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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.

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). 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. 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

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).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.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 mIn 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.

Graft-versus-host disease (GVHD) is an important challenge and a major cause of morbidity and mortality in children after hematopoietic stem cell transplant (HSCT). Herein we report our institution's experience of goal-oriented Bayesian monitoring for cyclosporine (CsA) used alone as GVHD prophylaxis during the post-transplant period in pediatric patients with thalassemia major (TM) or sickle cell anemia (SCA) undergoing HLA-matched HSCT. We also studied evolution of chimerism. Twenty-six consecutive patients (SCA, 14; TM, 12) underwent matched sibling donor (MSD) HSCT from 2004 to 2014. All patients received a myeloablative conditioning regimen. GVHD prophylaxis consisted of 20 mg/kg antithymocyte globulin in the conditioning regimens and then CsA alone in the post-transplant period. Target CsA trough blood concentration (TBC) was 150 ± 20 ng/mL. At last follow-up, all patients were alive and free of disease, even in cases of mixed chimerism. Engraftment occurred in all patients. No patient developed grades II to IV acute GVHD, 4 patients developed acute grade I skin GVHD, and only 1 presented with chronic pulmonary GVHD. A better control of GVHD and immunosuppression by a strict monitoring of CsA TBC as described herein is promising and could play a crucial role. Further investigations are required, but this study opens new perspectives to improve survival and safety of HSCT from alternative donors in TM and SCA to levels compatible with that obtained with MSDs.

We report the post-transplant lymphocyte subset recovery of 226 children treated with Unrelated Cord Blood transplant (UCBT) (n = 112) or Unrelated Bone Marrow Transplant (UBMT) (n = 114) for malignant or non-malignant diseases. Absolute numbers of natural killer (NK), B and T cells were monitored by flow cytometry up to 5 years post-transplant. Immunological endpoints were: time to achieve a CD 3+ cell count >0·5 and 1·5 × 10 9 /1, CD4 + > 0·2 and 0·5 × 10 9 /1, CD8 + > 0·25 × 10 9 /1, CD19 + > 0·2 × 10 9 /1, NK > 0·1 × 10 9 /1. These endpoints were analysed through the use of cumulative incidence curves in the context of competing risks. CD8 + T cell recovery was delayed after UCBT with a median time to reach CD8 + T cells > 0·25 x 10 9 /1 of 7·7 months whereas it was 2·8 months in UBMT (P 0·2 × 10 9 /1 of 3·2 months in UCBT and 6·4 months in UBMT (P = 0·03). Median time for CD4 + T cell and NK cell recovery was similar in UCBT and UBMT. CD4 + T cells recovery was negatively correlated to age (better reconstitution in younger patients, P = 0·002). CD8 + T cells recovery was shorter in recipients with a positive cytomegalovirus serology (P = 0·001 ).

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.

s / Biol Blood Marrow Transplant 19 (2013) S313eS341 S336 performed in the same laboratory. Survival rate at the time of analysis was 90%. We initially compared single parameters of PFTs including corrected diffusion limiting capacity of oxygen (DLCO), forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity (TLC) obtained before and after transplant. Post transplant, all PFT parameters showed some degree of reduction compared to pretransplant values. FEV1 and FEV1/FVC were significantly decreased (108 vs 92, P 1⁄4 .04 and 86 vs 80%, P 1⁄4 .04, respectively), with no difference between Caucasian and nonCaucasians. Overall, median values of corrected DLCOand TLC prior to and after transplant were only slightly reduced. However, in non-Caucasian patients a significant reduction of DLCO was observed (93% 31 vs 73% 11, P 1⁄4 .05). We analyzed intra-patient changes in DLCO and FEV1 values and no correlationwas found between these parameters and the development of chronic GVHD. This study shows an overall decrease in pulmonary function in patients without apparent lung disease following a myeloablative busulfan-based HSCT. However, a higher risk of a reduced DLCO was noted only among non-Caucasian patients. At this time it is not known if this observation is due to genetic, biologic or environmental causes.

