Publications by authors named "Thierry Leblanc"

139 Publications

COVID-19 Crisis Reduces Free Tropospheric Ozone Across the Northern Hemisphere.

Geophys Res Lett 2021 Mar 26;48(5):e2020GL091987. Epub 2021 Feb 26.

NOAA ESRL Global Monitoring Laboratory Boulder CO USA.

Throughout spring and summer 2020, ozone stations in the northern extratropics recorded unusually low ozone in the free troposphere. From April to August, and from 1 to 8 kilometers altitude, ozone was on average 7% (≈4 nmol/mol) below the 2000-2020 climatological mean. Such low ozone, over several months, and at so many stations, has not been observed in any previous year since at least 2000. Atmospheric composition analyses from the Copernicus Atmosphere Monitoring Service and simulations from the NASA GMI model indicate that the large 2020 springtime ozone depletion in the Arctic stratosphere contributed less than one-quarter of the observed tropospheric anomaly. The observed anomaly is consistent with recent chemistry-climate model simulations, which assume emissions reductions similar to those caused by the COVID-19 crisis. COVID-19 related emissions reductions appear to be the major cause for the observed reduced free tropospheric ozone in 2020.
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http://dx.doi.org/10.1029/2020GL091987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995013PMC
March 2021

COVID19 and acute lymphoblastic leukemias of children and adolescents: Updated recommendations (Version 2) of the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE).

Bull Cancer 2021 May 11;108(5):490-500. Epub 2021 Mar 11.

Université de Paris, service d'hémato-immunologie pédiatrique, hôpital universitaire Robert-Debré (APHP), boulevard Sérurier, 75019 Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bulcan.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951944PMC
May 2021

Should treatment of ALK-positive anaplastic large cell lymphoma be stratified according to minimal residual disease?

Pediatr Blood Cancer 2021 Jun 9;68(6):e28982. Epub 2021 Mar 9.

Children and Adolescent Oncology Department, Gustave Roussy Cancer Campus, Paris-Saclay University, Villejuif, France.

In anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALK+ ALCL), positive minimal residual disease (MRD+) after the first chemotherapy course was proven of strong prognostic significance. We aimed to validate these results in 138 French patients. Eighty-seven patients had a detectable minimal disseminated disease at diagnosis (MDD+). Early MRD assessment was performed in 33 of 87 patients and was positive in 18 and negative in 15 (MRD-). Three-year progression-free survival was significantly correlated with the MDD/MRD status: 81.1% in MDD-, 69.6% in MDD+/MRD-, and 15.2% in MDD+/MRD+ patients. In conclusion, we confirmed on an independent cohort that the MDD/MRD status has strong prognosis significance in ALK+ ALCL.
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http://dx.doi.org/10.1002/pbc.28982DOI Listing
June 2021

Assessment of Waldeyer's ring in pediatric and adolescent Hodgkin lymphoma patients-Importance of multimodality imaging: Results from the EuroNet-PHL-C1 trial.

Pediatr Blood Cancer 2021 Apr 3;68(4):e28903. Epub 2021 Feb 3.

Department of Radiation Oncology, University Hospital Vienna, Vienna, Austria.

Background: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging.

Patients, Materials, And Methods: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment.

Results: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient.

Conclusions: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.
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http://dx.doi.org/10.1002/pbc.28903DOI Listing
April 2021

Hypoxia favors chemoresistance in T-ALL through an HIF1α-mediated mTORC1 inhibition loop.

Blood Adv 2021 01;5(2):513-526

Team Niche and Cancer in Hematopoiesis, Unité 1274, INSERM, Fontenay-aux-Roses, France.

