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•We clinically characterized 3 additional, recurring KMT2A-r groups and identified specific ACAs of independent prognostic significance.•We present an optimized, fusion-based risk-group stratification of KMT2A-r pediatric AML.

Hypodiploidy, defined as modal numbers (MNs) 45 or lower, has not been independently investigated in pediatric acute myeloid leukemia (AML) but is a well-described high-risk factor in pediatric acute lymphoblastic leukemia. We aimed to characterize and study the prognostic impact of hypodiploidy in pediatric AML. In this retrospective cohort study, we included children below 18 years of age with de novo AML and a hypodiploid karyotype diagnosed from 2000 to 2015 in 14 childhood AML groups from the International Berlin-Frankfurt-Münster (I-BFM) framework. Exclusion criteria comprised constitutional hypodiploidy, monosomy 7, composite karyotype, and t(8;21) with concurring sex chromosome loss. Hypodiploidy occurred in 81 patients (1.3%) with MNs, 45 (n = 66); 44 (n = 10) and 43 (n = 5). The most frequently lost chromosomes were chromosome 9 and sex chromosomes. Five-year event-free survival (EFS) and overall survival (OS) were 34% and 52%, respectively, for the hypodiploid cohort. Children with MN≤44 (n = 15) had inferior EFS (21%) and OS (33%) compared with children with MN = 45 (n = 66; EFS, 37%; OS, 56%). Adjusted hazard ratios (HRs) were 4.9 (P = .001) and 6.1 (P = .003). Monosomal karyotype or monosomy 9 had particular poor OS (43% and 15%, respectively). Allogeneic stem cell transplantation (SCT) in first complete remission (CR1) (n = 18) did not mitigate the unfavorable outcome of hypodiploidy (adjusted HR for OS was 1.5; P = .42). We identified pediatric hypodiploid AML as a rare subgroup with an inferior prognosis even in the patients treated with SCT in CR1.

•Hypodiploidy is found in <2% of pediatric AML. No patient had modal number below 43.•Poor survival is observed in hypodiploid AML with aggravating prognosis in patients with modal number 43 to 44.

Splenectomy is effective in ∼70% to 80% of pediatric chronic immune thrombocytopenia (cITP) cases, and few data exist about it in autoimmune hemolytic anemia (AIHA) and Evans syndrome (ES). Because of the irreversibility of the procedure and the lack of predictions regarding long-term outcomes, the decision to undertake splenectomy is difficult in children. We report here factors associated with splenectomy outcomes from the OBS’CEREVANCE cohort, which prospectively includes French children with autoimmune cytopenia (AIC) since 2004. The primary outcome was failure-free survival (FFS), defined as the time from splenectomy to the initiation of a second-line treatment (other than steroids and intravenous immunoglobulins) or death. We included 161 patients (cITP, n = 120; AIHA, n = 19; ES, n = 22) with a median (minimum-maximum) follow-up of 6.8 years (1.0-33.3) after splenectomy. AIC subtype was not associated with FFS. We found that immunopathological manifestations (IMs) were strongly associated with unfavorable outcomes. Diagnosis of an IM before splenectomy was associated with a lower FFS (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.21-0.72, P = .003, adjusted for AIC subtype). Diagnosis of an IM at any timepoint during follow-up was associated with an even lower FFS (HR, 0.22; 95% CI, 0.12-0.39; P = 2.8 × 10−7, adjusted for AIC subtype) as well as with higher risk of recurrent or severe bacterial infections and thrombosis. In conclusion, our results support the search for associated IMs when considering a splenectomy to refine the risk-benefit ratio. After the procedure, monitoring IMs helps to identify patients with higher risk of unfavorable outcomes.

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients’ T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients’ blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very specific nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations. Here is the second version of these recommendations updated according to the evolution of knowledge on COVID19.

We included 255 patients from the L.E.A. French long-term follow-up cohort. All had received hematopoietic stem cell transplantation (HSCT) and/or testicular radiation for childhood acute leukemia and were older than 18 years at last L.E.A. evaluation. Total testosterone deficiency was defined as a <12 nmol/l level or by substitutive therapy, partial deficiency as normal testosterone with elevated luteinizing hormone (>10 UI/l). After myeloablative total body irradiation (n= 178), 55.6% had total deficiency, 15.7% partial deficiency, and 28.7% were normal. A 4–6 Gy testicular boost and a younger age at HSCT increased significantly the risk. After a Busulfan-containing myeloablative conditioning regimen (n= 53), 28.3% had total deficiency, 15.1% partial deficiency, 56.6% were normal (62.5% vs. 0% in patients without or with additional testicular radiation). A 24-Gy testicular radiation without HSCT induced total or partial deficiency in 71.4% and 28.6%, respectively (n= 21). Total testosterone deficiency increased the risk of metabolic syndrome: 25% vs. 12.1% in men with partial testosterone deficiency and 8.8% when Leydig cell function was normal (p= 0.031).