Introduction The rational of use of L-asparaginase (L-Aspa) is based on asparagine synthetase (ASNS) deficiency in leukemic cells. Its efficacy is due to its capacity to deplete plasmatic asparagine, starving the leukemic cells and subsequently inhibiting protein synthesis. It is a mainstay in the treatment of acute lymphoid leukemia (ALL), where it is established that resistance to treatment is in part related to detectable expression of ASNS (Aslanian et al., 2001; Su et al., 2008). In acute myeloid leukemia (AML), promising results have been obtained in clinical trials (Capizzi et al., 1988), with an improvement of complete remission rates from 18% to 54% in refractory patients 60 year old. More recently, it has been reported that leukemic cells from AML patients with M1, M4 and M5 FAB subtypes were more sensitive to L-Aspa (Okada et al., 2003).The aim of this study was to investigate the sensitivity to L-Aspa and the ASNS expression in an AML cell line (HL-60) and in primary leukemic cells from newly diagnosed AML patients. Materials and methods AML (HL-60) and ALL (MOLT-4) cell lines were grown according to ATCC recommendations. Primary leukemic cells from the bone marrow of 24 AML patients (median age: 69 years; range: 2-83) were harvested on EDTA and isolated by Ficoll density gradient within 72h. ASNS expression was determined by western-blot on isolated leukemic cells and expressed as a ratio ASNS/cyclophilin A. When a sufficient amount of leukemic cells was available, sensitivity to L-Aspa (expressed as an IC50 - concentration inhibiting 50% of cell viability) was evaluated in vitro by incubating various concentrations of L-Aspa (0.001 to 10 IU/mL) with the cells and by measuring the cell viability with a counting kit (CCK-8 viability assay) at day 4. Results Determination of IC50 for the HL-60 cell line demonstrated that these cells were equally sensitive to L-Aspa than the ALL cell line MOLT-4 in vitro (0.23 IU/mL versus 0.19 IU/mL, respectively). The expression of ASNS in the HL-60 cell line was low but higher than in MOLT-4 which is a well known ASNS deficient cell line. IC50 determination was possible on 17/24 patients. Seven displayed a high sensitivity to L-Aspa (IC50 < 0.01 IU/mL) whereas 5 displayed a moderate sensitivity (IC50 < 0.5 IU/mL). Remaining 5 patients were resistant to L-Aspa. The cells from the healthy subject were resistant (IC50 > 10 IU/mL). To date, ASNS expression has been evaluated on 16 patients with ratio ranges from 0 to 2.27: six were negative, 4 low positive (< 0.2), and 6 positive (> 0.5, amongst them 4 were > 1). No correlation was observed between ASNS expression and FAB grade. However, patients with blasts sensitive to L-Aspa had mainly M1 or M5 AML. Conclusion AML cell line HL-60 and 71% of primary cells from AML patients were found sensitive to L-Aspa. The sensitivity of cells from M1 and M5 AML patients is consistent with the findings of Okada et al. (2003). Globally, these results suggest that L-Aspa is effective for killing AML cells. Based on the epidemiology of AML subtypes (Selter et al., 2011) and our results, L-Aspa therapy may be beneficial for 50-70% of patients with AML. However, L-Aspa has only been used scarcely in the treatment of AML, mainly because of the commonly observed adverse effects that impair its use. A new formulation of L-Aspa encapsulated in homologous red blood cells was reported with a better safety profile, allowing its use even in elderly patients (Hunault et al., ASH 2012). A clinical study is currently recruiting patients unfit for intensive chemotherapy in order to evaluate its efficacy in combination with low-dose cytarabine (NCT01810705) in AML. In this study, L-Aspa sensitivity and ASNS expression in primary tumor cells at diagnosis will be explored to investigate the relationship with clinical response. Disclosures: Berlier: ERYTECH Pharma: Employment. Aguera:ERYTECH Pharma: Employment. Gallix:ERYTECH Pharma: Employment. Bertrand:ERYTECH Pharma: Principal Investigator Other. Thomas:ERYTECH Pharma: Principal Investigator Other; Orphan Europe: Consultancy. Godfrin:ERYTECH Pharma: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

Randomised trials in pediatric ALL show that multiple doses of E Coli Asparaginase (ASP) are associated with better outcome. In the EORTC 58951 protocol, all the patients except those with high risk features (HR or VHR) had 8 IV doses of ASP during induction Ia and were randomized during induction Ib to receive or not ASP (8 IV doses vs 0) and protocol II (8 IV doses vs 4), respectively long arm and short arm. The aim of this study was to report on safety, asparagine (ASN) depletion and antibody production in 28 consecutive patients with newly diagnosed previously untreated ALL. Methods. Twenty-eight patients included in the EORTC 58951 protocol were analyzed: one had very low risk features, 22 were average risk patients and 6 had HR features. Thirteen patients were randomized in the short ASP arm and 9 in the long ASP arm. ASN levels were assessed on days 35 of Ia, 27of Ib and 22 of IIa. The amino acid assays employed the HPLC method. Serum samples were taken for antibody titers against ASP analyzed by ELISA on days 12 and 35 of Ia, 17 and 27 of Ib (long arm only) and 8 and 22 of IIa, and before the start of maintenance therapy. Results. Twenty-eight patients aged 1year 3 months to 14 years 6 months (median 6 years) with newly diagnosed ALL (precursor B-cell: 25 ; T-cell: 3) were assessable. All patients achieved CR after induction phase Ia. Four patients had allogeneic bone marrow transplantation in first CR because of VHR features. Two other patients with HR features had intensified chemotherapy. Preliminary data showed that ASN depletion was obtained in all patients at the end of phase Ia, in all the patients “long arm” at the end of Ib and in one patient ” short arm” at the end of Ib All patients had depletion of ASN after protocol IIa We observed very few severe clinical allergic reactions in this series of patients (10%). Two patients were switched to Erwinia asparaginase because of clinical hypersensitivity. Investigation on correlation between the antibody production against ASP, clinical allergic reaction and depletion of ASN are in progress. Conclusions. Multiple doses of ASP given intravenously were well tolerated in this series of 28 consecutive patients with previously untreated ALL. Preliminary results reveal that the rate of antibodies production was low and depletion of ASN was obtained in near all the patients. Some patients presented with clinical allergic reactions but had low levels of ASN and no appearance of anti ASP antibodies. Other had antibodies without clinical allergy and with depletion of ASN.