Resistance to chemotherapy, a major therapeutic challenge in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), can be driven by interactions between leukemic cells and the microenvironment that promote survival of leukemic cells. The bone marrow, an important leukemia niche, has low oxygen partial pressures that highly participate in the regulation of normal hematopoiesis. Here we show that hypoxia inhibits T-ALL cell growth by slowing down cell cycle progression, decreasing mitochondria activity, and increasing glycolysis, making them less sensitive to antileukemic drugs and preserving their ability to initiate leukemia after treatment. Activation of the mammalian target of rapamycin (mTOR) was diminished in hypoxic leukemic cells, and treatment of T-ALL with the mTOR inhibitor rapamycin in normoxia mimicked the hypoxia effects, namely decreased cell growth and increased quiescence and drug resistance. Knocking down (KD) hypoxia-induced factor 1α (HIF-1α), a key regulator of the cellular response to hypoxia, antagonized the effects observed in hypoxic T-ALL and restored chemosensitivity. HIF-1α KD also restored mTOR activation in low O2 concentrations, and inhibiting mTOR in HIF1α KD T-ALL protected leukemic cells from chemotherapy. Thus, hypoxic niches play a protective role of T-ALL during treatments. Inhibition of HIF-1α and activation of the mTORC1 pathway may help suppress the drug resistance of T-ALL in hypoxic niches.
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http://dx.doi.org/10.1182/bloodadvances.2020002832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839374PMC
January 2021

Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden.

Haematologica 2021 Jan 14. Epub 2021 Jan 14.

Pediatric Oncology Immunology Hematology Unit, Armand-Trousseau University Hospital, AP-HP, Paris.

Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IMs). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS'CEREVANCE cohort. Median age at final follow-up was 18.5 (6.8-50.0) years and the median follow-up period was 11.3 (5.1-38.0) years. At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IMs increased with age: at 20 years old, 74% had at least one clinical cIM. A wide range of cIMs occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IMs. The number of cIMs was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio, 1.4; 95% confidence interval, 1.15-1.60; p = 0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 (1.7-31.5) years, and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, longterm outcomes of pES showed remission of cytopenias but frequent IMs linked to high secondline treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.
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http://dx.doi.org/10.3324/haematol.2020.271106DOI Listing
January 2021

Prospective Evaluation of the First Option, Second-Line Therapy in Childhood Chronic Immune Thrombocytopenia: Splenectomy or Immunomodulation.

J Pediatr 2021 04 17;231:223-230. Epub 2020 Dec 17.

Pediatric Hematology Unit, CIC1401, INSERM CICP, University Hospital of Bordeaux, Bordeaux, France; Centre de Référence National des Cytopénies Autoimmunes de l'Enfant (CEREVANCE), University Hospital of Bordeaux, Bordeaux, France. Electronic address:

Objective: To describe 4 subgroups of pediatric patients treated with splenectomy, hydroxychloroquine, azathioprine, or rituximab as the first-option, second-line treatment for chronic immune thrombocytopenia.

Study Design: Selection of patients with chronic immune thrombocytopenia from the French national prospective cohort of pediatric autoimmune cytopenia OBS'CEREVANCE and VIGICAIRE study, treated by splenectomy, hydroxychloroquine, azathioprine, or rituximab as a first second-line treatment.

Results: For 137 patients, treated between 1989 and 2016, the median follow-up after diagnosis and after treatment initiation was 8.5 (2.8-26.4) years and 4.7 (1.1-25.1) years, respectively. Median age at diagnosis and at initiation of treatment were 9 (0.7; 16) and 12 (2; 18.1) years, respectively without significant difference between subgroups. For the whole cohort, 24-month event-free survival was 62% (95% CI 55; 71). It was 85% (95% CI 77; 95) for the 56 patients treated with splenectomy, 60% (95% CI 44; 84) for the 23 patients treated with rituximab, 46% (95% CI 30; 71) for the 24 patients treated with azathioprine, and 37% (95% CI 24; 59) for the 34 patients treated with hydroxychloroquine (log-rank P < .0001). For the splenectomy subgroup, being older than 10 years at splenectomy tended to improve event-free survival (P = .05). Female teenagers with antinuclear antibody positivity benefited from hydroxychloroquine therapy.

Conclusions: This national study, limiting pitfalls in the analysis of the effects of second-line therapies, showed that splenectomy remains the treatment associated with the better response at 24 months.
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http://dx.doi.org/10.1016/j.jpeds.2020.12.018DOI Listing
April 2021

Frequent altered distribution of peripheral B-lymphocyte subsets in pediatric and adolescent patients with classical Hodgkin lymphoma.

Leuk Lymphoma 2021 02 23;62(2):300-307. Epub 2020 Oct 23.

