ABSTRACT:Data on the immunosuppressants azathioprine (AZA) and mycophenolate mofetil (MMF) in autoimmune cytopenia (AIC) are limited, and no direct comparison exists. We analyzed the failure-free survival (FFS; time from AZA/MMF initiation to another non-first-line treatment, or death) of both treatments in the prospective nationwide pediatric OBS'CEREVANCE cohort. We included 343 patients (chronic immune thrombocytopenia, n = 161; autoimmune hemolytic anemia, n = 74; Evans syndrome, n = 108). They received AZA (n = 276) or MMF (n = 104; 37 sequentially received both) as monotherapy for a median duration of 11.3 (range, 0.01-149.0) months. Older age was associated with higher FFS for AZA, whereas secondary AIC was associated with higher FFS for MMF. AIC type had no effect. In a propensity score (PS)-matched cohort, AZA and MMF showed similar FFS (adjusted hazard ratio, 0.91; 95% confidence interval, 0.54-1.52; P = .71), with 1-year FFS rates of 73% and 76%, respectively. In subgroup analyses, AZA was associated with higher FFS in PS-matched patients diagnosed at an age of ≥10 years, whereas MMF was associated with higher FFS in PS-matched patients diagnosed at an age of <10 years and in those with confirmed secondary AIC (although with suboptimal matching). Rates of grade ≥3 infection were similar between the 2 drugs, at ∼2% new cases per year. In summary, AZA and MMF demonstrated comparable overall FFS and infection risk. However, our data suggest that AZA may be more beneficial in children diagnosed at an age of ≥10 years, whereas MMF may be more beneficial in those diagnosed at an age of <10 years and possibly in patients with secondary AIC.

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.

Acute leukemias represent the first cause of cancer in children. Their prognosis has improved significantly due to remarkable advances in therapeutic management, despite the risk of long-term consequences, especially for patients who underwent allogenic hematopoietic stem cell transplantation (aHSCT). Through the Leukemia in Children and Adolescents (LEA) long-term follow-up cohort (clinicaltrials gov. Identifier: NCT01756599), we conducted a French national multicenter prospective study on the occurrence and risk factors of chronic kidney disease (CKD), differentiating glomerular and tubular dysfunctions, corresponding to the NephroLEA project. Among the 1,676 patients included, the median age at evaluation was 15.8 (interquartile range [IQR], 11.3-20.5) years, with a median follow-up of 9.2 (IQR, 5.8-13.9) years. aHSCT was performed on 343 (20.6%) patients, half of whom have undergone the procedure after achieving second or greater remission. A higher percentage of children among transplanted patients had diastolic and systolic blood pressure above the 95th, with 13.7% versus 5.2% (P=3x10-3) and 15% versus 6.5% (P=9x10-2), respectively. A total of 187 patients (11.1%) had a mild CKD (i.e., eGFR between 75 and 90 mL/min/1.73 m2), while 3% (N=50) exhibited mild to severe CKD (eGFR <75 mL/min/1.73 m2). Notably, no patient reached kidney failure. Twenty-one patients (1.3%) had decreased glomerular filtration rate associated with tubular impairment. The principal risk factors for developing CKD were aHSCT and leukemia relapse. In conclusion, CKD represents a long-term risk for patients who relapsed and/or underwent aHSCT. These patients could benefit from nephroprotection advice to further improve their long-term outcomes, which is becoming a public health issue.

