ABSTRACT:Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive pediatric myeloproliferative neoplasm for which hematopoietic stem cell transplantation (HSCT) is currently the only established curative therapy. However, a watch-and-wait (W&W) approach has shown promise for long-term survival in selected cases. In this real-world study, we analyzed outcomes of patients with JMML initially managed with a W&W strategy within a nationwide cohort of 161 genetically characterized cases. W&W was chosen for 35 patients, with increasing adoption over time, reaching 39% in the 2016-to-2021 period. Most patients carried mutations in CBL (43%), NRAS (34%), or homozygous germ line SH2B3 (14%). Over a median follow-up of 6.5 years, 30 of 35 (86%) achieved long-term survival with partial or complete resolution of myeloproliferative symptoms, although clonal hematopoiesis persisted in nearly all survivors (18/20). Disease progression occurred in 5 patients (CBL, n = 3; NRAS, n = 1; PTPN11, n = 1), mostly within 2 years after diagnosis. Overall, in the W&W cohort, the 5-year overall and event-free survivals were 93.1% and 84.5%, respectively. In NRAS-mutated cases, age of <30 months, normal to slightly elevated fetal hemoglobin, platelet counts of >45 × 109/L, the absence of additional somatic mutations, and low DNA methylation profile were associated with favorable outcomes. In CBL-driven JMML, no predictive factor of adverse evolution was identified. Notably, W&W was effective in all patients with homozygous germ line SH2B3. These findings support W&W as a viable alternative in up to 30% of patients with JMML, potentially sparing them from HSCT-associated risks. Given the persistence of clonal hematopoiesis and the risk of extrahematological complications, long-term monitoring remains essential.

Background Autoimmune neutropenia (AIN) is the main cause of chronic neutropenia in children, but its infectious consequences remain poorly studied. The primary objective of this study was to evaluate infectious events leading to emergency department or hospital admissions during the first 2 years following the diagnosis of AIN in children.Methods We performed a retrospective, multicentre analysis of medical records from 21 French university hospitals of patients aged under 18 years diagnosed with AIN with positive antineutrophils autoantibodies. We collected data on emergency room visits and hospitalisations in the 2 years following diagnosis, causes of these events, microbiology results, management and outcome.Results One hundred and sixty-eight patients were enrolled. Median age at diagnosis of AIN was 13 months. AIN was predominantly diagnosed during an infectious episode (n=120, 71%). In the 2 years of follow-up after diagnosis, 248 events of emergency room visits and/or hospitalisations were reported (0.77 per patient-year). The most frequent diagnoses were common childhood viral or bacterial infections. The incidence rate of severe infections was 0.003 per patient-year. Despite the predominance of viral infections, 177 episodes (71%) led to hospitalisation and 166 (68%) to the initiation of antibiotic therapy, for a median duration of 7 days (IQR 3-10).Conclusion The risk of severe infections in children with AIN is low. During follow-up, we suggest being attentive to signs of severity during fever, particularly in children over 3 years of age and/or with other immunological comorbidities but not proposing systematic hospitalisation or additional antibiotic therapy.

Les ateliers d’harmonisation du comité leucémie de la Société française des cancers de l’enfant (SFCE) ont pour but d’établir des recommandations pratiques établies, d’une part, à partir des données de la littérature et des recommandations internationales et, d’autre part, par consensus en l’absence de données formellement prouvées. Les adolescentes pubères et jeunes adultes qui bénéficient d’un traitement intensif par chimiothérapie peuvent présenter des saignements utérins abondants. Les données collectées auprès de 25 centres ont montré une grande hétérogénéité de prise en charge des saignements utérins abondants en situation aiguë ou en prophylaxie. L’analyse de la littérature montre que compte tenu de l’incidence de l’aménorrhée spontanée en cours de traitement par chimiothérapie, il n’y a pas d’indication à une prévention primaire systématique des saignements utérins abondants chez les patientes traitées pour une leucémie. En cas de saignements utérins abondants avérés, un traitement non hormonal et un traitement hormonal peuvent être instaurés en urgence. En prophylaxie secondaire, différents traitements hormonaux ayant pour objectif la mise en aménorrhée prophylactique peuvent être discutés.

