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•In 222 boys with severe hemophilia A and inhibitors of >5 BU, bleeding was reduced from 6.1 to 4.4 per year during ITI.•Before ITI, bleeding was independent of inhibitor titer; during ITI, bleeding increased with higher inhibitor titer and nondaily ITI.

La gestion au domicile d’un traitement par anticancéreux oral (AO) représente un enjeu majeur dans la sécurisation de la prise en charge médicamenteuse des enfants atteints de cancer (observance, forme galénique et modalité d’administration adaptées, gestion des effets secondaires). Depuis novembre 2022, l’équipe de pharmacie clinique a initié la mise en place de plans pharmaceutiques personnalisés (PPP) pour les enfants traités par AO dans le service d’onco-hématologie pédiatrique.

Information on bleeding phenotype in non-severe hemophilia may be used to determine target factor levels for prophylaxis or gene therapy in severe hemophilia.

Data on post-transplant iron overload (IO) are scarce in pediatrics. We conducted a prospective multicenter cohort study (Leucémie de l’Enfant et de l’Adolescent cohort) to determine the prevalence and risk factors of IO in 384 acute leukemia survivors transplanted during childhood. Prevalence of IO (ferritin level ⩾350 ng/mL) was 42.2% (95%CI 37.2–47.2%). Factors significantly associated with IO were: 1) in univariate analysis: older age at transplant (P<0.001), allogeneic versus autologous transplantation (P<0.001), radiation-based preparative regimen (P=0.035) and recent period of transplantation (P<0.001); 2) in multivariate analysis: older age at transplant in quartiles (Odds Ratio (OR)=7.64, 95% CI: 3.73–15.64 for age >12.7 years and OR=5.36, 95% CI: 2.63–10.95 for age from 8.2 to 12.7 years compared to age < 4.7 years), acute myeloid leukemia (OR=3.23, 95% CI: 1.47–7.13), allogeneic graft (OR=4.34, 95% CI: 2.07–9.12 for alternative donors and OR=2.53, 95% CI: 1.2–5.33 for siblings, compared to autologous graft) and radiation-based conditioning regimen (OR=2.45, 95% CI: 1.09–5.53). Graft-versus-host disease was an additional risk factor for allogeneic graft recipients. In conclusion, IO is a frequent complication in pediatric long-term survivors after transplantation for acute leukemia, more frequently observed in older children, those transplanted from alternative donors or with graft-versus-host disease.

L’hyperéosinophilie, définie comme un taux augmenté de polynucléaires éosinophiles (PE) au-delà de 500/mm3, est une anomalie de la formule leucocytaire fréquemment observée en pédiatrie. De multiples causes peuvent être responsables de cette augmentation : dans la plupart des cas, un interrogatoire exhaustif, un examen clinique détaillé et un bilan biologique simple alliant hémogramme, recherche parasitologique et tests immuno-allergiques orientés par l’interrogatoire permettront au praticien d’en trouver l’étiologie. Parmi les causes possibles, la plus fréquente en pédiatrie correspond aux infections parasitaires, principalement causées par les helminthes. Une augmentation du taux de PE peut aussi être secondaire à la prise de médicaments. Elle est également fréquemment rencontrée chez les enfants avec un terrain atopique, ou atteints de maladies inflammatoires (digestive, cutanée…). Une fois les causes secondaires d’hyperéosinophilie écartées et devant une hyperéosinophilie persistante, les syndromes hyperéosinophiliques, avec variant lymphocytaire ou myéloprolifératif, devront être évoqués, faisant porter l’indication d’examens complémentaires à la recherche d’une hémopathie (myélogramme, étude cytogénétique des cellules médullaires). Les conséquences cliniques de l’hyperéosinophilie sont directement causées par les substances libérées par les PE, responsable de dégâts tissulaires notamment pour le muscle cardiaque.

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L’annonce diagnostique d’une maladie hémorragique constitutionnelle rare et grave chez un enfant constitue un traumatisme psychique pour ses parents. Cela remet en question la dynamique familiale et marque le début de la construction d’une relation thérapeutique à long terme entre une famille et une équipe soignante. Afin d’accompagner au mieux ces familles dans l’appréhension de la maladie dès l’annonce du diagnostic, le Centre d’hémophilie de Marseille a mis en place depuis plus de dix ans un dispositif thérapeutique d’accompagnement basé sur la pluridisciplinarité : suivi médical et infirmier, programme d’éducation thérapeutique du patient, accompagnement psychologique, groupe de paroles, création d’un atelier axé sur la psychomotricité. L’Association française des hémophiles est partie prenante de ce dispositif, tout particulièrement au niveau du programme d’éducation thérapeutique. Une étude pilote a permis de s’interroger sur la pertinence de ce dispositif en analysant un groupe de 21 enfants dans des dimensions développementales et psychiques, ainsi qu’en étudiant leur qualité de vie et celle de leurs parents. Les résultats encourageants au niveau du développement psychomoteur, de l’état émotionnel et de la qualité de vie incitent à proposer l’extension de ce type de dispositif d’accompagnement du diagnostic d’hémophilie qui place le psychologue au cœur de l’équipe multidisciplinaire d’un centre de traitement de l’hémophilie.