Université Paris-Saclay, UVSQ, Univ. Paris-Sud, Inserm, Équipe "Exposome et Hérédité", CESP, Villejuif, France.

Peripheral lymphopenia is a well-known negative prognostic marker in classical Hodgkin lymphoma (cHL). We characterized the peripheral B-cell compartment in a prospective cohort of 83 pediatric cHL patients. We observed significantly low total B-cell counts (<100 cells/µl) in 31 of 83 patients (37%). More specifically, there was a smaller peripheral IgDCD27 naïve B-cell pool among B-cell lymphopenic patients than for non-B-cell lymphopenic patients ( < 0.01). The B-cell count was lower in patients without Epstein Barr Virus EBV) expression than among those with EBV expression ( = 0.03). Peripheral B-cell lymphopenia was associated with the presence of poor prognostic features, such as advanced lymphoma stage ( < 0.01) and the presence of B symptoms ( = 0.04). Of interest, B-cell lymphopenia resolved in all six studied patients in long-term remission. Our findings support that cHL tumor-associated factors interfere with the distribution of peripheral B-cell subsets.
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http://dx.doi.org/10.1080/10428194.2020.1834090DOI Listing
February 2021

T-Cell Acute Lymphoblastic Leukemia in a Young Adult With Thrombocytopenia-absent Radius Syndrome: A Case Report and Review of the Literature.

J Pediatr Hematol Oncol 2020 Aug 18. Epub 2020 Aug 18.

Hematology Adolescent and Young Adults Unit, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris.

Thrombocytopenia-absent radius (TAR) syndrome is a rare inherited bone marrow failure syndrome not generally associated with acute leukemia. The authors report a case of T-cell acute lymphoblastic leukemia in an adult female individual newly diagnosed with TAR syndrome. A 347-kb microdeletion of chromosome 1q21.1 involving the RBM8A gene was detected within a gain of whole chromosome 1. Next-generation sequencing on fibroblasts confirmed germline heterozygous deletion of RBM8A but on the other allele, noncoding low-frequency regulatory single-nucleotide polymorphism of RBM8A (rs139428292; rs201779890) were not found. The tolerance of the treatment was unusual and mostly marked by a slow hematopoietic recovery leading to a 6-month delay at the beginning of the maintenance phase. Only 5 cases of acute leukemia were reported in patients with TAR syndrome in the literature: 4 acute myeloid leukemia and one B-cell acute lymphoblastic leukemia. This is the first report of T-cell acute lymphoid leukemia occurring in the context of TAR syndrome.
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http://dx.doi.org/10.1097/MPH.0000000000001919DOI Listing
August 2020

In childhood mature B-NHL with CNS disease, patients with blasts in cerebrospinal fluid are at higher risk of failure.

Blood Adv 2020 08;4(15):3621-3625

Department of Pediatric and Adolescent Oncology, Gustave Roussy, Paris-Saclay University, Villejuif, France; and.

To identify the factors influencing outcome in childhood mature B-cell non-Hodgkin lymphoma and acute leukemia (B-NHL/AL) with central nervous system (CNS) disease (CNS+), we analyzed patients <18 years with newly diagnosed B-NHL/AL registered in 3 Lymphomes Malins B studies in France between 1989 to 2011. CNS+ was diagnosed on fulfillment of ≥1 of the following criteria: any L3 cerebrospinal fluid (CSF) blasts (CSF+), cranial nerve palsy, isolated intracerebral mass but also clinical spinal cord compression, and cranial or spinal parameningeal extension. Two hundred seventeen out of 1690 patients (12.8%) were CNS+. CNS+ was significantly associated with male gender, head/neck locations, Burkitt histology, high initial lactate dehydrogenase (LDH) level, and bone marrow involvement. CSF+ was the most frequent pattern of CNS+ (45%). For the 217 CNS+ patients, the 5-year event-free survival (EFS) and overall survival rates (95% confidence interval) were 81.5% (75.8% to 86.1%) and 83.9% (78.4% to 88.2%), respectively. In multivariate analysis, among CNS+ patients, low EFS was associated with CSF+, high initial LDH level, and poor response to cyclophosphamide, oncovin (vincristine), prednisone prephase. These findings have been considered for patient's stratification in the international randomized phase 3 trial Inter-B-NHL-ritux 2010 for children and adolescents with high-risk B-NHL/AL with CNS+ CSF+ patients only receiving intensified chemotherapy.
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http://dx.doi.org/10.1182/bloodadvances.2019001398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422110PMC
August 2020

Diamond-Blackfan anemia.

