Syndromes lymphoprolifératifs et immunosuppresseurs

Les syndromes lymphoprolifératifs compliquant l’évolution de pathologies liées à un déficit immunitaire, qu’il soit primitif ou acquis, sont des complications bien identifiées et d’évolution péjorative. Parmi les causes de déficit immunitaire acquis, les traitements immunomodulateurs dans le cadre de pathologies auto-immunes doivent faire l’objet d’observatoires afin de déterminer le rôle respectif des immunosuppresseurs et de la pathologie sous-jacente caractérisée par une stimulation lymphocytaire persistante et un déséquilibre cytokinique. Les syndromes lymphoprolifératifs survenant dans le contexte des greffes d’organe ou de moelle osseuse sont des complications des traitements immunosuppresseurs et probablement de la stimulation antigénique sous-jacente. Leur fréquence varie selon les traitements immunosuppresseurs utilisés, le type d’organe greffé et le statut de l’infection par le virus d’Epstein-Barr (EBV) du receveur. Ces proliférations tumorales développées aux dépens des cellules lymphoïdes du receveur, dérivant de cellules du centre germinatif ou post-centre germinatif, résultent de différents mécanismes de lymphomagenèse. Le rôle de l’EBV conférant un avantage prolifératif aux cellules lymphoïdes dans un contexte de déficit immunitaire est majeur dans les lésions précoces et polymorphes. Ce mécanisme physiopathogénique justifie la surveillance de la charge virale du sang périphérique et de la réponse immune anti-EBV chez les patients transplantés. Les anomalies génétiques plus fréquentes dans les proliférations lymphomateuses monomorphes et tardives correspondent soit à des pertes d’hétérozygotie, soit à des déséquilibres chromosomiques, soit à des mutations aberrantes, soit à des phénomènes d’instabilité des microsatellites aboutissant à des mutations affectant des gènes impliqués dans des phénomènes d’apoptose ou de recombinaison de l’ADN. La connaissance des mécanismes de lymphomagenèse chez ces patients immunodéficients permet une approche de dépistage par le suivi de marqueurs viraux et immunologiques et une attitude thérapeutique ciblée

Immunohematologic tolerance of chronic transfusion exchanges with erythrocytapheresis in sickle cell disease

International audienceBACKGROUND:Sickle cell disease (SCD) has become a major public health issue. Hydroxyurea and red blood cell (RBC) transfusion are the cornerstone treatments. Erythrocytapheresis (ECP) is an automated method for transfusion exchange. Given that ECP requires more blood than conventional transfusion, there is concern about alloimmunization and hemolytic transfusion reactions. We evaluate the incidence of hemolytic transfusion reactions and alloimmunization rates in patients receiving conventional blood transfusions and in patients participating in long-term blood exchange programs with ECP.STUDY DESIGN AND METHODS:All hemolytic transfusion reactions and alloimmunizations in SCD patients were recorded over the period 2006 to 2011. Conventional transfusions and ECP were compared.RESULTS:The cohort consisted of 188 SCD patients. The median (±SD) age was 23 (±14) years. The ECP and conventional transfusion groups comprised 49 and 139 patients, respectively. The prevalence of alloimmunization was 33% in the ECP group and 22% in the conventional transfusion group (p = 0.1797). The alloimmunization/RBC unit (RBCU) ratio was lower in the ECP group than in the conventional transfusion group (1.6 and 11.6 per 1000, respectively; p < 0.0001). Although patients in the ECP group received more than 10 times more RBCUs than patients in the conventional transfusion group (206 vs. 19 RBCUs per patient, respectively; p < 0.0001), none of the four recorded hemolytic transfusion reactions (n = 4) occurred.CONCLUSION:Regarding alloimmunization, ECP exhibits a good immunohematologic safety profile relative to conventional transfusion in a large SCD mainly adult cohort

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Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations.

X-linked Sideroblastic Anemia (XLSA) is the most common genetic form of sideroblastic anemia, a heterogeneous group of disorders characterized by iron deposits in the mitochondria of erythroid precursors. XLSA is due to mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. Thirteen different ALAS2 mutations were identified in 16 out of 29 probands with sideroblastic anemia. One third of the patients were females with a highly skewed X-chromosome inactivation. The identification of seven novel mutations in the ALAS2 gene, six missense mutations, and one deletion in the proximal promoter extends the allelic heterogeneity of XSLA. Most of the missense mutations were predicted to be deleterious, and 10 of them, without any published functional characterization, were expressed in Escherichia coli. ALAS2 activities were assayed in vitro. Five missense mutations resulted in decreased enzymatic activity under standard conditions, and two other mutated proteins had decreased activity when assayed in the absence of exogenous pyridoxal phosphate and increased thermosensitivity. Although most amino acid substitutions result in a clearly decreased enzymatic activity in vitro, a few mutations have a more subtle effect on the protein that is only revealed by in vitro tests under specific conditions

Prognostic value of high-sensitivity measurable residual disease assessment after front-line chemoimmunotherapy in chronic lymphocytic leukemia

International audienceMeasurable residual disease (MRD) status is widely adopted in clinical trials in patients with chronic lymphocytic leukemia (CLL). Findings from FILO group trials (CLL2007FMP, CLL2007SA, CLL2010FMP) enabled investigation of the prognostic value of high-sensitivity (0.7 × 10-5) MRD assessment using flow cytometry, in blood (N = 401) and bone marrow (N = 339), after fludarabine, cyclophosphamide, and rituximab (FCR)-based chemoimmunotherapy in a homogeneous population with long follow-up (median 49.5 months). Addition of low-level positive MRD < 0.01% to MRD ≥ 0.01% increased the proportion of cases with positive MRD in blood by 39% and in bone marrow by 27%. Compared to low-level positive MRD < 0.01%, undetectable MRD was associated with significantly longer progression-free survival (PFS) when using blood (72.2 versus 42.7 months; hazard ratio 0.40, p = 0.0003), but not when using bone marrow. Upon further stratification, positive blood MRD at any level, compared to undetectable blood MRD, was associated with shorter PFS irrespective of clinical complete or partial remission, and a lower 5-year PFS rate irrespective of IGHV-mutated or -unmutated status (all p < 0.05). In conclusion, high-sensitivity (0.0007%) MRD assessment in blood yielded additional prognostic information beyond the current standard sensitivity (0.01%). Our approach provides a model for future determination of the optimal MRD investigative strategy for any regimen