Institut d’Hématologie et d’Oncologie Pédiatrique

The interplay between graft-versus-host disease (aGVHD) and the graft-versus-leukemia (GVL) effect in children with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) remains complex. This EBMT Pediatric Diseases Working Party (PDWP) retrospective analysis of 2374 pediatric AML patients evaluated the impact of aGVHD on relapse incidence (RI), non-relapse mortality (NRM), overall survival (OS), and leukemia-free survival (LFS). Grade III/IV aGVHD significantly reduced RI (HR: 0.61, p = 0.01) while significantly increasing NRM (HR: 4.51, p < 0.001), offsetting any benefits in OS and LFS. Grade II aGVHD increased NRM (HR: 2.07, p = 0.002) without affecting RI or OS, while grade I aGVHD had no significant impact on these outcomes. Patients with Grade II or higher aGVHD were at greater risk of both chronic (c)GvHD (HR: 1.98 for Grade II; HR: 4.33 for Grade III/IV, p < 0.001) and extensive cGVHD (HR: 2.52 for Grade II; HR: 4.91 for Grade III/IV, p < 0.001). These findings highlight the challenge of mitigating NRM while preserving the GVL effect to optimize disease control and long-term survival in pediatric AML. This study provides critical insights for refining post-transplant strategies in this population.

ABSTRACTDistinguishing inherited bone marrow failure (IBMF) from acquired aplastic anemia (aAA) at diagnosis is a major clinical challenge and is essential for appropriate treatment and patients' counseling. Genetic testing to exclude IBMF is frequently subject to delays of several months and may not be available in all centers and could not be applied to all patients in a large number of countries. Our study aimed to develop a practical scoring system to identify patients who are unlikely to have IBMF. Patients in the training set (N = 150) were classified as having either aAA or IBMF based on genetic results and/or response to immunosuppressive therapy. We retrospectively recorded 33 clinical and laboratory characteristics at the time of diagnosis. The diagnostic algorithm was then constructed using recursive partitioning. This unbiased model handles missing values using conditional inference procedures. Model sensitivity addresses the ability to correctly predict aAA. Three of the variables of interest were selected by the model in the final algorithm: morphological abnormalities, PNH clone (≥ 0.1% on granulocytes), and acute onset of BMF (cytopenia < 1 year). In the training set, the algorithm achieved a sensitivity of 96.2% (IC95%: 91.4%–98.8%) and a specificity of 88.2% (IC95%: 63.6–98.5) in differentiating aAA from IBMF. We then applied this algorithm to a validation set of 465 patients (aAA n = 368 (79.1%); IBMF n = 97 (20.9%)) and obtained similar sensitivity of 95.7% (IC95: 93–97.5) and specificity of 91.8% (IC95%: 84.4–96.4) with a positive predictive value of 97.8% (IC95%: 95.7–99). This efficient and practical scoring system might help physicians to identify patients who do not need genetic screening, allowing prompt start of treatment. Positive predictive value may be improved in specific populations by adding telomere length, AFP and HbF values.

Bone sarcomas other than osteosarcoma, chondrosarcoma, and Ewing sarcoma represent a challenge in care because they are uncommon, especially in children, adolescents, and young adults (AYA). We conducted a retrospective review of patients aged 0-25years treated for non-osteosarcoma, non-chondrosarcoma, non-Ewing (and related) primary bone sarcomas in France between 2011 and 2021. Patients were identified through the French databases: ResOs and Conticabase. Forty-nine patients treated in 18 centers were analyzed. The median age was 15years (3.0-25.0), and the male/female ratio was 0.58. The median follow-up was 33.9months (IQR: 15.0-63.7). Twenty-three patients (46.9%) were diagnosed with adamantinomas, eight (16.3%) with chordomas, 15 (30.6%) with undifferentiated sarcomas, two (4.1%) with leiomyosarcomas, and one (2.0%) with angiosarcoma. Adamantinomas were treated by surgery, and chordomas by surgery and/or radiotherapy. High-grade tumors composed of undifferentiated sarcomas, leiomyosarcomas, and angiosarcomas were treated with an association of chemotherapy, surgery, and radiotherapy. None of the patients with adamantinoma relapsed. Half of the patients with chordoma relapsed without any deaths. The 5-year overall survival and progression-free survival rates for patients with high-grade tumors were 44.4% (95% CI: 14.9%-70.7%) and 37.5% (95% CI: 16.1%-59.1%), respectively. Non-classic primary bone sarcomas in children and AYA are extremely rare. Adamantinomas have an excellent outcome. Chordomas exhibit local aggressiveness and high recurrence rates, with a need to improve local control and systemic treatments. Other tumors are mainly undifferentiated sarcomas and have a poor prognosis, and no consensus as to adequate systemic treatment.

