Search

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

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin

Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT). This multinational, prospective, observational study (NCT03032016), performed by the EBMT, enrolled patients treated with defibrotide from April 2015 to July 2018. This analysis focused on defibrotide-treated patients with VOD/SOS post-HCT. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were enrolled: 62 had severe VOD/SOS and comprised the primary study population, including 36 with multi-organ dysfunction/failure (MOD/MOF). SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan–Meier–estimated Day 100 survival rate was 73% (95% CI: 60%, 82%) with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. MOD/MOF resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis. Results from this multicentre registry study build on prior defibrotide studies supporting the utility of defibrotide for the treatment of VOD/SOS post-HCT. These results provide additional real-world evidence of the effectiveness and safety of defibrotide in patients with VOD/SOS post-HCT.

International audience; Among 143 patients with elastase, neutrophil-expressed (ELANE)-related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte-colony stimulating factor (G-CSF), on G-CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem-cell transplantation. During the disease’s natural history period (without G-CSF; 1913 person-years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (3000/mm(3) ) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G-CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism.

Purpose Immunosuppressive therapy following pediatric hematopoietic stem cell transplantation is essential for the patient's prognosis, as the antibioprophylaxis and the isolation measures. But medication adherence is suboptimal for children and adolescents, from 52 to 73% in literature. The aim of this study is to provide an understanding of medication adherence after pediatric allogeneic stem cell transplantation (SCT), by identifying facilitators and barriers. Method Semi-structured interviews were conducted by a pharmacist with caregivers and healthcare providers in a pediatric centre . Four topics were discussed: transplantation, post-transplantation therapies, caregivers' experience and the healthcare system. Interviews were audiotaped, transcribed and analysed by inductive approach. Findings Semi-structured interviews with 15 caregivers and 21 healthcare providers identified factors of medication adherence and hygiene measures. The long-term nature of therapy and difficult transitions of care were identified as major barriers. Recognizing the benefits of medication and parental involvement are facilitators. Furthermore, caregivers expressed the need to take into consideration the family entity. They would like also to receive earlier information from healthcare providers before hospital discharge . Those needs were not always identified by healthcare providers. Conclusion This analysis revealed barriers and facilitators to the medication adherence and to the care. It demonstrated similarities and differences between caregivers and healthcare providers’ perceptions and has thereby initiated an improvement process of the healthcare system. As part of this process, medical and paramedical healthcare providers at this French pediatric centre are currently working on a support program for post-alloSCT hospital-home transition.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53–71%) for MMUD, versus 80% (66–95%) for HDs with only in vivo T cell depletion and 60% (47–73%) for HDs with in vivo and ex vivo T cell depletion (p =.22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73–99%) than for those transplanted from a MMUD 58% (48–68%) or those with graft manipulation 56% (42–69%) (p =.046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p =.005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts. © 2021 Wiley Periodicals LLC., The authors are particularly thankful to all centers from the Severe Aplastic Anemia Working Party and the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation, who kindly agreed to participate in this study (see Appendix S1). We would also like to thank Anne E. Lippinkhof, Study Coordinator, Severe Aplastic Anemia Working Party for her invaluable help.

Background There are currently few data on the outcome of acute myeloid leukemia (AML) in adolescents after allogeneic HSCT. The aim of this study is to describe the outcome and its specific risk factors for children, adolescents and young adults after a first allogeneic HSCT for AML. Methods In this retrospective study, we compared the outcome of AML patients receiving a first allogeneic HSCT between 2005 and 2017 according to their age at transplantation’s time: children (n = 564), adolescent and post-adolescent (APA) patients (15–25 years, n = 647) and young adults (26–40 years; n = 1434). Results With a median follow-up of 4.37 years (min–max 0.18–14.73 years), the probability of 2-year overall survival (OS) was 71.4% in children, 61.1% in APA patients and 62.9% in young adults (p = 0.0009 for intergroup difference). Both relapse and non-relapse mortality (NRM) Cumulative Incidence (CI) estimated at 2 years were different between the age groups (30.8% for children, 35.2% for APA patients and 29.4% for young adults—p = 0.0254, and 7.0% for children, 10.6% for APA patients and 14.2% for young adults, p p Conclusion Age is an independent risk factor for NRM and extensive chronic GVHD. This study suggests that APA patients with AML could be beneficially treated with a chemotherapy-based MAC regimen and bone marrow as a stem cells source.

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.