Blood 2020 09;136(11):1262-1273

Laboratory of Red Cell Physiology, New York Blood Center, New York, NY.

Diamond-Blackfan anemia (DBA) was the first ribosomopathy described and is a constitutional inherited bone marrow failure syndrome. Erythroblastopenia is the major characteristic of the disease, which is a model for ribosomal diseases, related to a heterozygous allelic variation in 1 of the 20 ribosomal protein genes of either the small or large ribosomal subunit. The salient feature of classical DBA is a defect in ribosomal RNA maturation that generates nucleolar stress, leading to stabilization of p53 and activation of its targets, resulting in cell-cycle arrest and apoptosis. Although activation of p53 may not explain all aspects of DBA erythroid tropism, involvement of GATA1/HSP70 and globin/heme imbalance, with an excess of the toxic free heme leading to reactive oxygen species production, account for defective erythropoiesis in DBA. Despite significant progress in defining the molecular basis of DBA and increased understanding of the mechanistic basis for DBA pathophysiology, progress in developing new therapeutic options has been limited. However, recent advances in gene therapy, better outcomes with stem cell transplantation, and discoveries of putative new drugs through systematic drug screening using large chemical libraries provide hope for improvement.
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http://dx.doi.org/10.1182/blood.2019000947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483438PMC
September 2020

Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome.

Blood 2020 10;136(17):1956-1967

Service d'Hématologie Biologique, Hospices Civils de Lyon, Lyon, France.

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.
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http://dx.doi.org/10.1182/blood.2019004776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582559PMC
October 2020

COVID-19 and acute lymphoblastic leukemias of children and adolescents: First recommendations of the Leukemia committee of the French Society for the fight against Cancers and Leukemias in children and adolescents (SFCE).

Bull Cancer 2020 Jun 30;107(6):629-632. Epub 2020 Apr 30.

Hôpital Universitaire Robert-Debré AP-HP, Université de Paris, service d'hémato-immunologie pédiatrique, Paris, France.

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.
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http://dx.doi.org/10.1016/j.bulcan.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190519PMC
June 2020

Favorable outcomes of hematopoietic stem cell transplantation in children and adolescents with Diamond-Blackfan anemia.

Blood Adv 2020 04;4(8):1760-1769

Robert Debré Hospital, Groupe Hospitalier, Assistance Publique-Hôpitaux de Paris Nord, Université de Paris, Paris, France.

Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia associated with congenital abnormalities and cancer predisposition. Allogeneic hematopoietic stem cell transplantation (HSCT) can correct the hematological phenotype and is indicated in transfusion-dependent patients. In 70 children reported to the German DBA and French HSCT registries, HSCT was performed from 1985 to 2017. Median age at HSCT was 5.5 years (range, 0.9-17.3 years). Two-thirds of patients (64%) were transplanted from a matched sibling donor (MSD), and most procedures were performed after the year 1999 (73%). Primary engraftment was achieved in all patients. One patient developed secondary graft failure. Cumulative incidence of acute graft-versus-host disease (GVHD) was 24% for °II-IV (95% confidence interval [CI], 16% to 37%) and 7% for °III-IV (95% CI, 3% to 17%); cumulative incidence of chronic GVHD was 11% (95% CI, 5% to 22%). The probability of chronic GVHD-free survival (cGFS) was 87% (95% CI, 79% to 95%) and significantly improved over time (<2000: 68% [95% CI, 47% to 89%] vs ≥2000: 94% [95% CI, 87% to 100%], P < .01). cGFS was comparable following HSCT from a MSD and an unrelated donor (UD). Of note, no severe chronic GVHD or deaths were reported following MSD-HSCT after 1999. The difference of cGFS in children transplanted <10 years of age compared with older patients did not reach statistical significance (<10 years: 90% [95% CI, 81% to 99%] vs 10-18 years 78% [95% CI, 58% to 98%]). In summary, these data indicate that HSCT is efficient and safe in young DBA patients and should be considered if a MSD or matched UD is available. HSCT for transfusion dependency only must be critically discussed in older patients.
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http://dx.doi.org/10.1182/bloodadvances.2019001210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189291PMC
April 2020

Genotype-phenotype association and variant characterization in Diamond-Blackfan anemia caused by pathogenic variants in .