Warm-antibody autoimmune hemolytic anemia (wAIHA) in children is a rare condition with limited data to predict outcomes or optimize therapy. Only two cohorts with more than 100 pediatric patients have been published. We took advantage of the national OBS'CEREVANCE cohort to clarify the long-term outcomes of wAIHA in children and determine whether initial clinical and biological characteristics are associated with distinct outcome patterns. We analyzed 241 children with wAIHA (excluding Evans syndrome) from the French multicenter OBS'CEREVANCE cohort (1990–2021) with a median follow-up of 4.7 years. Initial corticosteroid therapy was administered to 89% of patients. Among the 241 included patients, 42.2% (n=109) received subsequent-line therapy (SLT), with most (n=82) initiating treatment beyond 30 days (median time: 5.5 months, range 0–200 months). A total of 16.2% (n=39) received more than two lines of treatment. Rituximab was the most common second-line therapy (n=55), administered in 52.7% of cases within the first three months after diagnosis. One year post-diagnosis, 64.8% achieved complete remission without relapse (R) or SLT, including 19.9% still on corticosteroids. Meanwhile, 22.8% had SLT before corticosteroid discontinuation, and 12.4% relapsed after stopping corticosteroids. In the present study, we observed that SLTs were sometimes combined prematurely, before their optimal response window (6–8 weeks for rituximab, 3 months for immunosuppressants). While aggressive escalation may be justified in cases of severe, refractory hemolysis, each additional treatment increases infection risk, necessitates a careful risk-benefit assessment and appropriate anti-infective prophylaxis. During follow-up, 35.2% developed immunopathological manifestations (IM), including 10.3% with another autoimmune disease. A total of 15 patients (6.2%) were diagnosed with a primary immunodeficiency, with 5 diagnosed at the time of AIHA diagnosis and the remainder identified later. Identified PID cases during follow-up included ALPS, CVID, hyper IgM syndrome, and PID related to mutations in the following genes: RAG2, NFKB1, and ITK. Infectious complications were reported in 17.4% of patients, and two patients died. Among patients who received early rituximab within the first month, 17.6% relapsed or required subsequent-line therapy (R/SLT) after the expected 8-week response window. In patients treated with corticosteroids alone during the first month (77.5%), the cumulative incidence of relapse (CIR) or initiation of subsequent-line therapy (CIR-SLT) was 42.7% at 2 years and 46.2% at 5 years. Those with R/SLT were less likely to have inadequate reticulocytosis (33.7% vs 48.5%, P=0.03). Primary AIHA was more common in patients without R/SLT (72.3% vs 47.7%, P<0.001). An optimal corticosteroid duration to reduce CIR-SLT after discontinuation could not be determined. Interestingly, no patients had undergone splenectomy since 2010, reflecting a shift away from this approach in pediatric AIHA. These findings underscore the need for long-term follow-up and further study on corticosteroid duration and early SLT use. This study, the largest cohort analysis of pediatric wAIHA to date, provides valuable insights into treatment responses and long-term outcomes. Identifying underlying immune disorders, such as PID, at diagnosis, as well as associated IM, is crucial given their incidence in this population and their implications for tailored therapeutic management. While corticosteroids remain the cornerstone of treatment, nearly half of the patients required additional therapy. Future studies should focus on determining the optimal corticosteroid duration and evaluating the potential benefits of early rituximab use in childhood wAIHA, particularly in relation to associated IM and the prognostic value of BMRI at diagnosis.