CONTEXT Acute myeloid leukemia (AML) is a rare disease in children, with only 50% to 60% event-free survival. Among patients with AML, 10% do not respond to first-line chemotherapy. There is no recommendation concerning second-line treatments. Gemtuzumab ozogamicin (GO) is a monoclonal antibody targeting CD33, linked to calicheamicin. We report the efficacy and tolerance of a salvage regimen of fludarabin, cytarabine, and GO (FLA-GO) in patients refractory to first-line treatment. METHODS Eight patients (median age 14.5 years), who had more than 2% minimal residual disease (MRD) by flow cytometry (MRD flow), received gemtuzumab 3 mg/m² on days 1, 4, 7, associated with cytarabine 2000 mg/m² and fludarabin 30 mg/m² on days 1 to 5. RESULTS Six patients achieved complete remission (CR) (blast count morphology ≤5 × 10-2 , CR-MRD flow

Introduction: Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT) conditioning that may also develop after high-dose chemotherapy. Multiorgan failure (MOF) is associated with the most severe form of VOD/SOS and, if untreated, may result in a mortality rate of >80%. Defibrotide is approved for the treatment of hepatic VOD/SOS with renal or pulmonary dysfunction post-HCT in the US and for severe hepatic VOD/SOS post-HCT in patients aged >1 month (mo) in the EU. The DEFIFrance study collected real-world data on the efficacy and safety of defibrotide from HCT centers in France. This analysis presents final, long-term data on the primary study population: patients who received defibrotide treatment for severe/very severe VOD/SOS post-HCT. Methods: This post-marketing registry study collected retrospective and prospective real-world data on patients receiving defibrotide at 53 HCT centers in France. Diagnosis of VOD/SOS was at the investigator's discretion using standard criteria, per typical clinical practice. Disease severity was categorized using adult EBMT severity criteria in patients aged ≥18 years (y), and patients aged Results: Of 798 defibrotide-treated patients enrolled in the study, 251 patients received defibrotide for the treatment of severe/very severe VOD/SOS post-HCT (severe: 117 [47%]; very severe: 134 [53%]). Median age was 45 y (range: 0, 74) and 58 (23%) patients were 50%) risk factors included prior treatment with hepatotoxic drugs (150 [60%]), iron overload (133 [58%]), and relapsed/refractory disease (137 [55%]). Risk factors of interest included prior HCT (29/239 [12%]), and prior treatment with gemtuzumab ozogamicin (17/251 [7%]) and inotuzumab ozogamicin (6/251 [2%]). At diagnosis, 55/250 (22%) patients had anicteric VOD/SOS (bilirubin levels ≤2 mg/dL). Median (range) time from VOD/SOS diagnosis to defibrotide administration was 0 (-1, 24) days. The Kaplan-Meier (KM)-estimated Day 100 post-HCT survival rate was 61% (95% confidence interval [CI]: 55%, 67%) in patients with severe/very severe VOD/SOS, with a higher survival rate seen in patients with severe versus very severe disease. The post-HCT survival rate in patients with severe/very severe VOD/SOS was 50% at 6 mo and 43% at 12 mo (Figure). KM-estimated survival rates at 6 and 12 mo were also higher for those with severe versus very severe disease (Figure). The KM-estimated CR rate by Day 100 among patients with severe/very severe VOD/SOS post-HCT was 74% (95% CI: 66%, 81%). Similar to the pattern observed for the survival rate, a higher CR rate was observed by Day 100 in patients with severe (84% [95% CI: 74, 92]) versus very severe (63% [95% CI: 52, 74]) VOD/SOS. Treatment-emergent SAEs of interest occurred in 29% of patients with severe/very severe VOD/SOS post-HCT; the most common (≥2%) treatment-emergent SAE categories were infection (17%), hemorrhage (16%), and hypotension (2%). Mortality due to VOD/SOS at 12 mo was 15%. Conclusions: The DEFIFrance study represents the largest collection of real-world data on post-registration use of defibrotide. The efficacy and safety observed in this study add to evidence from prior studies supporting the utility of defibrotide for treating patients with severe/very severe VOD/SOS post-HCT in a real-world setting. Among patients receiving defibrotide for VOD/SOS post-HCT, outcomes were better in patients with severe versus very severe VOD/SOS, highlighting the importance of early VOD/SOS diagnosis and treatment, before patients reach the most severe stage of VOD/SOS. Figure 1 Figure 1. Disclosures Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Peffault De Latour: Amgen: Consultancy, Other, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Jazz Pharmaceuticals: Honoraria. Labopin: Jazz Pharmaceuticals: Honoraria. Detrait: Jazz Pharmaceuticals: Research Funding. Huynh: Jazz Pharmaceuticals: Honoraria. Renard: Jazz Pharmaceuticals: Research Funding. Asubonteng: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Delaval: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Dalle: Jazz Pharmaceuticals: Honoraria.