Haematologica 2021 05 1;106(5):1303-1310. Epub 2021 May 1.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.

Diamond Blackfan anemia (DBA) is predominantly an autosomal dominant inherited red cell aplasia primarily caused by pathogenic germline variants in ribosomal protein genes. DBA due to pathogenic RPL35A variants has been associated with large 3q29 deletions and phenotypes not common in DBA. We conducted a multi-institutional genotype-phenotype study of 45 patients with DBA associated with pathogenic RPL35A germline variants and curated the variant data on 21 additional cases from the literature. Genotype-phenotype analyses were conducted comparing patients with large deletions versus all other pathogenic variants in RPL35A. Twenty-two of the 45 cases had large deletions in RPL35A. After adjusting for multiple tests, a statistically significant association was observed between patients with a large deletion and steroid-resistant anemia, neutropenia, craniofacial abnormalities, chronic gastrointestinal problems, and intellectual disabilities (p<0.01) compared with all other pathogenic variants. Non-large deletion pathogenic variants were spread across RPL35A with no apparent hot spot and 56% of the individual family variants were observed more than once. In this, the largest known study of DBA patients with pathogenic RPL35A variants, we determined that patients with large deletions have a more severe phenotype that is clinically different from those with non-large deletion variants. Genes of interest also deleted in the 3q29 region that could be associated with some of these phenotypic features include LMLN and IQCG. Management of DBA due to large RPL35A deletions may be challenging due to complex problems and require comprehensive assessments by multiple specialists including immunologic, gastrointestinal, and developmental evaluations to provide optimal multidisciplinary care.
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http://dx.doi.org/10.3324/haematol.2020.246629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094096PMC
May 2021

Second-line treatment trends and long-term outcomes of 392 children with chronic immune thrombocytopenic purpura: the French experience over the past 25 years.

Br J Haematol 2020 06 4;189(5):931-942. Epub 2020 Mar 4.

Pediatric Hematology Unit, CIC1401, INSERM CICP, University Hospital of Bordeaux, Bordeaux, France.

Childhood chronic immune thrombocytopenic purpura (cITP) is a rare disease. In severe cases, there is no evidence for the optimal therapeutic strategy. Our aim was to describe the real-life management of non-selected children with cITP at diagnosis. Since 2004, patients less than 18 years old with cITP have been enrolled in the national prospective cohort, OBS'CEREVANCE. From 1990 to 2014, in 29 centres, 392 children were diagnosed with cITP. With a median follow-up of six years (2·0-25), 45% did not need second-line therapy, and 55% (n = 217) received one or more second lines, mainly splenectomy (n = 108), hydroxychloroquine (n = 61), rituximab (n = 61) or azathioprine (n = 40). The overall five-year further second-line treatment-free survival was 56% [95% CI 49·5-64.1]. The use of splenectomy significantly decreased over time. Hydroxychloroquine was administered to children with positive antinuclear antibodies, more frequently older and girls, and reached 55% efficacy. None of the patients died. Ten years after the initial diagnosis, 55% of the 56 followed children had achieved complete remission. Children with cITP do not need second-line treatments in 45% of cases. Basing the treatment decision on the pathophysiological pathways is challenging, as illustrated by ITP patients with positive antinuclear antibodies treated with hydroxychloroquine.
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http://dx.doi.org/10.1111/bjh.16448DOI Listing
June 2020

Risk and Response Adapted Treatment Guidelines for Managing First Relapsed and Refractory Classical Hodgkin Lymphoma in Children and Young People. Recommendations from the EuroNet Pediatric Hodgkin Lymphoma Group.

Hemasphere 2020 02 10;4(1):e329. Epub 2020 Jan 10.

University of Edinburgh and Department of Pediatrics, Royal Hospital for Sick Children, Edinburgh, Scotland, UK.

