Ce highlight en hématologie a été rédigé par des hématologues provenant de la Suisse entière, et se veut refléter un travail commun de la Société Suisse d'Hématologie.Les chapitres se déclinent sur les activités et maladies principales prises en charge par les intervenantes et intervenants de la spécialité.
Expansions of CD3+ large granular lymphocytes (LGLs) after allogeneic hematopoietic stem cell transplantation (HSCT) have been described. We sought to evaluate incidence, characteristics, and clinical significance of persistent T cell (T-)LGL after HSCT. Fourteen of 215 recipients (7%) were diagnosed with LGL expansions. Thirteen showed a CD3+/CD8+ immunophenotype, 5 of them with clonal TCR-γ rearrangement. The lymphocytes appeared at a median of 16 months (range, 3-58 months) after HSCT and lasted for a median time of 31 months (range, 2-179 months). Cytomegalovirus (CMV) reactivation (P = .001) and acute graft-versus-host disease (aGVHD) were associated with LGL expansion (P = .02). In the multivariate analysis, only CMV reactivation showed a significant association with T-LGL expansion (relative risk [RR]: 5.063; 95% confidence interval [CI]: 1.586-16.160; P = .006). The observed posttransplantation LGL expansions, even if monoclonal, showed a chronic, indolent course. Our data indicate that such expansions may be considered as an expression of chronic stimulation, triggered by CMV reactivation rather than a malignant transformation.
Die Hämatologie ist ein Fachgebiet, das sich sowohl im Laborbereich als auch bei der klinischen Behandlung von Patientinnen und Patienten stark entwickelt. Teil 1 einer Übersicht der jüngsten Entwicklungen.
Die Hämatologie ist ein Fachgebiet, das sich sowohl im Laborbereich als auch bei der klinischen Behandlung von Patientinnen und Patienten stark entwickelt. Teil 2 einer Übersicht der jüngsten Entwicklungen.
Alloimmunization and consecutive platelet transfusion refractoriness due to multiple antibodies can represent a major obstacle or even a contraindication to myeloablative allogeneic haematopoietic stem cell transplantation (HSCT) when no compatible platelet donors are available. Logistics may be complicated when multiple alloantibodies, including those to high-frequency antigens such as human platelet antigen (HPA)-5a, are present. Only 1–2% of the Caucasian population have been reported to be HPA-5bb homozygous (Santoso et al, 1993). To date, anti-HPA-5a alloimmunization has been reported in neonatal alloimmune thrombocytopenia (Mueller-Eckhardt et al, 1989; Davoren et al, 2004) and post-transfusion purpura (Anolik et al, 2001) but has only rarely been described in adults treated for haematological malignancy (Kiefel et al, 2001). We report the case of a 50-year-old woman with acute myeloid leukaemia who became alloimmunized to multiple human leucocyte antigen (HLA)-antigens and to HPA-5a during cytarabine-based induction chemotherapy. Platelet transfusion refractoriness, including to 3/4 or 4/4 HLA class-I matched products, occurred when the patient developed bilateral pneumonia with polymicrobial sepsis while in aplasia. Furthermore, diffuse gastrointestinal bleeding with haemorrhagic shock because of severe mucositis and refractory thrombocytopenia developed. A total of 23 single donor platelet products were administered. Anti-HLA class I, anti-HLA class II and anti-HPA-5a alloantibodies were detected; the patient was genotyped as HPA-5bb. The anti-HPA-5a antibody was considered relevant because of persisting refractoriness including to HLA-matched HPA-5-mismatched products. The patient recovered completely from the complications, and achieved a first complete remission. Myeloablative allogeneic HSCT from her HLA-identical brother (genotyped HPA-5ab) was planned. To monitor the anti-HPA-5a alloantibody during treatment, a quantitative method based on the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) procedure was developed (Bertrand et al, 2005, 2006). As there is no currently available international standard anti-HPA-5a serum, a pool of six sera was prepared and served as reference serum samples for quantification. They were collected from mothers immunized against HPA-5a fetal platelet alloantigen during pregnancy, reacting very strongly in the MAIPA technique. An assigned potency of 1000 arbitrary units (AU)/ml was attributed to the pool. As the level of glycoprotein (GP)IaIIa expression on platelets is lower than GPIIbIIIa carrying the HPA-1 antigenic system, a higher quantity of platelets per test was used. Sixty million HPA-5aa platelets from healthy donors were incubated with 15 μl P16 monoclonal antibody (International Blood Group Reference Laboratory, Bristol, UK) and 40 μl of serum initially diluted from 1 to 1:128 (eight dilutions tested per sample). Optical density was measured at 495 nm (Multiskan RC, Life Sciences, Cergy, France). A standard curve was constructed with eight dilutions of the pooled reference serum, and gave the best correlation with a 4-parameter logistic regression (R2 = 0·9989, Fig 1A). Quantification was performed using the Biolise software (Labsystems, Helsinki, Finland). Antibody concentrations and platelet counts in peripheral blood of the patient during treatment. (A) Validation of the monoclonal antibody-specific immobilization of platelet antigens method, standard curve. (B) Peripheral blood platelet counts (•) and anti-HPA-5a antibody concentration (□). Thrombaphereses (TcPh) were performed on days −10 and −9. Conditioning regimen consisted of cyclophosphamide (CY) 60 mg/kg on days −7 and −6, and busulfan (BU) 0·8 mg/kg every 6 h on days −5 to −2 pretransplant. HLA- and HPA- incompatible platelet transfusions (Tcincomp) and