BACKGROUND: NK cells play a crucial role in the immune surveillance of malignant hemopathies. They undergo fine regulation by the microenvironment and by integrating activating and inhibiting signals trough several receptor/ligand couple interactions, hereafter referred to as "NK synapse". The ligands are expressed by a variety of cell types in the hematopoietic niche, including most immature leukemic stem cells CD34+CD38-. High expression of inhibiting ligands on AML (acute myeloid leukemia) blasts was associated with adverse clinical outcome . This observation highlights the relevance of identifying new ligand/receptor (L/R) pairs that could be targeted to prevent inhibiting interactions at the NK synapse. Relevant interactions to be blocked would display both ligand and receptor expressions on the leukemic cells and NK cells respectively. PATIENTS AND METHODS: 23 pediatric AML patients from the pediatric MyeChild01 protocol including in CONECT-AML French national collaborative network project diagnosed between 2018 and 2019 were included in this study. Reference bone marrows used were regenerative (4) or healthy bone marrows (5) . Multicolour flowcytometry protocole used fresh EDTA bone marrow at AML diagnosis and immunostaining with fluorochrome-coupled antibodies using 14 colour panel of L/R couples (Figure 1). Data was acquired on the FORTESSA Becton Dickinson with the Diva software and analysis using script R-PCA and FlowJo . RESULTS: We studied 5 inhibiting NK synapses (iinhibitory ligand/receptor pairs) . Four out of five inhibiting synapses (TIGIT/CD155; PD1-1/PD-L1; CD94/HLA-E and KIR2DL/HLA-A-B-C), showed not significant expression of ligand associated with the corresponding receptor expression. The CD200/CD200R synapse was the only one in which high ligand expression in blasts was significantly associated with high receptor expression on NK cells (Figure 2). This synapse could thus be of interest to develop targeting therapies for CD200-positive pediatric AML, with the strong advantage that patient eligibility could be easily identified at diagnosis. We then realized a principal component analysis, using the R software (PCA), integrating the MFIs of the 5 inhibiting NK synapses and 6 activating NK synapses (Figure 1) for the pediatric AML cohort (ID #1 to #23 ) together with reference bone marrows (healthy donors (n=5; ID #24 to #28) and regenerative bone marrows (n=4; ID #29 to #32)) . The CD200/CD200R synapse was identified as the main variable, explaining the distribution of patients and healthy donors as both CD200 and CD200R expressions happened to be among the most contributive to PCA axes. Interestingly, healthy donors clustered together, close to regenerative bone marrows. Pediatric AML patients distributed heterogeneously (Figure 3). In parallel, we evaluated whether CD200 expression on bulk leukemia blasts including most immature CD34+CD38- LSC was associated with exhaustion markers on NK cells. We found that patients with high and intermediate expression of CD200 on blasts (MFI > 3 rd quartile and comprised between 2 nd and 3 rd quartile, respectively) displayed strong PD-1 and TIGIT expressions on NK cells. Reciprocally, patients with low CD200 expression (MFI< 2 nd quartile) displayed a moderate PD-1 expression on NK cells, and TIGIT expression was more heterogeneous among individuals (Figure 4). CONCLUSIONS: Here, we identified CD200 expression in AML blasts including LSC as a marker that could be associated with NK cell exhaustion. at diagnosis. A PCA strategy allowed to observe that this marker differentiated pediatric AML patients NK synapse profiles from healthy donors and regenerative bone marrows sugesting a potential deregulation of bone marrow niche including NK-LSC escape. This suggests that CD200 expression assessment on blasts at diagnosis could be a tool to evaluate NK cell antitumor potential. Indeed, direct NK cell assessment by flow cytometry can be challenging because of blast invasion in the bone marrow. Nevertheless, it remains to be elucidated whether this clustering and exhaustion markers on NK cells correlated with patient clinical outcomes and MRD kinetics including CD34+CD38- LSC flow frequency evaluation that should be useful in most clinical trials to overcome chemoresistance of LSC. These results should be confirmed in a prospectively larger cohort of patients in future clinical trials. Figure 1 Figure 1. Disclosures Renard: Jazz Pharmaceuticals: Research Funding.

Introduction : Hematological complications (HC) as Aplastic anemia (AA) and myelodysplasia and acute leukemia (MDS/AL) are frequent and life threatening in patients with Shwachman Diamond Syndrome (SDS) with SBDS mutations. The therapy of such events is based on Hematopoetic stem cell transplantation (HSCT), which results remain quite poor, especially in case of malignancy. So far, it is difficult to anticipate to such HC and a lot is expected from the study of clonal evolution prior HC. Methods: A Targeted panel of 43 genes involved in MDS/AL (sensibility 1%) has been evaluated in 80 patients with SBDS mutation, representative of a nation based cohort of 154 patients. This cross sectional study has been completed by a prospective study for 40 patients evaluated at several time points. Results: The evaluation was performed in various situations: steady state i.e. no haematological complication, in MDS/AL and AA and lastly after HSCT. At the first evaluation, somatic mutation was found in 21 patients (30%) among the 70 in steady state and in 7 of the 8 cases with HC (6/6 cases with MDS/AL, in 1 among the 2 cases with AA) while the 1 of the 2 patients long term survivors after HSCT have no mutation and the other one kept a TP53 clone with a normal blood count and a low (1.5%) variant allele frequency (VAF). Among the 40 patients with several time points, 17 have a mutation at the first time points, but 10 others had additional mutation later. Globally, the most frequent gene involved was TP53 (82%) while mutations in other genes have been observed rarely. VAF in patients with vs without HC is lower (median VAF 0% vs 22.8% respectively p < 0.001) . Complex caryotype, monosomy 7, Iso7q were associated with P53 clone while in Del20q, 8 patients out 14 have a P53 mutations. The comparison between blood and bone marrow results allow the possibility to monitor such mutations in blood. Clonal evolution in one patient who presents a MDS in the course of the follow up had shown a competition between clones. Conclusion: Acquired TP53 is extremely frequent in patients with SBDS mutations, even in the absence of HC, but the prevalence as well as the VAF increased in case of HC. When sequential evaluation could be performed, competition between clones is frequent and a clinical decision remains therefore difficult, just on the evaluation of a time point. Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, X4 Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot(ASSQF), the association Barth France for their support. Disclosures Sicre de Fontbrune: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Renard:Jazz Pharmaceuticals: Research Funding. Tournilhac:ABBVIE: Consultancy, Honoraria, Other: Travle grant; INNATE Pharma: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria, Other: Travel Grant; Takeda: Consultancy, Honoraria, Other: Travel grant; Janssen: Consultancy, Honoraria, Other: Travel grant.

