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Abstract: The EORTC Children''s Leukemia Group (CLG) is a spin-off from the EORTC Hemopathies Working Party (adults and children). After a decade of collaboration in the adult-pediatric group it became clear that there was not only a large difference in cure rates between children and adults, but many chemotherapeutic-toxic borders were substantially different. During the following decade the CLG was not only a witness of a very exciting battle against childhood leukemia, but it also contributed substantially to better cure rates for these diseases. The main activity of the CLG was concentrated on the field of acute lymphoblastic leukemia (ALL). Fine tuning of treatment elements using the BFM design as a backbone has been done very successfully over the past decades. The CLG has many achievements, and the major ones include: the 58831 trial showing the superfluity of the prophylactic Central Nervous System (CNS) radiotherapy in ALL patients when a adequate systemic and CNS directed chemotherapy is ascertained. The 58881 trial demonstrated that the assessment of minimal residual disease (MRD) at completion of induction in ALL is a key step in the process to categorizing and allocating patients into different risk groups, and that MRD is a powerful and independent prognostic factor. This same 58881 trial showed the clear difference in efficacy of different asparaginases resulting in an optimization of the use these drugs and a revival of interest for the asparaginases in the treatment of ALL. In the near future the CLG will focus mainly on translational research projects and innovative biologically targeted treatment approaches, on collaborations with other children''s leukemia groups in intergroup studies, and on the evaluation of the long-term outcome of childhood cancer survivors. [Copyright &y& Elsevier]

H2-deleted, HLA-A2, or HLA-B7 transgenic mice were used to identify new human cytomegalovirus (HCMV)-derived major histocompatibility complex class I-restricted epitopes. Three different approaches for mice immunization were compared for their ability to induce a cytotoxic CD8+ T cell (CTL) response: (1) inoculation of infectious HCMV, (2) injection of immunogenic synthetic peptides, and (3) infection with a newly designed HIV-derived central DNA flap positive lentiviral vector encoding the chimeric IE1-pp65 protein (Trip-IE1-pp65). Targets pulsed with either known immunogenic peptides or computer predicted ones were used to characterize CTL. Most of the mice immunized with the pp65 (495-NLVPMVATV-503) immunodominant peptide responded after one injection whereas only two of six mice responded to two successive inoculations with HCMV. Infection of mice with Trip-IE1-pp65 induced activation and expansion of CTL directed against peptides from both pp65 and IE1 and allowed identification of new epitopes. We further demonstrated the high capacity of monocyte-macrophage cells transduced with Trip-IE1-pp65 to activate and expand CTL directed against pp65 from peripheral blood mononuclear cells of HCMV-seropositive donors. Altogether these results suggest that Trip-IE1-pp65 is a powerful construct both to characterize new epitopes in combination with human leukocyte antigen-transgenic mice immunization and to provide an alternative to the use of known infectious and noninfectious approaches to expand effector T cells for adoptive immunotherapy. [Copyright &y& Elsevier]

Le diagnostic des aspergilloses invasives (AI) repose le plus souvent sur un faisceau d’arguments comprenant des critères d’hôte, cliniques et mycologiques, comme ceux définis conjointement par l’European Organisation for Research and Treatment of Cancer (EORTC) et le Mycosis Study Group (MSG). Des publications ont montré l’intérêt potentiel de la détection de l’ADN d’ Aspergillus fumigatus par PCR (non retenue à ce jour parmi les critères mycologiques). L’objectif de notre travail a été de comparer, dans le cadre d’une étude rétrospective monocentrique menée au CHU de Nice chez les patients d’hématologie clinique, les performances diagnostiques de la PCR Aspergillus sérique et du galactomannane. L’étude concerne la période du 1 er janvier 2014 au 30 septembre 2016. Une recherche de galactomannane (GM) couplée à une PCR Aspergillus dans le sérum a été effectuée chez 730 patients impliquant 3794 échantillons pour la PCR et 7279 échantillons pour le galactomannane. Les échantillons traités en PCR ont tous eu une recherche de galactomannane. Un diagnostic d’AI probable/possible selon les critères de l’EORTC/MSG, a été retenu respectivement dans 30 et 6 cas, soit un total de 36 aspergilloses invasives. À noter que durant cette période, il n’y a pas eu d’aspergillose prouvée. Sur les 36 cas d’AI selon l’EORTC/MSG, le GM sur sérum était positif chez 29 patients (80 %), et la PCR chez 14 patients (39 %) (11 AI probables avec GM+ et 3 AI possibles avec GM−). L’inclusion de la PCR Aspergillus dans les critères mycologiques, permettrait de reclasser 3 épisodes d’AI de possible en probable. Les sensibilités, spécificités et valeur prédictive négative sont respectivement de 42 %, 97 % et 97 % pour la PCR, et 80 %, 89 % et 99 % pour le GM. Combiner le GM avec la PCR sérique a amélioré le taux de détection de l’aspergillose invasive avec une sensibilité de 91 % et une VPN proche de 100 %. La détection de l’ADN sérique circulant d’ A. fumigatus par PCR manque encore de sensibilité, ce qui ne permet pas son utilisation seule dans le diagnostic des AI. Elle pourrait être un outil complémentaire pour l’amélioration du diagnostic d’AI. La combinaison des deux outils (PCR et GM) permet une excellente VPN pouvant éviter l’utilisation de traitement antifongique. [ABSTRACT FROM AUTHOR]