ABSTRACT:Hematological involvement (HI) is one of the life-threatening risk organs (ROs) in Langerhans cell histiocytosis (LCH). Lahey criteria have defined HI since 1975 as hemoglobin <10 g/dL, platelets <100 × 109/L, leukopenia (white blood cell count <4 × 109/L), and/or neutrophils <1.5 × 109/L. Among the 2313 patients aged <18 years enrolled in the French National Histiocytosis Registry (1983-2023), 331 developed HI (median age at diagnosis, 1 year); median follow-up lasted 8.1 years. Bone marrow aspirate smears and biopsies may show reactive histiocytes, hemophagocytosis, or myelofibrosis but never confirm the diagnosis. Fifty-eight patients (17%) developed macrophage-activation syndrome, sometimes related to acute Epstein-Barr virus or cytomegalovirus infection, sometimes months before typical LCH manifestations appeared. Hemoglobin and platelet thresholds for initiating transfusion(s) appear to accurately distinguish 2 groups: mild HI (MHI; >7 g/dL and >20 × 109/L, respectively) and severe HI (SHI; ≤7 g/dL and/or ≤20 × 109/L). Each entity has different organ involvements, laboratory parameters, mutational status, blood BRAFV600E loads, drug sensitivities, and outcomes (MHI and SHI 10-year survival rates, 98% and 73%, respectively). Since 1998, mortality first declined with combination cladribine-cytarabine therapy and then with MAPK inhibitors since 2014. Forty-one patients (12%) developed neurodegenerative complications that have emerged as a risk for long-term survivors. These results suggest limiting the HI-RO definition to SHI, because it encompasses almost all medical complications of LCH. Future clinical trials might demonstrate that targeted therapy approaches would be better adapted for these patients, whereas MHI can be managed with classic therapies.

IntroductionPoststreptococcal uveitis is among the immune complications following strep infections.Case descriptionA patient treated for acute myeloblastic leukemia presented with febrile neutropenia 22 days after consolidation chemotherapy including cytarabine. Diagnosed with Streptococcus mitis bacteremia, she subsequently presented with uveitis in her right eye, linked to the previous infection through positive anti-streptolysin O and negative microbiological test results. Topical treatment resulted in complete recovery.ConclusionThis unprecedented presentation of post-S. mitis uveitis reveals the potential for misdiagnosis of ocular manifestations after cytarabine treatment. Furthermore, neutropenia and profound lymphopenia should not prevent both the ophthalmologist and the hematologist from considering poststreptococcal immune complications.

In this article, we report the results of four years (2019-2023) of newborn blood spot screening for severe lymphopenia using TREC (T-cell receptor excision circle) quantification in the Pays de la Loire region in France. Our main objective was to analyze underlying causes of T-cell lymphopenia revealed by positive testing. During the study period, 156,892 newborns were screened and ten were identified with T-cell lymphopenia (1/13,260 births), of whom three were diagnosed with severe combined immunodeficiencies (SCID: 1/40,000 births). Our results confirm data from international reports and our previous nationwide study (DEPISTREC; 2015 to 2017). We conclude that routine newborn screening for T-cell lymphopenia is operational to detect and swiftly treat infants with SCID.

The harmonization workshops of the leukemia committee of the Société française des cancers de l'enfant (SFCE) aim to establish practical recommendations based on the one hand, on data from the literature and international recommendations and, on the other hand, by consensus in the absence of formally proven data. Adolescent pubescent girls and young adults undergoing intensive chemotherapy treatment may present with heavy uterine bleeding (HUB). Data collected from 25 French centers showed that there was considerable heterogeneity in the management of HUB either in prophylaxis or curative strategy. Analysis of the literature showed that, given the incidence of spontaneous amenorrhea during chemotherapy treatment, there is no indication for systematic prophylaxis of HUB in patients treated for leukemia. In case of proven HUB, non-hormonal treatment and hormonal treatment can be introduced as a matter of urgency. For secondary prophylaxis, various hormonal treatments aiming at achieving prophylactic amenorrhea may be discussed.