To identify the factors influencing outcome in childhood mature B-cell non-Hodgkin lymphoma and acute leukemia (B-NHL/AL) with central nervous system (CNS) disease (CNS+), we analyzed patients <18 years with newly diagnosed B-NHL/AL registered in 3 Lymphomes Malins B studies in France between 1989 to 2011. CNS+was diagnosed on fulfillment of ≥1 of the following criteria: any L3 cerebrospinal fluid (CSF) blasts (CSF+), cranial nerve palsy, isolated intracerebral mass but also clinical spinal cord compression, and cranial or spinal parameningeal extension. Two hundred seventeen out of 1690 patients (12.8%) were CNS+. CNS+was significantly associated with male gender, head/neck locations, Burkitt histology, high initial lactate dehydrogenase (LDH) level, and bone marrow involvement. CSF+was the most frequent pattern of CNS+(45%). For the 217 CNS+patients, the 5-year event-free survival (EFS) and overall survival rates (95% confidence interval) were 81.5% (75.8% to 86.1%) and 83.9% (78.4% to 88.2%), respectively. In multivariate analysis, among CNS+patients, low EFS was associated with CSF+, high initial LDH level, and poor response to cyclophosphamide, oncovin (vincristine), prednisone prephase. These findings have been considered for patient's stratification in the international randomized phase 3 trial Inter-B-NHL-ritux 2010 for children and adolescents with high-risk B-NHL/AL with CNS+CSF+patients only receiving intensified chemotherapy.

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations, even if data for this population are still scarce. They may have to evolve according to the rapid evolution of knowledge on COVID-19.

Splenectomy is effective in ~70-80% of pediatric chronic immune thrombocytopenia (cITP) and few data exist in autoimmune hemolytic anemia (AIHA) and Evans syndrome (ES). Because of the irreversibility of the procedure and the lack of predictor of long-term outcomes, splenectomy decision is difficult to take in children. We report here factors associated with splenectomy outcomes from the OBS'CEREVANCE cohort, which prospectively includes French children with autoimmune cytopenia (AIC) since 2004. The primary outcome was failure-free survival (FFS), defined as the time from splenectomy to the initiation of a second-line treatment (other than steroids and intravenous immunoglobulins) or death. We included 161 patients (cITP n = 120, AIHA n = 19, ES n = 22) with a median (min-max) follow-up of 6.8 years (1.0-33.3) after splenectomy. AIC subtype was not associated with FFS. We found that immunopathological manifestations (IMs) were strongly associated with unfavorable outcomes. Diagnosis of an IM before splenectomy was associated with a lower FFS (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.21-0.72, p= 0.003, adjusted for AIC subtype). Diagnosis of an IM at any timepoint during follow-up was associated with an even lower FFS (HR 0.22, 95% CI 0.12-0.39, p= 2.8x10-7, adjusted for AIC subtype) as well as with higher risk of recurrent or severe bacterial infections and thrombosis. In conclusion, our results support the search for associated IMs when considering a splenectomy to refine the risk-benefit ratio. After the procedure, monitoring IMs helps to identify patients with higher risk of unfavorable outcomes.