The objective of this guideline is to aid clinicians in making individual salvage treatment plans for pediatric and adolescent patients with first relapse or refractory (R/R) classical Hodgkin lymphoma (cHL). While salvage with standard dose chemotherapy followed by high dose chemotherapy and autologous stem cell transplant is often considered the standard of care in adult practice, pediatric practice adopts a more individualized risk stratified and response adapted approach to salvage treatment with greater use of non-transplant salvage. Here, we present on behalf of the EuroNet Pediatric Hodgkin Lymphoma group, evidence and consensus-based guidelines for standardized diagnostic, prognostic and response procedures to allocate children and adolescents with R/R cHL to stratified salvage treatments.
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http://dx.doi.org/10.1097/HS9.0000000000000329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000476PMC
February 2020

Management of childhood aplastic anemia following liver transplantation for nonviral hepatitis: A French survey.

Pediatr Blood Cancer 2020 04 11;67(4):e28177. Epub 2020 Jan 11.

Department of Pediatric Hematology and Immunology, AP-HP, Robert-Debré Hospital, Paris, France.

Background: Hepatitis-associated aplastic anemia (AA) is a rare syndrome combining acute hepatitis of variable severity and AA. Hepatitis may be severe enough to require urgent liver transplantation (LT). Herein, we describe clinical presentation and management of a cohort of pediatric patients diagnosed with AA after undergoing LT for nonviral hepatitis.

Methods: To describe this rare clinical situation, we performed a national survey and identified nine children treated for AA following LT during the last 10 years in France.

Results: All patients were treated first for hepatic failure with urgent LT. AA was diagnosed with a median delay of 34 days [21-200] from the diagnosis of hepatitis. Seven children were treated with antithymocyte globulin/cyclosporine, one with CSA alone and one received bone marrow transplantation. At the last visit (median follow-up: 4 years), outcomes were excellent: all patients were alive and in hematological remission (complete remission: 7; partial remission: 2). Immunosuppressive therapy was pursued in all patients due to the liver transplant. No unusual toxicities were reported.

Conclusion: AA after LT is considered a therapeutic challenge. Nevertheless, hematological outcome is good using a standard immunosuppressive approach.
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http://dx.doi.org/10.1002/pbc.28177DOI Listing
April 2020

Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism.

Nucleic Acids Res 2020 01;48(2):770-787

Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.
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http://dx.doi.org/10.1093/nar/gkz1042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954397PMC
January 2020

Maintenance Therapy With Interleukin-2 for Childhood AML: Results of ELAM02 Phase III Randomized Trial.

Hemasphere 2018 Dec 29;2(6):e159. Epub 2018 Nov 29.

Department of Pediatric Hematology and Oncology, Assistance Publique-Hôpitaux de Paris, GH HUEP, Armand Trousseau Hospital, Paris, France; Sorbonne Université, UMRS_938, Paris, France.

Despite significant progress in the treatment of pediatric acute myeloblastic leukemia (AML), relapse remains the commonest cause of death. Randomized ELAM02 trial questioned if maintenance therapy with interleukin-2 (IL2), for 1 year, improves disease-free survival (DFS). Patients aged 0 to 18 years, with newly diagnosed AML (excluding patients with acute promyelocytic leukemia or down syndrome AML) were enrolled. They received 1 course of induction treatment (cytarabine and mitoxantrone) and 3 courses of consolidation treatment (high-dose cytarabine in courses 1 and 3). According to the cytogenetics risk, patients not undergoing hematopoietic stem cell transplantation, still in complete remission (CR) after the third course of consolidation treatment, were eligible for randomization to 1 year of maintenance therapy with monthly courses of IL2 or no maintenance treatment. There were 438 evaluable patients, 154 of whom were randomized to the IL2/no maintenance groups. Relapse occurred in 28 patients from the IL2+ group and 29 patients in the IL2- group. Survival was similar in the 2 groups, with a 4-year DFS of 62% without IL2 and 66% with IL2 ( = 0.75). In the CBF population, 4-year DFS was 55% without IL2 and 78% with IL2 ( = 0.07). No deaths from toxicity or excess of serious adverse events related to IL2 treatment were recorded. Prolonged IL2 for maintenance therapy after intensive chemotherapy is feasible and safe in pediatric AML patients in their first CR. Such treatment did not improve DFS in this study, but a positive trend was observed in favor of IL2 maintenance therapy among core binding factor acute myeloblastic leukemia.
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http://dx.doi.org/10.1097/HS9.0000000000000159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745961PMC
December 2018

Managing the Unusual Causes of Fetal Anemia.

