and 8.3 years for MCD. The mean diagnosis delay was 8.2 months for UCD and 5.2 years for MCD. In UCD, the initial symptoms were: isolated lymph nodes (n = 10) or lymph node associated with other symptoms (n = 7), fever was present in 3 patients. Patients with MCD presented with fever (n=5), abdominal lymph nodes (n=5), failure to thrive (n=3), hepatomegaly and/or splenomegaly (n=3), arthralgia (n=2), abdominal pain (n=2), fatigue (n=2), facial oedema (n=1), isolated lymphadenopathy (n=1), trunk rash (n=1), vascular hepatopathy with oesophageal varicose veins (n=1), diarrhea (n=1) or cholestasis (n=1). One patient had a Duchenne muscular dystrophy. No patients had HIV or HHV8 infection. In MCD cases, one patient with recurrent fevers, had a heterozygous mutation in MEFV gene and another had a homozygous mutation in TNFRSF1A gene (P75L). A UCD patient experienced fever episodes and pericarditis two years after surgery. Genetic tests revealed one heterozygous mutation in IL10RA gene (V406L) and one in IL36RN gene (S113L). Nevertheless, our patient did not have any psoriasis or inflammatory bowel disease. Treatment of UCD was mainly surgical resection, steroids, and radiotherapy. Treatments of MCD were tocilizumab, rituximab, anakinra, steroids, chemotherapy and splenectomy. Overall survival after an average of 6 years of follow-up, was 100% for both unicentric and multicentric forms. Conclusion: Paediatric CD seems still underdiagnosed with a significant diagnosis delay specially for the MCD but new international criteria will help in future. In UCD, surgery is the main treatment. New drugs are used specially for the MCD, but more studies need to be conduct in children. The global survey is better in children than adults. Disclosure of Interests: Charlotte Borocco: None declared, Claire Ballot-Schmit: None declared, Oanez Ackermann: None declared, Nathalie Aladjidi: None declared, Jeremie Delaleu: None declared, Vannina Giacobbi-Milet: None declared, Sarah Jannier: None declared, Eric Jeziorski: None declared, Yves Perel: None declared, Francois Maurier: None declared, Christophe Piguet: None declared, Eric Oksenhendler: None declared, Isabelle Kone-Paut Grant/research support from: SOBI has supported drug product (anakinra) for the presented study, Consultant for: SOBI, Novartis, Pfizer, Abbvie, UCB, CHUGAI, ROCHE, Caroline Galeotti: None declared

Introduction : Les predispositions genetiques au cancer de l’enfant sont rares avec une proportion de 10% des cas retenue actuellement. La mise en evidence de ces predispositions fait partie des « indispensables » pour ameliorer la prise en charge de ces patients. Pour porter des indications justes, il convient de repertorier precisement les points d’appel qui permettent de s’interroger sur une predisposition genetique au cancer. Problematique : Devant la necessite de tester les enfants les plus a risque de predisposition en priorite, un outil d’aide a l’orientation pourrait etre utile au depistage des facteurs de risque dans un service d’oncologie pediatrique generaliste. La description et la quantification de ces situations a risque genetique ainsi que leur modalite de prise en charge, permettra de creer cet outil. Materiels et methodes : Ce travail a ete realise dans le centre specialise du CHU de Bordeaux sur tous les enfants pris en charge avec un diagnostic de cancer entre 2011 et 2012. Les facteurs de risque utilises, comprenait l’âge de moins d’un an au diagnostic, la multifocalite des lesions, le type de cancer presente (specifique de syndrome de predisposition), le caractere secondaire de la tumeur, l’histoire familiale de cancer et enfin les points d’appels de l’examen clinique. Resultats : 223 patients avec un diagnostic de cancer ont ete pris en charge au centre specialise du CHU de Bordeaux entre 2011 et 2012. Pour 76 patients soit 33,9%, il existait au moins un facteur de risque de predisposition genetique au cancer. Les 2 facteurs de risques les plus rencontres etaient l’âge de moins d’un an au diagnostic (26 soit 34,2%) et une histoire familiale de cancer (37 soit 48,7%). Pour 65,8% des patients presentant un risque de predisposition, celui-ci etait porte sur un seul facteur de risque. Au total 23 patients ont ete pris en charge en oncogenetique soit 30% des patients avec facteur de risque. Il s’agissait en priorite des patients avec une atteinte multifocale ou plusieurs facteurs de risque. Conclusion : Il existe une large proportion (33,9%) de patients pour qui une consultation d’oncogenetique serait necessaire. Ceci justifie pleinement la mise en place d’une consultation dediee d’oncogenetique pediatrique. Les consultations d’oncogenetique ont ete realisees chez des patients presentant des criteres visibles pour le clinicien. Une fiche systematique de recueil de donnees a mettre dans les dossiers des patients pour ameliorer l’acces a cette prise en charge faciliterait le depistage de ces patients a risque.

Background: Hypoxic environment is a pejorative prognostic factor in pediatric solid tumors (ST). It is favoring neoangiogenesis, tumor progression and resistance to treatments through the activation of mTor and HIF-1α pathways. Those hypoxic markers can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a dose-escalation phase I trial combining both drugs to inhibit tumor hypoxic mechanisms present in several pediatric refractory/relapsing ST. Procedure: Patients were enrolled in this 3+3 escalation trial with ten dose levels. The primary endpoint was to determine the maximum tolerated dose (MTD) of rapamycin when combined with irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m2/day) and associated biweekly with intravenous irinotecan (125 to 240 mg/m2/dose). Toxicities, pharmacokinetics (PK), efficacy analyses and pharmacodynamics (UGT1A1 status, cytokines/chemokines assessment, MRI markers and proteins' expression) were evaluated. Results: 42 patients were treated and had mild to moderate reversible toxicities. No MTD was present up to the tenth level. The PK were highly variable. Nevertheless, the usually targeted concentrations of rapamycin over time were reached at 1.5 mg/m2/day dose. When looking to the 2 partial responses (PR) and 19 stable diseases (SD) in 31 assessable patients, the mean irinotecan AUC was 363 min.mg/L and the mean D8 rapamycin AUC was 9.3 min.mg/L. No significant relationship was observed between dose escalation and response, but progressive tumors' subgroup (PD) had slightly lower mean irinotecan AUC (321 min.mg/L) and D8 rapamycin AUC (6.5 min.mg/L). The two main tumor groups were brain tumors (BTs) and sarcomas. A high proportion of those patients experienced tumor responses (3/4 ependymomas, 2/3 medulloblastomas, 1 rhabdoid tumor, 2/3 high-grade gliomas and 5/6 osteosarcomas). In all 17 assessable patients for immunohistochemistry, the two targeted proteins, mTor and HIF-1α, were expressed, but the resistance to this double strategy was significantly linked to the HIF-2α protein hyperexpression. In the BTs, lower ADC values in MRI were also a prerequisite for tumor responsiveness. Cytokine analyses, distinguished specific proinflammatory and angiogenic signatures during first course of treatment: PR patients had an increase of TNF, associated to a stable PIGF and a decrease of VEGF-C; the SD subgroup had a significant increase of VEGF-D and a stable or increase of sFLT1 and PD group had a constant increase of IL8 and VEGF-D. Conclusion: Despite no MTD, we can propose a next phase II trial with rapamycin dose of 1.5 mg/m2/day associated with 125 mg/m2 irinotecan in STs not expressing HIF-2α protein. A precise PK follow-up will be used to reach an irinotecan AUC up to 360 min.mg/L and a D8 rapamycin blood concentration of 10 µg/L. The cytokine evaluation will help us to predict during first cycle the potential tumor response. Citation Format: Sarah Jannier, Veronique Kemmel, Consuelo Sebastia, Agathe Chammas, Amelia-Naomi Sabo, Erwan Pencreach, Françoise Farace, Benoit Lhermitte, Birgit Geoerger, Isabelle Aerts, Didier Frappaz, Pierre Leblond, Nicolas Andre, Yves Perel, Nadège Corradini, Anne Isabelle Bertozzi, Florence Vincent, Natacha Entz-Werle. Phase I study with rapamycin combined with irinotecan, the SFCE RAPIRI I trial, a new way to target tumor hypoxia in pediatric refractory cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT136.