PURPOSE:Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HR-NBL) remain dismal. Here, we investigate addition of the anti-GD2 monoclonal antibody, dinutuximab beta (dB), to temozolomide (T)-based chemotherapy. MATERIALS AND METHODS:Patients with RR-HR-NBL were randomly assigned in a 1:2 ratio to receive chemotherapy alone or chemotherapy with dB, given concurrently as a 7-day infusion (10 mg/m2/24 h). The trial had a factorial design, with some patients also randomly assigned between chemotherapy regimens (T v T-topotecan [TTo]). Crossover to dB with To/cyclophosphamide was allowed for patients randomly assigned to chemotherapy alone with disease progression (PD). The primary outcome was best objective response (complete or partial) rate (overall response rate [ORR]) during six cycles of treatment. Progression-free (PFS), overall survival (OS), and safety were secondary outcomes. RESULTS:Sixty-five patients were randomly assigned to chemotherapy alone (3 T, 19 TTo) or with dB (6 dBT, 37 dBTTo). The median age was 4 years; 28 and 37 patients had refractory and relapsed diseases, respectively. Baseline characteristics were balanced between arms. The ORR was 30.2% (13 of 43) and 18.2% (4 of 22) in dB and non-dB arms, the median PFS was 11.1 months (95% CI, 4.3 to 15.5) for dB patients and 3.8 months (95% CI, 1.9 to 7.9) for non-dB patients, respectively. The median OS was 25.7 months (95% CI, 11.4 to not reached [NR]) for dB patients and 17.1 months (95% CI, 7.6 to 54.6) for non-dB patients (upper 95% CI, NR in dB arm). Thirteen of 22 patients in the non-dB arm crossed over to dB with cyclophosphamide/To because of PD. Neurotoxicity was more common in the dB arm (grade 1 and 2: 26% v 9%, grade 3: 2.3% v 4.5%), but other toxicities were similar. CONCLUSION:Within a randomized phase II setting, results observed with addition of dB to T-based chemotherapy in RR-HR-NB warrant further evaluation.

Neuroblastoma is the most common extracranial solid tumor in children, and congenital forms account for 5% of all neuroblastoma cases. In utero diagnosis is very rare, and the progression leading to premature delivery for urgent treatment is exceptional. In some of these cases, chemotherapy is required after birth, given tumor progression that threatens the functional prognosis (dumbbell neuroblastoma), or even survival (Stage MS). However, the optimal doses of chemotherapy in premature newborns are not known. We present a retrospective cohort of six patients treated in French pediatric oncology centers in order to analyze treatment modalities, and report on their tolerance (five Grade 4 hematological toxicity, three septicemias) as well as the outcome of these newborns (two deaths, four remissions).

Neuroblastoma is a common childhood tumor originating from neural crest progenitors with variable clinical behavior. Despite improved overall survival, factors such as stage, histoprognosis, MYCN status, and age still influence outcome. MCM6 regulates DNA replication and contributes to cancer progression. PRAME, first identified in melanoma, also acts on cell replication, epithelial-mesenchymal transition, and cell migration and has been associated with poor outcomes in several cancers, including neuroblastoma, using molecular biology techniques. The study aims to investigate MCM6 and PRAME expression and prognostic roles in neuroblastoma. A retrospective study was conducted, which included data of 84 patients with neuroblastoma diagnosed between 2000 and 2022, sourced from the pediatric tumor registry. Patient's characteristics and prognostic tumor factors were collected. Expression of MCM6 and PRAME proteins was evaluated using digital image analysis techniques. Univariate and multivariate analyses were performed using Cox regression to assess the impact of protein expression on survival and their associations with these prognostic factors. A total of 84 children diagnosed with neuroblastoma were included. MCM6 and PRAME were associated with unfavorable histologies (p = 0.03). PRAME was associated with bone marrow metastases (p < 0.01), high mitotic-karyorrhectic index (p = 0.04), and poor histoprognosis (p < 0.01). PRAME and MCM6 expression was correlated with several neuroblastoma prognostic factors. PRAME was significantly (p = 0.05) associated with poor event-free survival (EFS) and not significantly (p = 0.08) associated with overall survival (OS). Although statistical significance was not reached in multivariate analysis, the trends strongly suggested that the overexpression of MCM6 and PRAME was correlated with decreased survival.

