Publications by authors named "Felipe Suarez"

157 Publications

CXCR4 signaling controls dendritic cell location and activation at steady-state and in inflammation.

Blood 2021 Jan 22. Epub 2021 Jan 22.

University Paris-Saclay, Clamart, France.

Dendritic cells (DCs) encompass several cell subsets that collaborate to initiate and regulate immune responses. Proper DC localization determines their function and requires the tightly controlled action of chemokine receptors. All DC subsets express CXCR4, but the genuine contribution of this receptor to their biology has been overlooked. We addressed this question using natural CXCR4 mutants resistant to CXCL12-induced desensitization and harboring a gain of function that cause the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) Syndrome (WS), a rare immunodeficiency associated with high susceptibility to the pathogenesis of human papillomavirus (HPV). We report a reduction in the number of circulating plasmacytoid DCs (pDCs) in WHIM patients, whereas that of conventional DCs is preserved. This pattern was reproduced in an original mouse model of WS, enabling us to show that the circulating pDC defect can be corrected upon CXCR4 blockade and that pDC differentiation and function are preserved, despite CXCR4 dysfunction. We further identified proper CXCR4 signaling as a critical checkpoint for Langerhans-cell and DC migration from the skin to lymph nodes, with corollary alterations of their activation state and tissue inflammation in a model of HPV-induced dysplasia. Beyond providing new hypotheses to explain the susceptibility of WHIM patients to HPV pathogenesis, this study shows that proper CXCR4 signaling establishes a migration threshold that controls DC egress from CXCL12-containing environments and highlights the critical and subset-specific contribution of CXCR4 signal termination to DC biology.
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http://dx.doi.org/10.1182/blood.2020006675DOI Listing
January 2021

Infections in Patients with Chronic Granulomatous Disease Treated with Tumor Necrosis Factor Alpha Blockers for Inflammatory Complications.

J Clin Immunol 2021 Jan 4;41(1):185-193. Epub 2020 Nov 4.

Department of Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, AP-HP, Paris, France.

Purpose: Management of inflammatory complications of chronic granulomatous disease (CGD) is challenging. The aim of this study was to assess safety, with a focus on infections, and effectiveness of tumor necrosis factor alpha (TNF-α) blockers in CGD patients.

Methods: A retrospective, single-center cohort study of CGD patients treated by anti-TNF-α agents at Necker-Enfants Malades University Hospital (Paris, France) and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH).

Results: Between 2006 and 2019, 14 (X-linked: n = 10, 71.4%; autosomal-recessive: n = 4, 28.6%) CGD patients with gastrointestinal (n = 12, 85.7%), pulmonary (n = 10, 71.4%), cutaneous (n = 3, 21.4%), and/or genitourinary (n = 2, 14.3%) inflammatory manifestations received one or more doses of infliximab because of steroid-dependent (n = 7, 50%), refractory (n = 4, 28.6%) inflammatory disease or as first-line drug (n = 2, 14.3%; missing data, n = 1). All patients received adequate antimicrobial prophylaxis. Infliximab achieved complete (n = 2, 14.3%) or partial (n = 9, 64.3%) response in 11 (78.6%) patients. Seven (50%) patients were switched to adalimumab. During anti-TNF-α treatment, 11 infections (pneumonia, adenitis, invasive candidiasis, each n = 2; intra-abdominal abscess, bacteremic salmonellosis, Pseudomonas aeruginosa-related folliculitis, cat-scratch disease, proven pulmonary mucormycosis, each n = 1) occurred in 7 (50%) patients. All infectious complications had a favorable outcome. Anti-TNF-α treatment was definitively stopped because of infection in two patients. Nine (64.3%) patients finally underwent hematopoietic stem cell transplantation. No death occurred during follow-up.

Conclusions: Anti-TNF-α treatment could improve the outcome of severe inflammatory complications in CGD patients, but increases their risk of infections. We suggest that anti-TNF-α treatment might be of short-term benefit in selected CGD patients with severe inflammatory complications awaiting hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1007/s10875-020-00901-8DOI Listing
January 2021

Measuring beta-galactose exposure on platelets: Standardization and healthy reference values.

Res Pract Thromb Haemost 2020 Jul 2;4(5):813-822. Epub 2020 Jun 2.

Department of Biological Hematology Hôpital Necker AP-HP Paris France.

Background: Correct diagnosis of the cause of thrombocytopenia is crucial for the appropriate management of patients. Hyposialylation/desialylation (characterized by abnormally high β-galactose exposure) accelerates platelet clearance and can lead to thrombocytopenia. However, the reference range for β-galactose exposure in healthy individuals has not been defined previously.

Objective: The objective of the present study was to develop a standardized assay of platelet β-galactose exposure for implementation in a clinical laboratory.

Methods: β-Galactose exposure was measured in platelet-rich plasma by using flow cytometry and agglutinin (RCA). A population of 120 healthy adults was recruited to study variability.

