Order of Authors: Carlo L Balduini; Luigi Gugliotta; Mario Luppi; Luca Laurenti; Catherine Klersy; Carla Pieresca; Gerlando Quintini; Francesco Iuliano; Rossana Re; Pierangelo Spedini; Nicola Vianelli; Alfonso Zaccaria; Enrico M Pogliani; Roberto Musso; Enrico Bobbio Pallavicini; Giovanni Quarta; Piero Galieni; Alberto Fragasso; Gianluca Casella; Patrizia Noris; Edoardo Ascari Abstract: Therapeutic plasma exchange (PE) is the accepted therapy for thrombotic thrombocytopenic purpura (TTP). Because not all patients obtain remission, other treatment modalities have been used in addition to PE, but no randomized clinical trial evaluated their efficacy. The aim of this multicentric study was to compare the effectiveness of standard-versus high-dose methylprednisolone as an adjunctive treatment to PE in the acute phase of TTP. Sixty patients with idiopathic TTP were randomized to receive standard-dose (1 mg/kg/die i.v.) or high-dose methylprednisolone (10 mg/kg/die for three days, thereafter 2.5 mg/kg/die) in addition to PE. Both dosages of steroids were well tolerated. At the end of induction therapy (day 23), the percentage of patients failing to obtain complete remission was significantly higher in the standard-dose (16/30) than in the high-dose group (7/30). Also the number of cases without a good response at day 9 and the number of deaths were higher in the standard-dose arm, but the differences did not reach the statistical significance. Results of present study indicate that the association of PE with high-dose instead of standard-dose steroids reduces the percentage of TTP patients that fail to achieve complete remission.Response to Reviewers: Reviewer #1: The authors have proved that the association of plasma exchanged with high-dose methylprednisolone instead of standard-dose reduces the percentage of TTP patients that failed to achieve complete remission. This observation has important clinical implication. I have no major remarksMinor remarks: Activity of ADAMTS 13 and autoantibodies against ADAMTS 13 were not tested. In my opinion this paper can be published in Annals Of Hematology in the present form.Reviewer #2: General:In this randomized clinical trial Balduini and colleagues compared low-dose vs. high dose steroids as an adjunctive treatment to plasma exchange with fresh frozen plasma / cryosupernatant in 60 patients suffering from acute TTP. In the low-dose arm more patients (13/30 vs. 7/30, p= 0.17) failed to achieve a good response at day 9 (primary endpoint of the study) and also more patients failed to achieve complete remission (16/30 vs. 7/30; p= 0.03). Also the number of death (4 vs. 1) was higher, this was however not statistically significant. The authors conclude that plasma exchange in combination with high dose steroids is superior to low-dose steroids. Over the years the Italian TTP study group has been able to conduct several randomized clinical trials in the setting of acute TTP addressing open questions in the field where many other groups have failed to do likewise due to lack of sui...

Idiopathic thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a rare disease responsive to treatment with plasma exchange (PE) but with a high percentage of relapse or refractory patients. A severe deficiency of ADAMTS-13 (<5% of normal activity), congenital or caused by an autoantibody, may be specific for TTP and it has been proposed that severe ADAMTS-13 deficiency now defines TTP. B cells play a key role in both the development and the perpetuation of autoimmunity, suggesting that B-cell depletion could be a valuable treatment approach for patients with idiopathic TTP-HUS. This review of the literature focuses on the role of rituximab, a chimeric monoclonal antibody directed against CD20 antigen expressed by B lymphocytes, in patients with relapsing or refractory TTP-HUS with or without ADAMTS-13 deficiency, suggesting that rituximab may produce clinical remission in a significant proportion of patients. Rituximab therapy reduces plasma requirement and avoids complications related to salvage-immunosuppressive therapy. In conclusion, rituximab provides an effective, well-tolerated, and safe treatment option for patients with idiopathic TTP-HUS, thus giving an alternative approach to the current treatment based on PE.

BACKGROUND Splenic marginal zone cell lymphoma (SMZL) is a low grade B‐cell lymphoma in which patients can have circulating villous lymphocytes and can show a peculiar intrasinusoidal bone marrow (BM) infiltration. Splenectomy is the reported treatment of choice for these patients. The objective of this study was to evaluate the effects of splenectomy on patients with BM lymphomatous infiltration. METHODS BM biopsies of 16 patients with SMZL were studied morphologically and immunohistochemically. In 12 patients, BM biopsies were taken before and after splenectomy. Four patients did not undergo splenectomy, and their BM biopsies were performed with an approximately 1 year interval. RESULTS BM infiltration ranged from 10% to 40% of overall cellularity and was mostly of the intrasinusoidal type. After splenectomy, BM infiltration tended to become frankly nodular and showed an increase in tumor burden. Nonsplenectomized patients showed an unmodified picture. CONCLUSIONS Splenectomy seems to induce important changes in patients with BM infiltration, probably through the lack of microenvironmental factors on circulating cells. These effects suggest reconsidering the role of splenectomy in the treatment of patients with SMZL. Cancer 2001;91:294–301. © 2001 American Cancer Society.

International audienceThe evidence that leukocytes may contribute to the pathogenesis of thrombosis in Chronic Myeloproliferative Neoplasms is increasing but not definitive. To further enforces whether an increased leukocyte count is associated with thrombosis and whether this effect can be modulated by cytoreductive therapy, we analyzed the clinical course of 187 patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) followed at two Italian Institutions over a period of 7 years. The association was measured at diagnosis or before thrombotic events: a multivariable analysis was carried out using data at baseline and time-dependent covariates. We found that white blood cells (WBC) count above 9.5 × 10/L at diagnosis (baseline analysis) was associated with thrombosis during the follow-up (Hazard Ratio [HR] of 1.8, 0.03). At the time-dependent analysis, therapy with hydroxyurea (HU), lowering by 35% the baseline WBC level, reduced such strength of association giving a HR of 1.3 ( value non significant). We found a trend between WBC level and thrombosis in untreated low-risk patients (RR of 1.9, 95% CI 0.9 to 3.1); in high-risk patients treated with HU this correlation was clearly lost (RR 1.1, 95% CI 0.2 to 2.7). Finally, we could not identify the presence of as a risk factor for thrombosis. Properly designed prospective studies should corroborate such results

Although no strict morphological or immunophenotypical criteria able to allow an immediate diagnosis of underlying disease were pointed out, in most cases BMB proved to be an essential and reliable diagnostic tool. According to our experience, when HPS occurs, the first diagnosis to investigate is a neoplastic disease which sometimes can be latent or hidden.