Purpose:Medulloblastoma (MB) is the most prevalent paediatric brain tumour. Despite improvements in patient survival with current treatment strategies, the quality of life of these patients remains poor owing to the sequelae and relapse risk. An alternative, or, in addition to the current standard treatment, could be considered immunotherapy, such as Natural Killer cells (NK). NK cells are cytotoxic innate lymphoid cells that play a major role in cancer immunosurveillance. To date, the mechanism of cytotoxicity of NK cells, especially regarding the steps of adhesion, conjugation, cytotoxic granule polarisation in the cell contact area, perforin and granzyme release in two and three dimensions, and therapeutic efficacy in vivo have not been precisely described. Materials and Methods:Each step of NK cytotoxicity against the three MB cell lines was explored using confocal microscopy for conjugation, Elispot for degranulation, flow cytometry, and luminescence assays for target cell necrosis and lysis and mediators released by cytokine array, and then confirmed in a 3D spheroid model. Medulloblastoma-xenografted mice were treated with NK cells. Their persistence was evaluated by flow cytometry, and their efficacy in tumour growth and survival was determined. In addition, their effects on the tumour transcriptome were evaluated. Results:NK cells showed variable affinities for conjugation with MB target cells depending on their subgroup and cytokine activation. Chemokines secreted during NK and MB cell co-culture are mainly associated with angiogenesis and immune cell recruitment. NK cell cytotoxicity induces MB cell death in both 2D and 3D co-culture models. NK cells initiated an inflammatory response in a human MB murine model by modulating the MB cell transcriptome. Conclusion:Our study confirmed that NK cells possess both in vitro and in vivo cytotoxic activity against MB cells and are of interest for the development of immunotherapy.

Background This multicenter Phase I study (NCT03585465) evaluated nivolumab in combination with 3 metronomic chemotherapy (MC) regimens in children with refractory/relapsing solid tumors. Objectives: To evaluate the feasibility and safety of the three regimens Methods Patients aged <18 years were enrolled. Nivolumab was combined with cyclophosphamide and vinblastine (arm A), capecitabine (arm B), or cyclophosphamide, vinblastine and capecitabine (arm C). Arm A and B were allocated sequentially. Arm C opened only if A and B were deemed safe. Dose-limiting toxicities (DLTs) were evaluated over the first two cycles. Patients were evaluable if they received > 2 cycles and > 70% of the planned dose. Population Sixteen patients were enrolled, 3 in arm A, 6 in arm B, and 7 in arm C. Median age was 11.5 years (range, 5-19). Patients previously received a median of 3.5 (range, 1-4) lines of systemic treatment, 14 patients had surgery and 11 had radiotherapy. Results Median number of cycles was 2 (1-24), median treatment duration was 56 days (18-714). In arm C, median number of cycles was 4 with median treatment duration of 95 days. No DLT was observed. Grade 3 adverse events (AE) and serious AE were observed in 8 patients (50%) and 1 patient (6%), respectively, over the first 2 cycles. No grade 4 AE occurred. The 6-month PFS and OS were 12% and 44%, respectively, in the whole population. Prolonged stable disease was observed in a high-grade glioma and an atypical teratoid rhabdoid tumor. Conclusion Arm C appears safe. A randomized phase II trial evaluating the addition of nivolumab to the triple MC is ongoing.