Results: We determined an optimal RCA concentration of 12.5 μg/mL. The measure was stable for up to 4 hours (mean fluorescence intensity [MFI]-RCA: 1233 ± 329 at 0 hour and 1480 ± 410 at 4 hours). The platelet count did not induce a variation of RCA and the measure of RCA was stable when tested up to 24 hours after blood collection (MFI-RCA: 1252 ± 434 at day 0 and 1140 ± 297 24 hours after blood sampling). To take into account the platelet size, results should be expressed as RCA/forward scatter ratio. We used the assay to study variability in 120 healthy adults, and we found that the ratio is independent of sex and blood group.

Conclusion: We defined a normal range in a healthy population and several preanalytical and analytical variables were evaluated, together with positive and negative controls. This assay may assist in the diagnosis of thrombocytopenic diseases linked to changes in β-galactose exposure.
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http://dx.doi.org/10.1002/rth2.12369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586713PMC
July 2020

Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies.

J Immunol 2020 Dec 28;205(11):2979-2987. Epub 2020 Oct 28.

Imagine Institute, University of Paris, 75015 Paris, France.

Mutations in two genes can result in activated PI3Kδ syndrome (APDS), a rare immunodeficiency disease with limited therapeutic options. Seletalisib, a potent, selective PI3Kδ inhibitor, was evaluated in patients with APDS1 and APDS2. In the phase 1b study (European Clinical Trials Database 2015-002900-10) patients with genetic and clinical confirmation of APDS1 or APDS2 received 15-25 mg/d seletalisib for 12 wk. Patients could enter an extension study (European Clinical Trials Database 2015-005541). Primary endpoints were safety and tolerability, with exploratory efficacy and immunology endpoints. Seven patients (median age 15 years; APDS1 = 3; APDS2 = 4) received seletalisib; five completed the phase 1b study. For the extension study, four patients entered, one withdrew consent (week 24), three completed ≥84 wk of treatment. In the phase 1b study, patients had improved peripheral lymphadenopathy ( = 2), lung function ( = 1), thrombocyte counts ( = 1), and chronic enteropathy ( = 1). Overall, effects were maintained in the extension. In the phase 1b study, percentages of transitional B cells decreased, naive B cells increased, and senescent CD8 T cells decreased (human cells); effects were generally maintained in the extension. Seletalisib-related adverse events occurred in four of seven patients (phase 1b study: hepatic enzyme increased, dizziness, aphthous ulcer, arthralgia, arthritis, increased appetite, increased weight, restlessness, tendon disorder, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (aphthous ulcer). Serious adverse events occurred in three of seven patients (phase 1b study: hospitalization, colitis, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (stomatitis). Patients with APDS receiving seletalisib had improvements in variable clinical and immunological features, and a favorable risk-benefit profile was maintained for ≤96 wk.
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http://dx.doi.org/10.4049/jimmunol.2000326DOI Listing
December 2020

Safety and efficacy of brentuximab vedotin as a treatment for lymphoproliferative disorders in primary immunodeficiencies.

Haematologica 2020 09 1;105(9):e461-464. Epub 2020 Sep 1.

Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris; Paris University, Paris; INSERM UMR 1163, Institut Imagine, Paris.

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http://dx.doi.org/10.3324/haematol.2019.230276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556515PMC
September 2020

Vascular access for optimal hematopoietic stem cell collection.

J Clin Apher 2021 Feb 27;36(1):12-19. Epub 2020 Aug 27.

Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: Autologous and allogeneic hematopoietic stem cell transplantation of cytokine-mobilized peripheral blood stem cells (PBSCs) is increasingly used to treat patients with hematologic disorders. Different types of vascular access have been exploited for the apheresis procedure, including peripheral veins (PV) and central venous catheter (CVC). In some cases, PV access is unavailable. There are few published data on the efficiency and quality of harvesting with different types of vascular access. This study brings out complications and morbidity of this procedure linked to these different access.

Methods: We performed a comparative, retrospective, single-center study of hematopoietic stem cell collection using these two types of vascular access. We compared the efficiency and complication rate for 617 adults apheresis sessions in 401 patients and healthy donors, for PBSC collection via PV or CVC between 2010 and 2016. The quality of the HSC product was evaluated in terms of the total CD34 + count and neutrophil contamination.

Results: The PV and CVC groups did not differ significantly in terms of the quality of the apheresis product, mean ± SD CD34 + cells collected in PV group was 383.1 ± 402.7 × 10e6 and 298.8 ± 372.7 × 10e6 and the level of neutrophil contamination was 21.0 ± 17.8% in the PV group and 20.6 ± 18.4% in the CVC group. The complication rate did not differ between the two groups.

Conclusion: The type of vascular access for apheresis hematopoietic stem cell harvesting must be determined by trained staff. Successful harvesting can be performed via PV then CVC is not needed or not available.
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http://dx.doi.org/10.1002/jca.21828DOI Listing
February 2021

Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection.

J Exp Med 2020 Nov;217(11)

Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, Imagine Institute, Paris, France.

Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.
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http://dx.doi.org/10.1084/jem.20192262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596820PMC
November 2020

COVID-19 in MS and NMOSD: A multicentric online national survey in Chile.

Mult Scler Relat Disord 2020 10 12;45:102392. Epub 2020 Jul 12.

Neurology, Pontificia Universidad Católica de Chile, Santiago, Chile. Electronic address:

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http://dx.doi.org/10.1016/j.msard.2020.102392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354374PMC
October 2020

Randomized Trial Comparing Double Versus Triple Bortezomib-Based Regimen in Patients With Multiple Myeloma and Acute Kidney Injury Due to Cast Nephropathy.

J Clin Oncol 2020 08 23;38(23):2647-2657. Epub 2020 Jun 23.

Department of Hematology and Immunology, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, INSERM UMR 1126, Paris, France.

Purpose: We report a multicenter controlled trial comparing renal recovery and tolerance profile of doublet versus triplet bortezomib-based regimens in patients with initial myeloma cast nephropathy (CN) and acute kidney injury (AKI) without need for dialysis.

Methods: After symptomatic measures and high-dose dexamethasone, patients were randomly assigned to receive bortezomib plus dexamethasone (BD), or BD plus cyclophosphamide (C-BD). In patients with < 50% reduction of serum free light chains (sFLCs) after 3 cycles, chemotherapy was reinforced with either cyclophosphamide (BD group) or thalidomide (C-BD group).

Results: Ninety-two patients were enrolled in each group. At random assignment, characteristics of the 2 groups were similar, including median age (68 years) and serum creatinine level (305.5 and 273.5 µmol/L in BD and C-BD group, respectively). At 3 months, renal response rate (primary end point) was not different (41 47 responders in the BD and C-BD groups, respectively; relative risk [RR], 0.87; = .46). Very good partial response (free light chain reduction ≥ 90%) or more was achieved in 36 and 47 patients, respectively (RR, 0.76; = .10). After 1 cycle of chemotherapy, 69 in the BD group and 67 patients in the C-BD group had achieved sFLC level ≤ 500 mg/L. Serious adverse events were recorded in 30 and 40 patients, respectively. At 12 months, 19 patients had died (9 in the BD group 10 in the C-BD group), including 10 (6 in the BD group and 4 in the C-BD group) from myeloma progression and 3 (0 in the BD group and 3 in the C-BD group) from infection. Within median follow-up of 27 months, 43 and 42 patients switched to new therapy, respectively. Overall, 50 patients (24 in the BD group and 26 in the C-BD group) had died.

Conclusion: This randomized study did not show any benefit of C-BD compared with BD on renal recovery of patients with initial CN not requiring dialysis. Adding cyclophosphamide did not sufficiently improve the efficacy-toxicity balance. Patients with myeloma with AKI are fragile, and indication for doublet or triplet regimen should be adapted to frailty.
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http://dx.doi.org/10.1200/JCO.20.00298DOI Listing
August 2020

Chronic Granulomatous Disease with the McLeod Phenotype: a French National Retrospective Case Series.

J Clin Immunol 2020 07 19;40(5):752-762. Epub 2020 Jun 19.

Pediatric Immuno-Hematology and Rheumatology Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades University Hospital, Paris, France.

Background: X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype.

Methods: We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types.

Results: The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well.

Conclusion: This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.
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http://dx.doi.org/10.1007/s10875-020-00791-wDOI Listing
July 2020

Targeted deep sequencing reveals clonal and subclonal mutational signatures in Adult T-cell leukemia/lymphoma and defines an unfavorable indolent subtype.

Leukemia 2020 Jun 17. Epub 2020 Jun 17.

Service d'Hématologie Adultes, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Université Paris Descartes, 149-161 rue de Sèvres, 75015, Paris, France.

Adult T-cell leukemia/lymphoma (ATL) carries a poor prognosis even in indolent subtypes. We performed targeted deep sequencing combined with mapping of HTLV-1 proviral integration sites of 61 ATL patients of African and Caribbean origin. This revealed mutations mainly affecting TCR/NF-kB (74%), T-cell trafficking (46%), immune escape (29%), and cell cycle (26%) related pathways, consistent with the genomic landscape previously reported in a large Japanese cohort. To examine the evolution of mutational signatures upon disease progression while tracking the viral integration architecture of the malignant clone, we carried out a longitudinal study of patients who either relapsed or progressed from an indolent to an aggressive subtype. Serial analysis of relapsing patients identified several patterns of clonal evolution. In progressing patients, the longitudinal study revealed NF-kB/NFAT mutations at progression that were present at a subclonal level at diagnosis (allelic frequency < 5%). Moreover, the presence in indolent subtypes of mutations affecting the TCR/NF-kB pathway, whether clonal or subclonal, was associated with significantly shorter time to progression and overall survival. Our observations reveal the clonal dynamics of ATL mutational signatures at relapse and during progression. Our study defines a new subgroup of indolent ATLs characterized by a mutational signature at high risk of transformation.
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http://dx.doi.org/10.1038/s41375-020-0900-3DOI Listing
June 2020

Improving the diagnostic efficiency of primary immunodeficiencies with targeted next-generation sequencing.