• Graft failure or loss frequency was 3% among Francophone centers from 2011 to 2017. • Haploidentical donors were identified and harvested faster than unrelated donors. • Haploidentical transplant with PTCy for rescuing graft failure leads to acceptable overall survival. Prognosis of patients with graft failure is dismal, and retransplantation is the sole option for long-term survival. To address the interest of haploidentical transplantation as a salvage option in this context, we analyzed data from 24 patients with graft failure or loss retransplanted with a haploidentical donor who received post-transplant cyclophosphamide (PTCy) as graft-versus-host disease prophylaxis (GVHD). Fludarabine-based reduced-intensity conditioning was used in 23 patients and the Baltimore regimen in 14 patients. The median delay between previous and salvage transplantation for graft failure was 63 days (range, 39 to 98). In addition to PTCy, all patients received cyclosporine, and 22 patients also received mycophenolate mofetil for GVHD prophylaxis. With a median follow-up of 353 days (range, 16 to 2010), 1-year overall survival (OS) was 56% (95% confidence interval, 38% to 81%). Transplant complications accounted for 80% of deaths. The cumulative incidence of neutrophil engraftment at day +30 was 79%. Cumulative incidence of grades II to IV acute GVHD at day 100 was 14%, and 1-year cumulative incidence of chronic GVHD was 31%. One-year cumulative incidence of relapse was 13%. Stem cell source did not impact on engraftment, GVHD, relapse, or OS. Salvage haploidentical transplant with PTCy for rescuing graft failure patients leads to an acceptable 1-year OS and might be a valid option in this poor situation. [ABSTRACT FROM AUTHOR]

• The DIPSS was not predictive of survival in myelofibrosis secondary to essential thrombocythemia or polycythemia vera after stem cell transplantation. • The MYSEC-PM predicted survival and showed improved prognostic ability. • Although performance of the MYSEC-PM was still moderate, risk stratification may be improved by incorporating clinical, mutational, and transplant-related factors. We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C >.5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P =.78). Overall, the DIPSS was not significantly predictive of outcome (P =.28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P =.05), whereas groups with intermediate 2 and high risk showed no significant difference (P =.44). Assessment of prognostic utility yielded a C-index of.575 (95% CI,.502 to.648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of.636 (95% CI,.563 to.708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P =.04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P =.01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification. [ABSTRACT FROM AUTHOR]

Abstract Purpose We developed a prognostic scoring system to evaluate the prognosis of myelodysplastic syndrome (MDS) patients surviving more than 100 days allogeneic hematopoietic cell transplantation after (allo-HCT). Patients and methods We performed a landmark analysis on a derivation cohort of 393 cases to identify prognostic factors for 3-year overall survival. Potential predictor variables included demographic and clinical data, transplantation modalities and early post-transplant complications. The scoring system was tested against a validation cohort which included 391 patients. Results Complications occurring before day 100 such as relapse [HR = 6.7; 95%CI, 4.5-10.0] (4 points), lack of platelet recovery [HR, 3.6; 95%CI, 2.2-5.8] (2 points), grade-II acute GVHD [HR = 1.7; 95%CI, 1.2-2.5] (1 point) and grade-III/IV [HR = 2.6; 95%CI, 1.8 -3.8] (2 points) were the only independent predictors of 3-year OS. The 3-year OS associated with low (0), intermediate (1-3) and high (≥4) risk scores was respectively 70%, 46% and 6%. The model performed consistently in both cohorts, with good calibration. Conclusion This post-transplant scoring system is a powerful predictor of outcome after allo-HCT for MDS, and can provide useful guidance for clinicians. Additional studies are required to evaluate this scoring system for other hematologic malignancies. [ABSTRACT FROM AUTHOR]