Background With the growing rate of childhood cancer cure and the risks of sequelae, long-term follow-up (FU) of survivors is a central issue. Several models have been proven far from satisfactory. Shared care FU is the result of collaboration between general practitioners (GPs) and cancer centers. We sought to demonstrate the feasibility of setting up a shared care program based on the patient-centered education of GPs and to evaluate the impact of this model in an intervention study. Methods We compared the FU care achievement in two childhood cancer survivor cohorts in the same pediatric oncology center, (i) control group (n = 134) and (ii) intervention study cohort (n = 137), after setting up the program. Results The rate of survivors answering the survey and the rate of patients involved in FU by their GPs were higher in intervention study cohort than in baseline one (132/137 vs. 72/134 and 110/132 vs. 13/72; P ≤ 0.0001). The lack of any FU was definitely lower (10/132 vs. 18/72; P = 0.001) in the intervention study cohort. Conclusion In this shared care program, survivors overcame distrust in their GP's knowledge and entered the FU program after their GPs had been involved in patient-centered education. Personalized and incentive-based guidance was very useful in helping survivors to adhere to FU. Support of a dedicated long-term FU team was very useful. A nationwide organization, consideration of special needs in subgroups of survivors and sustained funding are needed to adjust the program in the very long term.

Nationwide prospective cohort study exploring (i) the factors associated with treatment initiation (vs. watchful waiting) in children with primary immune thrombocytopenia (ITP) followed in routine clinical practice and (ii) the predictors of chronicity at 12 months.Between 2008 and 2013, 23 centers throughout France consecutively included 257 children aged 6 months-18 years and diagnosed with primary ITP over a 5-year period. Data on ITP clinical features along with medical management were collected at baseline and 12 months. Multivariate logistic regressions were used to determine (i) and (ii) as defined above, providing odds ratio (OR) with 95% confidence interval (95% CI).One hundred thirty-seven (53%) children were males, median age was 4.6 years, median platelet count was 7 × 109/l, and 214 (81%) patients initiated medication. Factors independently associated with treatment initiation included platelet counts10 × 109/l (P0.0001) and mucocutaneous bleeding symptoms at baseline (P0.001). At 12 months, data were available for 211 (82%) children, of whom 160 (74%) had recovered. Predictors of chronicity included female gender (OR = 2.2; 95% CI = 1.0-4.8), age ≥10 years (OR = 2.6; 95% CI = 1.1-6.0), and platelet counts ≥10 × 10In routine clinical practice, the decision to apply a watchful waiting strategy seems to be driven by platelet counts even in the absence of bleeding symptoms, resulting in treatment being initiated in more than 80% of the children surveyed. Overall, younger children with ITP showed good prognosis, with lower platelet counts and, to a lesser extent, male gender predicting more favorable outcomes.

Objectifs Le lymphome est une hemopathie maligne rare chez l’enfant, habituellement suspecte devant un tableau associant syndrome tumoral ganglionnaire, fievre au long cours et alteration de l’etat general. La precocite du diagnostic histologique precis conditionne la strategie therapeutique. Nous rapportons ici une presentation atypique de lymphome T chez un enfant de 9 ans, se presentant avec une fievre a 40 °C evoluant depuis 15 jours et une discrete pancytopenie avec activation macrophagique, sans syndrome tumoral ni contexte infectieux associe. Materiels et methodes L’echographie abdominale et la radiographie thoracique sont normales. Plusieurs myelogrammes objectivent une hypoplasie granuleuse et erythroblastique avec 15–20 % de lymphocytes CD8+ et CD30+. Le bilan est complete par une biopsie osteo-medullaire (BOM) et une TEP/TDM au 18F-FDG (TEP). Resultats La BOM revele une infiltration medullaire par une lymphoproliferation clonale T CD8+, CD30+, ALK−. La TEP initiale montre un hypermetabolisme osteo-medullaire intense et diffus tres inhabituel (SUVmax = 13), predominant sur le squelette peripherique, sans atteinte morphologique osseuse, syndrome tumoral ni cible ganglionnaire. Les bilans infectieux et immunitaire sont negatifs. Une atteinte medullaire reactionnelle inflammatoire est initialement evoquee. Apres echec de plusieurs antibiotherapies d’epreuve, la corticotherapie est efficace sur la fievre et les signes biologiques, recidivant des l’arret, avec atteinte cutanee associee montrant la meme lymphoproliferation T CD8. Une nouvelle TEP est realisee, mettant en evidence une progression metabolique de l’atteinte osteo-medullaire plus heterogene et l’apparition d’adenopathies hypermetaboliques sus et sous-diaphragmatiques. La biopsie ganglionnaire retrouve l’infiltrat T CD8. La confrontation de l’analyse anatomopathologique et de l’evolution clinique et morpho-metabolique retient finalement le diagnostic de lymphome T CD8 cytotoxique inclassable, initialement osteo-medullaire. L’enfant est actuellement en remission au decours d’une chimiotherapie conventionnelle, suivie d’une allogreffe de moelle osseuse. Conclusion Le bilan d’extension d’un lymphome inclut de facon standardisee la TEP dans l’evaluation initiale. Un hypermetabolisme osteo-medullaire isole, intense et diffus, sans syndrome tumoral ou atteinte morphologique osseuse associee, n’avait pas ete jusque-la rapporte dans la litterature, et doit faire evoquer precocement un lymphome.

Background To improve outcome and overall survival (OS) in high-risk neuroblastoma, NB96 induction therapy was intensified using sequential high-dose chemotherapy and autologous stem cell rescue. Procedure Twenty children were included in this pilot study undertaken at seven reference centers in France, between May 1995 and October 1996. Induction began with one cycle of conventional chemotherapy followed by six sequential cycles of high-dose chemotherapy comprising two cycles of etoposide 800 mg/m2/day over 3 days, two cycles of cyclophosphamide 2,000 mg/m2/day over 3 days, and two cycles of carboplatin 400 mg/m2/day over 5 days, followed by stem cell rescue. Results Thirteen patients (13/20) received this induction with acceptable toxicity and adequate stem cell harvest. Of these, nine (9/13) underwent surgery according to the protocol, while one patient was given a consolidation regimen prior to surgery. No toxic death was recorded. At the end of induction, complete remission was achieved in 10 cases (50%), with six still alive in July 2009. The 5-year event-free survival and OS were 35 ± 11% and 40 ± 11%, respectively. Conclusion NB96 therapy is feasible and tolerated without lethal toxicity. Nevertheless, given the small sample size and absence of randomization in our study, the effectiveness of this strategy based on metastasis complete response rates and long-term outcome was not superior to other intensive chemotherapy regimens. Pediatr Blood Cancer 2011; 57: 965–971. © 2011 Wiley-Liss, Inc.

Background Traffic is a source of environmental exposures, including benzene, which may be related to childhood leukemia. Objectives A national registry–based case–control study [ESCALE (Etude Sur les Cancers et les Leucémies de l’Enfant, Study on Environmental and Genetic Risk Factors of Childhood Cancers and Leukemia)] carried out in France was used to assess the effect of exposure to road traffic exhaust fumes on the risk of childhood leukemia. Methods Over the study period, 2003–2004, 763 cases and 1,681 controls < 15 years old were included, and the controls were frequency matched with the cases on age and sex. The ESCALE data were collected by a standardized telephone interview of the mothers. Various indicators of exposure to traffic and pollution were determined using the geocoded addresses at the time of diagnosis for the cases and of interview for the controls. Indicators of the distance from, and density of, main roads and traffic nitrogen dioxide (NO2) concentrations derived from traffic emission data were used. Odds ratios (ORs) were estimated using unconditional regression models adjusted for potential confounders. Results Acute leukemia (AL) was significantly associated with estimates of traffic NO2 concentration at the place of residence > 27.7 μg/m3 compared with NO2 concentration < 21.9 μg/m3 [OR = 1.2; confidence interval (CI), 1.0–1.5] and with the presence of a heavy-traffic road within 500 m compared with the absence of a heavy-traffic road in the same area (OR = 2.0; 95% CI, 1.0–3.6). There was a significant association between AL and a high density of heavy-traffic roads within 500 m compared with the reference category with no heavy-traffic road within 500 m (OR = 2.2; 95% CI, 1.1–4.2), with a significant positive linear trend of the association of AL with the total length of heavy-traffic road within 500m. Conclusion This study supports the hypothesis that living close to heavy-traffic roads may increase the risk of childhood leukemia.

Background Autoimmune hemolytic anemia is a rare condition in children. Little is known about its initial presentation and the subsequent progression of the disease. Design and Methods 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. Results 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). Conclusions 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.

Background: Cushing’s syndrome (CS), rare in children, is due to pituitary or, less frequently, to adrenocortical tumors. Ectopic adrenocorticotropin (ACTH) secretion is exceptional. Method: A case of apparently ACTH-independent CS in a child is reported. Results: CS was due to an adrenal ganglioneuroma where neuroendocrine cells were immunopositive for ACTH responsible for the syndrome through a paracrine effect. Cortical cell hyperplasia was observed. Conclusion: Benign and differentiated tumors of the neural crest such as ganglioneuromas may be responsible for CS.

The association between acute childhood leukaemia and residing next to petrol stations and automotive repair garages was analysed in a national registry-based case-control study carried out in France in 2003-2004.Population controls were frequency matched with cases on age and gender. Data were collected by standardised telephone interview with the mothers. The latter were asked to report the proximity of their homes to petrol stations, automotive repair garages and other businesses from the conception of the index child to the diagnosis (for cases) or interview (for controls). Odds ratios were estimated using unconditional regression models adjusted for age, gender, number of children under 15 years of age in the household, degree of urbanisation and type of housing.765 cases of acute leukaemia and 1681 controls were included. Acute leukaemia was significantly associated with residence next to petrol stations or automotive repair garages (OR 1.6, 95% CI 1.2 to 2.2) and next to a petrol station (OR 1.9, 95% CI 1.2 to 3.0). The OR showed no tendency to increase with duration of exposure. The results were not modified by adjustment for potential confounding factors including urban/rural status and type of housing.The results support the findings of our previous study and suggest that living next to a petrol station may be associated with acute childhood leukaemia. The results also suggest that the role of low-level exposure to benzene in acute childhood leukaemia deserves further evaluation.

Purpose To identify prognostic factors and to evaluate the outcome of children with acute lymphoblastic leukemia (ALL) failure after induction therapy. Patients and Methods Between June 1993 and December 1999, 1,395 leukemic children were included in the French Acute Lymphoblastic Leukemia 93 study. Results Fifty-three patients (3.8%) had a leukemic induction failure (LIF) after three- or four-drug induction therapy. In univariate analysis, high WBC count (P = .001), mediastinal mass (P = .017), T-cell phenotype (T-ALL; P = .001), t(9;22) translocation (P = .001), and a slow early response (at day 8 and/or on day 21, P = .001) were predictive of LIF. The following three prognostic groups for LIF were identified by multivariate analysis: a low-risk group with B-cell progenitor (BCP) ALL without t(9;22) (odds ratio [OR] = 1), an intermediate-risk group with T-ALL and a mediastinal mass (OR = 7.4, P < .0001), and a high-risk group with BCP-ALL and t(9;22) or T-ALL without a mediastinal mass (OR = 28.4, P < .0001). Complete remission (CR) was subsequently obtained in 43 patients (81%). The 5-year overall survival (OS) rate of the 53 patients was 30% ± 6%. The 5-year OS rate among allogeneic graft recipients, autologous graft recipients, and after chemotherapy were 30.4% ± 9.6% (50% ± 26% after genoidentical transplantation), 50% ± 17.7%, and 41.7% ± 14.2%, respectively (P = .18). Fourteen patients (26%) were still in first CR after a median of 83 months (range, 53 to 117 months). Conclusion Three risk categories for LIF in children with ALL were identified. Approximately one third of patients with LIF can be successfully treated with salvage therapy overall. Subsequent CR after LIF is mandatory for cure.

International audience; The objective of the study was to assess acute neurotoxicity associated with triple intrathecal therapy (TIT)+/-high-dose methotrexate (HD MTX) in children with acute lymphoblastic leukemia (ALL). 1395 children were enrolled on FRALLE 93 protocol from 1993 to 1999. Lower-risk group (LR, n=182) were randomized to weekly low-dose MTX at 25 mg/m(2)/week (LD MTX, n=81) or HD MTX at 1.5 g/m(2)/2 weeks x 6 (n=77). Intermediate-risk group (IR, n=672) were randomized to LD MTX (n=290) or HD MTX at 8 g/m(2)/2 weeks x 4 (n=316). Higher-risk group (HR, n=541) prednisone-responder patients received LD MTX and cranial radiotherapy. HR group steroid resistant cases were grafted (autologous or allogenic). TIT (MTX, cytarabine and methylprednisolone) was given every 2 weeks during 16-18 weeks and every 3 months during maintenance therapy in LR and IR patients. 52 patients (3.7%) developed neurotoxicity. Isolated seizures: n=15 (1.1%), peripheral and spinal neuropathy: n=17 (1.2%) and encephalopathy: n=20 (1.4%). Age >10 years was significantly associated with neurotoxicity (P=0.01) and use of HD MTX is associated with encephalopathy (P=0.03). Sequels are reported respectively in 60 and 33% of spinal neuropathy and encephalopathy cases. Current strategies tailoring risk of neurological sequels has to be defined.

From 1989 to 1998, 341 children were included in the French multicentric LAME (Leucémie Aiguë Myéloblastique Enfant) trials. A total of 309 children were registered in the LAME 89/91 protocol. This intensive regimen included an induction phase (mitoxantrone plus cytarabine), two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine; 276 (90%) achieved a CR. The 5-year overall survival (OS) and event-free survival (EFS) were 60+/-4 and 48+/-4%, respectively. From 1997, timed-sequencing of the LAME SP induction chemotherapy led to an unacceptable frequency of consolidation delay; future improvements are unlikely to come from further increases in intensity. The role of allogenic bone-marrow transplantation from an HLA-identical sibling in CR1 was examined. The disease-free survival (DFS) was 52+/-4% for non-allografted patients and 57+/-7% for allografted patients (P=NS); a better OS for allografted patients was shown and could be related either to allo-BMT early in CR1 or to a second allo-BMT in CR2. For the complete responders after consolidation therapy, the 5-year OS was significantly better in patients randomized for no maintenance therapy (MT-) than in patients randomized for MT (77.6+/-8 vs 59+/-8%; P=0.05), while the 5-year DFS was not significantly different. Exposure to low-dose MT might contribute to clinical drug resistance and treatment failure in relapsing patients.

Revue d'oncologie hematologie pediatrique - Sous presse. Epreuves corrigees par l'auteur. Disponible en ligne depuis le mercredi 27 juillet 2016

Hoyeraal-Hreidarsson syndrome represents a severe variant of dyskeratosis congenita (Zinsser-Cole-Engman syndrome). This X-linked recessive, progressive, multisystemic disorder reported so far in 12 pedigrees is characterised by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, mental retardation, progressive combined immune deficiency and aplastic anaemia. Mutations in the DKC1gene on Xq28 have been identified in the X-linked form of dyskeratosis congenita and in some Hoyeraal-Hreidarsson syndrome patients. We report on two sibs and two other unrelated patients with the striking clinical features of Hoyeraal-Hreidarsson syndrome. Noticeably, all four had early digestive problems, with chronic, bloody diarrhoea and feeding problems causing one of the most difficult problems in the supportive treatment of this uniformly lethal condition. Pathological changes in the proliferative compartment of the digestive mucosa included alterations of the glandular architecture and focal rarefaction of the glands. This aspect seems consistent with altered telomerase function associated with a dyskerin mutation which may decrease the proliferative capacity of digestive epithelial cells. A missense mutation 146 C-->T (Thr49Met) in the DKC1gene was found in two unrelated patients, whereas mutation screening was negative for one single case. The absence of mutations of the DKC1gene in patients with Hoyeraal-Hreidarsson syndrome emphasises the probable implication of one or more other loci.

Purpose: To clarify treatment strategy for lymphocyte-predominant Hodgkin’s lymphoma (LPHL), the French Society of Pediatric Oncology initiated a prospective, nonrandomized study in 1988. Patients received either standard treatment for Hodgkin’s lymphoma or were not treated beyond initial adenectomy. Patients and Methods: From 1988 to 1998, 27 patients were available for study. Twenty-four patients were male, and median age was 10 years (range, 4 to 16 years). Twenty-two, two, and three patients had stage I, II, and III disease, respectively. Thirteen patients (stage I, n = 11; stage III, n = 2) received no further treatment after initial surgical adenectomy (SA). Fourteen patients received combined treatment (CT; n = 10), involved-field radiotherapy alone (n = 1), or chemotherapy alone (n = 3). The two groups were comparable for clinical status, treatment, and follow-up. Results: Twenty-three of 27 patients achieved complete remission (CR). With a median follow-up time of 70 months (range, 32 to 214 months), overall survival to date is 100%, and overall event-free survival (EFS) is 69% ± 10% (SA, 42% ± 16%; CT, 90% ± 8.6%; P < .04). If we considered only the patients in CR after initial surgery (n = 12), EFS was no longer significantly different between the two groups. Patients with residual mass after initial surgery (n = 15) had worse EFS if they did not receive complementary treatment (P < .05). Conclusion: Although based on a small number of patients, our study showed that (1) no further therapy is a valid therapeutic approach in LPHL patient in CR after initial lymph node resection, and (2) complementary treatment diminishes relapse frequency but has no impact on survival.

Malignant solid tumors have rarely been reported in children with Down syndrome (DS) and are not well known. The authors collected from 1980 to 2001 all cases of solid tumors observed in DS patients aged from birth to 19 years within the network of the Société Française d'Oncologie Pédiatrique (SFOP). Only 21 cases were observed, with a peculiar distribution: a lack of intracranial tumors and embryonal neoplasms combined with an overrepresentation of lymphomas and germ cell tumors. The treatment of solid tumors in DS is difficult, due to physical and psychological impairments, different pharmacogenetic profile, and associated malformations.

PURPOSE: To determine whether the use of maintenance therapy (MT) delivered after intensive induction and consolidation therapy confers any advantage in childhood acute myeloid leukemia (AML). PATIENTS AND METHODS: A total of 268 children with AML were registered in the Leucámie Aiquë Myéloïde Enfant (LAME) 89/91 protocol. This regimen included an intensive induction phase (mitoxantrone plus cytarabine) and, for patients without allograft, two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase, and amsacrine. In the LAME 89 pilot study, patients were given an additional MT consisting of mercaptopurine and cytarabine for 18 months. In the LAME 91 trial, patients were randomized to receive or not receive MT. RESULTS: A total of 241 (90%) of 268 patients achieved a complete remission. The overall survival and event-free survival at 6 years were 60% ± 6% and 48% ± 6%, respectively. For the complete responders after consolidation therapy, the 5-year disease-free survival was not significantly different in MT-negative and in MT-positive randomized patients (respectively, 60% ± 19% v 50% ± 15%; P = .25), whereas the 5-year overall survival was significantly better in MT-negative randomized patients (81% ± 13% v 58% ± 15%; P = .04) due to a higher salvage rate after relapse. CONCLUSION: More than 50% of patients can be cured of AML in childhood. Either drug intensity or each of the induction and postremission phases may have contributed to the outstanding improvement in outcome. Low-dose MT is not recommended. Exposure to this low-dose MT may contribute to clinical drug resistance and treatment failure in patients who experience relapse.

International audience; BACKGROUND:Primary immunodeficiencies (PIDs) are inherited diseases associated with a considerable increase in susceptibility to infections. It is known that PIDs can also predispose to cancer and immune diseases, including allergy, autoimmunity, and inflammation.OBJECTIVE:We aimed at determining the incidence of autoimmunity and inflammation in patients with PIDs.METHODS:We have retrospectively screened 2183 consecutive cases of PID in the Centre de Référence Déficits Immunitaires Héréditaires registry (CEREDIH; the French national PID registry) for the occurrence of autoimmunity and inflammation.RESULTS:One or more autoimmune and inflammatory complications were noted in 26.2% of patients, with a risk of onset throughout the patient's lifetime. The risk of autoimmune cytopenia was at least 120 times higher than in the general population, the risk of inflammatory bowel disease in children was 80 times higher, and the risk of other autoimmune manifestations was approximately 10 times higher. Remarkably, all types of PIDs were associated with a risk of autoimmune and inflammatory complications, although the greatest risk was associated with T-cell PIDs and common variable immunodeficiency. The occurrence of autoimmune disease is a negative prognostic factor for survival.CONCLUSIONS:Our results provide the basis for a detailed prospective evaluation of autoimmunity and inflammation in the context of PIDs, with a view to accurately assessing these risks and describing the possible effect of medical intervention.

L’anemie hemolytique auto-immune (AHAI) de l’enfant est une maladie rare qui atteint moins de 50 enfants par an en France. Elle constitue souvent une urgence vitale immediate par la brutalite et la profondeur de l’anemie, necessitant une discussion de transfusion de culot globulaire (CGR), malgre les risques d’allo-immunisation masquee ou d’exacerbation de l’hemolyse. La cohorte prospective nationale observationnelle OBS’CEREVANCE est coordonnee depuis 2004 a Bordeaux, et inclut en mars 2017, 385 enfants atteints d’une AHAI isolee: âge median: 3,8 ans (0,1–17,4), signes de gravite clinique de l’anemie pour 66 %, mediane du taux d’hemoglobine 5,7 g/dL (1,8–12,2) et de reticulocytes 148 G/L (1–805), test de Coombs IgG/IgG + complement dans 63 % des cas, suivi median 2,4 ans (0,0–27,5). Une corticotherapie a ete debutee dans la semaine du diagnostic chez 74 % des enfants. Une ou plusieurs transfusions de CGR ont ete necessaires pour 55 % des enfants, avec une tolerance le plus souvent bonne. Aucun des 7 deces n’a ete directement relie a l’anemie. La decision d’un support transfusionnel repose sur la tolerance clinique de l’anemie, sa brutalite, le taux d’hemoglobine, voire l’absence d’hyperreticulocytose. La corticotherapie est indiquee precocement pour attenuer l’hemolyse. Pour assurer la securite transfusionnelle, les examens immuno-hematologiques necessitent du temps en raison de la presence de l’auto-anticorps et le choix d’un CGR compatible est difficile, voire parfois impossible. Un dialogue entre le clinicien et le medecin de l’etablissement de transfusion est donc indispensable afin d’evaluer le ratio benefice/risque et le degre d’urgence clinique de la transfusion.

Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder that predisposes to the development of benign and malignant tumors with a birth incidence rate of 1 in 2500–3000. 50% of cases are sporadic. The diagnosis is exclusively based on clinical assessment with clinical diagnostic criteria such as cafe-au-lait spots, neurofibromas, axillary or groin freckling, Lisch nodules, optic pathway glioma, bony dysplasia and first-degree relative with NF1. We report a family with NF1 in which two members presented atypical clinical features in addition to the classical diagnostic criteria. Three relatives affected by NF1, a father and two of his three sons, are described. The clinical diagnosis was originally worn in all three cases, with the association many spots cafe-au –lait over the entire body and some axillary freckling as well as first-degree relative. One case presented an Acute Myeloid Leukemia (AML) type 2 at 10 years of age diagnosed before the revelation of bicytopenia associated pallor and isolated asthenia. A second case presented a nephrotic syndrome at 4 years of age due to the association of hydrops with headache and asthenia. Direct sequencing of NF1 led to identify the familial mutation, a previously unreported heterozygous missense mutation c.3443C > A, p.Ala1148Glu in exon 20 which segregated with all three affected patients. The family described in this report confirms the high clinical variability of NF1, even intrafamilial, and raises the question as to whether rare features such as AML and nephrotic syndrome are associated with NF1. Some NF1 patients presenting glomerular diseases or AML have rarely been reported, but due to the small number of cases described the mechanisms underlying these associations are poorly understood. However, it seems important to be aware of the possible occurrence of nephritic syndrome and/or malignant blood diseases in NF1 patients.

This study was undertaken to show that a high survival rate can be obtained in B-cell (Burkitt and large B-cell) lymphoma and L3 leukemia with multiagent chemotherapy adapted to the tumor burden (stage, resection status, percentage of blasts in bone marrow, and central nervous system [CNS] involvement) and early response to chemotherapy, to investigate actual prognostic factors, and to see if large B-cell lymphoma can be treated with the same regimen as Burkitt lymphoma. Patients were classified into 3 risk groups. Group A (resected stage I and abdominal stage II) received 2 courses of vincristine, cyclophosphamide, doxorubicin, and prednisone. Group B (patients not eligible for groups A or C) received 5 courses of chemotherapy with, in addition, high-dose methotrexate, 3 g/m(2) over 3 hours; infusional cytarabine; and intrathecal (IT) methotrexate. Group C (patients with CNS involvement and acute lymphoblastic leukemia with at least 70% of blasts in bone marrow) received 8 courses with, in addition, high-dose methotrexate, 8 g/m(2); high-dose cytarabine; etoposide; and triple IT. Except in group A, treatment started with a prephase (COP, low-dose vincristine and cyclophosphamide). It was intensified for patients who did not respond to COP in group B and any patient with residual viable cells after the consolidation phase. A total of 561 patients were enrolled in the SFOP LMB89 protocol (July 1989-June 1996). Five-year survival is 92.5% (95% confidence interval [CI], 90%-94%) and event-free survival (EFS) 91% (95% CI, 89%-93%). EFS is 98% (95% CI, 90%-100%), 92% (95% CI, 89%-95%), and 84% (95% CI, 77%-90%) for group A, B, and C, respectively. In group B, multivariate analysis of prognostic factors showed that a lactate dehydrogenase level more than 2-fold the normal value, no response after COP, and age of at least 15 years were associated with a lower EFS. CNS involvement was the only prognostic factor in group C. (Blood. 2001;97:3370-3379)

We investigated the pharmacokinetics and safety of an oral solution of itraconazole in two groups of neutropenic children stratified by age. Effective concentrations of itraconazole in plasma were reached quickly and maintained throughout treatment. The results indicate a trend toward higher concentrations of itraconazole in plasma in older children.

Purpose: The pharmacokinetics of DaunoXome were studied during a multicentric phase I-II study performed in children suffering from relapsed acute lymphoblastic leukaemia and treated on a weekly schedule. Patients and methods: A group of 18 patients were studied during the first course of treatment at dose levels between 40 and 120 mg/m2. Blood samples were obtained up to 72 h after infusion. The liposomal and free forms of daunorubicin, as well as daunorubicinol, were separated and quantified by HPLC using fluorometric detection, and data were analysed using a model-independent approach. Results: Unchanged liposomal daunorubicin disappeared from plasma following a monoexponential decay. Its AUC represented 95.8% of the total fluorescent species found in plasma and increased linearly with the dose administered. The elimination half-life was 5.23 h, total plasma clearance 0.344 l/h per m2, and volume of distribution at steady state 2.08 l/m2. Free daunorubicin and daunorubicinol were detected in plasma at all time-points studied. Their AUCs represented, respectively, 2.53% and 1.70% of total fluorescent species and their elimination half-lives were, respectively, 16.6 h and 22.3 h. The daunorubicinol/daunorubicin AUC ratio was 0.82%. Conclusions: This study is the first to demonstrate that free daunorubicin is present in plasma after DaunoXome administration and that it originates from in vivo release from the liposomes. The pharmacokinetics of free daunorubicin appeared to be comparable to those observed after conventional administration. However, the concentration of daunorubicinol appeared to be lower than that found after conventional administration of daunorubicin.

PURPOSE: The French Society of Pediatric Oncology MDH82 study demonstrated the effectiveness of 20 Gy irradiation of involved fields after doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or mechlorethamine, vincristine, procarbazine, and prednisone/ABVD chemotherapy in children with localized Hodgkin’s disease (HD). The response to primary chemotherapy was the only predictor of survival. To reduce long-term treatment complications without compromising efficacy, the MDH90 study was based on a new chemotherapy regimen devoid of both alkylating agents and anthracycline, followed by 20 Gy of radiotherapy (RT) for good responders. PATIENTS AND METHODS: From January 1990 to July 1996, 202 children were enrolled from 30 institutions. Good responders to four cycles of vinblastine, bleomycin, etoposide (VP16), and prednisone (VBVP) were given 20 Gy of RT and no further therapy. Poor responders were given vincristine, procarbazine, prednisone, and doxorubicin. After a second evaluation, good responders were given 20 Gy of RT, and poor responders were given 40 Gy of RT. RESULTS: One hundred seventy-one patients (85%) were good responders to VBVP, 27 (15%) were poor responders, and four did not respond. With a median follow-up of 74 months (range, 25 to 117 months), the 5-year overall survival rate (mean ± SD) is 97.5% ± 2.1%, and the event-free survival rate (mean ± SD) is 91.1% ± 1.8%. Significant predictors of worse event-free survival in multivariate analysis were hemoglobin < 10.5 g/L, “b” biologic class, and nodular sclerosis. CONCLUSION: These results suggest that most children with clinical stage I and II HD can be treated with chemotherapy devoid of alkylating agents and anthracycline, followed by low-dose RT.

PURPOSE: To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 × 109/L and platelet count was > 100 × 109/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval). RESULTS: CDI was significantly increased in the G-CSF group compared with the non–G-CSF group (mean ± 95% confidence interval, 105 ± 5% v 91 ± 4%; P < .001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups. CONCLUSION: G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control.

