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Here, we report the results of the prospective cohort study EORTC-CLG 58081 and compare them to the control arm of the randomized phase 3 trial EORTC-CLG 58951, on which treatment recommendations were built. In both studies, patients aged 1-18 years with BCR::ABL1 negative acute lymphoblastic leukemia of the B-lineage (B-ALL) or T-lineage (T-ALL) were treated using a BFM backbone without cranial irradiation. Similarly to the control arm of 58951, prednisolone (PRED) 60 mg/m 2 /day was used for induction therapy, but a few modifications were made. Dexamethasone (DXM) was used in average-risk 2 (AR2) T-ALL and B-ALL during induction, 10 and 6 mg/m 2 /day, respectively. Leucovorin rescue was delayed to 42 h instead of 36 h after initiation of high-dose methotrexate, and a postconsolidation MRD time point was added to stratify patients. Between 2011 and 2017, 835 patients were prospectively enrolled in the 58081 study. Overall, the 5-year event-free survival (EFS) was 84.8% versus 83.6% (hazard ratio [HR], 0.96 [95% confidence interval [CI]: 0.76-1.21]) for 58081 versus 58951 considered as a control group, respectively, 84.3% versus 84.9% (HR, 1.06 [99% CI: 0.75-1.49]) in B-ALL but 87.3% versus 76.6% (HR, 0.59 [99% CI: 0.28-1.24]) in T-ALL. The comparison between the two studies regarding EFS differed by risk group ( p  = 0.012). The HR was 2.15 (99% CI: 0.67-6.85) for very low-risk but 0.34 (99% CI: 0.13-0.89) for AR2. The particularly favorable results observed in the T-ALLs and AR2 subgroups suggest the benefit of using DXM in specific patient groups and highlight the importance of risk stratification., Competing Interests: All authors declare no conflict of interest., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

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., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: This study aims to compare the infections' risk between adolescents and young adults (AYAs), treated for acute lymphoblastic leukemia, and pediatric population. We also focused on their bacterial and fungal infection specificities., Methods: This case-control study investigated the occurrence of bacterial bloodstream infection (BSI) and proven and probable invasive fungal infection (IFI) in AYAs (15-25 years old) and children (1-14 years old) treated for acute lymphoblastic leukemia between January 2013 and December 2020 in 2 French tertiary pediatric and 2 referral adult hematological centers, independent of their treatment protocol. We also evaluated the impact of these infections on morbidity (necessity of intensive care) and mortality., Results: We analyzed 83 AYAs and 230 children and found that AYAs developed significantly more IFI than the pediatric population (22% vs. 10%, P = 0.007), regardless of their care center (adult or pediatric). Furthermore, the occurrence of BSI was similar between the 2 populations (48% vs. 51%, P = 0.66). Moreover, the occurrence of infection increased with the AYAs' risk group of treatment: standard, medium or high risk (P = 0.021 for BSI and P = 0.029 for IFI). Finally, the mortality rate is only 1.3% after a BSI whereas it increases to 4.9% after IFI., Conclusion: AYAs have their own specificity with an increased risk of fungal infection compared to children, independent of the care center. Antifungal prophylaxis should be contemplated, especially for patients classified in high-risk groups., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Neonatal acute myeloid leukemias (AML) occurred within the first 28 days of life and constitute only a small proportion of all AL. They are distinguished from leukemias of older children by their clinical presentation, which frequently includes cutaneous localizations ("blueberry muffin rash syndrome") and a leukocytosis above 50 ×10 9 /L. This proliferation may be transient, causing a transient leukemoid reaction in a background of constitutional trisomy 21 ("Transient Abnormal Myelopoieseis" or TAM) or Infantile Myeloproliferative Disease in the absence of constitutional trisomy 21 ("Infantile Myeloproliferative Disease" or IMD). In cases of true neonatal AML, the prognosis of patients is poor. Overall survival is around 35 % in the largest historical series. This poor prognosis is mainly due to the period of onset of this pathology making the use of chemotherapy more limited and involving many considerations, both ethical and therapeutic. The objective of this work is to review this rare pathology by addressing the clinical, biological, therapeutic and ethical particularities of patients with true neonatal AML or transient leukemoid reactions occurring in a constitutional trisomy 21 (true TAM) or somatic background (IMD)., (Copyright © 2024 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Pulmonary mucormycosis (PM) is a life-threatening invasive mold infection. Diagnosis of mucormycosis is challenging and often delayed, resulting in higher mortality., Research Question: Are the disease presentation of PM and contribution of diagnosis tools influenced by the patient's underlying condition?, Study Design and Methods: All PM cases from six French teaching hospitals between 2008 and 2019 were retrospectively reviewed. Cases were defined according to updated European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria with the addition of diabetes and trauma as host factors and positive serum or tissue PCR as mycologic evidence. Thoracic CT scans were reviewed centrally., Results: A total of 114 cases of PM were recorded, including 40% with disseminated forms. Main underlying conditions were hematologic malignancy (49%), allogeneic hematopoietic stem cell transplantation (21%), and solid organ transplantation (17%). When disseminated, main dissemination sites were the liver (48%), spleen (48%), brain (44%), and kidneys (37%). Radiologic presentation included consolidation (58%), pleural effusion (52%), reversed halo sign (26%), halo sign (24%), vascular abnormalities (26%), and cavity (23%). Serum quantitative polymerase chain reaction (qPCR) was positive in 42 (79%) of 53 patients and BAL in 46 (50%) of 96 patients. Results of transthoracic lung biopsy were diagnostic in 8 (73%) of 11 patients with noncontributive BAL. Overall 90-day mortality was 59%. Patients with neutropenia more frequently displayed an angioinvasive presentation, including reversed halo sign and disseminated disease (P < .05). Serum qPCR was more contributive in patients with neutropenia (91% vs 62%; P = .02), and BAL was more contributive in patients without neutropenia (69% vs 41%; P = .02). Serum qPCR was more frequently positive in patients with a > 3 cm main lesion (91% vs 62%; P = .02). Overall, positive qPCR was associated with an early diagnosis (P = .03) and treatment onset (P = .01)., Interpretation: Neutropenia and radiologic findings influence disease presentation and contribution of diagnostic tools during PM. Serum qPCR is more contributive in patients with neutropenia and BAL examination in patients without neutropenia. Results of lung biopsies are highly contributive in cases of noncontributive BAL., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. Coste has received a travel grant from the association Marie-Bertille. O. L. has received speaker's fees from MSD, Gilead, Astellas, Pfizer, and F2G, and is consultant for Gilead. F. L. has received personal fees from Gilead, F2G and Pfizer. R. H. has received a grant from Gilead and personal honoraria from Pfizer, Gilead, and Mundipharma. L. M. has received travel grants from Gilead and Pfizer. F. D. has received personal fees from Gilead, outside the submitted work. None declared (A. Conrad, R. P., S. P., P. P., C. D., V. L.-B., F. M., T. G., M.-E. B., F. S., G. N., D. D., F. A., C. H.-D., S. D.-L., F. B., G. G., S. A., D. B., M.-P. L., J.-E. H., C. R., G. M., E. B., O. P., D. G.-H.)., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