10056 Background: Larotrectinib is an FDA and EMA approved TRK inhibitor for TRK fusion solid tumors in patients with locally advanced or metastatic disease, or where surgical resection is likely to result in severe morbidity. Here we report the real-world activity and safety data on compassionate use and post-marketing authorization of larotrectinib collected in the SACHA-France study (NCT04477681), following the French Health Technology Assessment institution (HAS) request. Methods: All larotrectinib prescriptions made in France outside clinical trials since April 2019 for patients’ < 25 years-old were registered in the SACHA-France study. Safety and activity data were collected, with data cut-off of 23/01/2024. SACHA-France is open in all 31 French Society of Pediatric Oncology (SFCE) centers, it is approved as a real-world data source by the HAS and supported by the French National Agency for the Safety of Medicines and Health Products (ANSM). Results: 21 patients were included (4 compassionate use, 17 post-marketing authorization). Main cancer types were soft-tissue sarcomas (n=13, of them 7 infantile fibrosarcoma), followed by central nervous system (CNS) tumors (n= 7), and other solid extra-CNS tumors (n=1). All patients except one had a TRK fusion tumor: NTRK3 (n=10), NTRK2 (n=6, all CNS tumor) and NTRK1 (n=4). Median age at start of larotrectinib was 2.8 years (range: 0.2 -21.1). Ten patients had received no prior systemic therapy. Main reasons to start larotrectinib were to avoid mutilating surgery (n=9) and disease progression (n=9). Best objective response was reported as partial response in 13 out of 19 patients with evaluable disease (10/12 patients with soft tissue sarcomas, 2/6 patients with CNS tumors), with median time to response of 57 days. Of them, five patients with soft tissue sarcomas achieved a complete response after non mutilating surgery. Median treatment duration was 219 days (range: 10-1368, 5 patients still on therapy). Seven patients with soft tissue sarcomas stopped larotrectinib, after a median duration of 242 days (range: 122-1190), three of them after tumor surgery; none presented with tumor recurrence (follow-up: 350 days; range 40-636). At data cut-off, 8 patients had disease progression on-therapy (5/7 CNS tumors, 3/13 soft tissue sarcomas), with a NTRK resistance mutation identified in 2 out 3 patients with tumor biopsy. Adverse drug reaction (ADR) were reported in 2/21 patients (9%), including a grade 2 weight gain and a grade 3 neutrophil count decreased (1 patient each). Both ADRs were expected and required neither corrective treatment nor action on larotrectinib. Conclusions: Our real-world data confirm the favorable safety profile of larotrectinib with rapid and durable tumor-agnostic efficacy.

PURPOSE:Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). MATERIALS AND METHODS:Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. RESULTS:One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). CONCLUSION:The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.

Introduction Brigatinib is an orally administered second-generation anaplastic lymphoma kinase (ALK) inhibitor (ALKi) with good central nervous system penetration, approved for the treatment of ALK-positive (ALK+) non-small cell lung cancer in adults. The recommended dose in adults is 180 mg once daily (QD) after a 7-day lead-in at 90 mg QD. This report describes updated results of the phase 1 part of the BrigaPED trial (NCT04925609). This study is part of a Pediatric Investigation Plan, sponsored by the Princess Máxima Center and supported by Takeda Pharmaceuticals International Co. Methods The BrigaPED trial is a multicenter, non-randomized open label phase 1-2 study of brigatinib in pediatric and young adult patients. Patients aged ≥1 to <18 years and a body weight > 10 kg with relapsed or refractory ALK+ malignancies, including ALCL and inflammatory myofibroblastic tumors (IMT), were eligible for enrollment in the phase 1 part of this study. ALK positivity on immunohistochemistry was sufficient to enroll ALCL patients. Frontline ALK+ ALCL patients who were minimal residual disease (MRD) positive after one course of chemotherapy met the definition of refractory disease. Patients with IMT were also eligible in frontline in case of unresectable or metastatic disease. Previous treatment with other ALKi was allowed. Written informed consent and adequate organ function were required for study eligibility. In phase 1, brigatinib was dose escalated using the rolling-six design. The starting dose was allometrically scaled based on the adult approved dose, with one dose escalation, and a lower dose-level (DL) in case of dose-limiting toxicities (DLT). Brigatinib was administered once daily as tablets in 28-day cycles. DLTs were evaluated during the 7-day lead-in and the first cycle, to determine the recommended phase 2 dose (RP2D). Patients were assessed for safety, pharmacokinetics, activity, and efficacy. Response in ALCL was evaluated according to international pediatric non-Hodgkin lymphoma (IPNHL) response criteria and by response evaluation criteria for solid tumors (RECIST) for solid tumors. Qualitative MRD was assessed in ALCL patients using Reverse Transcriptase-PCR and digital PCR. Results Ten patients were enrolled between 08-2022 and 08-2023, 9 ALCL (3 frontline MRD+ and 6 relapsed), and 1 sarcoma NOS with an ALK fusion. Median age at inclusion was 9 years (range: 6-17 years). All patients were pretreated with chemotherapy and 3 with another ALKi. At database cut-off (21 June 2024), patients had received a median of 18 cycles (range 10-23 cycles). No DLT was observed on DL1 (n=4), and 1 on DL2 (n=6, grade (G)3 neutropenia > 7 days). Following dose reduction, this patient could resume brigatinib successfully. Common treatment-related adverse events (AE) were (n any G; n ≥ G3): asymptomatic CPK increase (8;2), nausea/vomiting (7;0), abdominal pain (6;0), and AST/ALT elevation (4;0). Reported AEs of special interest included ophthalmological events (3;0) and weight gain (3;2). No brigatinib related pulmonary toxicity or endocrine AEs were observed. Steady-state PK exposure on DL2 was within the predefined target range. Amongst 9 ALCL patients, 7 were MRD positive at screening and 8 had evaluable disease on imaging. The objective response rate (ORR) was 100%, with all ALCL patients achieving CR (n=6/8) or CRu (n=2/8), and a PR in the sarcoma patient. MRD negativity was obtained in 6/7 patients after a median of 1 cycle (range: 1-16 cycles). All ALCL patients were still on treatment with an ongoing response for a median duration of 18 months (range: 9-21 months). Conclusions Brigatinib monotherapy is well tolerated and demonstrated promising preliminary signs of activity in pediatric ALK+ ALCL, with no signs of cumulative toxicity. All ALCL patients are still on treatment. The RP2D was established at DL2, corresponding to 150 mg QD in patients 18-40 kg, or 240 mg QD in patients > 40 kg, which is higher than the adult approved dose. The phase 2 part of this study is currently open for accrual with disease-specific cohorts for ALK+ ALCL and IMT (age ≥1 - <26 years). An age-appropriate formulation is in development and will be used to confirm the RP2D in smaller children.

