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.

Hematopoietic stem cell transplantation (HSCT) is a curative treatment for high-risk childhood leukemia but may lead to chronic graft-versus-host disease (cGvHD), a severe long-term complication. This study analyzed data from the LEA cohort, including 446 childhood leukemia survivors treated with allogeneic HSCT. The standardized cGvHD evaluation, using the NIH consensus criteria, was conducted 8.7 ± 0.3 years post-HSCT. Long-term cGvHD was reported in 21% of patients (9% mild, 7% moderate, 5% severe), primarily affecting eyes, skin, lungs, and mouth, with some cases involving multiple organs. Most patients with long-term cGvHD were untreated (84%), while 11% received systemic and 5% local treatments. cGvHD was associated with other long-term complications. Administration of anti-thymocyte globulin was a significant determinant (OR 0.6, 95% CI 0.4-0.99, P = 0.045). Long-term cGvHD showed a marked detrimental effect on the quality of life (QoL), even after adjusting for the other long-term complications. The SF-36 physical and psychological adjusted composite scores in patients with versus without cGvHD were 50 ± 2 versus 55 ± 1 (P = 0.01) and 38 ± 2 versus 43 ± 1 (P = 0.01), respectively. Even mild and moderate forms significantly affected the QoL, especially on psychological dimensions. These findings support standardized cGvHD evaluation and management to improve long-term outcomes of transplanted childhood leukemia survivors.

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.

Hematopoietic stem cell transplantation (HSCT) is essential for curing high-risk or relapsed acute leukemia but entails lifelong morbidities. Adolescents and young adults may be particularly vulnerable; however, data on the global risk of long-term complications in survivors who underwent HSCT during adolescence are lacking. Using the French Leucémie Enfant Adolescent cohort, we compared late complications and quality of life (QoL) in survivors transplanted at ≥15 versus <15 yr. We included 168 adolescents (≥15 yr of age at HSCT) and 446 children (<15 yr of age at HSCT) matched at best 1:3 on sex, type of leukemia, total body irradiation use, history of relapse, and follow-up duration. Cumulative morbidity was modelled with a five-state multistate model (0 to ≥4 complications). After a mean follow-up of 8.8 yr for adolescents and 9.5 yr for children, adolescents had a mean of 2.1 ± 0.1 complications compared with 1.6 ± 0.1 in younger survivors (P < .001). Higher incidences were noted for cardiomyopathy, chronic kidney disease, secondary neoplasms, iron overload, and osteonecrosis. The multi-state model revealed earlier onset and faster accumulation of complications in adolescents. QoL scores did not differ between groups. HSCT during adolescence is associated with earlier and heavier long-term morbidity, underscoring the need for age-tailored survivorship care and integration of adolescent and young adults-specific risks into follow-up guidelines.

Total body irradiation (TBI)-based conditioning is the standard regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in high-risk or relapsed pediatric acute lymphoblastic leukemia (ALL), but is variably used before age 4 because of concerns about long-term toxicity. Long-term physical, educational, and quality-of-life outcomes were assessed in patients from the French long-term follow-up program LEA who underwent TBI-based HSCT for ALL at 2 to <4 years of age (younger group, n = 37) and compared with those of matched prepubertal older children transplanted at ≥4 years (older group, n = 105). After a mean follow-up of 15.6 years, the number of complications was similar in the two groups (3.3 vs 3.2, p = 0.90). Among the 20 complications analyzed, pulmonary dysfunction was the only event that differed significantly, being more frequent in the older group (43% vs 19%, p = 0.01). In a multivariate multistate model, age group was not associated with a higher risk of transition to a greater complication burden (HR 1.05, 95% CI 0.83-1.32; p = 0.70). Educational outcomes and quality of life were also comparable. These findings do not suggest greater long-term toxicity in children undergoing TBI-based HSCT at 2 to <4 years of age and support reconsideration of the lower age limit for its use.