Usually, after double umbilical cord blood transplantation (DUCBT), only 1 of the transplanted units persists in the long term. The characteristics of the winning cord blood unit (W-CBU) that determine unit dominance and how they influence the outcomes of DUCBT remain unclear. We retrospectively analyzed 347 patients with acute leukemia transplanted with a DUCBT (694 CBU) from 2005 to 2013 who had documented neutrophil engraftment and a W-CBU identified by chimerism analysis, to identify unit characteristics impacting on dominance. Median age at DUCBT was 40 years and median follow-up was 35 months. Among W-CBUs, 41% were ≥5/6 HLA matched to the recipient and 59% were ≤4/6. Multivariate analysis indicated that ≤4/6 HLA-matched W-CBUs led to lower leukemia-free survival (44% versus 56%; hazard ratio [HR], 1.5; P  = .032) and overall survival (49% versus 62%; HR, 1.5; P  = .028), increased nonrelapse mortality (26% versus 18%; HR, 1.9; P  = .027), and acute graft-versus-host disease (46% versus 35%; HR, 1.7; P  = .013). We were unable to predict unit dominance, but we demonstrated that outcomes were strongly influenced by the degree of HLA mismatch between W-CBU and recipient. Therefore, selection of both units with the lower number of HLA mismatches with the recipient is indicated. [ABSTRACT FROM AUTHOR]

To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS). Sixty-two patients underwent immunotherapy (IT group, second allo-HSCT or donor lymphocyte infusion), 39 received cytoreductive treatment alone (CRT group) and 46 were managed with palliative/supportive cares (PSC group). Two-year rates of overall survival (OS) were 32%, 6%, and 2% in the IT, CRT, and PSC groups, respectively ( P < .001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.26 to 2.67; P = .002), relapse within 6 months (HR, 2.69; 95% CI, .82 to 3.98; P < .001), progression to acute myeloid leukemia (HR, 2.59; 95% CI, 1.75 to 3.83; P < .001), and platelet count < 50 G/L at relapse (HR, 1.68; 95% CI, 1.15 to 2.44; P = .007). A prognostic score based on those factors discriminated 2 risk groups with median OSs of 13.2 versus 2.4 months, respectively ( P < .001). When propensity score, prognostic score, and treatment strategy were included in Cox model, immunotherapy was found to be an independent factor that favorably impacts OS (HR, .40; 95% CI, .26 to .63; P < .001). In conclusion, immunotherapy should be considered when possible for MDS patients relapsing after allo-HSCT. [ABSTRACT FROM AUTHOR]

Highlights: [•] GALIG is a cell death-related gene nested within the human galectin-3 locus. [•] GALIG pro-apoptotic function is counteracted by the anti-apoptotic Mcl-1. [•] During spontaneous neutrophil apoptosis, GALIG mRNAs are up-regulated. [•] In Acute Myeloid Leukemia cell samples, GALIG mRNAs are highly down-regulated. [ABSTRACT FROM AUTHOR]

Objective: CD4+CD25+ regulatory T lymphocytes (Treg) have been initially shown to prevent organ-specific autoimmunity. It is now accepted that Treg homeostasis depends in part on the peripheral conversion of naïve CD4+CD25– T cells. This conversion implicates acquisition of the Treg-specific markers, forkhead winged helix protein 3 (Foxp3), after CD28 costimulation. Because natural killer cells (NK) are critical for efficient cytotoxic T-cell priming and TH1 polarization, we investigated their role in Foxp3 induction in CD4+ T lymphocytes. Materials and Methods: Human CD4+CD25– T lymphocytes were activated in vitro by CD28 costimulation in the presence of interleukin-2–activated NK. Three days after initial activation, Foxp3 protein and RNA expression were determined by flow cytometry and reverse transcription polymerase chain reaction. In vivo influence of activated NK on Foxp3 expression was studied in an adoptive transfer model of CD45.2+ CD4+CD25– lymphocytes into CD45.1+ mice. Results: Interleukin-2–activated NK decreased Treg conversion of adoptively transferred murine CD4+CD25– T cells in vivo. Likewise, human-activated NK, but not resting NK, decreased CD28-driven Foxp3 expression in CD4+CD25– T lymphocytes, while at the same time increasing proliferation and interferon-γ (IFN-γ) production. Neutralization of IFN-γ partially restored Treg conversion and prevented TH1 polarization after CD28 costimulation. Conclusion: The current study suggests that activated NK interfere with CD28-mediated Foxp3 expression in CD4+CD25– T lymphocytes. Our experiments further underline a molecular interaction between IFN-γ and Foxp3 downstream of CD28 signaling. Together, these results demonstrate that activated NK play a critical role at the initiation step of immune responses by modulating peripheral Treg differentiation. [Copyright &y& Elsevier]