Oxygen-gradient ektacytometry (oxygenscan) has been recently used in the context of sickle cell disease (SCD) to determine the ability of red blood cells (RBCs) to deform in normoxia and during deoxygenation. While several studies focused on the determinants of oxygenscan parameters in the homozygous form of SCD (i.e., HbSS), very few studies focused on hemoglobin SC disease (HbSC). Oxygenscan parameters were compared between HbSS (N = 304) and HbSC (N = 58) patients, with or without hydroxyurea (HU). RBC deformability measured in normoxia or at low oxygen level was lower in HbSS patients without HU compared to HbSS patients with HU and HbSC patients with or without HU. The propensity of RBCs to sickle during deoxygenation was greater in HbSS than in HbSC patients. Although no significant impact of HU was observed on RBC deformability/sickling in HbSC patients, those with HU had lower blood viscosity. The ability of RBC to recover their maximum deformability after a deoxygenation/reoxygenation cycle was lower in HbSC compared to HbSS patients. Finally, oxygenscan parameters and routine hematological parameters correlated differently in HbSS and HbSC patients. Our study showed difference in oxygenscan parameters between HbSS and HbSC individuals that could partly explain the difference in the clinical expression of SCD.

10008 Background: Regorafenib monotherapy has shown interesting but limited activity against relapsed Ewing sarcoma. We present the first results of the phase Ib study to identify the maximum tolerated dose (MTD) of regorafenib in combination with standard multimodal treatment in patients with newly diagnosed multi-metastatic Ewing sarcoma (NCT05830084). Methods: International multi-center phase Ib study of the combination of regorafenib with interval-compressed chemotherapy (VDC/IE) in patients aged 2-50 years with newly diagnosed metastatic (excluding lung/pleura only) Ewing sarcoma. VDC/IE chemotherapy was administered at the standard doses. Regorafenib was given orally for 21 days of a 28-day cycle (from day 5) at a starting dose level of 66 mg/m 2 /day (capped at 120 mg, DL0, 80% of the pediatric recommended phase 2 dose (RP2D)) and escalated to 82 mg/m 2 /day (100% RPD2, capped at 160 mg, DL1) or de-escalated to 50 mg/m 2 /day (60% RPD2, DL-1). The study implemented the Bayesian Optimal Interval (BOIN) design (Yuan et al, Clin Cancer Res 2016). Primary tumour local treatment was surgery and/or radiotherapy. Adjuvant therapy consisted of VC/IE cycles or high dose chemotherapy consolidation with Busulfan/Melphalan (BuMel) and autologous stem cell rescue (ASCR). Regorafenib was given concomitant to adjuvant VC/IE cycles and primary tumor radiotherapy to the extremities but permanently discontinued in those receiving BuMel/ASCR or primary tumour radiotherapy to sites other than extremities. Results: Thirteen patients (DL0: n=2, DL1: n= 11) with a median age of 15.2 years (range, 8.1-23.5), were enrolled between June 2023 and December 2024 in 7 centres and 3 countries. All were evaluable for toxicity. One dose-limiting toxicity (DLT) occurred in one patient at DL1 (pressure ulcer grade 2, requiring regorafenib dose interruption and reduction in a 17-year old patient). After the DLT period, one patient had regorafenib dose interruption/reduction. One patient presented with a grade 3 veno-occlusive disease after Bu-Mel/ASCR. Detailed toxicity data after the DLT period and pharmacokinetic data will be presented. At data cut-off of 21/01/2025, two patients had experienced disease progression before primary tumour local treatment, eight patients had finished all treatment cycles (three received Bu-Mel/ASCR consolidation) and three patients were on therapy. Conclusions: Regorafenib combined with VDC/IE chemotherapy is well tolerated with a MTD of 82 mg/m 2 /day (capped 160 mg). The efficacy of the addition of regorafenib to standard multimodal treatment in newly diagnosed patients with metastatic Ewing sarcoma will be tested in the Inter-Ewing-1 trial developed by the Euro Ewing Consortium (planned initiation in Q3 2025). Recruitment to the Rego-Inter-Ewing-1 continues at DL1 (maximum 24 patients), until Inter-Ewing-1 initiates. Clinical trial information: NCT05830084 .