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.

Objective: Central-line-associated bloodstream infections (CLABSIs) are associated with significant morbidity among pediatric oncology-hematology patients, and risk factors remain largely unknown in the setting of hospital at home (HAH). Children in HAH receive intensive treatment (eg, chemotherapy and parenteral nutrition), with frequent central-line handling; thus, they may be at higher risk for CLABSI., Methods: We conducted a monocentric retrospective study of patients with a central line included in our HAH program from January 1 to December 31, 2016. HAH patient characteristics for children developing CLABSIs were compared to those who did not, based on blood cultures positive for infection and clinical data of all patients included., Results: Overall, 492 HAH stays were analyzed, with 144 patients. The overall CLABSI rate in these patients was 2.6 per 1,000 central-line days. Children who developed CLABSIs were younger (median age, 2.5 vs 8.8 years; P < .001), suffered more from hematological pathologies (malignant or nonmalignant, 75% vs 52%; P = .02), and had more frequently undergone hematopoietic stem-cell transplantation (30.8% vs 6.5%; P = .01). In addition, these patients often had a tunneled externalized catheter as the central line and were more frequently given parenteral nutrition at home (46% vs 8%; P < .001)., Conclusions: CLABSI rates for children in HAH were more similar to those of inpatients than to rates previously reported for ambulatory patients. The factors associated with infection identified herein should be further validated in multicentric studies and considered to improve HAH practices, parallel to prevention measures used in the inpatient setting.

Background: Allogenic hematopoietic stem cell transplantation (a-HCT) remains a therapeutic treatment for many pediatric hematological diseases. The occurrence of invasive fungal infections (IFIs) is a complication for which ECIL-8 recommends primary antifungal prophylaxis. In this study, we evaluated the impact of our local strategy of not systematically administering primary antifungal prophylaxis in children undergoing a-HCT on the occurrence and mortality of IFIs., Methods: We performed a retrospective monocentric study from 2010 to 2020. We retained all proven and probable IFIs diagnosed during the first year post a-HCT., Results: 308 patients were included. Eighteen patients developed twenty IFIs (thirteen proven, seven probable) (6.5%) among which aspergillosis ( n = 10, 50%) and candidosis ( n = 7, 35%) were the most frequently diagnosed infections. Only 2% of children died because of an IFI, which represents 14% of all deaths. Multivariate analysis found that age > 10 years (OR: 0.29), the use of a therapeutic antiviral treatment (OR: 2.71) and a low neutrophil count reconstitution (OR: 0.93) were significantly associated with the risk of IFI occurrence. There was also a trend of malignant underlying disease and status ≥ CR2 but it was not retained in multivariate analysis., Conclusions: IFI occurrence was not higher in our cohort than what is reported in the literature with the use of systematic antifungal prophylaxis, with a good survival rate nonetheless. Thus, a prophylaxis could be considered for children with a high risk of IFI such as those aged over 10 years.