La maltraitance à enfants a longtemps été ignorée. Les récents plans ministériels prévoient de nombreuses mesures de protection dont le déploiement d’unités d’accueil pédiatriques des enfants en danger (UAPED). Malgré toutes ces avancées, le diagnostic reste sous-estimé dans le secteur de la santé avec une prévalence de l’ordre de 1 enfant sur 10 dans les pays à hauts revenus, toutes catégories de maltraitance confondues. La fréquence de décès serait de 1 enfant tous les 5jours en France. Les violences subies durant l’enfance représentent une lourde perte de chance en termes d’espérance de vie, de santé, de développement et d’insertion. Le rapport est limité aux maltraitances physiques chez l’enfant (MPE) et n’aborde donc pas les maltraitances sexuelles. Le maître-mot est la nécessité d’hospitaliser l’enfant pour une protection immédiate, une évaluation multidisciplinaire, les soins et l’alerte des autorités en temps utile. Les résultats de l’étude montrent une réelle prise de conscience de la MPE dans le secteur pédiatrique. Toutefois, le diagnostic peut être sous-estimé et banalisé chez l’enfant, ce qui signifie que l’étiologie « traumatisme infligé » doit être évoquée largement par le médecin quel que soit son lieu d’intervention. Il y a une amélioration nette de la formation dans ce domaine. Toutefois, le rapport met en évidence une insuffisance persistante des moyens humains dans les secteurs des UAPED, de médecine scolaire, de PMI et de pédopsychiatrie. Le psychotraumatisme doit être pris en charge à court, moyen et long terme. Le diagnostic différentiel permet d’éliminer toutes les étiologies confondantes telles que traumatisme accidentel, maladie rare ou autres. Tout médecin doit pouvoir être guidé, accompagné et protégé pour les situations de MPE. Les médecins référents « Violences » des conseils départementaux de l’Ordre des médecins (CDOM) doivent avoir une compétence dans le domaine de la MPE. L’Académie nationale de médecine propose 6 recommandations : une hospitalisation prioritaire de tout enfant victime ou suspect de MPE jusqu’à ce que tous les éléments du diagnostic soient établis ; un renforcement des moyens humains des UAPED en y intégrant un temps de pédopsychiatrie ; un renforcement du repérage des situations à risque dès la maternité ; un renforcement de la protection et de l’accompagnement des médecins afin que ceux-ci n’hésitent plus à signaler les situations de MPE ; l’extension du périmètre du numéro 119 aux médecins et personnels de santé ; la création d’un registre national pour suivre l’épidémiologie et juger de l’efficacité des mesures prises.

•SLE occurs in 22% of children with ANA-associated AIC.•Children of age >10 years and ANA titer >1/160 must be monitored long-term, for progression to SLE.

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M− group). The M+ group displayed more severe disease than the M− group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

Despite constant progress in prognostic risk stratification, children with acute myeloid leukemia (AML) still relapse. Treatment failure and subsequent relapse have been attributed to acute myeloid leukemia-initiating cells (LSC), which harbor stem cell properties and are inherently chemoresistant. Although pediatric and adult AML represent two genetically very distinct diseases, we reasoned that common LSC gene expression programs are shared and consequently, the highly prognostic LSC17 signature score recently developed in adults may also be of clinical interest in childhood AML. Here, we demonstrated prognostic relevance of the LSC17 score in pediatric non-core-binding factor AML using Nanostring technology (ELAM02) and RNA-seq data from the NCI (TARGET-AML). AML were stratified by LSC17 quartile groups (lowest 25%, intermediate 50% and highest 25%) and children with low LSC17 score had significantly better event-free survival (EFS: HR = 3.35 (95%CI = 1.64–6.82), P< 0.001) and overall survival (OS: HR = 3.51 (95%CI = 1.38–8.92), P= 0.008) compared with patients with high LSC17 scores. More importantly, the high LSC17 score was an independent negative EFS and OS prognosticator determined by multivariate Cox model analysis (EFS: HR = 3.42 (95% CI = 1.63–7.16), P= 0.001; OS HR = 3.02 (95%CI = 1.16–7.85), P= 0.026). In conclusion, we have demonstrated the broad applicability of the LSC17 score in the clinical management of AML by extending its prognostic relevance to pediatric AML.

Background:Outcomes for pediatric acute myeloid leukemia (AML) remain disappointing, particularly for patients with poor risk cytogenetic/molecular genetic abnormalities and those who fail to achieve complete remission following course 1 of induction chemotherapy. Despite upfront allogeneic hematopoietic stem cell transplantation (HSCT) for these patients, high rates of relapse persist. The optimal approach to chemotherapy intensification and timing of HSCT for high risk (HR) patients remains unknown, with variable approaches employed by cooperative trial groups.

Introduction:Hematopoietic stem cell transplantation (HSCT) remains a key treatment of high-risk childhood leukemia despite a wide range of long-term complications. Chronic graft-versus-host disease (cGvHD) is a severe complication of HSCT characterized by the immune response of transplanted cells against the recipient's organs. Adults undergoing HSCT are particularly susceptible to experiencing cGvHD. This complication is generally considered to be much less common when HSCT is performed during childhood and adolescence, though very limited long-term data is available. The present study from the LEA program aims to provide a better understanding of cGvHD and its long-term impact in long-term childhood leukemia survivors.