10017 Background: Brigatinib is a potent ALK inhibitor (ALKi), with good CNS penetration and durable efficacy in adults with ALK-positive ( ALK+) non-small cell lung cancer at 180 mg/day after a 7-day lead-in at 90 mg/day. This report presents the results of a pediatric phase 1 study (NCT04925609) in patients (pts) with ALK+ malignancies. The study is sponsored by the Princess Máxima Center and supported by Takeda Pharmaceuticals International Co. Methods: This multicenter, non-randomized, open-label phase 1 study enrolled pediatric pts aged ≥ 1 to < 18 years, with ALK+ newly diagnosed unresectable/metastatic or relapsed/refractory (R/R) IMT, R/R ALCL, or other solid tumors. ALK+ ALCL pts who were MRD positive after one course of frontline chemotherapy were considered refractory disease. A proven ALK gene aberration was required, except in ALCL, where ALK+ by immunohistochemistry was sufficient. Pts had to be able to swallow tablets and to weigh more than 10 kg at trial entry. Brigatinib was administered as tablets once daily in 28-day cycles, and was dose-escalated according to the rolling-six design to a maximum of 3 dose levels (DL). Dose limiting toxicities (DLTs) were evaluated during 35 days (1st cycle preceded by a 7-day lead-in phase), to determine the RP2D. Pts were assessed for safety, pharmacokinetics (PK) and efficacy. Results: Ten pts were enrolled (5 centers, 2 countries) over 12 months, including 9 ALCL, and 1 sarcoma NOS, with an ALKfusion. Median age was 9 years (range: 6-17) and 2 pts were pretreated with another ALKi. No pts less than 6 years were included due to the lack of age-appropriate formulation (AAF). At database cut-off, a median of 13 cycles (range 4-17) were administered. No DLTs were observed on DL1 (n = 4), and only 1 on DL2 (N = 6, grade (G)3 neutropenia > 7 days). Common treatment related adverse events (AE) were (n any G; n ≥G3): abdominal pain (6;0), CPK increase (7;1), nausea/vomiting (6;0), AST/ALT elevation (4;0). Reported AEs of special interest included ophthalmological events (3;0) and weight gain (2;1), no brigatinib related pulmonary toxicity or endocrine AEs were observed. PK exposure at DL2 was equivalent to that reported in adults at the approved dose. The sarcoma patient had progressive disease after 12 cycles. All 9 ALCL patients are still on therapy with an ongoing response. Conclusions: The RP2D of brigatinib was established at DL2, corresponding to 150 mg (18-40 kg), or 240 mg ( > 40 kg) once daily. In general, the drug was well tolerated, with no instances of patients discontinuing dosing due to safety concerns. Brigatinib monotherapy demonstrated promising preliminary signs of efficacy in pediatric ALCL, although follow-up is still limited. The phase 2 part of this study has recently opened for accrual, and an AAF will soon be available for smaller children to define the RP2D in this population. Clinical trial information: NCT04925609 .