Documenting bacteremia at the onset of fever in immunosuppressed children is challenging; therefore, it leads to the early administration of broad-spectrum antibiotics. We aimed to analyse the evolution of antibiotic resistance profiles of bacterial bloodstream infections (BSI) and gut colonisations in a large cohort of immunocompromised children carrying a central venous catheter, in comparison with a prior, similar study conducted in our centre from 2014 to 2017. A retrospective, observational cohort study was conducted from January 2018 to December 2021, in a tertiary centre for paediatric immuno-haematology and oncology. Empirical antibiotic therapy was adapted to the immunosuppression risk group and prior bacterial colonisation. There was a mean of 6.9 BSI/1000 patient bed days. Multidrug-resistant bacteria (MDRB) associated BSI accounted for 35/273 (12.8%). The incidence of MDRB gum/gut colonisation and MDRB associated BSI increased annually and correlated with the level of immunosuppression ( p = 0.024). One third (34.7%) of the BSI episodes were not associated with neutropenia. As compared to the previous study, an alarming emergence of MDRB responsible for gut colonisations and BSI in immunosuppressed children was reported over the last four years. The degree of immunosuppression directly correlates with the risk of having an MDRB gut colonisation or MDRB BSI.

Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4 triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells in vitro and in vivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects., Competing Interests: Declaration of interests J.S. is scientific advisor for STRM.BIO, Inc (Boston, USA)., (Copyright © 2023. Published by Elsevier Inc.)

Osteonecrosis (ON) is a known complication of acute leukemia (AL) management, affecting 1%-10% of young patients and resulting in long-term morbidity. Widespread access to MRI over the past decade has allowed earlier detection and more accurate assessment. This study investigated clinical and MRI features of the 129 (2.5%) patients with symptomatic ON retrospectively recruited from the French LEA (Leucémies de l'Enfant et de l'Adolescent, or child and adolescent leukemias ) cohort ( n  = 4,973). We analyzed data concerning ON risk factors, multifocal involvement, severe lesions detected by MRI, and patient quality of life (QoL). ON patients tended to be >10 years old at the time of AL diagnosis (odds ratio [OR]: 22.46; p  < 10 -6 ), female (OR: 1.8; p  = 0.002), or treated for relapse (OR: 1.81; p  = 0.041). They more frequently suffered from other sequelae ( p  < 10 -6 ). Most necroses involved weight-bearing joints, and they were multifocal in 69% of cases. Double-blinded review of MRIs for 39 patients identified severe lesions in 14, usually in the hips. QoL of adolescents and adults was poor and permanently impacted after onset of ON. In conclusion, age >10 at time of AL diagnosis, female sex, and relapse occurrence were risk factors for multifocal ON; MRI revealed severe ON in a third of the patients considered; and ON was associated with persistently poor QoL affecting multiple domains. Future studies should include prospective data addressing ON management and seek to identify genetic markers for targeted screening enabling early ON detection and treatment.