International audience; Background We conducted a national multicenter retrospective study in France to evaluate the efficacy and tolerance of ruxolitinib in children with steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplant. Procedure Patients were recruited from the 15 pediatric transplantation centers. Transplanted patients were eligible if they met the following criteria aged = 2, and treated with ruxolitinib for steroid-refractory aGVHD. Results Twenty-nine patients received ruxolitinib for steroid-refractory aGVHD. Six patients achieved a complete response at day 28 after the start of treatment but finally 19 patients (65.5%) achieved a complete response (CR) with a median delay of 41 days (5-93 days). Two patients had a partial response. All patients who achieved CR or partial response discontinued corticosteroid treatment. Eight patients showed treatment failure. The overall response rate was 72.4%. Twenty-three of 29 patients were alive at a median follow-up of 685 days (177-1042 days) after the hematopoietic stem cell transplantation. Viral replication was observed in 41.4% of cases. We did not observe severe hematological adverse events and cytopenia requiring a modification of ruxolitinib doses always resolved. The median initial dose of ruxolitinib was 12.6 mg/m(2)/day with an important range. We could not demonstrate any relationship between initial dose and effectiveness. Conclusion Ruxolitinib may constitute a promising second-line treatment for children with steroid-refractory aGVHD that should be validated in a prospective large-scale pharmacokinetic and efficacy trial.

(1) Background: The aim of the present study was to compare oxygen gradient ektacytometry parameters between sickle cell patients of different genotypes (SS, SC, and S/+) or under different treatments (hydroxyurea or chronic red blood cell exchange). (2) Methods: Oxygen gradient ektacytometry was performed in 167 adults and children at steady state. In addition, five SS patients had oxygenscan measurements at steady state and during an acute complication requiring hospitalization. (3) Results: Red blood cell (RBC) deformability upon deoxygenation (EImin) and in normoxia (EImax) was increased, and the susceptibility of RBC to sickle upon deoxygenation was decreased in SC patients when compared to untreated SS patients older than 5 years old. SS patients under chronic red blood cell exchange had higher EImin and EImax and lower susceptibility of RBC to sickle upon deoxygenation compared to untreated SS patients, SS patients younger than 5 years old, and hydroxyurea-treated SS and SC patients. The susceptibility of RBC to sickle upon deoxygenation was increased in the five SS patients during acute complication compared to steady state, although the difference between steady state and acute complication was variable from one patient to another. (4) Conclusions: The present study demonstrates that oxygen gradient ektacytometry parameters are affected by sickle cell disease (SCD) genotype and treatment.

The question of the best donor type between haploidentical (HAPLO) and matched-related donors (MRD) for patients with advanced HL receiving an allogeneic hematopoietic cell transplantation (allo-HCT) is still debated. Given the lack of data comparing these two types of donor in the setting of non-myeloablative (NMA) or reduced-intensity (RIC) allo-HCT, we performed a multicentre retrospective study using graft-vs.-host disease-free relapse-free survival (GRFS) as our primary endpoint. We analysed the data of 151 consecutive HL patients who underwent NMA or RIC allo-HCT from a HAPLO (N = 61) or MRD (N = 90) between January 2011 and January 2016. GRFS was defined as the probability of being alive without evidence of relapse, grade 3-4 acute GVHD or chronic GVHD. In multivariable analysis, MRD donors were independently associated with lower GRFS compared to HAPLO donors (HR = 2.95, P

To study the risk of catheter-associated thrombosis (CAT) between peripherally inserted central catheters (PICCs) and tunneled central venous catheters in children with leukemia.We analyzed all PICCs and conventional tunneled catheters placed in patients aged18 years and admitted to our institute for leukemia treatment between February 2008 and April 2014. Cases of symptomatic CAT were confirmed by ultrasound and treated with low-molecular-weight heparin.During the study period, 157 PICCs and 138 conventional tunneled catheters were placed in 192 patients with leukemia. CAT incidence was 1.5% (n = 2) in the conventional tunneled catheter group and 10.2% (n = 16) in the PICC group. The OR for CAT occurrence after PICC vs conventional tunneled catheter placement was 5.6 (95% CI, 1.2-26.5).Our results suggest that the use of PICCs in children with leukemia increases the risk of CAT in comparison with the use of conventional tunneled catheters. Further randomized controlled studies are needed to characterize this risk and to better define indications.