Background Blinatumomab, inotuzumab or autologous anti-CD19 chimeric antigen receptor (CAR)-T cells have revolutionized the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, tumor escape through antigenic modulation accounts for almost 40% of subsequent relapses. Multi-antigen targeting strategies should be developed, and it is urgent to identify new targets.Methods We investigated the extensive immunophenotyping of 13 BCP-ALL from pediatric patients by using the BioLegend Human Cell Surface Marker Screening Kit. Then, to assess whether targeting each antigen with monoclonal antibodies could lead to leukemic cell lysis, long-term antibody-dependent cellular cytotoxicity (ADCC) assays were performed using murine monoclonal antibodies and human T cells armed with murine CD16.Results 13 highly expressed antigens were selected. With the antibodies tested here, the most significant lysis was observed by targeting CD24 and CD156c. The double targeting of CD24-CD123 appeared to be even more effective. Triple targeting was associated with a reduction in ADCC activity.Conclusion CD24 therefore emerged as an effective target in BCP-ALL, and the combination of CD24 and CD123 as a potential effective double-targeting strategy. The combination of different recognition modalities (eg, a CAR and CD16) should be tested to determine whether it provides synergistic cytotoxic activity in triple targeting.

BACKGROUND:Abusive Head Trauma (AHT) is a leading cause of morbidity and mortality in infants requiring rapid neuroimaging performance and prognostic rapid diagnosis. The Pittsburgh Infant Brain Injury Score (PIBIS) clinical prediction rule (CPR) was derived to identify infants most likely to present brain injury, whose diagnosis would benefit from head CT. Our study aimed to externally validate the PIBIS CPR in a pediatric French population. METHODS:A retrospective study was conducted in a French pediatric emergency department between 2015 and 2017. We included all consecutive infants who underwent a neurological imaging. Medical data were collected, and PIBIS score was determined, both retrospectively. RESULTS:We included 129 infants among which 33 cases (including 20 with a diagnosis of AHT). The sensitivity and specificity of the PIBIS CPR were 75.8 % (95 % CI 57.7-88.9) and 61.4 % (51.0-71.2) and negative and positive predictive values 88.1 % (77.8-94.7) and 40.3 % (33.0-48.2). Among the 20 infants with a diagnosis of AHT, 19 (95.0 %) were correctly identified by the PIBIS CPR. CONCLUSION:Our external validation study found a lower diagnostic value of the PIBIS CPR than in the original study. This argues for adding biomarkers to improve its performance, notably in the context of suspected AHT.

En France, à ce jour, les unités de thérapie cellulaire hospitalière n’ont pas d’autorisation à produire en routine des lymphocytes T Chimeric antigen receptor (CAR-T cells) qui seraient alors qualifiés de CAR-T cells académiques. Les CAR-T cells sont qualifiés de médicament de thérapie innovante et correspondent à des lymphocytes T modifiés génétiquement ex vivo. Le procédé de production de CAR-T cells est complexe et nécessite une expertise scientifique et technique pour répondre aux critères d’acceptation du système qualité pharmaceutique. La méthode la plus utilisée pour modifier génétiquement les lymphocytes T est la transduction virale (lentivirale ou rétrovirale) nécessitant au préalable l’accès à un lot de vecteur viral de grade Bonne Pratique de Fabrication (BPF). Du fait de son coût, ce réactif est le principal facteur limitant pour développer des CAR-T cells. Un CAR-T cell produit par un industriel est onéreux (environ 350 000 € l’injection) et le temps de mise à disposition au clinicien par le fabricant peut aller de trois à cinq semaines. En répondant aux enjeux économiques et écologiques, les structures académiques peuvent-elles permettre une amélioration de l’accessibilité aux CAR-T cells ? Dans cet article, nous présentons des éléments nécessaires pour la faisabilité de la mise en place d’une production de CAR-T cells dans une structure académique.

In France, hospital cell therapy units have not been authorised to routinely produce chimeric antigen receptor T lymphocytes (CAR -T cells), which would then be referred to as academic CAR -T cells. CAR -T cells are classified as advanced therapy medicinal products and correspond to genetically modified T lymphocytes ex vivo. The CAR -T cell production process is complex and requires scientific and technical expertise to meet the acceptance criteria of the pharmaceutical quality system. The most commonly used method for genetically modifying T lymphocytes is viral transduction (lentiviral or retroviral), which requires prior access to a batch of good manufacturing practice (GMP) grade viral vector. Because of its cost, this reagent is the main limiting factor for developing CAR -T cells. A CAR -T cell produced by an industrial company is expensive (around euro350,000 per injection) and the time taken by the manufacturer to make it available to the clinician can vary from three to five weeks. By meeting the economic and ecological challenges, can academic structures improve access to CAR -T cells? In this article, we present the elements necessary for the feasibility of setting up CAR -T cell production in an academic structure.