Refractory chronic immune thrombocytopenia (r-cITP) is one of the most challenging situations in chronic immune thrombocytopenia (cITP). Pediatric r-cITP is inconsistently defined in literature, contributing to the scarcity of data. Moreover, no evidence is available to guide the choice of treatment. We compared seven definitions of r-cITP including five pediatric definitions in 886 patients with cITP (median [min-max] follow-up 5.3 [1.0-29.3] years). The pediatric definitions identified overlapping groups of various sizes (4%-20%) but with similar characteristics (higher proportion of immunopathological manifestations [IM] and systemic lupus erythematosus [SLE]), suggesting that they adequately captured the population of interest. Based on the 79 patients with r-cITP (median follow-up 3.1 [0-18.2] years) according to the CEREVANCE definition (≥3 second-line treatments), we showed that r-cITP occurred at a rate of 1.15% new patients per year and did not plateau over time. In multivariate analysis, older age was associated with r-cITP. One patient (1%) experienced two grade five bleeding events after meeting r-cITP criteria and while not receiving second-line treatment. The cumulative incidence of continuous complete remission (CCR) at 2 years after r-cITP diagnosis was 9%. In this analysis, splenectomy was associated with a higher cumulative incidence of CCR (hazard ratio: 5.43, 95% confidence interval: 1.48-19.84, p = 7.8 × 10-4). In sum, children with cITP may be diagnosed with r-cITP at any time point of the follow-up and are at increased risk of IM and SLE. Second-line treatments seem to be effective for preventing grade 5 bleeding. Splenectomy may be considered to achieve CCR.

SACHA-France (NCT04477681) is a prospective real-world study that collects clinical safety and efficacy data of novel anticancer therapies prescribed off-label or on compassionate use to patients <25 years. From March 2020 until February 2024, 640 patients with solid tumors or lymphomas were included, with 176 (28%) reported objective tumor responses. Centralized medical monitoring of local radiological/functional imaging reports by the SACHA coordinating investigator led to response modification in 45 out of 176 cases (26%), highlighting the relevance of the medical review of study data. We suggest this pragmatic approach for improving clinical trial data when centralized radiological review is not performed.

Abstract Background To investigate the educational outcomes of siblings of childhood leukemia survivors, explore determinants of school difficulties, and compare the rates of repeating grades between siblings and the general population. Methods A cross‐sectional study of childhood leukemia survivors' siblings recruited through the Leucémies de l'Enfant et de l'Adolescent cohort, a French long‐term follow‐up program, was conducted, and education‐related data were obtained via self‐report questionnaires. Adjusted logistic regression models were used to identify variables associated with school difficulties and time since diagnosis. Rates of repeating a grade in middle school were compared between siblings and the general population of the same generation. Results A total of 564 siblings with a mean time from diagnosis of 14.1 ± 6.4 years were included, among whom 139 (24.6%) repeated a grade, at an average of 6.4 ± 4.5 years after diagnosis. In multivariate analysis, the risk factors for repeating a grade were older siblings (odds ratio [OR] 2.3, p = 0.006), family financial difficulties (OR 2.8, p = 0.008), and history of repetition in survivors (OR, 2.5, p = 0.001). Sibling hematopoietic stem cell donors were at greater risk of repeating a grade long‐term after diagnosis (p = 0.018). Overall, siblings did not have a higher risk of educational delays at the end of middle school than the general population. Conclusion Although the results are reassuring, socioeconomic and cancer‐related factors may have an impact on siblings' schooling long after diagnosis. Paying attention to siblings contributes to identifying the most vulnerable families, allowing more attention and appropriate resources to avoid long‐term repercussions. Additionally, supportive and targeted interventions can be developed to improve the organization of education and the health care system.