International audience; BACKGROUND:Sickle cell anaemia (SCA) is a severe hereditary haemoglobinopathy characterised by haemorheological abnormalities, which play a role in the occurrence of several acute and chronic clinical complications. While βS -haplotypes and alpha-thalassaemia modulate SCA clinical severity, their effects on blood rheology have been incompletely described. The aim of this study was to test the effects of these genetic modifiers on the haemorheological properties and clinical complication of children with SCA.PROCEDURE:Steady-state haemorheological profile, biological parameters, βS -haplotypes, alpha-globin status, vaso-occlusive crisis (VOC) and acute chest syndrome frequencies were analysed in 128 children (aged 5 to 18 years) with SCA.RESULTS:Patients with alpha-thalassaemia showed increased red blood cell (RBC) deformability and aggregation compared to those without. Median VOC rate was higher in patients with homozygous alpha-thalassaemia compared to those with a normal alpha genotype. Conversely, the haemorheological profile and clinical complications were not influenced by the βS -haplotypes in our study.CONCLUSION:Our results demonstrate that alpha-thalassaemia is associated with higher risk for VOC events in children with SCA, which may be due in part to its effects on RBC deformability and aggregation.

Continuous intravenous (IV) infusion has been shown to be the best option to administer vancomycin because of its time-dependent bactericidal activity. Available IV vancomycin dosing guidelines in pediatrics with normal renal function leads to less than 50% of patients achieving a vancomycin serum concentration (Css) in the target range (15-20 mg/L). The primary objective of this study was to prospectively validate an age-based dosing regimen in pediatric oncology-hematology. The secondary objective was to investigate the influence on Css attainment of different variables. A continuous IV dosing nomogram was built by retrospective study (2000-2010) on Bayesian dosing adjustments performed in 161 patients. This study assessed the prospective validation of this age-based nomogram and the influence on Css attainment of variables as the gender, underlying disease (oncology or hematology), and hematopoietic stem cell transplantation (HSCT) before receiving vancomycin therapy. A total of 94 patients aged from 4.3 months to 17.9 years old with normal renal function were eligible for the prospective validation. Fifty-five of those patients (58.5%) achieved the target range of vancomycin Css. There was no significant difference between age groups (P = 0.816) and no influence of gender (P = 0.500). There was a nonsignificant trend to a better target attainment in oncology patients (69.2% vs. hematology 54.4%, P = 0.142) and patients who did not undergo HSCT (63.3% vs. 33.3%, P = 0.031). This study proposed an age-based nomogram prospectively validated which near 60% of patients of each age class achieving the target range of Css.

OBJECTIVES Because of the increased hemolytic rate, a significant proportion of patients with sickle cell disease (SCD) are prone to develop cholelithiasis. The present study investigated the role of several genetic factors (UGT1A1 promoter (TA)n repeat polymorphism, alpha-globin status), hematological parameters, clinical severity, and hydroxyurea (HU) therapy on the occurrence of cholelithiasis in SCD. METHODS One hundred and fifty-eight children (2-18 yr old) regularly followed at the University Hospital of Lyon (France) were included. A multivariate Cox model was used to test the associations between cholelithiasis and the different parameters analyzed. RESULTS We confirmed that alpha-thalassemia and low basal reticulocyte (RET) count were independent protective factors for cholelithiasis while 7/7, 8/8 and 7/8 UGT1A1 (TA)n genotypes were independent predisposing factors for this complication. We also showed for the first time that HU treatment decreased the risk for cholelithiasis while frequent vaso-occlusive crises and acute chest syndrome events increased that risk. CONCLUSIONS Our findings demonstrate that UGT1A1 (TA)n polymorphism is not the only factor triggering gallstone formation in SCD. Cholelithiasis is also modulated by RET count, the number of deleted alpha-genes, HU therapy and the frequency of vaso-occlusive events.

Resume La lacidipine semble, chez l’adulte, denuee de pouvoir inhibiteur du cytochrome P450 3A4 (CYP3A4). Cette caracteristique la rend particulierement interessante en vue d’une association aux traitements metabolises par le CYP3A4, tels que la ciclosporine. A notre connaissance, aucune etude d’efficacite et de tolerance de cet anticalcique n’a encore ete menee en pediatrie. Trente-neuf enfants hypertendus (0,13 a 14 ans) traites par lacidipine, en onco-hematologie, pendant 75 jours en moyenne, ont ete inclus retrospectivement dans cette etude. Les causes de l’hypertension arterielle etaient : une tumeur renale ( n = 7), une tumeur secretrice de catecholamines ( n = 4), la corticotherapie ( n = 5), un traitement par ciclosporine ( n = 23). La dose initiale de 0,05 mg/kg/j avait ete suffisante chez 41 % des enfants. Les autres enfants avaient necessite une augmentation des doses par paliers de 0,03 mg/kg/j, jusqu’a une dose efficace moyenne de 0,1 mg/kg/j. La lacidipine a permis une diminution significative de 30 (±14) mmHg des tensions arterielles systoliques et de 26 (±13) mmHg des tensions arterielles diastoliques. Un schema therapeutique avec deux administrations quotidiennes n’avait pas ete significativement plus efficace qu’un schema ne comportant qu’une administration. La lacidipine avait ete bien toleree, aucun arret premature pour toxicite n’ayant ete releve. Pour 22 enfants traites concomitamment par ciclosporine et lacidipine, la fonction renale ne s’etait pas alteree au cours du temps, suggerant une nephroprotection par la lacidipine. Aucune elevation significative des concentrations sanguines de ciclosporine n’a ete mise en evidence. La lacidipine semble un anticalcique de choix en onco-hematologie pediatrique, efficace, bien tolere, potentiellement nephroprotecteur et sans risque d’interaction lors d’association a la ciclosporine.