Information about Diamond-Blackfan anemia syndrome (DBAS), a ribosomopathy associated with anemia, congenital anomalies and cancer predisposition is limited in adults. Using the French DBAS registry, 235 adult patients with DBAS were analyzed for hematological outcomes. At last follow-up, anemia, neutropenia, thrombocytopenia, and pancytopenia affected respectively 78%, 31%, 15%, and 11% of the patients. There was no severe aplastic anemia outside of clonal evolution. Among patients without DBAS-specific treatment (e.g., steroids or red blood cell transfusions), the incidence of anemia, neutropenia, and thrombocytopenia was 52%, 35%, and 10%, highlighting that treatment independence does not mean hematologic remission. Four patients developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), all associated with poor-risk features and dismal outcomes. Observed to expected ratios were 155 for MDS and 55.4 for AML, confirming a major risk-excess despite stringent criteria for MDS diagnosis. With a median follow-up of 32.2 years (IQR 26-44), overall survival (OS) was 98.0% (95% CI, 95.8-100), 90.6% (95% CI, 84.2-97.5), and 70.7% (95% CI, 57.3-87.2) at 30, 40, and 50 years respectively. Solid and hematologic cancers were the main cause of death. This study demonstrates, in a large cohort of adults with DBAS, that cytopenias beyond anemia are frequent and persistent. Myeloid neoplasms occur with a high incidence and dismal outcomes. These findings highlight the need for risk stratification, tailored surveillance, and optimized therapeutic strategies in this vulnerable population.

Children with relapsed acute leukemia have a poor prognosis; current relapse treatments are toxic, and novel treatments are needed. The anti-CD38 antibody isatuximab is approved for relapsed-refractory multiple myeloma in adults. We present results of the ISAKIDS study (NCT03860844) investigating isatuximab in children with relapsed-refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). This Phase 2, single-arm, multicenter, open-label study enrolled children aged 28 days to <18 years. Patients received isatuximab 20 mg/kg induction on Day 1, then weekly for 5 weeks (ALL) or 3 weeks (AML). Standard salvage chemotherapy was added on Day 8. Participants showing possible response could receive consolidation with every-other-week isatuximab (two doses) plus chemotherapy (T-ALL, B-ALL) or optional second induction (AML). The primary endpoint was the complete response (CR) rate (proportion with CR or CR with incomplete peripheral recovery [CRi]). CR/CRi was observed for 32/59 (54%) evaluable patients (B-ALL, 13/25 [52%]; T-ALL, 5/11 [45%]; and AML, 14/23 [61%]). Secondary endpoints included minimal residual disease (MRD) status and safety. Based on local and central analysis, 56% (18/32) of CR/CRi patients reached MRD negativity using 10-4 sensitivity threshold for ALL and 10-3 sensitivity threshold for AML. One event of fatal cytokine release syndrome was reported in a patient with a high baseline white blood cell count, leading to trial adaptation. The toxicity of isatuximab with chemotherapy was otherwise manageable. Despite initial evidence of efficacy of isatuximab combined with intensive chemotherapy, CR/CRi rates did not meet stringent prespecified criteria to proceed to ISAKIDS Stage 2 (≥60% [T-ALL] and ≥70% [B-ALL and AML]).