J Allergy Clin Immunol 2021 Feb 10;147(2):734-737. Epub 2020 Jun 10.

University of Paris, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1163, Imagine Institute, Paris, France; Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children-Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM-UMR 1163, Paris, France; Pediatric Immuno-Hematology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France; French National Reference Center for Primary Immune Deficiencies, Le Centre de Référence Déficits Immunitaires Héréditaires, Necker Hospital for Sick Children, AP-HP, Paris, France.

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http://dx.doi.org/10.1016/j.jaci.2020.05.046DOI Listing
February 2021

Allogeneic stem cell transplantation for peripheral T cell lymphomas: a retrospective study in 285 patients from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

J Hematol Oncol 2020 05 19;13(1):56. Epub 2020 May 19.

Department of Hematology, Hôpital Pitié Salpêtrière, Paris, France.

Background: Peripheral T cell lymphomas form a heterogeneous group with a usually dismal prognostic. The place of allogeneic stem cell transplantation to treat PTCL is debated.

Methods: We retrospectively analyzed the overall survival (OS), event-free survival (EFS), relapse, and transplant-related mortality (TRM) and associated variables in 285 adults with non-primary cutaneous PTCL (PCTL-NOS (39%), angioimmunoblastic T cell lymphomas (29%), anaplastic T cell lymphomas (15%), and other subtypes (17%)), who received alloSCT in 34 centers between 2006 and 2014.

Results: AlloSCT was given as part of front-line therapy (n = 138) to 93 patients in first complete response (CR) and 45 in first partial response (PR), and of salvage therapy (n = 147) to 116 patients for second or more CR/PR and 31 for progressive disease. Reduced-intensity conditioning (RIC) was given to 172 patients (62%), while 107 (38%) received myeloablative conditioning (MAC). The median follow-up was 72.4 months. The 2- and 4-year OS were 65% and 59%, respectively, and the cumulative incidence of relapse was 18% after 1 year and 19% after 2 years. TRM was 21% at 1 year, 24% after 2 years, and 28% after 4 years. In multivariate analysis, grade III-IV acute GvHD (HR = 2.57, 95% CI 1.53-4.31; p = 0.00036), low Karnofsky score < 80% (HR = 5.14, 95% CI 2.02-13.06; p = 0.00058), and progressive disease status before transplant (HR = 2.21, 95% CI 1.25-3.89; p = 0.0062) were significantly associated with a reduced OS.

Conclusions: The data demonstrate in the largest retrospective cohort of non-cutaneous PTCL so far reported that alloSCT after RIC or MAC is an effective strategy, even in chemoresistant patients.
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http://dx.doi.org/10.1186/s13045-020-00892-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236365PMC
May 2020

Hippo-YAP1 Is a Prognosis Marker and Potentially Targetable Pathway in Advanced Gallbladder Cancer.

Cancers (Basel) 2020 Mar 25;12(4). Epub 2020 Mar 25.

Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.

Gallbladder cancer is an aggressive disease with late diagnosis and no efficacious treatment. The Hippo-Yes-associated protein 1 (YAP1) signaling pathway has emerged as a target for the development of new therapeutic interventions in cancers. However, the role of the Hippo-targeted therapy has not been addressed in advanced gallbladder cancer (GBC). This study aimed to evaluate the expression of the major Hippo pathway components mammalian Ste20-like protein kinase 1 (MST1), YAP1 and transcriptional coactivator with PDZ-binding motif (TAZ) and examined the effects of Verteporfin (VP), a small molecular inhibitor of YAP1-TEA domain transcription factor (TEAD) protein interaction, in metastatic GBC cell lines and patient-derived organoids (PDOs). Immunohistochemical analysis revealed that advanced GBC patients had high nuclear expression of YAP1. High nuclear expression of YAP1 was associated with poor survival in GBC patients with subserosal invasion (pT2). Additionally, advanced GBC cases showed reduced expression of MST1 compared to chronic cholecystitis. Both VP treatment and YAP1 siRNA inhibited the migration ability in GBC cell lines. Interestingly, gemcitabine resistant PDOs with high nuclear expression of YAP1 were sensitive to VP treatment. Taken together, our results suggest that key components of the Hippo-YAP1 signaling pathway are dysregulated in advanced gallbladder cancer and reveal that the inhibition YAP1 may be a candidate for targeted therapy.
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http://dx.doi.org/10.3390/cancers12040778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226626PMC
March 2020

Arsenic trioxide (AsO) as a maintenance therapy for adult T cell leukemia/lymphoma.

Retrovirology 2020 03 21;17(1). Epub 2020 Mar 21.

Service d'Hématologie Adultes, Institut Imagine, Hôpital Universitaire Necker Enfants Malades, APHP, Université de Paris, 149-161 rue de Sèvres, 75743, Paris Cedex 15, France.