Severe hepatic VOD/SOS is a potentially life-threatening complication of HCT conditioning that may also develop after high-dose chemotherapy. The most severe form of VOD/SOS is often accompanied by multi-organ failure (MOF) and is associated with a mortality rate of >80% when managed with supportive care alone. As part of the marketing authorization in Europe, there was an obligation to set up a disease registry of patients with severe VOD/SOS post-HCT who were treated with defibrotide. The goal of this registry was to collect safety and outcome data and assess patterns of defibrotide utilization in the post-approval setting. This multicenter, multinational, prospective observational study (NCT03032016) was performed by the European Society for Blood and Marrow Transplantation (EBMT). The study included patients with severe VOD/SOS post-HCT who were treated with defibrotide and enrolled from April 2015 to July 2018. Participating centers were members of the EBMT. Physicians registered patients diagnosed with severe VOD/SOS, as assessed by the investigator using classical/standard criteria (including but not limited to hyperbilirubinemia, hepatomegaly, ascites, and weight gain >5%), who consented to participate in the study. In addition, patients who were prescribed defibrotide for purposes other than the approved indication (eg, VOD/SOS prophylaxis, treatment of non-severe VOD/SOS or thrombotic microangiopathy) and consented to participate were registered and information collected. There were no specific exclusion criteria; however, treating physicians were alerted to contraindications, special warnings, and precautions detailed in the defibrotide summary of product characteristics. After inclusion, patient information was collected from participating centers at 100 days, 6 months, and 12 months post-HCT. The primary objective was to assess the incidence of specific serious adverse events (SAEs) of interest, which were hemorrhage and site of bleeding, hypotension, coagulopathy, allergic or hypersensitivity reactions, injection-site reaction, infection and septicemia, and thromboembolic events. Secondary endpoints included Day 100 survival, and overall rate of VOD/SOS (and MOF, if present) resolution (based on standard criteria). Summary statistics were calculated for baseline data and safety variables; outcome analyses are descriptive. Here we report an analysis of data with a cutoff of June 18, 2019. Database lock is planned for October 2019, and the presentation will be updated to include the final data. A total of 61 patients with severe VOD/SOS were included; MOF was diagnosed at registration in 34 (56%) patients. The median age of patients with severe VOD/SOS was 14.4 (range: 0-68) years, 34 (56%) aged An SAE of interest occurred in 19 (31%; 95% confidence interval [CI]: 20%-43%) patients with severe VOD/SOS. The most common SAEs of interest by category were infection (n = 13 [21%; 95% CI: 11%-32%]) and bleeding events (n = 8 [13%; 95% CI: 5%-22%]). The most common individual SAEs of interest (≥5% of patients) were pneumonia (8%), gastrointestinal bleeding (8%), and sepsis (5%). Death occurred in 30 (49%) patients within 1 year, with VOD/SOS indicated as a cause of death in 13/30 (43%) patients. The Kaplan-Meier-estimated survival rate at Day 100 for patients diagnosed with severe VOD/SOS post-HCT who were treated with defibrotide was 74% (95% CI: 61%-83%). At latest follow-up, the survival rate was 51%, with median Kaplan-Meier-estimated survival post-HCT not yet reached. VOD/SOS resolved in 46 (75%) patients; the cumulative rate of VOD/SOS resolution at Day 100 was 87% (95% CI: 72%-94%). Resolution of MOF was achieved in 19/34 (56%) patients who had MOF at VOD/SOS diagnosis. In conclusion, among patients with severe VOD/SOS post-HCT (with/without MOF), the incidence of SAEs of interest was consistent with that observed in previous defibrotide clinical trials. Treatment with defibrotide resulted in high rates of Day 100 survival and VOD/SOS resolution. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Blaise:Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Pierre Fabre medicaments: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Hanvesakul:Jazz Pharmaceuticals: Employment, Equity Ownership. Ryan:Jazz Pharmaceuticals: Employment, Equity Ownership. Lawson:Jazz Pharmaceuticals: Consultancy, Honoraria.