Fetal Diagn Ther 2020 10;47(2):156-164. Epub 2019 Sep 10.

Department of Fetal Medicine, Hôpital Trousseau, Paris, France.

Background: Rare causes of fetal anemia requiring intrauterine transfusion (IUT) are challenging for fetal medicine specialists.

Objectives: The aim of this study was to describe the perinatal patterns and prognosis in a consecutive series of fetuses transfused for fetal anemia of rare or unknown etiology, and to propose a protocol of investigation for fetal anemia of undetermined cause and for the management of subsequent pregnancies.

Method: We conducted a retrospective descriptive study on fetuses transfused for severe anemia of rare or unknown etiology managed in our national referral center (Centre National de Référence d'Hémobiologie Périnatale) and born between 2010 and 2017.

Results: During the study period, 584 IUT were performed in 253 fetuses. Among those IUT, 23 (3.9%) were performed for a rare or unknown cause of anemia in 13 fetuses (5.1% of transfused fetuses). The median gestational age at diagnosis was 26 weeks of gestation (WG; range 21-33). Hemoglobin levels ranged from 1.6 to 9.1 g/dL (0.18-0.83 multiples of median) before the first IUT. The fetuses received between 1 and 6 IUT (39% received at least 2 IUT). The definitive etiologies for central anemia were: congenital syphilis, neonatal poikilocytosis, type II congenital dyserythropoietic anemia (CDA), and neonatal hemochromatosis. There was 1 case with suspected type I CDA and 1 with suspected Diamond-Blackfan anemia. There was 1 case of peripheral anemia, secondary to cerebral hemorrhages of different ages, related to a variant of the COL4A1 gene. In 6 fetuses corresponding to 4 mothers, no precise diagnosis was found despite a complete workup. In our series, there were 8 live births, 4 terminations of pregnancy, and 1 intrauterine fetal death.

Conclusions: Fetal anemia of rare or unknown diagnosis represents 5% of all transfused fetuses in our cohort. Fetal and neonatal anemias can be recurrent in further pregnancies, with variable expressivity.
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http://dx.doi.org/10.1159/000501554DOI Listing
November 2020

Genotype/phenotype correlations of childhood-onset congenital sideroblastic anaemia in a European cohort.

Br J Haematol 2019 11 23;187(4):530-542. Epub 2019 Jul 23.

CHU de Bordeaux, Hôpital Pellegrin, Bordeaux, France.

Congenital sideroblastic anaemia (CSA) is a rare disease caused by germline mutations of genes involved in haem and iron-sulphur cluster formation, and mitochondrial protein biosynthesis. We performed a retrospective multicentre European study of a cohort of childhood-onset CSA patients to explore genotype/phenotype correlations. We studied 23 females and 20 males with symptoms of CSA. Among the patients, the most frequently mutated genes were ALAS2 (n = 10; 23·3%) and SLC25A38 (n = 8; 18·6%), causing isolated forms of microcytic anaemia of varying severity. Five patients with SLC19A2 mutations suffered from thiamine-responsive megaloblastic anaemia and three exhibited the 'anaemia, deafness and diabetes' triad. Three patients with TRNT1 mutations exhibited severe early onset microcytic anaemia associated with thrombocytosis, and two exhibited B-cell immunodeficiency, inflammatory syndrome and psychomotor delay. The prognoses of patients with TRNT1 and SLC2A38 mutations were generally dismal because of comorbidities or severe iron overload. No molecular diagnosis could be established in 14/43 cases. This study emphasizes the frequency of ALAS2 and SLC25A38 mutations and provides the largest comprehensive analysis to date of genotype/phenotype correlations in CSA. Further studies of CSA patients with data recorded in an international registry would be helpful to improve patient management and establish standardized guidelines.
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http://dx.doi.org/10.1111/bjh.16100DOI Listing
November 2019

Outcome of relapse in children and adolescents with B-cell non-Hodgkin lymphoma and mature acute leukemia: A report from the French LMB study.