Introduction: To date, invasive fungal infections (IFIs) are still responsible for a high mortality rate in children managed for haematological malignancy. Although Candida and Aspergillus infections remain in the majority, emerging fungal infections are increasingly common. Children differ from adults in their pathology and treatment, as well as in their prior fungal colonisation and unique pharmacokinetics. Therefore, we propose here specific paediatric management recommendations for IFIs in haematology., Methods: We based our recommendations on a review of the literature, including the latest ECIL recommendations, an analysis of practices and a collection of expert opinions., Results and Discussion: In France, approximately 5% of children treated for haematological malignancy or who have received a bone marrow allograft present an IFI. These IFIs are equally divided between yeast infections (mainly due to Candida albicans) and filamentous infections (mainly aspergillosis) and 16% are IFIs due to emerging fungi, half of which are due to Mucorales. In these recommendations, we recall the diagnostic criteria for proven or probable IFI according to the Donnelly classification, then we propose strategies for screening, diagnosing, evaluating the extension and treating these three types of IFI. We also detail the diagnostic and therapeutic management of chronic disseminated candidiasis. We also discuss prophylactic measures, including environmental measures which are of primary importance in children., (Copyright © 2022 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Allogenic hematopoietic stem cell transplantation (aHSCT) remains the treatment of choice for some malignant hemopathies in children, albeit with the risk of long-term consequences, including chronic kidney disease (CKD)., Methods: In our single tertiary referral center, we retrospectively assessed the long-term renal outcome in a cohort of children and adolescents who had undergone aHSCT for malignant hemopathies between 2003 and 2017. We distinguished glomerular and tubular dysfunctions and assessed the accuracy of the most common formula(s) to estimate glomerular filtration rate (GFR) during standard clinical follow-up., Results: Among the 166 patients who had received aHSCT, 61 underwent kidney functional assessment 1 to 10 years post-transplantation. Twenty-seven patients (44.3%) had a CKD with glomerular impairment, including 20 patients with a GFR < 90 mL/min/1.73 m 2 , and among these, 5 patients < 60 mL/min/1.73 m 2 . Patients with tubular signs had a significantly higher baseline GFR: 112 mL/min/1.73 m 2 [100; 120] versus 102 [99.0; 112.5] for patients without kidney involvement, and 76 [61; 86] for patients with CKD (p < 0.01). Schwartz, CKiDU25, and EKFC formulas significantly overestimated mGFR, with a P30% ≤ 30%, which could lead to overlooking CKD diagnosis in this population. No patient reached kidney failure., Conclusions: In conclusion, our study shows that CKD represents an important long-term sequela for children and adolescents who undergo aHSCT for malignant hemopathies, either with glomerular dysfunction or with the more insidious tubular dysfunction which could potentially impact growth. These patients could benefit from specialized long-term nephrology follow-up. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Defibrotide (DF) is indicated for the treatment of severe sinusoidal obstruction syndrome (SOS) following hematopoietic stem cell transplantation (HSCT), but its prophylactic use against SOS is not recommended yet. This study describes the impact of the preventive and curative use of DF on reducing the incidence and severity of SOS in children. Patients aged 0-19 years, who received allogenic HSCT after myeloablative conditioning regimen with busulfan or total body irradiation in our comprehensive cancer center, between 2013 and 2017, were included. The Baltimore or modified Seattle criteria were used for SOS diagnosis. SOS was graded using the 2017 European Society for Blood and Marrow Transplantation classification defining severity criteria of SOS in children. SOS occurrence tended to decrease with prophylactic DF, but no significant difference was observed in terms of severity. When not treated with preventive DF, 50% (19/38) of the patients with SOS were graded severe to very severe, but only 37% (7/19) had organ dysfunction. Curative DF was administered at a median of 2 days post-HSCT, for a median of 6.5 days. The absence of fatal SOS supports the use of early curative DF with acceptable toxicities and questions the optimal duration of DF treatment., Competing Interests: The authors have no competing financial interest in relation to the work described., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: In 2017, international guidelines proposed new management of febrile neutropenia in children with cancer, adapted to the risk of severe infection by clinical decision rules (CDRs). Until now, none of the proposed CDRs has performed well enough in high-income countries for use in clinical practice. Our study aimed to build and validate a new CDR (DISCERN-FN) to predict the risk of severe infection in children with febrile neutropenia., Methods: We did two prospective studies. First, a prospective derivation study included all episodes of febrile neutropenia in children (aged <18 years) with a cancer diagnosis and receiving treatment for it who were admitted for an episode of febrile neutropenia, excluding patients already treated with antibiotics for this episode, febrile neutropenia not induced by chemotherapy, those receiving palliative care, and those with a stem cell allograft for less than 1 year, from April 1, 2007, to Dec 31, 2011 from two paediatric cancer centres in France. We collected the children's medical history, and clinical and laboratory data, and analysed their associations with severe infection. Sipina software was used to derive the CDR as a decision tree. Second, a prospective, national, external validation study was done in 23 centres from Jan 1, 2012, to May 31, 2016. The primary outcome was severe infection, defined by bacteraemia, a positive bacterial culture from a usually sterile site, a local infection with a high potential for extension, or an invasive fungal infection. The CDR was applied a posteriori to all episodes to evaluate its sensitivity, specificity, and negative likelihood ratio., Findings: The derivation set included 539 febrile neutropenia episodes (270 episodes in patients with blood cancer [median age 7·5 years, IQR 3·7-11·2; 158 (59 %) boys and 112 (41%) girls] and 269 in patients with solid tumours [median age 6·6 years, IQR 2·9-14·2; 140 (52 %) boys and 129 (48%) girls]). Significant variables introduced into the decision tree were cancer type (solid tumour vs blood cancer), age, high-risk chemotherapy, level of fever, C-reactive protein concentration (at 24-48 h after admission), and leucocyte and platelet counts and procalcitonin (at admission and at 24-48 h after admission). For the derivation set, the CDR sensitivity was 98% (95% CI 93-100), its specificity 56% (51-61), and the negative likelihood ratio 0·04 (0·01-0·15). 1806 febrile neutropenia episodes were analysed in the validation set (mean age 8·1 years [SD 4·8], 1014 (56%) boys and 792 (44%) girls), of which 332 (18%, 95% CI 17-20) were linked with severe infection. For the validation set, the CDR had a sensitivity of 95% (95% CI 91-97), a specificity of 38% (36-41), and a negative likelihood ratio of 0·13 (0·08-0·21). Our CDR reduced the risk of severe infection to a post-test probability of 0·8% (95% CI 0·2-2·9) in the derivation set and 2·4% (1·5-3·9) in the validation set. The validation study is registered at ClinicalTrials.gov, NCT03434795., Interpretation: The use of our CDR substantially reduced the risk of severe infection after testing in both the derivation and validation groups, which suggests that this CDR would improve clinical practice enough to be introduced in appropriate settings., Funding: Ligue Nationale Contre le Cancer., Competing Interests: Declaration of interests AM declares paid appointments for lectures, consultancy, or advice, and invitations to European Society for Paediatric Infectious Diseases meetings from GlaxoSmithKline and Pfizer. FD received expenses from Sanofi-Pasteur and Takeda for scientific experts' meetings in 2020 and 2021. MD, FG, HB, AT, HS-B, AL, SA, SP, ST-D, IP, LM, CPi, CPa, LB, ET, DP, PB, PSc, CG, PSi, CD, HP, MLM, CPl, CV, GP, and AD declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Context: A negative association between a history of allergy and childhood acute lymphoblastic leukemia (ALL) has been reported in previous studies, but remains debated. This work aimed to investigate this association accounting for genetic polymorphisms of the Th2 pathway cytokines (IL4, IL10, IL13, and IL4R)., Methods: Analyses were based on the French case-control study ESTELLE (2010-2011). The complete sample included 629 ALL cases and 1421 population-based controls frequency-matched on age and gender. The child's medical history was collected through standardized maternal interview. Biological samples were collected, and genotyping data were available for 411 cases and 704 controls of European origin. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders., Results: In the complete sample, a significant inverse association was observed between ALL and reported history of allergic rhinitis or sinusitis (OR = 0.65 [0.42-0.98]; P = 0.04), but there was no obvious association with allergies overall. There was an interaction between genetic polymorphisms in IL4 and IL4R (P interaction = 0.003), as well as a gene-environment interaction between IL4R-rs1801275 and a reported history of asthma (IOR = 0.23; P int  = 0.008) and eczema (IOR = 0.47; P int  = 0.06). We observed no interaction with the candidate polymorphisms in IL4 and IL13., Conclusion: These results suggest that the association between allergic symptoms and childhood ALL could be modified by IL4R-rs1801275, and that this variant could also interact with a functional variant in IL4 gene. Although they warrant confirmation, these results could help understand the pathological mechanisms under the reported inverse association between allergy and childhood ALL., (© 2021 Wiley Periodicals LLC.)