Introduction: Treatment of acute promyelocytic leukemia (APL) has been revolutionized over the past two decades by the introduction of both all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), leading to the use of chemotherapy-free protocols in standard-risk (SR) adult patients. In October 2019, a multicenter European pediatric trial from the International Consortium for Childhood (ICC) APL delivering a non-chemotherapy-based treatment for children with newly diagnosed SR and High Risk (HR) APL was started [NCT04793919]. Here, we report the results of the second planned interim analysis of the ICC-APL-02 study. Methods: ICC-APL-02 Study is an open-label prospective, non-randomized, multicenter trial for children and adolescents (up to the age of 18) with newly diagnosed APL delivering a risk-stratified treatment [according to the modified pediatric criteria (Testi, Blood 2018)] based on the use of ATRA and ATO, plus gemtuzumab ozogamicin (GO) only in HR patients. During induction, ATO was given at the dose of 0.15 mg/kg/day iv and ATRA at 25 mg/m2/day orally. Treatment started on day 1 and was continued until achievement of hematological complete remission (CR), for at least 28 days and for a maximum of 60 days. In HR patients only, GO was administered on days +2 and +4 of induction treatment, at the dose of 3 mg/m2 iv (maximum 5 mg/dose). During consolidation, ATO was given at the same dose employed during induction for 5 days/week, 4 weeks on and 4 weeks off, for 4 courses, while ATRA (25 mg/m2/day) was administered 2 weeks on and 2 weeks off for 7 courses. In the HR group only, triple intrathecal therapy was administered at the beginning of the 1st and 3rd consolidation. The primary endpoint was to evaluate the efficacy in terms of event-free survival (EFS) of the treatment regimen. Early death, death in CR, resistant disease and hematological relapse were considered as events. Results: The trial was opened in 52 centers across 5 countries (Italy, France, Czech Republic, Netherlands and Sweden). From 10/2019 to 06/2025, 110 patients were enrolled; 73 were SR (66.4%) and 37 HR (33.6%). Median white blood cell count at diagnosis for SR and HR patients was 2.5x109/L (0.6-9.9) and 18.0x109/L (10.55-151.00), respectively. Median age at diagnosis was 12 years (range 1-17); 45% of patients were females; 49% of patients were FLT3-ITD mutated. Median duration of induction was 37 days (range 28-59), with 36 patients (29 SR and 7 HR) interrupting the treatment for a median of 5 days (range 1-23), due to toxicity which resolved in all cases. During induction, 19 patients (17.3%) developed differentiation syndrome (DS) at a median time of 12 days (range 4-25) from treatment start, which resolved in all patients. Pseudotumor cerebri occurred in 14 patients (12.7%). Four patients experienced clinically-relevant prolongation of the QTc interval, which was successfully managed in all patients (in 3 with temporary ATO discontinuation). One patient developed myocarditis following GO which completely resolved without sequelae; no other drug-related side effect was registered. One 16-year old, FLT3-ITD+ HR patient died of cerebral hemorrhage during induction (day +30). All patients achieved hematological CR at the end of induction. All but one evaluated patients achieved molecular CR after the third consolidation course. The only positive patient (HR) remained MRD+ also after the end of treatment; he obtained the molecular remission with 2 additional doses of GO and was then treated with autologous hematopoietic stem cell transplantation; he is now alive and disease-free. One SR patient experienced molecular relapse 1 year after completing the treatment protocol; he was re-treated with ATRA-ATO and he is now alive with negative MRD. With a median follow-up of 21 months (range 2-68.7), the 2-yr overall and EFS of the whole cohort are 99% (95% CI 93.4-99.9) (SR 100% vs HR 97.1%, p=n.s.) and 96.4% (95% CI 88.6-98.9) (SR 97.4% vs HR 94.2%, p=n.s.), respectively. Nineteen patients are still on treatment. Conclusions: This is the first large prospective pediatric trial delivering a non-chemotherapy-based treatment for children with newly diagnosed SR and HR APL.We confirm that ATRA/ATO treatment is safe and highly effective in SR patients. More importantly, the combination of ATRA, ATO and GO in HR subjects showed an excellent safety profile and efficacy in pediatric patients with de novo APL.

L’utilisation des réservoirs d’Ommaya pour l’administration intraventriculaire de chimiothérapie dans les leucémies aiguës pédiatriques reste hétérogène, bien qu’elle représente une alternative précieuse en cas d’échec ou d’impossibilité de ponction lombaire. Cette étude avait pour objectif d’évaluer les pratiques nationales et d’élaborer des recommandations harmonisées, sous l’égide du comité leucémies de la Société française de lutte contre les cancers et les leucémies de l’enfant et de l’adolescent (SFCE). Un questionnaire national de 34 items a été diffusé auprès de 83 pédiatres hémato-oncologues du réseau SFCE explorant les indications, les modalités chirurgicales, les posologies, les pratiques au lit du patient et la gestion des complications. Trente-deux réponses provenant de 24 centres ont été analysées. La pose d’un réservoir d’Ommaya est principalement indiquée en cas de ponction lombaire non réalisable. En situation de méningite leucémique réfractaire ou récidivante, les données pharmacocinétiques justifient son usage, avec une meilleure diffusion du méthotrexate dans le liquide cérébro-spinal. Une réduction de 50 % des doses intrathécales (méthotrexate, cytarabine, hydrocortisone) est recommandée, en raison d’une efficacité équivalente et d’une meilleure tolérance. Le respect strict des mesures d’asepsie est crucial pour limiter les infections (5–8 %). En cas d’infection, un retrait temporaire du dispositif est préconisé. Le réservoir d’Ommaya constitue une alternative efficace et sûre à la voie lombaire dans des situations sélectionnées. Ces recommandations visent à homogénéiser les pratiques et à renforcer la sécurité des soins.