Effective physician-patient communication is crucial to compassionate healthcare, particularly when conveying life-altering diagnoses such as those associated with congenital heart diseases. Despite its importance, medical practitioners often face challenges in communicating effectively. Because of these gaps, we aim to introduce a simulation-based training protocol to improve pediatric cardiology trainee’s communication skills. This study will be conducted in collaboration with associations supporting caregivers of children with congenital heart disease. It strives to demonstrate how specific training programs can efficiently foster humanistic, patient-centered care in standard medical practice. This multicenter, open-label randomized controlled trial will be conducted in pediatric cardiac units and simulation centers of across 10 universities in France. The study population comprises pediatric cardiologists in training (including pediatric cardiac fellows or specialist assistants). The SIMUL-CHD intervention will consist of simulation-based training with standardized patients, focusing on improving communication skills for pediatric cardiology trainees during diagnostic counselling. Patients and caregivers have been recruited from a National Patient Association named “Petit Cœur de Beurre”. The primary outcome is the quality of physicians’ communication skills. The evaluation committee, which will review video recordings of the sessions, will be blinded to which participants received simulation-based training (group of interest) and which received theory-based training (control group). Secondary outcomes are the effect of SIMUL-CHD on empathy and anxiety levels in young pediatric cardiologists. Baseline scores pre and post-intervention will be compared, and skill improvement resulting from the intervention measured. Simulation-based training has proven efficacy in teaching technical skills in various scenarios however its application to communication skills in pediatric cardiology remains unexplored. The involvement of experienced parents provides a unique perspective, incorporating their profound understanding of the emotional challenges and specific hurdles faced by families dealing with congenital heart disease. This trial is registered with the OSF registry (registered https://osf.io/ed78q ).

Background: In adults, there is a link between socioeconomic status (SES) and cancer prognosis, notably due to increased time to diagnosis (TTD) in deprived population leading to the spread of the disease. In children, such an association has not been clearly reported. The objective of our study was to assess the impact of SES on TTD of childhood cancer and its potential consequences on cancer prognosis. Methods: We carried out a multicenter retrospective study based on the LOGAFTER multicentric database. We studied the SES at the individual and ecological levels. Results: Overall, 854 children were included. The median time to diagnosis was 28 days [12;64]. A usual care pathway did not seem to impact TTD, but the use of alternative medicine and an initial management by professionals not usually involved in the specific childhood cancer context increased TTD. None of the SES ecological variables were strictly associated with a significant impact on TTD. However, we noted strong trends for single-parent families and children whose fathers had died who presented with an increased TTD. Conclusions: In the current study, the impact of SES on TTD in children on both the individual and ecological levels was not clear. However, we noted some keys at the individual scale that require further investigation to explain a potential association between deprivation and TTD.

For most patients with childhood myelodysplastic syndrome (cMDS), allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option. In the case of increased blasts (cMDS-IB), the benefit of pretransplant cytoreductive therapy remains controversial. In this multicenter retrospective study, the outcomes of all French children who underwent allo-HSCT for cMDS reported in the SFGM-TC registry between 2000 and 2020 were analyzed (n = 84). The median age at transplantation was 10.2 years. HSCT was performed from matched sibling donors (MSD) in 29% of the cases, matched unrelated donors (MUD) in 44%, haploidentical in 6%, and cord blood in 21%. Myeloablative conditioning was used in 91% of cases. Forty-eight percent of patients presented with cMDS-IB at diagnosis (median BM blasts: 8%). Among them, 50% received pretransplant cytoreductive therapy. Five-year overall survival (OS), cumulative incidence of nonrelapse mortality (NRM), and relapse were 67%, 26%, and 12%, respectively. Six-month cumulative incidence of grade II-IV acute graft-versus-host disease was 46%. Considering the whole cohort, age under 12, busulfan/cyclophosphamide/melphalan conditioning or MUD were associated with poorer 5-year OS. In the cMDS-IB subgroup, pretransplant cytoreductive therapy was associated with a better OS in univariate analysis. This seems to be mainly due to a decreased NRM since no impact on the incidence of relapse was observed. Overall, those data may argue in favor of cytoreduction for cMDS-IB. They need to be confirmed on a larger scale and prospectively. image