Ten to fifteen percent of children with acute lymphoblastic leukemia (ALL) relapse following treatment. Of these, less than 2% display ophthalmic relapses, which owing to their scarcity, are largely undocumented, leaving clinicians with few diagnostic and therapeutic recommendations, despite serious functional sequelae. We conducted a French multicenter retrospective study to collect all clinical, radiological, biological, and therapeutic data, and outcomes for children with ALL ophthalmic relapses. From 2000 to 2020, 20 ophthalmic relapses occurring after first-line therapy performed before January 1 st , 2017 were included in our study: 14 B-ALL and 6 T-ALL. Fifteen patients (75%) had concomitant involvement of the central nervous system, and 11 (55%) a combined bone marrow relapse. Only 1 had an isolated ophthalmic relapse. Eight children (40%) died, 7 from a refractory disease and 1 from toxic death, and 4 patients relapsed. With a median follow-up of 63.1 months, 8 patients are currently alive in continuous complete remission with only 2 displaying severe ophthalmic sequelae. Although rare, ophthalmic relapse could have a significant impact on the functional prognosis of survivors. Their management must be multidisciplinary, with a central role given to ophthalmologists., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT)., Study Design: We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units., Results: From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with "emergent" fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P < .0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10 -4 ) compared with a-HSCT recipients who did not receive antifungal prophylaxis. The main cause of IFI in children receiving prophylaxis was emergent pathogens (41%), such as mucormycosis and fusariosis, which were resistant to the prophylactic agents., Conclusions: The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Bacterial infections remain a major cause of morbidity and mortality in immunocompromised children. From the onset of fever, an early administration of broad-spectrum antibiotics is begun; this strategy could induce emergence of multi-drug resistant bacteria (MDR). We describe the incidence and microbiological spectrum, including MDR bacteria of bacterial documented blood-stream infections (BSI) in immunocompromised children. A retrospective, descriptive study was conducted in a tertiary referral centre in France from January 2014 to December 2017. Our cohort included a large scale of patients with febrile neutropenia: haematological and oncological malignancies, haematopoietic stem cell transplantations, severe combined immunodeficiency syndromes. BSI were defined by positive blood culture samples associated with fever. Among 760 febrile neutropenia episodes in 7301 admitted patients, we identified 310 documented BSI with a mean of 7.4 BSI/1000 patient bed days. Only 2.9% BSIs were caused by MDR bacteria, none vancomycin resistant. Coagulase-negative staphylococci were identified in 49.7% BSI and Staphylococcus aureus caused 6.5% infections. Gram-negative bacilli accounted for 21.6% of isolated bacteria, Pseudomonas for 4.8%. The incidence of BSI annually decreased by 0.75% (p = 0.002).Conclusion: With a step-down strategy at 48 h of initial broad-spectrum antibiotic therapy, we reported a low number of MDR bacteria, no deaths related to BSI. What is Known: • Bacterial bloodstream infections are a leading cause of morbidity and mortality in immunocompromised children • Multi-drug resistant bacteria are emerging worldwide. What is New: • Initial broad-spectrum antibiotic therapy with a step-down strategy at 48 h: no deaths related to bloodstream infections with a low number of resistant bacteria. • Parental and nurse stewardship to decrease bloodstream infections incidence with a drop of staphylococcal infections., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very specific nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations. Here is the second version of these recommendations updated according to the evolution of knowledge on COVID19., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Over the years, the prognosis of adolescents treated for acute lymphoblastic leukemia (ALL) has improved. However, this age group still represents a challenge with an overall survival (OS) of 60% compared to 85% in younger children. Herein, we report the outcome of adolescents treated in the European Organisation for Research and Treatment of Cancer (EORTC) 58951 clinical trial. EORTC 58951 clinical trial included patients with de novo ALL between 1998 and 2008. For this study, we analyzed data of all adolescents between 15 and under 18. Data from 97 adolescents were analyzed, 70 had B-lineage and 27 had T-lineage ALL. The 8-year event-free survival (EFS) and OS for the B-cell precursor ALL cases were 72.3% (59.4%-81.7%) and 80.8% (67.4%-89.1%), respectively. For the T-lineage, the 8-year EFS and OS were 57.4% (36.1%-74.0%) and 59.0% (36.1%-76.2%), respectively. "B-other" ALL, defined as BCP-ALL lacking any known recurrent genetic abnormalities were more frequent in our adolescent population (52.8%) than in younger children (27.1%). Outcome of adolescents in the EORTC 58951 study is supporting the findings that adolescents have better outcome in pediatric compared to adults' trials. Nevertheless, in pediatric studies, adolescents still have a worse prognosis than younger children. Despite the fact that specific unfavorable characteristics may be linked to the adolescent population, a careful study and characterization of adolescents "B-other" genetic abnormalities in ALL is critical to improve the outcome of this population., (© 2020 John Wiley & Sons Ltd.)