Background: Adult T-cell leukemia-lymphoma (ATL) is an aggressive mature lymphoid proliferation associated with poor prognosis. Standard of care includes chemotherapy and/or the combination of zidovudine and interferon-alpha. However, most patients experience relapse less than 6 months after diagnosis. Allogeneic stem cell transplantation is the only curative treatment, but is only feasible in a minority of cases. We previously showed in a mouse model that Arsenic trioxide (AsO) targets ATL leukemia initiating cells.

Results: AsO consolidation was given in 9 patients with ATL (lymphoma n = 4; acute n = 2; and indolent n = 3), who were in complete (n = 4) and partial (n = 3) remission, in stable (n = 1) and in progressive (n = 1) disease. Patients received up to 8 weeks of AsO at the dose of 0.15 mg/kg/day intravenously in combination with zidovudine and interferon-alpha. One patient in progression died rapidly. Of the remaining eight patients, three with indolent ATL subtype showed overall survivals of 48, 53 and 97 months, and duration of response to AsO of 22, 25 and 73 months. The other 5 patients with aggressive ATL subtype had median OS of 36 months and a median duration of response of 10 months. Side effects were mostly hematological and cutaneous (one grade 3) and reversible with dose reduction of AZT/IFN and/or AsO discontinuation. The virus integration analysis revealed the regression of the predominant malignant clone in one patient with a chronic subtype.

Conclusion: These results suggest that consolidation with AsO could be an option for patients with ATL in response after induction therapy and who are not eligible for allogeneic stem cell transplantation.
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http://dx.doi.org/10.1186/s12977-020-0513-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085150PMC
March 2020

HAVCR2 mutations are associated with severe hemophagocytic syndrome in subcutaneous panniculitis-like T-cell lymphoma.

Blood 2020 03;135(13):1058-1061

Department of Dermatology, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), INSERM U976, Université de Paris, Paris, France.

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http://dx.doi.org/10.1182/blood.2019003811DOI Listing
March 2020

How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?

Authors:
Francine Garnache-Ottou Chrystelle Vidal Sabeha Biichlé Florian Renosi Eve Poret Maïder Pagadoy Maxime Desmarets Anne Roggy Estelle Seilles Lou Soret Françoise Schillinger Sandrine Puyraimond Tony Petrella Claude Preudhomme Christophe Roumier Elisabeth A MacIntyre Véronique Harrivel Yohan Desbrosses Bérengère Gruson Franck Geneviève Sylvain Thepot Yuriy Drebit Thibaut Leguay François-Xavier Gros Nicolas Lechevalier Pascale Saussoy Véronique Salaun Edouard Cornet Zehaira Benseddik Richard Veyrat-Masson Orianne Wagner-Ballon Célia Salanoubat Marc Maynadié Julien Guy Denis Caillot Marie-Christine Jacob Jean-Yves Cahn Rémy Gressin Johann Rose Bruno Quesnel Estelle Guerin Franck Trimoreau Jean Feuillard Marie-Pierre Gourin Adriana Plesa Lucile Baseggio Isabelle Arnoux Norbert Vey Didier Blaise Romaric Lacroix Christine Arnoulet Blandine Benet Véronique Dorvaux Caroline Bret Bernard Drenou Agathe Debliquis Véronique Latger-Cannard Caroline Bonmati Marie-Christine Bene Pierre Peterlin Michel Ticchioni Pierre-Simon Rohrlich Anne Arnaud Stefan Wickenhauser Valérie Bardet Sabine Brechignac Benjamin Papoular Victoria Raggueneau Jacques Vargaftig Rémi Letestu Daniel Lusina Thorsten Braun Vincent Foissaud Jérôme Tamburini Hind Bennani Nicolas Freynet Catherine Cordonnier Magali Le Garff-Tavernier Nathalie Jacques Karim Maloum Damien Roos-Weil Didier Bouscary Vahid Asnafi Ludovic Lhermitte Felipe Suarez Etienne Lengline Frédéric Féger Giorgia Battipaglia Mohamad Mohty Sabrina Bouyer Ouda Ghoual Elodie Dindinaud Caroline Basle Mathieu Puyade Carinne Lafon Thierry Fest Mikael Roussel Xavier Cahu Elsa Bera Sylvie Daliphard Fabrice Jardin Lydia Campos Françoise Solly Denis Guyotat Anne-Cécile Galoisy Alice Eischen Caroline Mayeur-Rousse Blandine Guffroy Christian Recher Marie Loosveld Alice Garnier Vincent Barlogis Maria Alessandra Rosenthal Sophie Brun Nathalie Contentin Sébastien Maury Mary Callanan Christine Lefebvre Natacha Maillard Patricia Okamba Christophe Ferrand Olivier Adotevi Philippe Saas Fanny Angelot-Delettre Delphine Binda Eric Deconinck

Blood Adv 2019 12;3(24):4238-4251

University of Bourgogne Franche-Comté, INSERM, Établissement Français du Sang Bourgogne/Franche-Comté, Unite Mixte de Recherche (UMR) 1098, RIGHT (Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique), Besançon, France.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)-like, acute lymphoid leukemia (ALL)-like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])-like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.
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http://dx.doi.org/10.1182/bloodadvances.2019000647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929390PMC
December 2019

Primary immunodeficiency-related bronchiectasis in adults: comparison with bronchiectasis of other etiologies in a French reference center.