Pediatr Blood Cancer 2019 09 17;66(9):e27873. Epub 2019 Jun 17.

Department of Pediatric Oncology, Gustave Roussy Cancer Campus, Villejuif, France.

Introduction: In order to describe relapsed B-cell non-Hodgkin lymphoma and mature acute leukemia in children/adolescents treated with the Lymphomes Malins B (LMB) regimen and their outcome in the rituximab era, relapses in the French LMB2001 study were reviewed.

Methods: Between February 2001 and December 2011, 33 patients out of 773 (4.3%) relapsed; 27 had Burkitt lymphoma and six large B-cell histology. Median age at diagnosis was 10.1 years. One patient was initially treated in risk group A, 21 in group B, and 11 in group C.

Results: Median time to relapse after diagnosis was 4.5 months (range 2.4-13.6). Thirty-two patients received salvage therapy. Twenty-seven received rituximab mainly in addition to high-dose cytarabine and etoposide (n = 18) and/or ifosfamide, carboplatin, and etoposide (n = 7). First-line salvage chemotherapy response rate was 66% with 47% being complete remission (CR). Twenty-one patients received high-dose chemotherapy (HDC) followed by autologous (n = 13) or allogeneic (n = 8) transplant. With a median follow-up of 6.8 years, the 5-year survival rate after relapse was 36.4% (95% confidence interval [CI] 22-53%). Twelve patients were still alive; all but one (group A) received consolidation treatment. Achieving CR before consolidation was significantly associated with better survival, with a 5-year survival rate of 75% (95% CI 46.8-91.1%) for patients in CR before HDC, 33% (95% CI 9.7-70%) for patients in partial remission, and 0% for nonresponders (P = .033).

Conclusion: Survival of children/adolescents with mature B-cell lymphoma/leukemia remains poor after relapse with no apparent improvement with rituximab. Response rates to salvage chemo-immunotherapies are insufficient and new drugs are urgently needed to improve disease control.
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http://dx.doi.org/10.1002/pbc.27873DOI Listing
September 2019

Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes.

Blood 2019 07 2;134(1):9-21. Epub 2019 Apr 2.

Centre de Référence National des Cytopénies Auto-immunes de l'Enfant (CEREVANCE) and.

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (, , , , , , , , and ), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.
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http://dx.doi.org/10.1182/blood-2018-11-887141DOI Listing
July 2019

Regulation of globin-heme balance in Diamond-Blackfan anemia by HSP70/GATA1.

Blood 2019 03 30;133(12):1358-1370. Epub 2019 Jan 30.

INSERM U1149/ERL 8252, Inflammation Research Center, Paris, France.

Diamond-Blackfan anemia (DBA) is a congenital erythroblastopenia that is characterized by a blockade in erythroid differentiation related to impaired ribosome biogenesis. DBA phenotype and genotype are highly heterogeneous. We have previously identified 2 in vitro erythroid cell growth phenotypes for primary CD34 cells from DBA patients and following short hairpin RNA knockdown of RPS19, RPL5, and RPL11 expression in normal human CD34 cells. The haploinsufficient RPS19 in vitro phenotype is less severe than that of 2 other ribosomal protein (RP) mutant genes. We further documented that proteasomal degradation of HSP70, the chaperone of GATA1, is a major contributor to the defect in erythroid proliferation, delayed erythroid differentiation, increased apoptosis, and decreased globin expression, which are all features of the RPL5 or RPL11 DBA phenotype. In the present study, we explored the hypothesis that an imbalance between globin and heme synthesis may be involved in pure red cell aplasia of DBA. We identified disequilibrium between the globin chain and the heme synthesis in erythroid cells of DBA patients. This imbalance led to accumulation of excess free heme and increased reactive oxygen species production that was more pronounced in cells of the RPL5 or RPL11 phenotype. Strikingly, rescue experiments with wild-type HSP70 restored GATA1 expression levels, increased globin synthesis thereby reducing free heme excess and resulting in decreased apoptosis of DBA erythroid cells. These results demonstrate the involvement of heme in DBA pathophysiology and a major role of HSP70 in the control of balanced heme/globin synthesis.
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http://dx.doi.org/10.1182/blood-2018-09-875674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428670PMC
March 2019
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