Background: Fanconi anemia (FA) is the most frequent genetic cause of bone marrow failure (BMF) due to a DNA repair mechanism defect. The natural history of FA is marked by progressive BMF during early childhood. Throughout life, the hematopoietic situation may change by clonal evolution toward myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure in FA patients. The role of HSCT for FA patients with AML or advanced MDS is less defined. Currently, HSCT first line result offers 50% Overall Survival (OS) for patients with cytogenetic abnormalities only and 30% OS for patients with advanced MDS or AML in FA (Ayas et al., JCO 2013; Mitchell et al., BJH 2014). We previously reported a FLAG-sequential approach in 6 patients with FA (5 AML and 1 advanced MDS), all alive at a median follow-up of 28 months (Talbot et al., Hematologica 2014). We update here those patients and report 12 more patients treated by FLAG-sequential since then. Materials & Methods: This retrospective study (2006-2019) was conducted in 7 centers in France and Brazil on behalf of the French Reference Center for Aplastic Anemia to evaluate FLAG-sequential in FA patients with morphological clonal evolution (no patients with cytogenetic abnormalities only). The study was conducted in accordance with the Declaration of Helsinki. Anonymous data collection was declared to the appropriate authorities. The FLAG-sequential treatment consisted of FLAG, Fludarabine 30 mg/m²/d for five days and Cytarabine 1 g/m²x2/d with G-CSF for five days, which was followed three weeks later by Cyclophosphamide 10 mg/kg/d for four days, Fludarabine 30 mg/m²/d for four days and TBI 2 Gy (Fig 1A). In a haploidentical setting, Cyclophosphamide at 30 mg/kg/d was performed only in post-transplantation, at Days +4 and +5 (Fig 1B). Results: Eighteen patients were included with 14 AML, 1 acute lymphoblastic leukemia (ALL), and 3 RAEB-2 (Table 1). The median age at the time of HSCT was 22 years (4-37 years). Fifteen patients (83%) were older than 10 years at the time of HSCT. The median follow-up was 31 months (3- 153 months). Eight patients (44%) had complex karyotype. None of the included patients had a history of solid malignancies before HSCT. All patients engrafted. The cumulative incidence of neutrophil engraftment at Day 60 was 94% (95% CI 63-100%) with a median of 18 days (12-343 days). The cumulative incidence of platelet engraftment at Day 60 was 83% (95% CI 50%-96%) with a median of 25 days (17-245 days). The donor chimerism was complete at Day +100 for 15 patients. The three patients without full donor chimerism at Day +100 either had a relapse (n=1) and 2 early deaths before Day+100 from steroid-refractory aGVHD (n=1) or septic shock (n=1). None of the patients received a second HSCT. Non-relapse mortality (NRM) at 3 years was 32% (95% CI 6-58%) (Fig 2). Cumulative incidence of grades II to IV aGVHD was 56% (35% grades III to IV). Cumulative incidence of extensive cGVHD was 16%. Infectious complications during HSCT include the following: CMV (n=8), EBV (n=2), adenovirus (n=4), BK virus (n=7), respiratory syncytial virus (n=1), candidaemias (n=2) and invasive aspergillosis (n=3). Progression free survival (PFS) and OS at 3 years were 53% (95%CI 32-89%) and 53% (95%CI 32-89%), respectively (Fig 2). Cumulative incidence of relapse at 3 years was 13% (95%CI 0-31%) (Fig 2). Seven patients died during the study. Causes of death were relapse (n=2), aGVHD (n=2), cGVHD (n=1), septic shock (n=1), and respiratory syncytial virus associated with invasive aspergillosis (n=1). GVHD-relapse free survival (GRFS) at 3 years was 48% (95%CI 29-78%). One patient had anal epidermoid carcinoma at 4 years after HSCT, which required multiple surgical ablations. Conclusion: With almost 3 years follow-up, which is long enough for our results to be considered robust, we report an OS and PFS of 53%, which compares favorably to historical controls since all of our 18 patients were treated with florid disease at time of HSCT (and not with cytogenetic abnormality only, known to be associated with a better prognosis). Toxicity is still a concern in this particular population of FA patients with notably a high rate of infectious complications. Future well designed prospective clinical trials will refine this sequential strategy, which appears promising in this particular difficult clinical situation. Disclosures Socie: Alexion: Consultancy. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

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 ).

Transplantation of 2 unrelated cord blood (UCB) units instead of 1 has a been proposed to increase the cell dose. We report a prospective a randomized study, designed to compare single-vs double-UCB a transplantation in children and young adults with acute leukemia in a remission or myelodysplasia. Eligible patients had at least two 4-6 a HLA-identical UCBs with >3x10(7) nucleated cells/kg for the first and a >1.5x10(7) for the second. The primary end point was the 2-year a cumulative incidence of transplantation strategy failure, a composite a end point including transplant-related mortality (TRM), engraftment a failure, and autologous recovery. Randomized patients who did not a proceed to transplantation due to refractory disease were considered a transplantation failures. A total of 151 patients were randomized and a included in the intent-to-treat analysis; 137 were transplanted. a Double-UCB transplantation did not decrease transplantation strategy a failure (23.4% 6 4.9% vs 14.9% +/- 4.2%). Two-year posttransplant a survival, disease-free survival, and TRM were 68.8% +/- 6.0%, 67.6% a +/- 6.0%, and 5.9% +/- 2.9% after single-unit transplantation a compared with 74.8% +/- 5.5%, 68.1% +/- 6.0%, and 11.6% +/- 3.9% a after double-unit transplantation. The final relapse risk did not a significantly differ, but relapses were delayed after double-unit a transplantation. Overall incidences of graft-versus-host disease (GVHD) a were similar, but chronic GVHD was more frequently extensive after a double-UCB transplantation (31.9% +/- 5.7% vs 14.7% +/- 4.3%, a P=.02). In an exploratory subgroup analysis, we found a significantly a lower relapse risk after double-unit transplantation in patients a receiving total body irradiation without antithymocyte globulin (ATG), a whereas the relapse risk was similar in the group treated with busulfan, a cyclophosphamide, and ATG. Single-UCB transplantation with adequate cell a dose remains the standard of care and leads to low TRM. Double-unit a transplantation should be reserved for patients who lack such units. a This trial was registered at www. clinicaltrials. gov as #NCT01067300.

