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Objectives: To report the long-term prophylaxis management of a child with type 3 von Willebrand disease by switching to Wilate (Octapharma AG), a plasma-derived, double virus-inactivated concentrate of freeze-dried of a 1 to 1 ratio of active Von Willebrand Factor and Factor VIII (pdVWF:pdFVIII) recently marketed as Eqwilate in France., Methods: This is a case report of 12.6-year-old boy with congenital Type 3 VWD who had a history of frequent bleeds. Prophylaxis started at the age of 38 months with FVIII-poor pdVWF concentrate (Wilfactin, LFB) and FVIII (Wilstart, LFB). Pharmacokinetics and thrombin generation assay were performed. Annualized bleeding rate was derived from the bleeding episodes documented in the medical record during a 24-month period before and after starting pdVWF:pdFVIII concentrate., Results: Both product injections promptly raised the endogenous thrombin potential (ETP). However, the maximal concentration of formed thrombin was higher following pdVWF:pdFVIII injection. Due to a high bleeds frequency and better results regarding FVIII levels and thrombin generation, the prophylaxis regimen was changed to the same dose and frequency of pdVWF:pdFVIII concentrate (42 IU/kg per day, three times a week). During the last 24 months, annualized total, trauma, and spontaneous bleeding rates were 7.5, 4.5, and 3, respectively. These rates decreased to 2, 1.5, and 0.5 respectively during the next two years. The mother reported a marked improvement in the quality of life of his son and hers., Conclusion: Switch to pdVWF:pdFVIII concentrate for long-term prophylaxis in a young type 3 VWD patient was safe and effective in reducing bleeds.

Importance: Innovative anticancer therapies for children, adolescents, and young adults are regularly prescribed outside their marketing authorization or through compassionate use programs. However, no clinical data of these prescriptions is systematically collected., Objectives: To measure the feasibility of the collection of clinical safety and efficacy data of compassionate and off-label innovative anticancer therapies, with adequate pharmacovigilance declaration to inform further use and development of these medicines., Design, Setting, and Participants: This cohort study included patients treated at French pediatric oncology centers from March 2020 to June 2022. Eligible patients were aged 25 years or younger with pediatric malignant neoplasms (solid tumors, brain tumors, or hematological malignant neoplasms) or related conditions who received compassionate use or off-label innovative anticancer therapies. Follow up was conducted through August 10, 2022., Exposures: All patients treated in a French Society of Pediatric Oncology (SFCE) center., Main Outcomes and Measures: Collection of adverse drug reactions and anticancer activity attributable to the treatment., Results: A total of 366 patients were included, with a median age of 11.1 years (range, 0.2-24.6 years); 203 of 351 patients (58%) in the final analysis were male. Fifty-five different drugs were prescribed, half of patients (179 of 351 [51%]) were prescribed these drugs within a compassionate use program, mainly as single agents (74%) and based on a molecular alteration (65%). Main therapies were MEK/BRAF inhibitors followed by multi-targeted tyrosine kinase inhibitors. In 34% of patients at least a grade 2 clinical and/or grade 3 laboratory adverse drug reaction was reported, leading to delayed therapy and permanent discontinuation of the innovative therapy in 13% and 5% of patients, respectively. Objective responses were reported in 57 of 230 patients (25%) with solid tumors, brain tumors, and lymphomas. Early identification of exceptional responses supported the development of specific clinical trials for this population., Conclusions and Relevance: This cohort study of the SACHA-France (Secured Access to Innovative Medicines for Children with Cancer) suggested the feasibility of prospective multicenter clinical safety and activity data collection for compassionate and off-label new anticancer medicines. This study allowed adequate pharmacovigilance reporting and early identification of exceptional responses allowing further pediatric drug development within clinical trials; based on this experience, this study will be enlarged to the international level.