plasmapheresis (PPh) for immunadsorption were performed shortly prior to haematopoietic stem cell transplant (HSCT). HSCT was performed with mobilized peripheral blood containing 12 × 106 CD34+ cells/kg body weight. Thereafter, platelet transfusions from HLA- and HPA- compatible donors (Tccomp) were given. Post-transfusion corrected count increments were 39 and 33, respectively. The two transfusions on days 3 and 8 were given even though the platelet count in the patient was well above 20 × 109/L due to logistic reasons of the directed donations. Graft-versus-host disease prophylaxis included methotrexate and cyclosporine A. In preparation for the transplant, HLA- and HPA-5-compatible platelet donors were selected. Cross-match analyses identified a few compatible available donors. Because of the high-risk situation for refractory bleeding events, the patient was submitted to two thrombaphereses (TcPh) immediately prior to conditioning for cryopreservation of autologous platelets as backup (Valeri & Ragno, 2006). This procedure artificially induced a thrombocytopenia due to peripheral consumption, resulting in stimulated thrombopoiesis. The conditioning regimen consisted of cyclophosphamide/busulfan. Immunadsorption for reduction of circulating antibodies was attempted by transfusion of HLA- and HPA-incompatible platelet products on days −4 to −1 and a single plasmapheresis (PPh) on day −1. HSCT was performed on day 0. The post-transplant course was uneventful, platelet counts were maintained at levels >20 × 109/l with two compatible transfusions only (Fig 1B). The backup autologous platelet products were not used. The patient remains now, 1 year post-transplant, in complete remission. We believe that a multi-step approach in the management of the described patient was successful and enabled the patient to undergo curative myeloablative allogeneic HSCT. First, HLA-and HPA-compatible platelet donors were identified within the registries of many blood donation centres in several countries. Because of the low frequency of the HPA-5bb genotype, only few donors were available. No donors identical for HLA class I and HPA-5 could be identified. However, nine potential HPA-5bb donors were tested by cross-match analyses for anti-HLA alloreacitvity and four non-reactive donors were scheduled for directed platelet donations. Second, artificial platelet consumption was induced by two TcPh prior to start of the conditioning regimen. This resulted in an unexpectedly high platelet rebound because of increased platelet production. Platelet levels increased during chemotherapy and remained unusually high early post-transplant. Third, HLA-and HPA-incompatible platelet products were transfused for in vivo adsorption of circulating antibodies during the conditioning regimen. It can be assumed that new antibody production was largely prevented by the ongoing conditioning regimen. Fourth, ex vivo antibody reduction was performed the day before HSCT by a single PPh. The in vivo and ex vivo immunadsorption strategies were performed analogous to the standard procedures used in ABO-incompatible allogeneic HSCT where immunoglobulin (Ig)M- and IgG-isoagglutinin titres can be reduced significantly (Osterwalder et al, 1986; Stussi et al, 2006). Anti-HPA-5a antibody concentrations were monitored quantitatively during the treatment course. Transfusion of incompatible platelet products resulted in a significant reduction of alloantibody levels from 300 AU/ml to 209 AU/ml; however PPh on day −1 was the most efficient single intervention, reducing the titre to 66 AU/ml. Early post-transplant, antibody levels increased again, with persisting high levels at day 100 post-transplant. No platelet bound antibodies were detected at that time; platelet counts were normal (Fig 1B). This correlates with observations in ABO-incompatible HSCT where immune IgG can persist for up to 6–12 months post-transplant either with or without accompanying pure red cell aplasia (Stussi et al, 2006). For alloimmunized patients with haematological malignancies, HLA- and HPA-typing of platelet donors is of great importance. National registries allow rapid identification of potential donors for alloimmunized patients. Furthermore, we demonstrate that allogeneic myeloablative HSCT is feasible and safe even in a heavily alloimmunized patient when a combined antibody reduction strategy is pursued. Quantitative measurement of alloantibodies can provide clinicians with useful information concerning the efficiency of the antibody reduction during HSCT and can guide transfusion policies. This work was supported by a grant of the Regional Cancer League Basel-Stadt (C.A.) and a grant of the Swiss National Research Foundation 3200B0-106105/1 (A.G.). We thank the blood donation centers in Switzerland, Germany and France for donor identification and cross-match analyses.
Leukaemogenesis is a stepwise process of a delimited number of genetic aberrations, which lead to maturation impairment and promote proliferation and/or survival of the neoplastic clone.1 In acute myeloid leukaemia (AML) with t(8;21)(q22;q22)/ RUNX1-RUNX1T1 , genetic aberrations additional to the core-binding factor rearrangement are well known.2 Presumably further aberrations are also involved in leukaemogenesis of such AML, but are yet to be discovered.
Decrease/loss of function of the transcription factor GATA1 plays a central role in transient myeloproliferative disorders (TMDs) of newborns with trisomy 21.3–6 The presence of a short protein isoform, generated by a mutation, is complementary to trisomy 21 to initiate TMD.6 7 Since the potent oncogene RUNX1 is located …
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