We analyzed prognostic factors of response, response duration, and possible impact on survival of epoetin ␣, epoetin , or darbepoetin ␣ (DAR) with or without granulocyte colony-stimulating factor in 403 myelodysplastic syndrome (MDS) patients. Sixty-two percent (40% major and 22% minor) and 50% erythroid responses were seen, and median response dura-
IntroductionImmune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by low platelet counts and may be responsible for mucocutaneous bleeding of variable severity. 1 ITP is usually chronic (Ͼ 6 months) in adults and, after this time, the probability of spontaneous remission is low. Standard management is to initiate steroids, anti-Rh 0 (D) immune globulins, and/or intravenous immunoglobulins (IVIgs) for the more severe forms. [2][3][4][5] The response rate is high but most often transient. That the spleen plays a major role in the removal of damaged platelets has long been known and, to date, splenectomy is still considered the "gold standard" treatment in many countries for the management of chronic ITP with platelet counts less than 30 ϫ 10 9 /L, especially when hemorrhagic complications are present. Approximately two thirds of chronic ITP patients who undergo splenectomy achieve lasting responses. 6 As suggested in the guidelines of the American Society of Hematology (ASH) 7 and the British Committee for Standards in Hematology (BCSH), 8 splenectomy should be considered the main second-line therapy for patients who fail to respond durably to first-line therapy, with persistent platelet counts less than 30 ϫ 10 9 /L. However, increasing numbers of patients are reluctant to undergo splenectomy and physicians are hesitant to recommend it. 9,10 In addition, the risk of overwhelming postsplenectomy infections, although rare, is not predictable and represents a major concern. 11-13 Moreover, some authors reported that, despite initial good responses to splenectomy, the risk of late relapse persists during long-term follow-up 14,15 and severe morbidity resulting from surgery is associated with 11% to 30% postoperative complications requiring prolonged hospitalization or readmission. 11,16 For these reasons, an effective and safe alternative to splenectomy would improve management of chronic ITP.Rituximab is a chimeric, humanized monoclonal antibody directed against the CD20 determinant on B cells. It was initially developed for the treatment of malignant lymphoma but has also been used in autoantibody-mediated disorders, such as rheumatoid arthritis, 17 systemic lupus erythematosus, 18 autoimmune hemolytic anemia, 19 or thrombotic thrombocytopenic purpura. 20 Case reports and several uncontrolled studies described its promising results in ITP patients. Arnold et al 21 conducted a systematic review of published reports on rituximab use in adults with chronic ITP. A complete response, usually observed 3 to 8 weeks after the first infusion, was obtained in 46% of patients. The median response duration was 10.5 months (interquartile range [IQR]: 6.3-17.8 months), but long-term For personal use only. on May 10, 2018. by guest www.bloodjournal.org From responses were not mentioned in all published studies. Arnold et al 21 pointed out the heterogeneity of patients' prior rituximab use and particularly their splenectomy status. Moreover, the short follow-up in some reports and the possible bias due to th...
Key Points• Despite a low frequency of mutations, BCOR might be considered as a key gene in risk stratification. • Deep sequencing technologiesshow that BCOR mutations commonly arise after other concomitant mutations in MDS.Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to acute myeloid leukemia (AML) remain a challenge in disease management. Using whole-exome sequencing of an MDS patient, we identified a somatic mutation in the BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified 4.2% and 0.8% of mutations respectively. BCOR mutations were associated with RUNX1 (P 5 .002) and DNMT3A mutations (P 5 .015). BCOR is also mutated in chronic myelomonocytic leukemia patients (7.4%) and BCORL1 in AML patients with myelodysplasia-related changes (9.1%). Using deep sequencing, we show that BCOR mutations arise after mutations affecting genes involved in splicing machinery or epigenetic regulation. In univariate analysis, BCOR mutations were associated with poor prognosis in MDS (overall survival [OS]: P 5 .013; cumulative incidence of AML transformation: P 5 .005). Multivariate analysis including age, International Prognostic Scoring System, transfusion dependency, and mutational status confirmed a significant inferior OS to patients with a BCOR mutation (hazard ratio, 3.3; 95% confidence interval, 1.4-8.1; P 5 .008). These data suggest that BCOR mutations define the clinical course rather than disease initiation. Despite infrequent mutations, BCOR analyses should be considered in risk stratification. (Blood. 2013;122(18):3169-3177)
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