We report the case of a 14-year-old boy with a completely normal medical and social background (good student and handball practice). A dentist monthly followed this patient for an orthodontic treatment. Facing with symptoms associating purpura, pancytopenia, and limbs pain, the first diagnosis that came to mind to emergency pediatricians was acute leukemia and the patient was addressed to a hematology department. However, additional psychiatry investigations revealed an avoiding restrictive food intake disorder (ARFID) associated with serious vitamin deficiencies (Vitamins B9 and D) and responsible for scurvy, mimicking acute leukemia onset. Strikingly, this young patient has been undergoing a close medical follow-up since infancy because of a selective diet. Since growth, education, and development were normal, the risk of pursuing this unbalanced diet has been neglected and this child was admitted at diagnosis in a life-threatening condition.

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations, even if data for this population are still scarce. They may have to evolve according to the rapid evolution of knowledge on COVID-19., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

In absence of red blood cells disease or immune defect, parvovirus B19 (PVB-19) is usually considered as a benign condition. Here, we report the case of a 10-year-old boy, previously healthy, presenting with a PVB-19 infection revealed by a bicytopenia and a voluminous axillary adenopathy. Pathophysiology examination showed reactional lymphoid population. Nine months later and in the absence of remission, a new biopsy of the same adenopathy revealed a Hodgkin lymphoma with area of T-cell rich aggressive large B-cell lymphoma. This case suggests PVB-19 as potential trigger of this malignant childhood hemopathy. Although no definitive conclusion can be drawn, our clinical case questions the role of PVB-19 in lymphomagenesis., (© 2019 John Wiley & Sons, Ltd.)

Genotypic diagnosis of HSV drug resistance can be performed routinely in a clinically relevant time. Nevertheless, data about HSV mutations (polymorphism or resistance) is not exhaustive which hinders the interpretation of such tests. The UL23, UL30, and UL5 genes are of greatest interest as these encode, respectively, thymidine kinase, DNA polymerase, and helicase, which, if mutated may affect the effectiveness of acyclovir, foscarnet, cidofovir, and helicase-primase inhibitors. The present study aimed to extensively characterize UL23, UL30, and UL5 genes. A total of 239 clinical HSV1 recovered from patients admitted to the hematology departments of the Lyon teaching hospitals were included in this single-center retrospective study. Drug resistance was evaluated using the neutral red dye-uptake assay, and sequencing using the Sanger method. Additional information on HSV1 natural polymorphism and resistance is now available. Twenty-two amino acid substitutions related to polymorphism were described on UL23 (E43A, L50M, L68R, Q109K, A133V, A136N, S150L, D258N, S263L, P280S, N301S, A316S, M322L, I326V, D330A, D338H, Q342H, T344I, Q349R, V352L, R370W, E371D), and 6 amino acid substitutions on UL30 (G641R, G645D, E649G, G679D, R681L, I966M). Moreover, the UL23 substitution L242P was added to ACV resistance-related mutations. There were 12 substitutions on UL23 (A37S, V70M, S74L, H151N, P154S, P155Q, L159R, E225L, Y248H, Q270R, N303Y, M372I), and 8 on UL5 (L49I, L138V, S173L, A280T, A575V, V600A, A602T, D862N) that remain of unclear significance with regards to drug resistance. The mean (±standard deviation, SD) number of natural polymorphisms in UL23 was 2.53 (±2.55), in UL30 it was 0.83 (±1.02), and in UL5 it was 5.00 (±1.59) There was no association between HSV1 phenotype and the frequency of substitutions. The results reported herein provide valuable new information concerning HSV1 mutations that will assist the interpretation of genotypic assays., (Copyright © 2019. Published by Elsevier B.V.)

Fanconi anemia (FA) causes bone marrow failure early during childhood, and recent studies indicate that a hematopoietic defect could begin in utero. We performed a unique kinetics study of hematopoiesis in Fancg -/- mouse embryos, between the early embryonic day 11.5 (E11.5) to E12.5 developmental window (when the highest level of hematopoietic stem cells [HSC] amplification takes place) and E14.5. This study reveals a deep HSC defect with exhaustion of proliferative and self-renewal capacities very early during development, together with severe FA clinical and biological manifestations, which are mitigated at E14.5 due to compensatory mechanisms that help to ensure survival of Fancg -/- embryos. It also reports that a deep HSC defect is also observed during human FA development, and that human FA fetal liver (FL) HSCs present a transcriptome profile similar to that of mouse E12.5 Fancg -/- FL HSCs. Altogether, our results highlight that early mouse FL could represent a good alternative model for studying Fanconi pathology., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders ( GATA2 , RUNX1 ), telomeropathies ( TERC , TERT , RTEL1 ), ribosome disorders ( SBDS , DNAJC21 , RPL5 ), and DNA repair deficiency ( LIG4 ). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling., (© 2018 by The American Society of Hematology.)