Approximately 20% of pediatric patients presenting with acute leukemia (AL) receive an allogeneic hematopoietic stem cell transplantation (HSCT) either in the first or subsequent complete remission. Survivors are exposed at adulthood to fertility impairment, which is one of the most worrisome long-term side effects of pre-HSCT myeloablative conditioning regimens, while conventional chemotherapy is associated with a low risk of infertility. Thus, fertility preservation is highly recommended in young patients before HSCT. Testicular tissue cryopreservation (TTC) is the only option offered to prepubertal or peripubertal patients, with the perspective of restoring fertility from the spermatogonia contained in the immature tissue. Our study presents the largest series published to date about the testicular tissue content of spermatogonia in young patients with AL after administration of first-line chemotherapies. It shows that non-alkylating chemotherapies administered before TTC do not significantly reduce the spermatogonial pool. Our work also confirms in a large population that CCD over 4 g/m2 causes sharp depletion of the spermatogonial pool. This study provides new valuable information regarding the reproductive potential of testicular tissue collected before HSCT from children with AL previously exposed to first-line chemotherapies including alkylating agent or not.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementA-S.G. was supported by a grant from the ARC Fondation pour la Recherche contre le Cancer (DOC20180507400). The human Spermatogonial Stem Cell research project (A.-S.G., C.L., L.R., J.-P.W., P.F., and V.B.-L.) was funded by grants from the Agence de Biomedecine and Electricite De France. It also received funding from the Laurette Fugain and the EGMOS Associations.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study was approved by the Research Ethics Committee of Cochin Hospital, Paris, France (AAA-2019-08014) and was conducted in accordance with the Declaration of Helsinki.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

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.

The use of Ommaya reservoirs for intraventricular chemotherapy in pediatric acute leukemias remains heterogeneous, despite being a valuable alternative when lumbar puncture (LP) is unsuccessful or contraindicated. This study aimed to evaluate national practices and develop harmonized recommendations under the auspices of the French Society for the Fight Against Childhood and Adolescent Cancers and Leukemias (SFCE) Committee. A national 34-item questionnaire was distributed to 83 pediatric hemato-oncologists within the SFCE network, covering indications, surgical procedures, dosing, bedside practices, and complication management. Thirty-two responses from 24 centers were analyzed. The primary indication for Ommaya reservoir placement was the inability to perform LP. In cases of refractory or relapsed leukemic meningitis, pharmacokinetic data support its use due to improved methotrexate distribution in cerebrospinal fluid (CSF). A 50% dose reduction for intrathecal medications (methotrexate, cytarabine, hydrocortisone) is recommended, ensuring equivalent efficacy and improved tolerance. Strict aseptic techniques are essential to minimize infection risk (5-8%). In the event of infection, temporary removal of the device is advised. The Ommaya reservoir represents an effective and safe alternative to the lumbar route in selected cases. These recommendations aim to standardize practices and enhance patient safety.