Dans un essai contrôlé randomisé, le vaccin grippal haute dose (HD) a démontré une efficacité vaccinale relative (eVR) supérieure de 24,2% (9,7;36,5%) par rapport aux vaccins à dose standard (SD) pour prévenir la chez les 65+ [1]. Le HD a été introduit en France pour les 65+ à partir de la saison 2021-2022, au cours de laquelle nous avions rapporté une rVE de 23,3% (8.4%-35.8%) contre les hospitalisations pour grippe. Nous présentons ici les résultats de la deuxième saison. MéTHODES: Nous avons mené une étude de cohorte rétrospective à partir du SNDS. Les personnes âgées de 65 ans et plus vivant en communauté et vaccinées contre la grippe au cours de la saison 2022-2023 ont été inclues et suivies depuis la date de vaccination jusqu'au 30 juin 2023/admission en maison de retraite/décès. Les hospitalisations pour grippe et autres causes ont été recueillies à partir de 14 jours après la vaccination. Après un appariement sur score de propension (1:4) avec contrainte exacte sur les groupes d'âge, le sexe, la semaine de vaccination et la région, les ratios de taux d'incidence ont été estimés via modèles de régression. RéSULTATS: 675 412 individus avec HD ont été appariés à 2 701 648 individus avec SD. Au sein de la cohorte appariée, le HD était associé à une diminution de 27,4 % (19,8%-34,3%) des hospitalisations pour grippe par rapport au SD. Certaines hospitalisations non liées à la grippe étaient légèrement plus fréquentes chez les patients ayant bénéficié de l'HD, ce qui suggère un biais résiduel dû à des facteurs de confusion non mesurés. Ce résultat, cohérent avec la littérature et l'analyse 2021-2022 [2], renforce le niveau de preuve quant au bénéfice du vaccin HD sur la réduction des hospitalisations liées à la grippe par rapport au vaccin SD en vie réelle. L'utilisation d'un vaccin HD adapté à la population des 65 ans et plus pourrait contribuer à réduire le fardeau lié aux infections respiratoires.