INTRODUCTION:Despite poor survival for patients with relapsed or refractory neuroblastoma, only 10-16% of patients are reported to be included in early phase trials. This study aimed to explore the impact of molecular profiling within the prospective precision cancer medicine trial MAPPYACTS (NCT02613962) on subsequent early phase trial recruitment and treatment by matched targeted therapies in this population. METHODS AND MATERIALS:Clinical data from all French patients with relapsed/refractory neuroblastoma enrolled in MAPPYACTS were analyzed for subsequent matched/non-matched targeted treatment based on clinical tumor board (CMTB) recommendations. RESULTS:From 93 patients with neuroblastoma included in French centers, 78 (84%) underwent whole exome and RNA sequencing and were discussed in the CMTB. Higher rate of successful sequencing analysis was observed in patients with relapsed disease compared to those with refractory disease (p = 0.0002). Among the 50 patients that presented with a new disease relapse/progression after the CMTB recommendations, 35 patients (70%) had at least one actionable alteration identified on the tumor at the time of relapse. Eighteen patients (36%) were included in an early phase clinical trial, 11 of these with a matched agent, 7 with a non-matched treatment; 13 patients were included in the AcSé ESMART trial. Five patients (10%) received a matched targeted therapy outside a clinical trial. CONCLUSION:Patients with neuroblastoma in the European MAPPYACTS trial were more likely to be included in early phase trials compared to previous reports. Early deep sequencing at first treatment failure, comprehensive therapeutic discussions in molecular tumor boards and innovative trials like AcSé -ESMART improve access to innovative therapies for patients with relapsed/refractory neuroblastoma. CLINICAL TRIAL REGISTRATION:NCT02613962.

Autoimmune cytopenia (AIC) in children may be associated with positive antinuclear antibodies (ANA) and may progress to systemic lupus erythematosus (SLE). We evaluated the risk of progression to SLE of childhood-onset ANA-associated AIC. In the French national prospective OBS'CEREVANCE cohort, the long-term outcome of children with ANA-associated AIC (ANA titer >= 1/160) and a subgroup of children who developed SLE were described. ANA were positive in 355 of 1803 (20%) children with AIC. With a median follow-up of 5.8 (range, 0.1-29.6) years, 79 of 355 (22%) patients developed SLE at a median age of 14.5 (1.1-21.4) years; 20% of chronic immune thrombocytopenic purpura, 19% of autoimmune hemolytic anemia, and 45% of Evans syndrome. None of the patients with ANA-negative test developed SLE. Severe manifestations of SLE were observed in 21 patients, and 2 patients died. In multivariate analysis including patients with positive ANA within the first 3 months after AIC diagnosis, age >10 years at AIC diagnosis (relative risk [RR], 3.67; 95% confidence interval [CI], 1.18-11.4; P = .024) and ANA titer >1/160 (RR, 5.28; 95% CI, 1.20-23.17; P = .027) were associated with the occurrence of SLE after AIC diagnosis. ANA-associated AIC is a risk factor for progression to SLE, especially in children with an initial ANA titer >1/160 and an age >10 years at AIC diagnosis. ANA screening should be recommended in children with AIC, and patients with ANA should be monitored long-term for SLE, with special attention to the transition period.