Introduction MRC AML 15 reported that high dose cytarabine (HD AraC) was not inferior to an anthracycline containing regimen as consolidation therapy in patients with non-high risk AML (Burnett, JCO 2013). Fludarabine and cytarabine (FLA) is a commonly used regimen particularly in relapsed AML. MyeChild01 aimed to test if FLA was superior to HD AraC as consolidation therapy in standard risk (SR) patients; both regimens anthracycline sparing and reducing the risk of cardiotoxicity. This paediatric trial for AML, high risk myelodysplastic syndrome (MDS > 10% blasts) or isolated myeloid sarcoma (IMS) delivered risk stratified treatment based on genetic subtype, remission status post course 1 and measurable residual disease (MRD). 360 patients were randomised to FLA or HD AraC as course 3 and 4 in consolidation from Jan-2017 to Oct-2022; 180 to each arm. Methods At diagnosis 97% patients were allocated mitoxantrone and cytarabine (MA) with 79% receiving 1 or 3 doses of GO in course 1 (Gibson, Blood; 144, Suppl 1, 2024). Subsequent treatment was stratified by genetic subtype, remission status post course 1 and MRD. SR patients had either good risk (GR) genetics and MRD negativity post course 2, or intermediate risk (IR) genetics and MRD negativity post course 1 and 2. SR patients received a second course of MA followed by two courses of either HD Ara C (3g/m2bd on days 1, 3, 5) or FLA (Fludarabine 30 mg/m2 and cytarabine 2g/m2on days 1-5) based on randomisation. Randomisation was stratified by age; diagnosis (AML, MDS, and IMS); disease type (de novo, secondary); number of gemtuzumab ozogamicin (GO) doses. Statistical analyses were Bayesian with primary outcome of relapse-free survival (RFS) defined as time from randomisation to relapse or death from any cause. Results Patient characteristics were: males 59%; median age 8yr; AML 96%, MDS 2%, IMS 2%; de novo 99.7%; genetic GR 54%, IR 44%. Induction therapy was MA 97%; with: no GO 14%; 1 dose GO 38%; 2 doses GO 7%; 3 doses GO 41%. Of the 360 patients 178 received HD AraC and 180 FLA; baseline characteristics were well balanced. Efficacy analysis included all patients;7 patients were excluded from safety summaries due to ineligibility/not receiving treatment. Median follow-up is 3.6 years. The 2yr RFS for HD AraC was 78% (72%, 85%) and for FLA 70% (64%, 77%) with a 2yr overall survival (OS) for HD AraC of 97% (94%, 99%) and for FLA 90% (86%, 95%). The Bayesian probability that FLA was superior to HD AraC was 7% for RFS and 8% for OS. No substantial differences in RFS were seen within subgroups of age, diagnosis, disease type, GO doses and genetic risk group. The 2yr cumulative incidence of relapse (CIR) for HD AraC was 22% (16%, 28%) and for FLA 29% (22%, 35%) indicating no difference (p=0.17). Only 2 deaths in remission were reported, both patients received FLA. Analysed by genetic risk group 97 GR and 78 IR patients received HD AraC while 96 GR and 80 IR received FLA; 9 patients without a risk group were excluded. In GR patients, 2yr RFS was 84% (78%, 92%) and 79% (71%, 88%), 2yr OS 98% (95%, 100%) and 98% (95%, 100%) and CIR 16% (9%, 23%) and 21% (14%, 30%) for HD AraC and FLA respectively. IR patients had a 2yr RFS of 69% (59%, 80%) and 62% (52%, 74%), 2yr OS of 95% (90%, 100%) and 81% (72%, 90%) and CIR of 31% (21%, 42%) and 35% (25%, 46%) for HD AraC and FLA respectively. IR patients consistently did worse than GR patients irrespective of treatment but had substantially worse OS rates with FLA. 67 patients with a KMT2A rearrangement were considered IR. At 2yr those who received HD AraC had RFS of 73% (60%, 89%), OS of 92% (84%, 100%) and CIR of 27% (14%, 42%) while those receiving FLA had RFS of 50% (35%, 72%), OS of 73% (58%, 91%) and CIR of 47% (28%, 63%). Incidence of grade ≥3 adverse reactions or any grade serious adverse events (SAE) for HD AraC was 56% and for FLA 53%. 54%of patients receiving HD AraC and 44% receiving FLA had at least one grade ≥3 SAE. There were two grade 5 SAEs both in the FLA arm; heart failure unrelated to FLA and CNS infection possibly related to FLA. The median time from the start of course 3 to course 4 was 38 days for HD AraC and 41 for FLA. Conclusion FLA is not superior to HD AraC as consolidation therapy in children with SR AML. Patients with IR genetics, particularly those with a non-high risk KMT2A rearrangement had a worse outcome with FLA. High Dose AraC should remain standard of care in consolidation for patients with SR AML.