Ovarian function impairment and infertility are among the most frequent late effects after hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate ovarian function, occurrence of premature ovarian insufficiency (POI), and spontaneous pregnancy in a large cohort of adult survivor women who had undergone HSCT for leukemia before puberty. We conducted a retrospective observational study in women from the national cohort L.E.A., the long-term French follow-up program after childhood leukemia. The median follow-up duration was 18 years (14.2-23.3) after HSCT. Among 178 women, 106 (60%) needed pubertal induction with hormone substitution treatment, whereas 72 (40%) had spontaneous menarche. After spontaneous menarche, 33 (46%) developed POI, mostly within 5 years of HSCT. Older age at time of HSCT and cryopreservation of ovarian tissue appeared as significant risk factors for POI. More than 65% of patients who underwent HSCT before the age of 4.8 years had spontaneous menarche, and almost 50% didn't have POI at last evaluation, whereas more than 85% with HSCT after the age of 10.9 years didn't have spontaneous menarche and needed induction of puberty with hormone replacement therapy. Twenty-two women (12%) had at least one spontaneous pregnancy, with 17 live-births, 14 miscarriages, 4 legal abortions, and 2 therapeutic abortions. These results add supplementary data to better counsel patients and their families on the chances of ovarian residual function and pregnancy after HSCT, as well as on the potential interest of fertility preservation., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: To study the impact of hematopoietic stem cell transplantation (HSCT) on the uterine volume of childhood acute leukemia (AL) survivor depending on age at HSCT and the type of myeloablative conditioning regimen., Setting: Thirteen French University Teaching Hospitals., Design: Prospective cohort study., Patient(s): Eighty-eight women who underwent HSCT during childhood or adolescence for AL compared to a control group., Intervention(s): A multicentric prospective national study compared the uterine volume in a cohort of childhood AL survivor adult women treated with HSCT, matched 1:1 to control women. Pelvic magnetic resonance imaging scans included diffusion-weighted imaging sequences. Scans were centralized for a double-blinded reading by 2 radiologists., Main Outcome Measure(s): Uterine volume, uterine body-to-cervix ratio, and apparent diffusion coefficient., Result(s): The mean age at HSCT was 9.1 ± 0.3 years with a mean follow-up duration of 16.4 ± 0.5 years. The cohort of 88 HSCT survivor women was composed of 2 subgroups depending on the myeloablative conditioning regimen received: an alkylating agent-based regimen group (n = 34) and a total body irradiation (TBI)-based regimen group (n = 54). Among the 88 women, 77 were considered as having a "correct hormonal balance" with estrogens supplied by hormone replacement therapy (HRT) for premature ovarian insufficiency (POI) or because of a residual ovarian function. In the control group (n = 88), the mean uterine volume was 79.7 ± 3.3 mL. The uterine volume significantly decreased in all HSCT survivor women. After the alkylating agent-based regimen, the uterine volume was 45.3 ± 5.6 mL, corresponding to a significant volume reduction of 43.1% (28.8-57.4%) compared with that of the control group. After TBI, the uterine volume was 19.6 ± 1.9 mL, corresponding to a significant volume reduction of 75.3% (70.5%-80.2%) compared with that of the control group. After the alkylating agent-based regimen, the uterine volume dramatically decreased in women with POI without HRT compared with that in those with a correct hormonal balance (15.2 ± 2.6 vs. 49.3 ± 6 mL). In contrast, after TBI, the uterine volume was similar in all women, with no positive effect of hormonal impregnation on the uterine volume (16.3 ± 2.6 vs. 20.1 ± 2.2 mL, respectively)., Conclusion(s): The uterine volume was diminished after HSCT, regardless of the conditioning regimen. The physiopathology needs to be further investigated: specific impact of a high dose of an alkylating agent; impact of hormone deprivation around puberty; poor compliance to HRT; or different myometrial impact of HRT compared with endogenous ovarian estrogens?, Clinical Trial Registration Number: ClinicalTrials.gov/NCT03583294 (enrollment of the first subject, November 11, 2017; enrollment of the last subject, June 25, 2021)., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The prevalence of the metabolic syndrome among adults from the French LEA childhood acute leukemia survivors' cohort was prospectively evaluated considering the type of anti-leukemic treatment received, and compared with that of controls. The metabolic profile of these patients was compared with that of controls. A total of 3203 patients from a French volunteer cohort were age- and sex-matched 3:1 to 1025 leukemia survivors (in both cohorts, mean age: 24.4 years; females: 51%). Metabolic syndrome was defined according to the National Cholesterol Education Program's Adult Treatment Panel III criteria. Metabolic syndrome was found in 10.3% of patients (mean follow-up duration: 16.3±0.2 years) and 4.5% of controls, (OR=2.49; P <0.001). Patients transplanted with total body irradiation presented the highest risk (OR=6.26; P <0.001); the other treatment groups also showed a higher risk than controls, including patients treated with chemotherapy only. Odd Ratios were 1.68 ( P =0.005) after chemotherapy only, 2.32 ( P =0.002) after chemotherapy and cranial irradiation, and 2.18 ( P =0.057) in patients transplanted without irradiation. Total body irradiation recipients with metabolic syndrome displayed a unique profile compared with controls: smaller waist circumference (91 vs 99.6 cm; P =0.01), and increased triglyceride levels (3.99 vs 1.5 mmol/L; P <0.001), fasting glucose levels (6.2 vs 5.6 mmol/L; P =0.049), and systolic blood pressure (137.9 vs 132.8 mmHg; P =0.005). By contrast, cranial irradiation recipients with metabolic syndrome had a larger waist circumference (109 vs 99.6 cm; P =0.007) than controls. Regardless of the anti-leukemic treatment, metabolic syndrome risk was higher among childhood leukemia survivors. Its presentation differed depending on the treatment type, thus suggesting a divergent pathophysiology. This study is registered at clinicaltrials.gov identifier: 01756599 ., (Copyright© 2018 Ferrata Storti Foundation.)

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 × 10 9 /L, gHiR classifier, and MRD ≥10 -4 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 10 9 /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 × 10 9 /L, it identifies a significant subgroup of patients with a low risk of relapse., (© 2018 by The American Society of Hematology.)