La survenue d’un anticorps inhibiteur, évènement iatrogène fréquent, est actuellement la complication la plus grave du traitement par facteur VIII chez les jeunes enfants atteints d’hémophilie A sévère. L’inhibiteur, habituellement détecté au cours des premières dizaines de journées de traitement, peut compromettre gravement son efficacité. Les PUPs (previously untreated patients) représentent la population la plus appropriée pour étudier ce risque. Parmi les différents facteurs de risque d’inhibiteur, les plus anciennement documentés sont d’ordre génétique. Ces facteurs de risque directement liés au patient lui-même sont non modifiables. On a aussi identifié des facteurs environnementaux liés aux modalités et circonstances de mise en œuvre du traitement. Les traitements intensifs initiaux représentent un facteur de risque fort alors que les études récentes suggèrent un rôle protecteur de la prophylaxie. Enfin, des facteurs spécifiquement liés au concentré de facteur VIII restent discutés. Les publications font état d’un risque différentiel d’inhibiteur, soit favorable aux concentrés plasmatiques, soit non significativement différent entre produits plasmatiques et recombinants. De manière inattendue, trois larges études PUPs contemporaines (cohortes internationales RODIN, nationales FranceCoag et UKHCDO) ont récemment montré un risque d’inhibiteur différent selon le type de facteur VIII recombinant utilisé chez les PUPss atteints d’hémophilie A sévère. La prise en compte des facteurs de risque d’inhibiteur lors de l’initiation du traitement par facteur VIII chez ces enfants représente un enjeu majeur pour leur état de santé, leur qualité de vie et aussi d’un point de vue économique. Les études récentes soulignent l’intérêt des cohortes pour la connaissance épidémiologique.

Le purpura thrombopénique immunologique (PTI) de l’enfant se caractérise par un syndrome hémorragique cutanéo-muqueux variable, le plus souvent modéré et une évolution habituellement spontanément favorable. L’hémorragie intracrânienne (HIC) est une complication exceptionnelle mais d’une gravité extrême. Peu de données sont disponibles dans la littérature concernant les facteurs de risque, les circonstances de survenue et la prise en charge de cet accident dramatique.

Phenotypic variability is well recognized in severe hemophilia A. A few studies, mainly in adults treated lifelong on demand, suggest that bleeding phenotype correlates with factor VIII gene (F8) mutation type. Because treatment regimens influence outcomes to a large extent, examining bleeding phenotype during the first years of life may be the most suitable way to define this variability. We set out to analyze the very early phenotypic expression of severe hemophilia A in 621 consecutively enrolled, well-characterized previously untreated patients and to correlate this with patients’ F8 mutation. Detailed information was collected on bleeds and treatment of the first 75 exposure days or until inhibitor development. F8 mutation type was known for 531 patients; 402 had null mutations and 129 had non-null mutations. Considering only patients who had not started prophylaxis or developed an inhibitor before select bleeding events, we found that patients with null mutations experienced their first bleed and first joint bleed at younger median ages than patients with non-null mutations (9.7 vs 10.9 months and 13.8 vs 16.1 months, respectively). We conclude that F8 mutation type accounts for only a small component of the significant phenotypic variability found among patients with severe hemophilia A.