Respir Res 2019 Dec 4;20(1):275. Epub 2019 Dec 4.

Service de Pneumologie, Hôpital Foch, Suresnes, France.

Background: Bronchiectasis is a heterogeneous disease depending on etiology. It represents the most frequent non-infectious pulmonary complication of primary immunodeficiencies (PID). We investigated whether bronchiectasis associated with PID had a distinct course in comparison to bronchiectasis of other causes.

Methods: Retrospective single-center study of adult patients diagnosed with non-cystic fibrosis bronchiectasis with more than 5 years of follow-up and at least 4 pulmonary functional tests available at one year apart. They were divided into three groups: PID- related bronchiectasis, idiopathic/post infectious-related bronchiectasis and other causes of bronchiectasis. Respiratory functional data and clinical outcomes were compared.

Results: Of 329 patients with bronchiectasis diagnosed in Foch Hospital (Suresnes, France), 98 patients fulfilled the selected criteria (20 PID-related cases, 39 idiopathic or post-infectious cases, and 39 cases with other causes). Median time of follow-up was 9.5 years. Groups were similar concerning initial characteristics (female 70.4%, never smokers 59.2%, mild severity bronchiectasis according to the FACED score and median FEV1 at diagnosis 73.5% predicted values [Q1-Q3: 53.75-90.5]), except PID patients who were younger (median age of 51.5 vs 62 years, p = 0.02). Eighty-five percent of PID patients received immunoglobulin substitution (median trough level was measured at 10.5 g/dl [10;10.92]). Global median FEV1 annual decline was 25.03 ml/year [8.16;43.9] and 19.82 ml/year [16.08;48.02] in the PID patients group. Forty-five percent of patients had bacterial colonization, pneumoniae occurred in 56% of patients and median exacerbation annual rate was 0.8 [0.3-1.4]. Hemoptysis occurred in 31.6% of patients. Global mortality rate was 11.2%. We did not record any significant difference for all clinical and functional outcomes between patients with PID and other etiologies. The median decline in FEV1 was similar in the three groups.

Conclusions: The course of PID-related bronchiectasis was similar to bronchiectasis of other causes. Provided that patients receive immunoglobulin replacement, the course of PID-related bronchiectasis seems to be independent of the underlying immune disorder.
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http://dx.doi.org/10.1186/s12931-019-1242-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894192PMC
December 2019

[When should we think to primary immune deficiency in adult patients ?]

Rev Prat 2019 Jun;69(6):659-665

Hématologie clinique, hôpital Necker-Enfants malades, AP-HP, Paris, France ; université Paris-Descartes, Sorbonne Paris-Cité, Institut Imagine ; centre de référence des déficits immunitaires héréditaires (CEREDIH).

Primary immune deficiencies (PIDs) include rare and heterogeneous syndromes due to genetic abnormalities involving the immune system. In the registry of the French National Reference Center for Primary Immune Deficiencies (CEREDIH), the median age of clinical onset is 2 years, but 25% of patients develop the first symptoms after 15 years. A diagnosis of PID should be considered in the presence of an unusual association of infections, autoimmune pathologies, granulomatous disease, polyclonal lymphoproliferation or atypical lymphoma. PID management currently benefits from new antibiotic prophylaxis, the improvement of allogeneic hematopoietic stem cell transplantation procedure and the development of gene therapy. In addition, the understanding of the pathophysi ological mechanisms led to new treatments targeting the pathways implicated by the genetic defects. In this review, we briefly recall the classification of PID. We illustrate the problem of PID in adults with clinical cases and then summarize the main principles of management in adults PID patients.
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June 2019