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure with a high infection risk. Strict isolation of patients is the rule to prevent such condition., Objective: We compared the occurrence of severe infections (bacteremia and invasive fungal infection, IFI) in children undergoing alloHSCT before and after the move to a new protected unit with decreases in isolation methods., Methods: The study was conducted over a 10-year period. Unit 1 (2002-2007) consisted of laminar airflow rooms where caregivers were required to wear a sterile outfit (gown, gloves, hat, and mask). Unit 2 (2008-2012) included spacious positive air pressure rooms with HEPA filters where only a clean gown and mask were required to be worn., Results: Two hundred eighty-six alloHSCTs were performed (144 in Unit 1 and 142 in Unit 2). We reported a total incidence of 4.78 infections/1000 hospital-days including 4.4 episodes of bacteremia and 0.38 episodes of IFI. There was no statistical difference in the incidence of infections: n = 4.98/1000 hospital-days in Unit 1 vs. n = 4.6/1000 in Unit 2 (P = 0.63)., Conclusion: The lack of difference in the occurrence of severe infection supports our decision to decrease unnecessary high protection in alloHSCT units to improve children's daily life., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Noonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation - n = 121) or Costello syndrome (with HRAS mutation - n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Invasive aspergillosis (IA) is associated with a high mortality rate despite the introduction of new antifungal agents. Several therapeutic strategies have been proposed to improve mortality rates in IA, including combination of drugs., Methods: Here, we report the outcome of treatments based on a combination of antifungal agents on IA, including voriconazole and liposomal amphotericin B, in a pediatric population from 2001 to 2010. Our population included children with diverse hematological diseases or with bone marrow transplantation., Results: Over a 10-year period, we diagnosed 19 cases (2,8%) of invasive pulmonary aspergillosis with an overall survival rate of 58%., Conclusion: Compared with the previous study conducted from 1986 to 2000, the overall survival rate (bone marrow transplantation excluded) greatly improved (12.5% to 58%), especially for patients treated for acute leukemia.

Dexamethasone could be more effective than prednisolone at similar anti-inflammatory doses in the treatment of childhood acute lymphoblastic leukemia. In order to check if this "superiority" of dexamethasone might be dose-dependent, we conducted a randomized phase III trial comparing dexamethasone (6 mg/m(2)/day) to prednisolone (60 mg/m(2)/day) in induction therapy. All newly diagnosed children and adolescents with acute lymphoblastic leukemia in the 58951 EORTC trial were randomized on prephase day 1 or day 8. The main endpoint was event-free survival; secondary endpoints were overall survival and toxicity. A total of 1947 patients with acute lymphoblastic leukemia were randomized. At a median follow-up of 6.9 years, the 8-year event-free survival rate was 81.5% in the dexamethasone arm and 81.2% in the prednisolone arm; the 8-year overall survival rates were 87.2% and 89.0% respectively. The 8-year incidences of isolated or combined central nervous system relapse were 2.9% and 4.5% in the dexamethasone and prednisolone arms, respectively. The incidence of grade 3-4 toxicities during induction and the frequency of osteonecrosis were similar in the two arms. In conclusion, dexamethasone and prednisolone, used respectively at the doses of 6 and 60 mg/m(2)/day during induction, were equally effective and had a similar toxicity profile. Dexamethasone decreased the 8-year central nervous system relapse incidence by 1.6%. This trial was registered at www.clinicaltrials.gov as #NCT00003728., (Copyright© Ferrata Storti Foundation.)

Cryptosporidium is recognized as a cause of diarrhea associated with a high mortality in immunocompromised patients. We report on 2 pediatric cases of cryptosporidiosis during maintenance chemotherapy of acute lymphoblastic leukemia. The patients presented severe diarrheas, 1 of them was complicated by a cholangitis. Withdrawal of immunosuppressive treatments and adjunction of an adequate antiparasitic treatment cured the Cryptosporidium infection in both cases.