No relevant conflicts of interest to declare.

Introduction

Pediatric acute promyelocytic leukemia (APL) can be cured with all-trans retinoic acid (ATRA) and anthracycline. However, most published trials have employed high cumulative doses of anthracyclines. Here, we report the outcome of newly diagnosed APL patients enrolled in the International Consortium for Childhood APL (ICC-APL-01) trial, which reduced anthracycline exposure but extended that of ATRA. The study recruited 258 children/adolescents with molecularly/cytogenetically proven APL. Patients were stratified into standard-risk (SR) and high-risk (HR) groups according to baseline white blood cell counts (<10 × 109/L or ≥10 × 109/L); both groups received identical induction treatment with ATRA and 3 doses of idarubicin. Two or 3 blocks of consolidation therapy were administered to SR and HR patients, respectively, while maintenance therapy with low-dose chemotherapy and ATRA cycles was given to all patients for 2 years. The cumulative dose of daunorubicin equivalent anthracyclines in SR and HR patients was lower than that of previous studies (355 mg/m2 and 405 mg/m2, respectively). Hematologic remission was obtained in 97% of patients; 8 children died of intracranial hemorrhage in the first 2 weeks following diagnosis. Five-year overall and event-free survival for the whole cohort were 94.6% and 79.9%, respectively; they were 98.4% and 89.4% in SR patients and 84.3% and 74.2% in HR patients (P = .002 and P = .043, respectively). These data demonstrate that extended use of ATRA coupled to a risk-adapted consolidation can achieve high cure rates in childhood APL and limit anthracycline exposure. The trial was registered at www.clinicaltrials.gov as EudractCT 2008-002311-40.

Pediatric acute promyelocytic leukemia (APL) can be cured with all-transretinoic acid (ATRA) and anthracycline. However, most published trials have employed high cumulative doses of anthracyclines. Here, we report the outcome of newly diagnosed APL patients enrolled in the International Consortium for Childhood APL (ICC-APL-01) trial, which reduced anthracycline exposure but extended that of ATRA. The study recruited 258 children/adolescents with molecularly/cytogenetically proven APL. Patients were stratified into standard-risk (SR) and high-risk (HR) groups according to baseline white blood cell counts (<10 × 109/L or ≥10 × 109/L); both groups received identical induction treatment with ATRA and 3 doses of idarubicin. Two or 3 blocks of consolidation therapy were administered to SR and HR patients, respectively, while maintenance therapy with low-dose chemotherapy and ATRA cycles was given to all patients for 2 years. The cumulative dose of daunorubicin equivalent anthracyclines in SR and HR patients was lower than that of previous studies (355 mg/m2and 405 mg/m2, respectively). Hematologic remission was obtained in 97% of patients; 8 children died of intracranial hemorrhage in the first 2 weeks following diagnosis. Five-year overall and event-free survival for the whole cohort were 94.6% and 79.9%, respectively; they were 98.4% and 89.4% in SR patients and 84.3% and 74.2% in HR patients (P= .002 and P= .043, respectively). These data demonstrate that extended use of ATRA coupled to a risk-adapted consolidation can achieve high cure rates in childhood APL and limit anthracycline exposure. The trial was registered at www.clinicaltrials.govas EudractCT 2008-002311-40.

Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in core-binding factor (CBF) acute myeloid leukemias (AMLs), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers, but the mechanisms underlying this process remain unclear, and its prognostic impact remains unknown. We analyzed a cohort of 445 adult and pediatric patients with CBF AML treated with intensive chemotherapy and with deep sequencing of 6 signaling genes (KIT, NRAS, KRAS, FLT3, JAK2, CBL). A total of 152 (34%), 167 (38%), and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference), respectively. Clonal interference of signaling mutations was associated with older age (P = .004) and inv(16) subtype (P = .025) but not with white blood cell count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with a single clone or clonal interference (P = .14). The repertoire of KIT, FLT3, and NRAS/KRAS variants differed between groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but it did convey inferior event-free survival (P < 10−4), whereas the presence of a single signaling clone did not (P = .44). This inferior outcome was independent of clinical parameters and of the presence of specific signaling clones. Our results suggest that specific clonal architectures can herald distinct prognoses in AML.

Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in core-binding factor (CBF) acute myeloid leukemias (AMLs), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers, but the mechanisms underlying this process remain unclear, and its prognostic impact remains unknown. We analyzed a cohort of 445 adult and pediatric patients with CBF AML treated with intensive chemotherapy and with deep sequencing of 6 signaling genes (KIT, NRAS, KRAS, FLT3, JAK2, CBL). A total of 152 (34%), 167 (38%), and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference), respectively. Clonal interference of signaling mutations was associated with older age (P= .004) and inv(16) subtype (P= .025) but not with white blood cell count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with a single clone or clonal interference (P= .14). The repertoire of KIT, FLT3, and NRAS/KRASvariants differed between groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but it did convey inferior event-free survival (P< 10−4), whereas the presence of a single signaling clone did not (P= .44). This inferior outcome was independent of clinical parameters and of the presence of specific signaling clones. Our results suggest that specific clonal architectures can herald distinct prognoses in AML.

Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.

Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9and SAMD9L(N = 16 of the 86 patients, 18.6%), MECOM/EVI1(N = 6, 7.0%), and ERCC6L2(N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9and SAMD9Lpatients often experienced transient aplasia and monosomy 7, whereas MECOMpatients presented early-onset severe aplastic anemia, and ERCC6L2patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.

Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/FBXW7/RAS and PTEN alterations. Patients with NOTCH1/FBXW7 (N/F) mutations and RAS/PTEN (R/P) germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with N/F GL and R/P GL mutations or N/F and R/P mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10−4, 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ≥200 × 109/L, gHiR classifier, and MRD ≥10−4 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 109/L, gLoR classifier, and MRD <10−4 had a very low risk of relapse, with a 5-year CIR of only 2%. In childhood T-ALL, the N/F/R/P mutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ≥200 × 109/L, it identifies a significant subgroup of patients with a low risk of relapse.

Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/FBXW7/RASand PTENalterations. Patients with NOTCH1/FBXW7(N/F) mutations and RAS/PTEN(R/P) germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with N/FGL and R/PGL mutations or N/Fand R/Pmutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10−4, 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ≥200 × 109/L, gHiR classifier, and MRD ≥10−4demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 109/L, gLoR classifier, and MRD <10−4had a very low risk of relapse, with a 5-year CIR of only 2%. In childhood T-ALL, the N/F/R/Pmutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ≥200 × 109/L, it identifies a significant subgroup of patients with a low risk of relapse.

Central nervous system (CNS) involvement at diagnosis of pediatric acute myeloid leukemia (AML) is not considered as an independent prognostic factor. This study describes the prognostic value of pediatric AML with CNS involvement at diagnosis. Pediatric patients were treated for de novo AML in the French multicenter trial ELAM02. Lumbar puncture was carried out in the first week, and the treatment was adapted to the CNS status. No patient received CNS radiotherapy. The patients were classified into 2 groups: CNS+ and CNS−. Of the 438 patients, 16% (n=70) had CNS involvement at diagnosis, and 29% showed clinical signs. The patients with CNS disease were younger (40% were below 2 y old), had a higher white blood cell count (median of 45 vs. 13 G/L), and had M4 and M5 morphologies. The complete remission rate was similar at 92.8% for CNS+ and 88.5% for CNS−. There was no significant difference between the CNS+ and the CNS− group in overall survival (76% and 71%, respectively) and event-free survival (57% and 52%, respectively). Regarding the occurrence of first relapse, the CNS+ group had a higher combined relapse rate of 26.1% compared with 10% for the CNS− group. The results indicate that CNS involvement at diagnosis of pediatric AML is not an independent prognostic factor. Triple intrathecal chemotherapy combined with high-dose intravenous cytarabine should be the first-line treatment for CNS disease.

The most common cause of thrombocytopenia in children is immune thrombocytopenia. Nevertheless, some atypical cases should evoke the hypothesis of genetic thrombocytopenia. Indeed, in the past years, 30 new genes had been described in the field of inherited thrombocytopenia. We report a series of 11 cases of a newly diagnosed entity: ACTN1-related macrothrombocytopenia. Mutations in the gene ACTN1cause mild macrothrombocytopenia characterized by elevated mean platelet volume and elevated immature platelet fraction, and low bleeding tendency. Its transmission is autosomal dominant. Molecular diagnosis is made by sequencing the ACTN1gene. Its potential role in hematological malignancy predisposition remains unclear and should be clarified. Conclusion: We identified 11 patients with ACTN1-related macrothrombocytopenia diagnosed through pediatric probands. The aim was to underline the specificities of this entity, especially in children, and bring it to the knowledge of pediatricians.

Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells in vitroand in vivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects.