Clinical and Molecular Characteristics and Best Response in All Patients Included With (A) Various Malignancies (n=34) and (B) Ewing Sarcoma (n=36)

Background The clinical value of thrombophilia testing in pediatric patients remains debated, especially in the absence of clear, age-specific guidelines. We aimed to assess the real-life indications, results, and clinical impact of thrombophilia testing in a French tertiary pediatric center. Methods We conducted a retrospective, single-center study of all children (<18 years) who underwent hereditary thrombophilia testing at Armand Trousseau Hospital (AP-HP.Sorbonne Université) during 2019. Clinical indications, test results, thrombotic events, and their consequences for clinical management were analyzed. Results A total of 129 patients (median age 6.7 years; 39.5% female) were included. The five most frequent indications were hematologic malignancy (55.0%), suspected or confirmed thrombotic events (18.6%), pre-kidney transplant evaluation (6.2%), family history of thrombophilia or thrombosis (6.2%), and preoperative assessment (3.9%). At least one abnormality was identified in 29.5% of patients, but only 10 had confirmed hereditary thrombophilia: protein S deficiency (n = 1), factor V Leiden mutation (homozygous n = 2; heterozygous n = 4), and heterozygous prothrombin G20210A mutation (n = 3). Most natural anticoagulant deficiencies were observed in children with leukemia and were not retested, thus remaining unconfirmed. Eleven patients (8.5%) experienced a venous thromboembolism (VTE); ten had at least one transient risk factor. Thrombophilia testing led to a change in clinical management in five patients (3.9%). Among patients with confirmed thrombophilia, preventive counseling was inconsistently documented. Conclusion Thrombophilia testing in children should be carefully targeted, guided by established recommendations, and reserved for situations with clear clinical relevance. Testing should be deferred during acute illness, repeated to confirm lifelong diagnoses, and, if confirmed, accompanied by appropriate preventive counseling. Efforts should also focus on providing standardized, practical advice when a thrombophilia is identified.

BACKGROUND:Oral abnormalities resulting from childhood leukemia treatment may significantly impact long-term health outcomes. OBJECTIVES:This prospective study aims to evaluate oral health, to assess oral health-related quality of life (OHRQoL) among leukemia survivors, its impact on general Health Related Quality of Life (HRQoL) and to identify risk factors for oral health impairments. METHODS:Dental examination was proposed to patients included in the LEA cohort (long-term follow-up of childhood/adolescent leukemia survivors) in two pediatric hematology centers. For cavities, Decayed/Missing/Filled/Teeth (DMFT/dmft) index was determined. Quantitative and qualitative saliva analyses were performed. Orthopantomograms were independently reviewed. OHRQoL was assessed using age-adapted questionnaires. Patient characteristics, treatment history, socio-economic status and HRQoL were extracted from LEA database. Statistical analyses were performed using SPSS software. Pearson's Chi2/Fisher's exact test/Student's t-test/Spearman correlation test/Adjusted multivariate logistic regression model were used when appropriate. RESULTS:Eighty-nine patients were included with a mean follow-up from diagnosis of 12.5 ± 0.8 years. Females represented 48% of the cohort, acute lymphoblastic leukemia 76%. A history of leukemia relapse concerned 27% of patients; 45% of the cohort underwent hematopoietic stem cell transplantation (HSCT). Eighty-five patients had ≥1 oral abnormalities (excluding cavities); 53 required treatment intervention. Mean DMFT/dmft index was 2.3 ± 0.4; lower parents' education level was linked with higher index (p = 0.029). Younger age at diagnosis (<6 years old) was associated with enamel defects (p = 0.001). History of relapse was associated with teeth number, morphology and eruption abnormalities (p < 0.05). HSCT was associated with morphology abnormalities (p < 0.05). Among transplanted patients, no significant impact of total body irradiation on oral abnormalities was found as compared to busulfan-based conditioning regimen. In children, altered OHRQoL tend to have a negative impact on body image and physical well-being. CONCLUSION:The high prevalence of oral abnormalities in pediatric leukemia survivors necessitates proactive dental monitoring and early interdisciplinary collaboration between pediatrician and dentists.

Bosutinib, an orally administered dual Src and Bcr-Abl tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia, newly diagnosed or resistant/intolerant to previous treatment of one or more TKIs in adults and children ≥ 1 years (by the US Food and Drug Administration) and ≥ 6 years (by the European Medicines Agency). Owing to the limitations of non-compartmental analysis in pharmacokinetic (PK) characterization, this study applies a prior population PK modeling approach to describe the pediatric PK of bosutinib on the basis of its phase I dose-finding trial and the available bosutinib adult PK knowledge. From 26 pediatric patients in the phase I part of the ITCC-054/COG AAML1921 trial, 235 plasma bosutinib concentration samples were analyzed. A published adult bosutinib population PK (popPK) model was used as the reference model; the frequentist prior modeling approach was used during model development to integrate adult PK information, especially for parameters with poor identifiability. Bosutinib pediatric PK was well characterized by a two-compartment model with first-order absorption, an absorption lag time of 0.467 h, and allometric scaling with fixed exponents. The typical clearance was 74.9 L/h (normalized to 70 kg), higher than the reported adult value (56.3 L/h). Model-based simulations validated that the bosutinib recommended phase II dose (RP2D) could achieve the target exposure observed in adults and demonstrated the influence of higher clearance in pediatric patients. This study presents the first pediatric bosutinib popPK model, integrating prior adult PK knowledge to enable robust PK characterization using a small pediatric dataset from an early trial stage. In addition, the model confirms a higher clearance in children and supports the RP2D concluded in the phase I dose-finding part of the ITCC-054/COG AAML1921 trial.

Comparison of Homologous Recombination Deficiency (HRD) Scores and Tumor Mutational Burden (TMB) Between Treatment Responders and Non-Responders.

Somatic Driver Mutations (A), Focal Amplification/deletions (B) or Gene Fusions (C) and Germline Mutations (D) Detected in 65 Patients Explored in the Molecular Analysis.

Abstract LZTR1 negatively regulates RAS family proteins via proteasomal degradation. Germline loss-of-function variants cause Noonan syndrome, with emerging evidence implicating LZTR1 in predisposition to childhood acute lymphoblastic leukemia (ALL), though its role in hematopoiesis remains poorly defined. Screening 1,587 children with ALL identified LZTR1 variants in 44 patients (2.8%). Germline variants were detected in 32 patients (2.0%), a frequency comparable to that observed in the general population (1.75%; 1,925/110,017; p=0.50). Somatic LZTR1 alterations were identified in 22 patients (1.4%) and were predominantly bi-allelic, arising through either a germline-plus-somatic or dual somatic configuration. They persisted at relapse. Despite enrichment in favorable-risk subtypes ( ETV6::RUNX1 , high-hyperdiploid, ERG/DUX4), bi-allelic LZTR1 -mutated cases showed delayed minimal residual disease clearance and higher late relapse risk, identifying a subgroup unsuitable for treatment de-escalation. LZTR1 expression was increased in most wild-type leukemias, consistent with a compensatory response to aberrant RAS pathway activation. Bi-allelic LZTR1 inactivation abolished RAS regulation, leading to deregulated canonical RAS expression and ectopic expression of the non-canonical RIT1 protein, whose involvement in ALL has not previously been reported. These findings establish LZTR1 as a classical tumor suppressor in ALL via a two-hit model. Monoallelic alterations show insufficient signaling perturbation and low germline penetrance, whereas bi-allelic inactivation acts as a driver event linked to a high risk of late relapse despite favorable genomics.

ABSTRACT Introduction The epidemiology of acute leukemia (AL) in children in Afro‐descendant (AD) populations is poorly described, and survival is often considered worse in these populations. The aim of this study is to describe the epidemiology and prognosis of childhood AL in the AD population of the French West Indies/French Guiana (FWI/FG). Methods This is a multicenter, retrospective, descriptive cohort study of children aged 0–17 years old, resident of the FWI/FG and diagnosed with AL between January 2010 and December 2022. Patients were identified via the French National Childhood Cancer Registry and cross‐referenced with lists from each reference center and local registry. The Kaplan–Meier method was used to estimate 5‐year overall survival (5y‐OS) and event‐free survival (5y‐EFS). Results A total of 107 patients were included, 67% B‐Acute lymphoblastic leukemia (ALL), 18% AML, and 14% T‐ALL. The age standardized incidence rate for childhood AL was 32.9 (21.4–46.2) per million‐year for children. The 5y‐OS rate for all children was 90.9% (95% CI: 84.1–98.2), and 93.1% (95% CI: 85.8–100) for B‐ALL, 91.7% (95% CI: 77.3%–100%) for T‐ALL and 83.1% (95% CI: 64.1%–100%) for AML. The 5y‐EFS were respectively 75.8% (95% CI: 66.3–86.5), 78.3% (95% CI: 67.6–90.8) and 83.9% (95% CI: 65.7–100) for all children, B‐ALL and T‐ALL. Seven patients (7%) died, mostly due to disease progression (57%). Conclusion This is the largest epidemiological study reported on childhood AL in an AD population and in the Caribbean/Latin America zone. Survival rates in our AD population were similar to those described in European and North American studies and much better than in the Caribbean and Latin American zone.

Autoimmune hemolytic anemia (AIHA) with an isolated C3d(+) direct antiglobulin test is a rare and understudied condition in children. It typically encompasses cold agglutinin syndrome and paroxysmal cold hemoglobinuria, both transient, infection-triggered disorders collectively referred to as cold AIHA. We report a national cohort of 142 pediatric patients with isolated C3d(+) AIHA, representing 21.6% of all childhood AIHA cases enrolled in the French OBS'CEREVANCE cohort over a 32-year period. The median age at diagnosis was 3.2 years (male-to-female ratio, 1.3), and median follow-up was 2.8 years. Infectious symptoms were present in 63.4% of cases. At diagnosis, median hemoglobin was 6.4 g/dL; 69.7% of patients had inadequate reticulocytosis (bone marrow responsiveness index of <121), and 90.4% required transfusions. Eighteen patients (12.7%) had or developed immunopathological manifestations (IM) including 5 diagnosed with primary immunodeficiency (4 with autoimmune lymphoproliferative syndrome). Among 8 (5.6%) patients with relapsing disease, 6 had no IM at diagnosis but 4 developed IM at relapse. Nine patients were antinuclear antibodies (ANA) positive; none progressed to systemic lupus over a median follow-up of 4.9 years. Corticosteroids were administered to 82.4% of patients (median duration, 4.5 months), with no clear benefit over untreated patients regarding hospital stay or transfusion needs. No deaths were reported. In conclusion, pediatric isolated C3d(+) AIHA generally follows a favorable course. However, a minority of patients may reveal underlying immune disorders, highlighting the importance of tailored evaluation at diagnosis. Cold agglutinin testing with thermal amplitude and Donath-Landsteiner testing, rarely performed in this cohort, warrant further study for their impact on diagnosis and clinical management.

Dose Levels of Arm D and Probabilities of Toxicity at the End of Dose Escalation (n=24 Patients Evaluable for DLT) and after the Whole Study (n=65 Patients Evaluable for DLT)

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.

The European LeukemiaNet has periodically issued guidelines for the diagnosis and management of acute myeloid leukemia (AML) in adults. These consensus recommendations, most recently updated in 2022, incorporate recent advances in genomic testing, disease detection methods, target identification, and response assessment. Whilst similarities exist between AML in children and adults, pediatric AML is frequently characterized by unique cytogenetic and molecular features, which require distinct genetic and immunophenotypic diagnostics, therapeutic approaches, response assessment criteria, and supportive care strategies. To address these specific needs, an international panel of pediatric hematologist-oncologists, biologists, geneticists, and laboratory medicine scientists convened to develop recommendations for the diagnosis and management of AML in children, adolescents, and young adults (hereafter termed pediatric AML) that are discussed in this special report.

PURPOSE:Metabolic syndrome (MetS) is a common complication in survivors of childhood acute lymphoblastic and myeloid leukemia (AL), and a major risk factor for premature cardiovascular disease, type-2-diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Lifestyle interventions, including a healthy diet and physical activity, are the cornerstone of the management of MetS. In long-term childhood AL survivors with MetS, the benefits of classical lifestyle interventions remain poorly documented. METHODS:We conducted a one-year dietary and behavioral intervention with monthly dietitian coaching in this specific population. We assessed clinical, biological metabolic parameters, noninvasive biomarkers of hepatic steatosis and fibrosis, and eating habits at baseline and after one year of coaching. RESULTS:We enrolled 48 patients from the LEA cohort, diagnosed with MetS. The mean age was 32 years. At baseline, 62.2% of patients had hepatic steatosis and 15% had fibrosis F3-F4 (VCTE > 8 kPa). Daily energy intakes were already limited (average, 1611 Kcal/day). After one year of lifestyle coaching, the body mass index (27.1 vs. 26.5 kg/m2, p = 0.041) and the waist circumference (91.9 vs. 89.5 cm, p = 0.027) had decreased. Daily intakes had significantly decreased (1213 Kcal/day) with a healthier diet. Hepatic and metabolic parameters had not significantly improved in the study population. Liver steatosis was improved only in the subgroup of patients who lost weight and/or waist circumference. CONCLUSION:Survivors of childhood AL have a high prevalence of MASLD at a young age. Classical lifestyle intervention appears incompletely efficient in improving metabolic and hepatic parameters in this specific population. New therapeutic approaches to reduce MetS and its complications in this unique population need to be studied.

Duration of Treatment Overall and per Dose Level: 66 Patients Receiving a Total of 348 Cycles

Oncoplot of Somatic Variants Across Patient Cohorts.

Objective Response Rates in 66 Patients Treated Overall and per Dose Escalation or Dose Expansion in Other Malignancies and Ewing Sarcoma.

Oncoplot of Germline Cancer Risk Variants Across Patient Cohorts.

Representativeness of Study Participants