Patients with mild/moderate hemophilia A (MHA) may develop inhibitors to factor VIII (FVIII). In this condition, FVIII clotting activity (FVIII:C) baseline levels may remain stable for some patients, but may be reduced to less than 0.01 U/mL for others. Several risk factors for the development of inhibitors in MHA have been proposed. Genetic factors, such as mutations in the FVIII gene, may play a central role; however, other influences, such as intensive treatment with FVIII products, may also be important. Optimal treatment regimens have yet to be determined, not only for the eradication of inhibitors, but also for the management or surgical prophylaxis of hemorrhages associated with this condition. Several treatment options for the control of bleeding in patients with MHA and inhibitors (MHAI) are currently available, and the choice of therapeutic strategy should be given careful consideration; some treatments may produce an anamnestic response, thus delaying the return to FVIII:C baseline levels and adversely affecting the duration of the severe bleeding phenotype. To increase our knowledge of MHAI, a retrospective collection of data is currently being performed among hemophilia centers in France and Belgium. Based on five examples of patients with MHAI collated from preliminary study data, we illustrate the impact on inhibitor outcome of the therapeutic choices used to treat bleeding episodes in these patients.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of developing thymocytes afflicting both children and adults. Although the outcome has significantly improved over the past decades, further advances in targeted therapy will require an accurate stratification of T-ALL subtypes based on the precise understanding of the mechanisms involved. TAL1 is among the most frequently deregulated oncogenes in T-ALL. Studies on TAL1 transgenic animals have recently shown that leukemic growth and survival is largely dependent on the NOTCH1-controlled c-Myc pathway. We recently identified a particular aggressive paediatric T-ALL with t(1;14)(p32;q11)-mediated TAL1 overexpression and, in agreement with a central role of c-Myc in human T-ALL, displaying high levels of c-Myc transcripts. However, the absence of NOTCH1/FBW7 mutations in this case suggested an alternative c-Myc deregulation process. Multicolour FISH analysis indeed revealed a cryptic t(7;8)(q34;q24) within the same t(1;14)+ T-ALL clone, and breakpoint cloning confirmed the juxtaposition of c-Myc to the TCRβ locus. To further investigate the likely scenario of neoplastic development in this patient, we undertook a detailed geno/phenotyping of the tumor sample. In good agreement with the proposed oncogenic role of TAL1 in blocking thymocytes at late stages of maturation, immunophenotypic, transcriptional and genotype profiles clearly converged towards a maturation arrest of the malignant clone at the late cortical CD8 SP stage. By contrast, analysis of translocation breakpoints indicated that both events resulted from V(D)J recombination mistakes, and congruently occurred during the early stages of TCRδ and TCRβ rearrangements (DN2/DN3). Thus, the activation of both c-Myc and TAL1 was clearly decoupled from maturation arrest. As thymocyte progression from DN3 to SP includes extensive proliferation at the ISP/DP transition before rearrangement of the TCRα chain, the tumor clone was expected to show polyclonal TCRα rearrangements. Instead, LR-LMPCR and TCRα multiplex PCR revealed the presence of a monoclonal TCRα rearrangement. Thus, out of hundreds of thymocytes carrying t(1;14) and t(7;8), only one progressed towards malignant transformation after the onset of TCRα rearrangements, suggesting the necessity of yet a “3rd hit”. Most importantly, this indicates that in absence of NOTCH1, TAL1 and c-Myc cooperation was not sufficient to trigger aggressive proliferation. One likely candidate for this 3rd hit is LMO2, which we also found significantly over-expressed in the tumour clone. As previously underlined in animal models, the synergy between LMO2, TAL1 and c-MYC oncogenes likely accounts for the aggressive tumor phenotype in this patient, and illustrates the complex cooperative oncogenic pathways in human T-ALL pathogenesis. Intriguingly, the lack of major mediastin involvement in a clone with such a fulgurating growth raises the alternative possibility that proliferation was actually fired in the periphery through cognate triggering of the expressed TCRαβ, and thus that proliferation is uncoupled from differentiation block.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of developing thymocytes afflicting both children and adults. Although the outcome has significantly improved over the past decades, further advances in targeted therapy will require an accurate stratification of T-ALL subtypes based on the precise understanding of the mechanisms involved. TAL1is among the most frequently deregulated oncogenes in T-ALL. Studies on TAL1transgenic animals have recently shown that leukemic growth and survival is largely dependent on the NOTCH1-controlled c-Myc pathway. We recently identified a particular aggressive paediatric T-ALL with t(1;14)(p32;q11)-mediated TAL1overexpression and, in agreement with a central role of c-Mycin human T-ALL, displaying high levels of c-Myctranscripts. However, the absence of NOTCH1/FBW7mutations in this case suggested an alternative c-Mycderegulation process. Multicolour FISH analysis indeed revealed a cryptic t(7;8)(q34;q24) within the same t(1;14)+T-ALL clone, and breakpoint cloning confirmed the juxtaposition of c-Mycto the TCRβ locus. To further investigate the likely scenario of neoplastic development in this patient, we undertook a detailed geno/phenotyping of the tumor sample. In good agreement with the proposed oncogenic role of TAL1 in blocking thymocytes at late stages of maturation, immunophenotypic, transcriptional and genotype profiles clearly converged towards a maturation arrest of the malignant clone at the late cortical CD8 SP stage. By contrast, analysis of translocation breakpoints indicated that both events resulted from V(D)J recombination mistakes, and congruently occurred during the early stages of TCRδ and TCRβ rearrangements (DN2/DN3). Thus, the activation of both c-Mycand TAL1was clearly decoupled from maturation arrest. As thymocyte progression from DN3 to SP includes extensive proliferation at the ISP/DP transition before rearrangement of the TCRα chain, the tumor clone was expected to show polyclonal TCRα rearrangements. Instead, LR-LMPCR and TCRα multiplex PCR revealed the presence of a monoclonal TCRα rearrangement. Thus, out of hundreds of thymocytes carrying t(1;14) and t(7;8), only one progressed towards malignant transformation after the onset of TCRα rearrangements, suggesting the necessity of yet a “3rdhit”. Most importantly, this indicates that in absence of NOTCH1, TAL1 and c-Myc cooperation was not sufficient to trigger aggressive proliferation. One likely candidate for this 3rdhit is LMO2, which we also found significantly over-expressed in the tumour clone. As previously underlined in animal models, the synergy between LMO2, TAL1 and c-MYC oncogenes likely accounts for the aggressive tumor phenotype in this patient, and illustrates the complex cooperative oncogenic pathways in human T-ALL pathogenesis. Intriguingly, the lack of major mediastin involvement in a clone with such a fulgurating growth raises the alternative possibility that proliferation was actually fired in the periphery through cognate triggering of the expressed TCRαβ, and thus that proliferation is uncoupled from differentiation block.