Background: Pediatric myelodysplastic syndromes (cMDS) are rare and biologically different from that seen in adults. In addition to a specific genomic landscape, they are characterized by the high frequency of hypoplastic forms, and the recurrent association with germline predispositions (Khoury et al. 2022; Locatelli et Strahm 2018). For most patients, allogenic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option. In case of cMDS with increased blasts (cMDS-IB), pre-tranplant cytoreductive chemotherapy may be considered, but remains controversial (Strahm et al. 2011). Methods This multicenter retrospective study included all cMDS patients (<18y.o.) reported to the SFGM-TC registry who underwent an allo-HSCT between 2000 and 2020. Data have been obtained through ProMISe (internet-based system shared by all EBMT transplantation centers). All patients have given signed informed consent. Results Eighty-four cMDS patients from 17 centers were included. Median age at transplant was 10.2 years (IQR: 7.2, 14.2). Fifty-two percent of patients presented with increased blasts at diagnosis. Germline predispositions were known in 24% of patients. GATA 2 mutations were the most frequent (14%). Eighty-two percent of patients presented with hematologic cytogenetic abnormalities, including 64% of monosomy 7. Myeloablative conditioning was used in most of cases (91%). Busulfan/melphalan was the most frequent conditioning regimen (58%). HSCT were performed from sibling donors in 29% of the cases, matched unrelated donors (MUD) in 44%, umbilical cord blood (UCB) in 21% and haploidentical in 6%. Stem cell source was bone marrow in 68% of the cases. Considering the whole cohort, 5y overall survival (OS) and disease-free survival (DFS) were 67% (IC95% 57-78%) and 63% (IC95% 54-74%) respectively (Figure 1). Five years cumulative incidences of non-relapse mortality (NRM) and relapse were 26% (IC95% 17-35%) and 12% (IC95% 5.6-20%) respectively. Of the 21 cases of reported toxic death, 15 were related to acute GVH (aGVHD). Six months cumulative incidences of grade II-IV and III-IV acute graft vs host disease were 46 % and 24 % respectively. In univariate analysis, patients under 12 years (p=0,018) or who received a BuCyMel conditioning (p=0,004) or a graft from a MUD (p=0,030) had worst 5y OS and PFS. As expected, OS increased with time (p=0,014) reflecting improvements in supportive care and HSCT procedures (Figure 2A). These results were confirmed in multivariate analysis, except for MUD. Twenty-four patients received pre-transplant cytoreductive therapy, most often intensive chemotherapy (20/24). In the overall population, pre-transplant cytoreduction was not associated with an improved survival. However, subgroup analysis of the 40 patients with cMDS-IB showed a significant improvement of the OS probability (HR 0.18 [0.04-0.83], p=0.014) in patients who received a pre-transplant cytoreductive therapy in univariate analysis (Figure 2B). Cytoreductive therapy did not appear to be associated with a reduced risk of relapse, but with a lower risk of NRM. Although not statistically significant, the incidence of aGVHD was higher in patients who did not receive any cytoreductive therapy (HR 0.60 [0.09-3.85]). Conclusion: This retrospective study reports the outcomes of 84 patients who underwent allo-HCT for childhoodMDS. This study seems to show a benefit associated with the pre-transplant cytoreduction therapy in the subgroup of patients with cMDS-IB, notably through a reduction of aGVHD and NRM occurrence. BuCyMel conditioning, currently recommended for cMDS-IB, appears here, to be associated with excess of toxic mortality. This study also confirms the high aGVH-related toxic mortality rates already reported in cMDS (Strahm et al. 2011). Recent retrospective data have shown a benefit of post-transplantation cyclophosphamide (PTCy) in GATA2 patients transplanted with sibling or matched unrelated donors (Nichols-Vinueza et al. 2022). Prospective data on the use of PTCy in cMDS are therefore needed. Acknowledgment: This research is funded by the non-profit organization Etoile de Martin/SFCE.