The aim of this study was to test the association between hematological/genetic factors and cerebral vasculopathy in children with sickle cell anemia (SCA). A group with cerebral vasculopathy (VASC) was composed of children who had stroke (n = 6), silent infarct (n = 11), or an abnormal transcranial Doppler (n = 5). Eighty-four patients had neither positive history of stroke or silent infarct, nor abnormal transcranial Doppler (NORM group). An intermediate group (COND; n = 15) was composed of SCA children with a conditional transcranial Doppler. Biological analyses were performed on samples obtained at steady state and before the beginning of any chronic treatment. The comparisons of the three groups demonstrated a protective effect of α-thalassemia against cerebral vasculopathy through its effects on hemoglobin and reticulocyte levels. Moreover, we observed higher frequency of G6PD deficiency in the VASC group compared with the other groups. Our study confirms the key role of α-thalassemia and G6PD status in the pathophysiology of cerebral vasculopathy in SCA children.

L’architecture de reconstruction du Havre, œuvre de l’architecte Auguste Perret, inscrite sur la liste du patrimoine mondial de l’Unesco en 2005, est un exemple intéressant d’une patrimonialisation orchestrée par les experts (nationaux et internationaux) et le pouvoir local : les premiers étant conscients de la valeur intrinsèque de l’œuvre de Perret et de la place qu’elle occupe dans l’histoire de l’architecture contemporaine ; les seconds étant persuadés que l’inscription du Havre pourrait permettre de disposer d’un outil de valorisation et de reconstruction identitaire de cette ville-martyre. Dans ce processus de patrimonialisation du Havre, que nous pouvons qualifier de top-down, la population Havraise a été quasiment absente. Ce processus correspond par conséquent à une dynamique portée par des acteurs extérieurs et instrumentalisée par le politique, mais dans laquelle les résidents ont joué un rôle marginal. Nous avons souhaité nous poser la question de l’évolution de ce schéma de patrimonialisation. La littérature de plus en plus abondante sur le patrimoine mondial semble confirmer que celui-ci agit comme un formidable moteur à différents niveaux : économique, identitaire, touristique et ce sont ces entrées que nous avons explorées dans le cadre de cet article. Nous faisons l’hypothèse d’une patrimonialisation sans appropriation qui, cinq ans après l’inscription, continue à fonctionner par l’intermédiaire du regard extérieur : le regard touristique tend aujourd’hui à succéder au regard des experts. The architecture of reconstruction of Le Havre, work of the architect Auguste Perret, inscribed in 2005 at the Unesco World Heritage list, is an interesting example of heritage building orchestrated by national and international experts and by the local power: the first being aware of the merits of Perret’s architecture and the latter convinced that Le Havre listing could provide a recovery tool for the reconstruction of the identity of this martyr city. In this process, we can qualify for top-down, Le Havre residents was virtually absent. Le Havre heritage-building process is therefore an impulse coming from “outsiders” and instrumented by the local power, but in which residents have played a marginal role. We wished in this paper to examine the evolution of this heritage-building schema. A more and more abundant literature on World Heritage seems to confirm that the latter acts as apowerful and positive engine at different levels: economic, identity, tourism; these are the entries we explore in this paper. We make the hypothesis of a heritage-building process without appropriation that, 5 years after the listing, continues to operate thanks to the external insight: the tourist gaze today tends to succeed to the one of the experts.

Results: 22 of 51 patients (43%) experienced clinically significant weight loss. For all patients, a simple model using late stage disease only performed best: sensitivity, 91%; specificity, 41%; PPV, 54%; NPV, 86%. In patients treated with curative intent, a model using late stage disease and concurrent chemotherapy performed best: sensitivity, 94%; specificity, 55%; PPV, 60%; NPV, 92%. Conclusion: A simple risk prediction model based on disease stage was modestly effective in predicting patients likely to experience clinically significant weight loss. It successfully identified most patients who did not experience 5% weight loss, but only half those identified as ‘at risk’ subsequently experienced 5% weight loss. In patients receiving curative radiotherapy, a model based on late stage disease and concurrent chemotherapy performed similarly.