9Pathology, CHUPurpan, Toulouse, France Summary Purpose: to study response to chemotherapy and the outcome of children treated for a relapsed anaplastic large-cell lymphoma (ALCL) and to evaluate the role of bone marrow transplantation (BMT) in these patients. Patients and methods: Clinical data concerning the 41 relapses that occurred in 119 patients with ALCL enrolled in 3 consecutive studies since 1975 were analysed. First-line treatment consisted of intensive chemotherapy according to the COPAD protocol for the first series of 12 patients treated between 1975 and 1989 and to the SFOP (French Society of Pediatric Oncology) HM protocols for the 30 patients treated between 1989 and 1997. Twenty-eight patients were treated with CV(B)A (CCNU, vinblastine, ara-C with or without bleomycin), and the others with miscellaneous protocols for recurrent disease. Fifteen patients underwent autologous BMT and 1 allogeneic BMT while in CR2. Results: Thirty-six of forty-one (88%) patients achieved CR2. With a median follow-up of 5 years, 12 patients died, 9 of their disease and 29 patients are alive in CR2 (20 patients), CR3 (5 patients), CR4 (2 patients), CR5 (1 patient) or CR6 (1 patient). Overall and disease-free survival are respectively 69% (53%-82%) and 44% (29%-61%) at three years. In univariate analysis, patients treated with ABMT while in CR2 did not appear to have a better outcome than the other. Remarkably, a long-lasting remission was obtained in 8 of 13 patients treated with weekly vinblastine for a relapse including 6 relapses occurring after ABMT. Conclusions: Relapsed ALCL are highly chemosensitive but over 40% of the patients experience several relapses. Prolonged conventional chemotherapy based on vinblastine might, in some cases, be as efficient as short intensive treatment with ABMT.

An understanding of the pathogenesis of second cancers may help in their prevention. We report on two children who were treated for acute lymphoblastic leukemia (ALL), with an exclusively cranial prophylactic irradiation (18 Gy) and who presented with a thyroid carcinoma (TC) 12 and 13 years later. From a thorough review of the literature of TC after ALL and of radiation-induced TC, a strong case can be made that these tumors are caused by late effects of scattered radiation. The risk is at its highest in small children. After cranial irradiation, patients require clinical monitoring of the thyroid and cervical area for nodules, continued indefinitely. We suggest that, in most cases, an alternative form of neuromeningeal prophylaxis should be offered in small children with ALL.

Recombinant hepatitis B vaccine is usually well tolerated. Clinical and laboratory test manifestations with immunologic mechanisms have nonetheless been described following use of this vaccine. We retrospectively report 7 cases of thrombocytopenia occurring within 3 months (7 weeks on the average) of 1 or following injections of recombinant hepatitis B vaccine. Four boys and 3 girls, average age 12 y, were involved. Three had a history of immune thrombocytopenic purpura. Four had haemorrhagic manifestations. The haemogram showed thrombocytopenia (24 x 10(9)/l on the average) without alterations of the other lines. Infectious and immune aetiologies were excluded in all cases. The course varied after treatment by corticosteroids, high-dose intravenous immunoglobulin, or both. After describing the different manifestations subsequent to recombinant hepatitis B vaccination, we discuss post-vaccinal thrombocytopenias (vaccines in question, mechanisms) and the reality of this entity.

This report documents the occurrence of a nephrotic syndrome in five children with Hodgkin disease. In two cases the nephrotic syndrome predated the diagnosis of lymphoma by 6 months and 12 months respectively, while in the other three, the two disorders occurred simultaneously. The nephrotic syndrome resolved in four cases during effective treatment for active Hodgkin disease, while proteinuria remained unchanged in the fifth case with partial control of the lymphoma. The occurrence of a nephrotic syndrome as a manifestation of active Hodgkin disease suggests that some immunological abnormalities play a role in the pathogenesis of the association.The possibility of glomerular dysfunction although rare must be considered and actively looked for in all cases of Hodgkin disease. Similarly, any unusual sign or symptom noted in patients with nephrotic syndrome, particularly receiving or having received immunosuppressants, requires thorough investigation to determine the presence or absence of lymphoma.

Summary This study aimed to describe the clinical features and outcome of anaplastic large cell lymphoma (ALCL) with leukaemic presentation in children. Among 267 patients included in the French paediatric ALCL database between 1989 and 2012, nine (3%) were described as having cytologically detectable circulating tumour cells. Clinical features combined fever (8/9), nodal and extra-nodal disease (9/9), including hepato-splenic (9/9) and lung involvement (7/9). The level of hyperleucocytosis ranged from 30 to 120 × 109/l, with 12–90% of tumour cells. Diagnosis relied on a lymph node biopsy, with a positive ALK+ antibody immunostain in all nine cases, a T-cell immunophenotype in 7/9 cases and CD3 positivity in 5/9 cases. A small cell component was present in 6/9 cases. Only four patients achieved a complete remission with first-line therapy and 3/4 relapsed. Four patients are alive with a median follow-up of 31 months, two of them after allogeneic haematopoietic stem cell transplantation (HSCT), and five patients died, two of them of disease. In conclusion, ALCL with leukaemic presentation is very unusual and should be considered as high-risk lymphoma requiring new therapeutic strategies. The respective role of new agents and allogeneic HSCT in first complete remission still has to be assessed.

Screening for G-CSF receptor mutations in patients with secondary myeloid or lymphoid transformation of severe congenital neutropenia. A report from the French neutropenia register

Blinatumomab is a monoclonal bispecific antibody, combining two binding sites: a CD3 site for T cells and a CD19site for the target B cells. Blinatumomab has demonstrated efficacy and safety in adult relapsed/refractory B-precursor ALL (R/R ALL) populations, but also in the pediatric R/R ALL population as shown by interim results from the Phase 1b/2 study MT103-205 (Gore L et al, ASH 2014). Patients and methods: this retrospective study aims to evaluate safety and efficacy of Blinatumomab in 17 pediatric pts with B-precursor ALL treated in 4 french hematological centers between April 2013 and December 2015 within a compassionate use frame. These 17 pts represent the whole population of French children treated with Blinatumomab outside a clinical trial but under a Temporary Authorization for Use (ATU) given by the French Regulatory Agency (ANSM) within this period. Median age was 6.6 years (8 months - 16.6 years). Results: 1)7 pts (41%) received Blinatumomab at a dose of 15 mcg/m2/day for 28 days/cycle in first or second complete remission for minimal residual disease (MRD) persistence. Six of those 7 pts had a molecular remission (MRD Enterococcus faecalis, n=1 and Staphylococcus haemolyticus, n=1). One patient had a grade 3 soft tissue mucormycosis. Three pts (18%) had hepatic toxicity (≥ grade 3 increased ALAT, n=2). One patient had a grade 4 pericarditis without documented infection. No neurological event was observed. Conclusion: Although our numbers are small 1) Blinatumomab is an effective bridge to HSCT for pts with persisting high MRD after intensive chemotherapy. 2) A 40% MRD response rate has been found for R/R pts but with a dismal final outcome. 3) Toxicity is manageable with a low neurological event rate (none in this study). Blinatumomab should be developed in less advanced B lineage ALL in children. Disclosures Baruchel: Amgen: Consultancy. Brethon:Amgen: Consultancy.