A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

Authors:
Hélène Coignard-Biehler Nizar Mahlaoui Benoit Pilmis Vincent Barlogis Pauline Brosselin Nathalie De Vergnes Marianne Debré Marion Malphettes Pierre Frange Emilie Catherinot Isabelle Pellier Isabelle Durieu Antoinette Perlat Bruno Royer Alain Le Quellec Eric Jeziorski Alain Fischer Olivier Lortholary Laurent Aaron Daniel Adoue Claire Aguilar Nathalie Aladjidi Alexandre Alcais Zahir Amoura Philippe Arlet Corinne Armari-Alla Brigitte Bader-Meunier Sophie Bayart Yves Bertrand Boris Bienvenu Stéphane Blanche Damien Bodet Bernard Bonnotte Raphaël Borie Patrick Boutard Claire Briandet Jean-Paul Brion Jacques Brouard Sarah Cohen-Beaussant Laurence Costes Louis-Jean Couderc Pierre Cougoul Virginie Courteille Geneviève de Saint Basile Catherine Devoldere Anne Deville Jean Donadieu Eric Dore Fabienne Dulieu Christine Edan Natacha Entz-Werle Claire Fieschi Amandine Forestier Fanny Fouyssac Vincent Gajdos Lionel Galicier Virginie Gandemer Martine Gardembas Catherine Gaud Gaelle Guillerm Eric Hachulla Mohamed Hamidou Olivier Hermine Cyrille Hoarau Sébastien Humbert Arnaud Jaccard Serge Jacquot Jean-Philippe Jais Roland Jaussaud Pierre-Yves Jeandel Kamila Kebaili Anne-Sophie Korganow Olivier Lambotte Fanny Lanternier Claire Larroche Anne-Sophie Lascaux Emmanuelle Le Moigne Vincent Le Moing Yvon Lebranchu Marc Lecuit Guillaume Lefevre Richard Lemal Valérie Li Thiao Te Aude Marie-Cardine Nicolas Martin Silva Agathe Masseau Christian Massot Françoise Mazingue Etienne Merlin Gérard Michel Frédéric Millot Béatrice Monlibert Fabrice Monpoux Despina Moshous Luc Mouthon Martine Munzer Bénédicte Neven Raphaëlle Nove-Josserand Eric Oksenhendler Marie Ouachée-Chardin Caroline Oudot Anne Pagnier Jean-Louis Pasquali Marlène Pasquet Yves Perel Capucine Picard Christophe Piguet Dominique Plantaz Johan Provot Pierre Quartier Frédéric Rieux-Laucat Pascal Roblot Pierre-Marie Roger Pierre-Simon Rohrlich Hervé Rubie Valéry Salle Françoise Sarrot-Reynauld Amélie Servettaz Jean-Louis Stephan Nicolas Schleinitz Felipe Suarez Laure Swiader Sophie Taque Caroline Thomas Olivier Tournilhac Caroline Thumerelle François Tron Jean-Pierre Vannier Jean-François Viallard

J Clin Immunol 2019 10 10;39(7):702-712. Epub 2019 Aug 10.

Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.

Purpose: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles.

Methods: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included.

Results: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04).

Conclusion: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.
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http://dx.doi.org/10.1007/s10875-019-00658-9DOI Listing
October 2019

Impact of genotype in relapsed and refractory acute myeloid leukaemia patients treated with clofarabine and cytarabine: a retrospective study.

Br J Haematol 2019 10 18;187(1):65-72. Epub 2019 Jun 18.

Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.

The treatment of relapsed/refractory (R/R) acute myeloid leukaemia (AML) remains a challenge. Among salvage chemotherapy regimens, the clofarabine and cytarabine (CLARA) combination has been widely evaluated and has a favourable safety/efficacy balance. Predictive factors of efficacy in patients with R/R AML are unclear, particularly the impact of AML-related gene mutations. We report our single-centre experience on 34 R/R AML patients treated with CLARA, with a focus on the genetic characterization of our cohort. CLARA yielded a 47% response rate among this poor-prognosis AML population, while two patients (5·8%) died due to treatment-related toxicity. The two-year progression-free survival and overall survival rates were 29·4% and 35·3%, respectively. Nine patients (26%) had long-term response with a median follow-up of 39·5 months among the responders, of whom six underwent haematopoietic stem cell transplantation. Adverse karyotype did not correlate with response or survival, and secondary AML were more frequent among responders to CLARA, suggesting that this combination may successfully salvage R/R AML patients regardless of adverse prognostic markers. We also observed that a low mutational burden and absence of splice mutations correlated with prolonged survival after CLARA, suggesting that extensive genotyping may have prognostic implications in R/R AML.
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http://dx.doi.org/10.1111/bjh.16045DOI Listing
October 2019

Distal ischemia as the initial presentation of hypereosinophilic syndrome-related arterial involvement: A case study and literature review.

Autoimmun Rev 2019 Aug 7;18(8):828-830. Epub 2019 Jun 7.

Service de Médecine Interne, Centre de Référence Maladies Autoimmunes et Systémiques Rares d'Ile de France, Hôpital Cochin, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.autrev.2019.06.004DOI Listing
August 2019

Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France.

Haematologica 2020 01 16;105(1):91-101. Epub 2019 May 16.

Hematology, Transplantation, AP-HP Hôpital Saint Louis, Paris, France.

Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning [busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG)]. Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells <5%) as events, the 5-year event-free survival was 97.9% (95% confidence interval: 95.5-100%), confirming, since the year 2000, an at least 95% chance of cure. In the overall cohort (n=234, median follow up 7.9 years), event-free survival was not associated with age, but chronic-graft--host disease (cGvHD) was independently associated with recipient's age >15 years (hazard ratio=4.37; =0.002) and lower (5-15 20 mg/kg) ATG dose (hazard ratio=4.55; =0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells <50%. Myeloablative transplantation with matched-sibling donor currently has a higher event-free survival (98%) in patients under 30 years of age than that reported for non-myeloablative conditioning (88%). Nevertheless, the risk of cGvHD in older patients and the need to preserve fertility might be indications for a non-myeloablative conditioning.
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http://dx.doi.org/10.3324/haematol.2018.213207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939536PMC
January 2020

Refractory sarcoidosis-like systemic granulomatosis responding to ruxolitinib.