Cytogenetic, molecular and phenotyping features of malignant hematologic diseases succeeded in improving their management by a more accurate stratification of patients according to several groups of risk and by providing a rational for targeted therapy. Three major types of treatment (excluding cellular therapy) are currently available in onco-hematology: conventional chemotherapy, small molecules for targeted therapy and monoclonal antibodies. Conventional chemotherapy with optimization of doses and multidrug-based regimens allowed to substantially improve survival of patients and keeps a place of choice in treatment of these diseases. Targeted treatments came from the cytogenetic and molecular characterization of hemopathies. Thus, the kinase Bcr-Abl, as a result of the translocation t(9;22)(q34;q11), has been successfully targeted by tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Molecular abnormalities like internal-tandem duplication/point activating mutations in FLT3 in some acute myeloblastic leukemia or epigenetic dysregulations in some blood malignancies can also be targeted by small molecules. Hematopoietic malignant cells are phenotypically characterized by expression of cluster of differentiation (CD) on their surface. These CD are detected by flow cytometry using specific antibodies. Monoclonal antibodies targeting different CD have been developed for treatment. Rituximab, an anti-CD20 antibody, was the first monoclonal antibody successfully developed for treatment of malignant hematologic diseases. Since rituximab, many other monoclonal antibodies are being developed. Trends in malignant hematologic diseases presented here will include treatments, which have at least entered phase I/II clinical trials in adult or childhood leukemia. They include some novel drugs of conventional chemotherapy like second-generation nucleoside analogues. We will give an overview of the small molecules targeting the different cellular pathways and we will highlight those appearing as the most promising like novel TKIs. The large field of monoclonal antibodies will be also approached focusing on antibodies developed in leukemias.

l-asparaginase encapsulated within erythrocytes (GRASPA(®) ) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005-01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA(®) for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA(®) (50 iu/kg: n = 6,100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l-asparaginase (E. colil-ASNase) control group. GRASPA(®) was effective at depleting l-asparagine. One single injection of 150 iu/kg of GRASPA(®) provided similar results to 8 × 10,000 iu/m(2) intravenous injections of E. colil-ASNase. The safety profile of GRASPA(®) showed a reduction in the number and severity of allergic reactions and a trend towards less coagulation disorders. Other expected adverse events were comparable to those observed with E. colil-ASNase and there was also no difference between the three doses of GRASPA(®) ., (© 2011 Blackwell Publishing Ltd.)

The p16(INK4a) protein is considered to regulate the cell cycle progression mainly by inhibiting cyclin-dependent kinases (CDKs) 4 and 6 activity and leading to an arrest in G(0)/G(1). Here, we report that ectopic expression of p16(INK4a) in three p16-/pRb(Wt)/p53(Wt) human cancer cell lines MCF7, U2OS and U87 induces S-phase lengthening along with G(1) accumulation. S-phase lengthening is suggested by the discrepancy between the unchanged or even increased percentage of cells in S phase found by flow cytometry DNA content analysis and the drop of BrdU labelling, and demonstrated by IdU/BrdU double labelling. p16(INK4a) induces a profound decrease in the CDK4/6-mediated pRb phosphorylation on Ser-807/811, a downregulation of CDK2 and CDK1 protein expression independently of G(1) accumulation, and a decrease in Thr/Pro phosphorylation in part carried out by CDKs. In MCF7 cells, overexpression of the p16 G101W mutant, which is unable to inhibit CDK4/6 kinase activity and shows a modified subcellular localization, does not provoke the S-phase lengthening and the inhibition of Ser807/811-pRB and of Thr/Pro phosphorylation as wild-type p16(INK4a) does. Our results demonstrate that p16(INK4a) induces a S-phase lengthening independently of cellular origin. The CDK4/6 kinase activity inhibition together with the reduced expression of CDK2 and CDK1 acting downstream of G(1) phase may prevent cells from any possible kinasic compensatory mechanisms, and thus lead to a cell cycle progression inhibition.

Indirubin-3'-monoxime (IO) is a derivative of indirubin, an active compound of a traditional Chinese medicinal recipe used to treat various inflammatory and malignant diseases. The main in vitro targets of IO (i.e. cyclin dependent kinases, glycogen synthase kinase-3beta, Stat 3 and Aryl hydrocarbon receptor) are regulators of lymphocyte activation. We investigated the interest of IO and its derivative 6-bromo-indirubin-3'oxime (6BIO) for inhibiting the growth of malignant lymphoid cells. IO (1-20 microM) induced cell cycle inhibition and cell death in malignant B- (IM9, Reh6) and T- (Jurkat, CEM-T) lymphoid cell lines depending to cell type, doses, and duration of treatment. IO and 6BIO (10 microM) treatment for 24 and 48 h were compared: 6BIO treatment resulted in a stronger cytotoxicity and more profound inhibition of cell proliferation. Taken together, these results showed that IO and, moreover, its derivative 6BIO may be potent antiproliferative agents in malignant lymphoid cells.

We report on the efficiency of treatment of first isolated extramedullary relapse of B-cell precursor acute lymphoblastic leukaemia. Sixty-eight children and adolescents were included in the trial COPRALL-97. Stratification criteria were time to relapse: first complete remission duration of less than 24 months for group G3A (n=35), relapse beyond 24 months for group G3B (n=33). Treatment consisted of risk-adapted alternating short course multiagent systemic and intrathecal chemotherapy and irradiation (18Gy). Event free survival (EFS) and overall survival (OS) for all registered patients at 6 years were 43% and 55%, respectively. EFS at 4 years for patients of group G3A and G3B were, respectively, 31% and 61% (p=0.0071) while OS at 4 years were, respectively, 40% and 76% (p=0.065). Our analyses highlighted two independent risks factors predictive of decreased EFS: early relapse and age at the initial diagnosis above 6 years. Early central nervous system relapses have a bad prognosis, and new therapeutic strategies are needed.