Objectifs La neurolymphomatose est une manifestation rare du lymphome non hodgkinien, en particulier chez les enfants. Elle est souvent diagnostiquee tardivement, et le succes de la prise en charge repose sur la reconnaissance precoce de cette complication neurologique. Cas clinique : un garcon de huit ans est adresse aux urgences pour l’apparition progressive de douleurs dorsales et des membres inferieurs, puis apparait une paresie des membres superieur et inferieur gauches. Une premiere ponction lombaire est d’abord en faveur d’une meningite lymphocytaire devant la presence de lymphoblastes sans germe identifie. A ce stade, un processus infectieux, un syndrome de Guillain-Barre ou une hemopathie maligne etaient envisages. Une seconde ponction lombaire realisee une semaine plus tard met en evidence des cellules tumorales malignes dont l’immunophenotypage est en faveur d’un lymphome B de haut grade, avec un profil immunohistochimique CD20+ CD5−. Materiels et methodes Examens complementaires : le bilan d’extension est complete par un TDM thoraco-abdomino-pelvien negatif, une IRM cerebrale et medullaire montrant une infiltration des racines cervicales, sacrees et de la queue de cheval. Une TEP au 18F-FDG est demandee pour finaliser le bilan. Resultats La TEP-FDG confirme l’infiltration hypermetabolique intense des racines cervicales et lombo-sacrees, mais identifie egalement une fixation de l’emergence des nerfs crâniens IX, X et XI a la sortie du foramen jugulaire passee inapercue sur l’IRM ainsi que de multiples foyers osseux hypermetaboliques dissemines du squelette axial et peripherique. La realisation d’un premier cycle de chimiotherapie par COP permet une reponse clinique complete avec disparition des douleurs et des symptomes neurologiques. La reponse radiologique est alors nette mais partielle. Enfin, la TEP de suivi a 5 cures montre une reponse metabolique complete. Conclusions Les neurolymphomatoses sont des presentations rares de LMNH surtout chez l’enfant. La TEP FDG est utile dans leur staging en montrant des lesions nerveuses passees inapercues a l’IRM ou des localisations secondaires non identifiees. Son utilite a aussi ete montree dans l’evaluation de la reponse therapeutique du lymphome primaire epidural spinal en detectant une reponse plus precoce que l’IRM.

The prognosis of patients with relapses of ETV6/RUNX1-positive acute lymphoblastic leukemia remains to be evaluated, particularly with regards to the frequency of late relapses. We performed a long-term, follow-up retrospective study to address the outcome of patients with ETV6/RUNX1-positive leukemia relapses.Among the 713 children tested for ETV6/RUNX1 enrolled into the FRALLE 93 protocol, 43 ETV6/RUNX1-positive patients relapsed (19.4%). Most were initially stratified in the low or intermediate risk groups. The median follow-up after relapse was 54.2 months. All but three received second-line salvage therapy and 16 underwent allogeneic transplantation.ETV6/RUNX1 had a strong effect on overall survival after relapse (3-year survival= 64.7% for positive cases versus 46.5% for negative cases) (P=0.007). The 5-year cumulative incidence of relapse was 19.4% and testes were more frequently involved in ETV6/RUNX1-positive relapses (P=0.04). In 81.4% of cases the relapses were late, early combined or isolated extramedullary relapses. The 5-year survival rate of patients with ETV6-RUNX1-positive acute lymphoblastic leukemia relapses reached 80.8% when the relapse occurred after 36 months (versus 31.2% when the relapse occurred earlier). In univariate analysis, female gender was associated with a poor survival, whereas site of relapse, age at diagnosis, leukocytosis and consolidation strategy had no effect. In multivariate analysis, only the duration of first remission remained associated with outcome.We found an excellent outcome for patients with ETV6/RUNX1-positive leukemia relapses that occurred more than 36 months after diagnosis. The duration of first complete remission may, therefore, be a guide to define the treatment strategy for patients with relapsed ETV6/RUNX1- positive leukemia.

There is little data available regarding children and adolescents with Hodgkin lymphoma (HL) who relapse after combined-modality treatment, even though they have a substantial chance of cure. The purpose of this national retrospective study was to evaluate the outcome of patients with recurrent/refractory HL and determine adverse prognostic factors. From 1990 to 2006, 70 patients (median age 13·9 years) with refractory (n = 31) or first relapse (n = 39) HL were identified. Median time from end of treatment to relapse was 6 months (3-56). Relapses occurred in irradiated areas in 43/70 patients. Salvage therapy consisted of chemotherapy and 50 patients received high-dose chemotherapy with autologous stem cell transplantation. Radiotherapy was performed in 29 cases, tandem autologous transplantation in five and allograft in three. With a median follow-up of 40 months (2-140), significant prognostic factors were time to progression/relapse and response to therapy before autograft. Event-free survival and overall survival in patients with refractory disease, early relapse and late relapse were 35 ± 9%, 67 ± 11%, 76 ± 10% and 48 ± 11%, 89 ± 7% and 80 ± 10%, respectively. As progression3 months was a major adverse prognostic factor, novel therapeutic approaches are needed for this group of patients. By contrast, patients have substantial chance of long term second remission in case of relapse3 months.

Metanephric stromal tumor is a rare benign entity belonging to the group of metanephric renal tumors in children. Although metanephric stromal tumors can be cured by simple nephrectomy, differential diagnosis based on histopathologic criteria with other pediatric renal tumors requiring aggressive chemotherapy can be difficult. To our knowledge, cytogenetic characterization of metanephric stromal tumor has never been reported. We describe conventional ("R-bands" karyotyping) and molecular [fluorescence in situ hybridization (FISH), multicolor FISH, oligo array-comparative genomic hybridization] cytogenetic examinations of a metanephric stromal tumor in a 3-year-old boy. Cytogenetic analysis revealed a complex homogeneous gain between bands 17q22 and 17q25.3, resulting in partial triplication of the segment between bands 17q22 and 17q24.3, and duplication of the segment between bands 17q24.3 and 17q25.3. Cytogenetic confirmatory studies in metanephric stromal tumors are currently needed to assess 17q22q25.3 gain as a recurring cytogenetic abnormality of metanephric stromal tumors.

Aim To determine the epidemiology of myeloid leukaemia (ML) in children with Down syndrome (DS) and the efficacy of two approaches, low-dose cytarabine-based regimen (LDC) and standard-dose intensive chemotherapy (SD). Procedure All children with Down syndrome aged from 2 months to 15 years with ML/myelodysplasia registered in the French registry between January 1990 and December 2003 were included. Results Forty-four patients were included. The median age was 1.75 years. The French–America–British subtypes were as follows: M7: 24, M0: 6, M2: 5, M6: 2. Forty-three patients were treated with curative prospect, 20 patients with LDC regimen and 22 according to SD protocols, 1 was given the LDC regimen plus autologous stem-cell transplantation. The event-free survival (EFS) and overall survival (OS) at 5 years were 64.4% and 76.8%. At 5 years, OS in LDC and SD groups were 65% and 85.9% (P = 0.08). EFS were 45% and 80.3% respectively (P

To improve outcome and overall survival (OS) in high-risk neuroblastoma, NB96 induction therapy was intensified using sequential high-dose chemotherapy and autologous stem cell rescue.Twenty children were included in this pilot study undertaken at seven reference centers in France, between May 1995 and October 1996. Induction began with one cycle of conventional chemotherapy followed by six sequential cycles of high-dose chemotherapy comprising two cycles of etoposide 800 mg/m(2)/day over 3 days, two cycles of cyclophosphamide 2,000 mg/m(2)/day over 3 days, and two cycles of carboplatin 400 mg/m(2)/day over 5 days, followed by stem cell rescue.Thirteen patients (13/20) received this induction with acceptable toxicity and adequate stem cell harvest. Of these, nine (9/13) underwent surgery according to the protocol, while one patient was given a consolidation regimen prior to surgery. No toxic death was recorded. At the end of induction, complete remission was achieved in 10 cases (50%), with six still alive in July 2009. The 5-year event-free survival and OS were 35 ± 11% and 40 ± 11%, respectively.NB96 therapy is feasible and tolerated without lethal toxicity. Nevertheless, given the small sample size and absence of randomization in our study, the effectiveness of this strategy based on metastasis complete response rates and long-term outcome was not superior to other intensive chemotherapy regimens.