Ann Rheum Dis 2019 11 10;78(11):1606-1607. Epub 2019 May 10.

Internal Medicine, Universite Cote d'Azur, Nice, France.

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http://dx.doi.org/10.1136/annrheumdis-2019-215387DOI Listing
November 2019

Functional classification of ATM variants in ataxia-telangiectasia patients.

Hum Mutat 2019 10 17;40(10):1713-1730. Epub 2019 May 17.

Institut Curie, PSL Research University, INSERM U830, Paris, France.

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.
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http://dx.doi.org/10.1002/humu.23778DOI Listing
October 2019

Lymphoproliferative disease in patients with Wiskott-Aldrich syndrome: Analysis of the French Registry of Primary Immunodeficiencies.

J Allergy Clin Immunol 2019 06 20;143(6):2311-2315.e7. Epub 2019 Feb 20.

Clinical Hematology, Necker University Hospital, AP-HP, Paris, France; Paris Descartes University, Sorbonne Paris Cité University, Imagine Institute, Paris, France; INSERM UMR1163 & CNRS URL 8254, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutical implications, Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker University Hospital, AP-HP, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.01.046DOI Listing
June 2019

Evaluation of infectious complications after haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide following reduced-intensity and myeloablative conditioning: a study on behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC).

Bone Marrow Transplant 2019 10 15;54(10):1586-1594. Epub 2019 Feb 15.

Institut de Cancérologie Lucien Neuwirth, Saint-Etienne, France.

Several approaches have been developed to overcome historical barriers associated with poor outcomes in the setting of HLA-haploidentical allogeneic transplantation (HaploSCT). Here, we examine the outcome of patients with various hematological disorders undergoing HaploSCT with high-dose, post-transplantation cyclophosphamide. We performed a retrospective study on 381 patients from 30 centers between January 2013 and December 2015. At the last follow-up, a total of 1058 infectious episodes were diagnosed, affecting 90.3% of the cohort. Median time to first infection was 13 days for bacterial, 32 days for viral and 20 days for fungal infections. Around 41% of these infections were of bacterial origin and 35% of viral origin, among which 48.8% of patients presented CMV reactivation. Median of GVHD relapse-free survival, progression-free survival and overall survival were 7.1 months, 19.9 months and 33.5 months, respectively. HSCT procedure was the primary or contributing cause of death (55.6%), followed by relapse of the original disease (34.2%). Infections accounted for 45.7% of the HSCT-related deaths. The present multicenter data on a large cohort of patients receiving HaploSCT with PTCy confirmed the feasibility of the procedure with an acceptable incidence of infectious complications, not different as compared to other haploidentical platforms or HLA-matched transplantation.
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http://dx.doi.org/10.1038/s41409-019-0475-7DOI Listing
October 2019

Epstein-Barr Virus (EBV)-Related Lymphoproliferative Disorders in Ataxia Telangiectasia: Does ATM Regulate EBV Life Cycle?

Front Immunol 2018 4;9:3060. Epub 2019 Jan 4.

INSERM U1163/CNRS ERL8254 - Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, IMAGINE Institute, Paris, France.

Epstein-Barr virus (EBV) is an ubiquitous herpesvirus with a tropism for epithelial cells (where lytic replication occurs) and B-cells (where latency is maintained). EBV persists throughout life and chronic infection is asymptomatic in most individuals. However, immunocompromised patients may be unable to control EBV infection and are at increased risk of EBV-related malignancies, such as diffuse large B-cell lymphomas or Hodgkin's lymphomas. Ataxia telangiectasia (AT) is a primary immunodeficiency caused by mutations in the gene and associated with an increased incidence of cancers, particularly EBV-associated lymphomas. However, the immune deficiency present in AT patients is often too modest to explain the increased incidence of EBV-related malignancies. The ATM defect in these patients could therefore impair the normal regulation of EBV latency in B-cells, thus promoting lymphomagenesis. This suggests that ATM plays a role in the normal regulation of EBV latency. ATM is a serine/threonine kinase involved in multiple cell functions such as DNA damage repair, cell cycle regulation, oxidative stress, and gene expression. ATM is implicated in the lytic cycle of EBV, where EBV uses the activation of DNA damage repair pathway to promote its own replication. ATM regulates the latent cycle of the EBV-related herpesvirus KSHV and MHV68. However, the contribution of ATM in the control of the latent cycle of EBV is not yet known. A better understanding of the regulation of EBV latency could be harnessed in the conception of novel therapeutic strategies in AT and more generally in all ATM deficient EBV-related malignancies.
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http://dx.doi.org/10.3389/fimmu.2018.03060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329310PMC
October 2019