Retrieval strategies for children, adolescents, and young adults with relapsed classic Hodgkin lymphoma (cHL) aim to maintain efficacy while minimizing long-term toxic effects. Children, adolescents, and young adults with low-risk, relapsed cHL may benefit from replacing high-dose chemotherapy and autologous stem cell transplant with less intensive involved-site radiotherapy (ISRT). To evaluate a risk-stratified, response-adapted, transplant-free approach for treatment of children, adolescents, and young adults with low-risk relapsed cHL with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response and ISRT (30.0 to 30.6 Gy). CheckMate 744 (R1 cohort) was a phase 2, nonrandomized, single-arm study enrolling children, adolescents, and young adults aged 5 to 30 years with low-risk cHL between September 25, 2017, and December 16, 2020, across the US, Canada, and Europe. Data were analyzed from September 2017 to November 2022. Patients received 4 cycles of nivolumab plus BV induction; patients with complete metabolic response (CMR) received an additional 2 cycles of nivolumab plus BV while patients with suboptimal response received 2 cycles of BV plus bendamustine intensification. Patients with CMR after induction or intensification received ISRT consolidation. Prespecified coprimary end points were CMR rate (Lugano 2014 classification) any time before ISRT and 3-year event-free survival (EFS) rate, per blinded independent central review (BICR). Of 28 included patients treated in the low-risk cohort, 18 (64%) were female, and the median (range) age was 17 (6-27) years. At a median (range) follow-up of 31.9 (2.2-55.3) months, CMR per BICR any time before ISRT was 93% (26 of 28; 90% CI, 79.2-98.7; objective response rate [ORR], 100%), and 23 of 28 (82%) achieved CMR per BICR after 4 cycles of nivolumab plus BV (ORR, 96.4%). Kaplan-Meier estimates of EFS and progression-free survival rates at 3 years were 87% (3 of 18; 90% CI, 69.5-94.7) and 95% (1 of 18; 90% CI, 76.7-99.0), respectively. During induction, 22 patients (79%) had treatment-related adverse events, including 7 with grade 3 or 4 adverse events, 2 with anemia, 1 with neutropenia, and 6 with immune-mediated adverse events. Serious adverse events leading to discontinuation occurred in 2 patients. This nonrandomized clinical trial found that for children, adolescents, and young adults with low-risk, relapsed cHL, a transplant-free, risk-adapted, response-based approach with nivolumab plus BV and ISRT offered high CMR rates and high 3-year EFS rate, with a safety profile consistent with that of each agent used. ClinicalTrials.gov Identifier: NCT02927769.

CNS embryonal tumors with PLAGL amplification (ET, PLAGL) are a recently described tumor type marked by amplification of one of the PLAG family genes, PLAGL1 or PLAGL2. Separately, a supratentorial, ependymoma-like CNS tumor type with PLAG family alteration, namely PLAGL1 fusion, was also reported (NET_PLAGL1). Here, we use DNA methylation profiling in combination with copy number, RNA-seq, and histological analysis to characterize and classify a novel group of CNS embryonal tumors harboring PLAG1 gene fusions (n=12). Through our screening, we identified a subset of CNS tumors (n=12) epigenetically distinct from other known CNS tumor types, but clustering close to the PLAGL1- and PLAGL2-amplified ET, PLAGL subtypes in our t-SNE analysis. Copy number profiles indicated putative PLAG1 fusions, which were confirmed in 9/12 tumors (not determined in 3/12). Different 5’ fusion partners (ASAP1, ADGRG1, TMEM68, TCF4, CHD7, NCALD, HNRNPK, LOC105378102) were identified that upregulate wild-type PLAG1 through promoter hijacking. Expression analysis shows upregulation of PLAG1 as well as IGF2, DLK1, Desmin, CYP2W1, and RET, which are also robustly expressed in PLAGL1/2-amplified tumors. Patient characteristics, survival data, and clinical/imaging analysis show additional similarities to PLAGL1/2-amplified tumors. Median age at diagnosis was 5 years, tumors were located throughout the neuroaxis, and original histological diagnoses were heterogeneous. The tumors demonstrated morphologic heterogeneity, with most composed of densely cellular areas of primitive small blue cells, alongside focal regions showing clear cell morphology, microcystic changes, and ependymoma-like perivascular pseudorosettes. Applied treatment regimens were also heterogeneous, but some favorable responses to therapy were observed. In summary, we describe a third subtype of PLAG family-altered pediatric CNS embryonal tumor characterized by PLAG1 gene fusion, which leads to upregulation of PLAG1 and downstream genes. We therefore propose to rename ET, PLAGL to ET, PLAG (CNS embryonal tumor with PLAG family gene alteration) together with a specification of the respective subtype.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00401-025-02917-z.