Abstract: Broad immune responses, in particular specific for the NS3 protein and mediated by both CD8+ and CD4+T lymphocytes, are thought to play a critical role in the control of hepatitis C virus (HCV) infection. In this study, we searched for novel HLA-B*0702 NS3 restricted epitopes following an optimized NS3NS4 immunization protocol in transgenic mice expressing HLA-B*0702 molecule. Combining predicted and overlapping peptides, we identified two novel epitopes, WPA10 (aa 1111–1120) and LSP10 (aa 1153–1162), which triggered significant IFN-γ-producing T cell frequencies and high CTL responses. Both epitopes were shown to be immunogenic when used as synthetic peptides to immunize mice. The relevance of these epitopes to humans was demonstrated, as both were able in vitro to recall specific IFN-γ and IL10-producing cells from peripheral blood mononuclear cells of HCV infected patients. Such epitopes enlarge the pool of NS3-specific CD8+T cell epitopes available to perform immunomonitoring of HCV infection and to develop vaccines. [Copyright &y& Elsevier]

Nous décrivons le cas d’un patient suivi au CHU de Nice, atteint d’une granulomatose septique chronique associée au phénotype McLeod (XK-). En 2012, dans le cadre d’une infection neurologique à pronostic vital engagé, ce patient âgé de 35 ans a bénéficié pendant 5 semaines d’une série de 18 transfusions de concentrés de granulocytes d’aphérèse (CGA), en complément d’une lourde antibiothérapie. L’infection a été enrayée, mais au prix de nombreux évènements indésirables immédiats et retardés. Les délais entre dons et transfusions ont été à chaque fois respectés malgré la distance entre les sites préleveur (Paris) et receveur (Nice). Deux points critiques méritent d’être discutés̊: la faible quantité de principe actif (QPA) des produits et la sélection des donneurs sur le plan du phénotype sanguin, malgré la désérythrocytation systématique des produits. La poly-immunisation massive (RH, HLA) de ce jeune adulte en situation d’impasse transfusionnelle du fait de son phénotype sanguin exceptionnel et le risque important de réitérer de nouveaux évènements septiques dramatiques ont contribué à la décision de traitement par allogreffe de CSH, seule échappatoire thérapeutique possible. Ce cas clinique atypique permet de refaire le point sur les particularités de la chaîne transfusionnelle des granuleux en France, telle qu’elle est organisée actuellement. La nécessité de disposer de produits les plus frais et riches possibles en cellules fonctionnelles, associée aux contraintes réglementaires et procédés de fabrication particuliers mobilise en urgence toutes les équipes intervenantes, notamment dans la coordination des étapes, du don jusqu’à la transfusion des produits. [ABSTRACT FROM AUTHOR]

Objective: To report the first case of restoration of ovarian activity and live birth after cryopreserved ovarian tissue autograft in a patient without cancer treated by allogeneic bone marrow transplantation. Design: Case report. Setting: University hospital. Patient(s): One woman with homozygous sickle cell anemia. Intervention(s): An orthotopic autotransplantation of ovarian cortical strips was performed after freeze-thawing. Main Outcome Measure(s): Cryopreservation of ovarian tissue, bone marrow transplantation, ovarian autograft, and restoration of ovarian function. Result(s): In autumn 2005, biopsy samples of ovarian tissue were cryopreserved before chemotherapy followed by bone marrow transplantation. In spring 2008, because the patient had been menopausal for 2.5 years as a result of the conditioning therapy, an orthotopic autotransplantation of thawed ovarian cortex was performed. The patient conceived spontaneously in a natural cycle in autumn 2008, and delivered a healthy female child in June 2009. Conclusion(s): Cryopreservation of ovarian tissue with subsequent autotransplantation is an emerging procedure for preserving the fertility of young patients with a high risk of premature ovarian failure (POF) resulting from gonadotoxic treatment. This case opens up new perspectives in cases of nonmalignant diseases. [Copyright &y& Elsevier]