Background: Ecthyma gangrenosum is characterized by necrotic ulcerations surrounded by an erythematous halo. It is secondary to Pseudomonas aeruginosa infection. Most lesions are located in the anogenital and axillary areas, but the route of infection is generally difficult to establish. Objective: We report six children with perineal ecthyma gangrenosum and discuss predisposing factors, origin, and route of infection. Methods: This was a retrospective clinical study. Results: Three children had blood cultures positive for P. aeruginosa, and one died. Predisposing factors were present in all cases; two had received chemotherapy (neuroblastoma, acute lymphoblastic leukemia), and two had idiopathic granulocytopenia. The last two patients previously had received treatment with systemic antibiotics and had abnormal granulocyte killing several months later. Conclusion: Septicemic ecthyma gangrenosum can be rapidly fatal in young children and requires aggressive antibiotic therapy. Benign ecthyma gangrenosum in healthy infants may result from a modification of bowel microflora after antibiotic therapy in conjunction with maceration in the diaper area. However, careful evaluation and long-term follow-up must be done to detect neutropenia, functional abnormalities of granulocytes, or a possible immune deficiency.

Capillary haemangiomas are frequent benign tumours in infancy. The authors report a case of capillary haemangioma of the greater omentum, discovered in a child of 5 months of age and studied with US, CT and MRI. The localization of such a lesion in the greater omentum is exceptional. Abdominal US revealed a heterogeneous, multinodular intraperitoneal mass. Doppler study demonstrated hypervascularity of the lesion. CT localized the mass to the greater omentum. The mass was hypodense on the unenhanced scan and enhanced massively after injection. The infant suffered a reaction to contrast medium during the CT. MRI demonstrated a mass which was hypointense on T1-weighted images and hyperintense on T2-weighted images. Laparotomy confirmed the location of the mass within the greater omentum and allowed resection of the tumour.

The safety and efficacy of rituximab have been retrospectively assessed in 17 children with Evans syndrome. Patients received 4 or 3 weekly doses of rituximab (375 mg/m(2) per dose) associated with prednisone, alone (14 patients) or associated with other immunosuppressive drugs. Complete or partial remission of at least one cytopenia was achieved in 13 out of the 17 patients (76%), and lasted in 11 of them with a mean follow-up of 2.4 years (range 0.5-7 years). Steroid therapy was stopped or tapered at 50-100% of the baseline dosage in all long-term responders. Moderate side effects and infection occurred only in 4 and 1 children respectively.

Le diagnostic de microangiopathie thrombotique (MAT) est suspecte devant l’association d’une anemie, d’une thrombopenie et d’une schizocytose. Observation Un nourrisson de 21 semaines consulte aux urgences pour refus des tetees et asthenie. Elle est metisse, sa mere est guineenne aux antecedents d’anemie non etiquetes. Cette petite fille est nee en France a terme, sans antecedents particuliers. A l’arrivee, l’examen clinique retrouve une hypotonie globale et une pâleur sans autre anomalie. La numeration formule sanguine fait suspecter une MAT : Hb 7,2 g/dL, VGM 75 fL, reticulocytes 12 G/L, leucocytes 10,37 G/L, polynucleaires neutrophiles : 0,41 G/L, plaquettes a 217 G/L, 10 % de schizocytes, rares polynucleaires de grande taille et hypersegmentes. Les LDH sont a 9877 UI/L, l’haptoglobine indosable, la bilirubine totale est normale (11,6 μmol/L). La creatinine, l’uree, la ferritine et le bilan hepatique sont normaux. Sur les 4 premiers jours, les nadirs d’Hb et de plaquettes baissent respectivement a 4,5 g/dL et 76 G/L, les schizocytes restent entre 5 et 10 %. Le dosage de G6PD est normal. Le test de Coombs est negatif. Le dosage du C3 et C4 est normal. Sur la chromatographie des acides amines sanguins, l’homocysteine totale est a 96 μmol/L (3–15), la methionine a 8 μmol/L (20–34) ; et la chromatographie des acides organiques urinaires montre une excretion massive de l’acide methylmalonique. Le myelogramme montre une moelle « bleue » typique d’une carence en vitamine B9 ou B12. Une carence profonde en vitamine B12 est confirmee ( Le traitement initial associe une transfusion en culot globulaire, supplementation en hydroxycobalamine par voie intramusculaire puis per os. L’hemoglobine, le dosage de vitamine B12 et l’ensemble des anomalies metaboliques sont normalises a 6 semaines. Discussion Ce cas illustre un tableau trompeur de MAT et une presentation atypique de carence en vitamine B12 profonde, qui a fait suspecter une maladie metabolique. Dans un contexte de pseudo-MAT, des valeurs tres elevees de LDH sont evocatrices d’une carence en vitamine B12 et imposent son dosage [1] . Cette presentation de carence en vitamine B12 mimant une MAT est une entite rare, estimee a 2,5 % des MAT et a laquelle il faut penser par l’existence d’un traitement substitutif simple et rapide [2] , [3] , [4] . Conclusion Un tableau de MAT sans reticulocytose ni atteinte renale et avec des LDH tres elevees doit faire rechercher une carence en vitamine B12.

Introduction Les anemies sideroblastiques congenitales sont des pathologies rares liees a des mutations de genes impliques dans la synthese de l’heme, du fer et des proteines mitochondriales. Materiel et methodes Il s’agissait d’une etude descriptive retrospective multicentrique realisee a partir des donnees de la cohorte des Anemies sideroblastiques congenitales (ASC) elaboree au sein du departement de genetique du CHU Bichat-Claude-Bernard entre 2004 et 2015. L’objectif de notre etude etait de rechercher une correlation genotype phenotype dans ces pathologies. Resultats Au total 43 patients (21 filles, 22 garcons) ont ete analyses. Les deux formes les plus frequentes etaient l’anemie sideroblastique liee a l’X ( n = 9) et la forme de transmission autosomique recessive liee a la mutation de SLC25A38 de decouverte plus recente ( n = 9). Le phenotype associe a la mutation ALAS2 etait celui d’une anemie microcytaire de severite et de survenue variables. Comme pour les patients presentant une mutation du gene ALAS2 , 66,7 % des patients presentant une ASC avec mutation SLC25A38 etaient asymptomatiques lors du diagnostic. A noter l’existence chez 2 patients porteurs de la mutation du gene ALAS2 , la presence d’une anomalie cardiaque. Concernant les patients presentant une anemie megaloblastique repondant a la thiamine (TRMA) impliquant le gene SLC19A2 , 3 patients de notre cohorte presentaient la triade caracteristique diabete sucre, surdite et anemie megaloblastique. Dans une proportion relativement elevee de patients (37 %) aucune anomalie genetique n’a pu etre identifiee, suggerant l’implication d’autres genes non identifies a ce jour dans les ASC. Conclusion Certaines correlations deja connues ont ete retrouvees pour les genes les plus frequents ( ALAS2 ou SLC25A38 ) ou bien ceux associes a des formes syndromiques (syndrome de Pearson, mutation SLC19A32 ). En ce qui concerne les patients sans identification genetique, la sous-classification tenant compte entre autres de la severite de l’anemie, du VGM, de l’âge au diagnostic, des symptomes presents pourrait etre une aide precieuse pour orienter la recherche de certaines mutations.