Peter Hillmen

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..001). These results show that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH. This study is registered at http://clinicaltrials.gov (study ID no. NCT00122317)...

..Administration of eculizumab to patients with renal dysfunction or damage was well tolerated and was usually associated with clinical improvement...

..Efficacy and safety should be fully tested in a randomized Phase III trial...

..We conducted a randomized trial to evaluate the efficacy and safety of intravenous alemtuzumab compared with chlorambucil in first-line treatment of chronic lymphocytic leukemia (CLL)...

..We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH)...

..This article reviews recent advances in identifying patients who have poor-risk disease and explores the potential importance of MRD status as an outcome measure of CLL therapy...

..This may be due to C3-mediated clearance of paroxysmal nocturnal hemoglobinuria red blood cells through the reticuloendothelial system...

..The aim of this study was to screen for cell surface markers that could discriminate CLL-type MBL from CLL or identify CLL cases likely to have stable disease...

..This article reviews our current understanding of MRD eradication and analyzes whether it is a desirable goal in the routine clinical treatment of CLL, which will optimize the management of individual patients...

..Asymptomatic persons with fewer CLL-phenotype cells have monoclonal B-cell lymphocytosis (MBL). The goal of this study was to investigate the relation between MBL and CLL...

..Eculizumab continued to be safe and well tolerated, and all patients completed the study. The close relationship between sustained terminal complement inhibition, hemolysis, and symptoms was demonstrated...

..These data demonstrated that intravascular haemolysis in PNH produces a state of NO catabolism leading to signs of PH, including elevated NT pro-BNP and dyspnoea that are significantly improved by treatment with eculizumab...

..We tested the clinical efficacy of eculizumab, a humanized antibody that inhibits the activation of terminal complement components, in patients with PNH...

..Complement inhibition has been sustained for over 2 years and results in resolution of intravascular hemolysis and amelioration of symptoms associated with smooth muscle contractions...

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..In both these developments, flow cytometry played a critical role. In the first instance, in monitoring direct response to a new therapeutic agent; second, in demonstrating the phenotypic/genotypic link in a new form of GPI deficiency...

..There was no evidence of complement blockade from cord blood samples taken at delivery. Eculizumab appears safe to use in this setting and is likely to prevent many of the complications usually observed...

..In this chapter we briefly review the existing methods for MRD assessment, the clinical relevance of MRD eradication in CLL, and the therapies available to attain this endpoint...

..If validated in prospective studies, blood monitoring at 2 and 4 weeks may be used to optimize therapy...

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..07 vs. CHOP), and a median duration of response of 11 months (4-25+ months). This study demonstrates that FC is a highly active regimen in patients relapsing following CHOP chemotherapy...

..Thus, rhCD59-P corrects the CD59 deficiency in vitro and can bind to erythrocytes in an in vivo murine model, protecting the cells from the activity of human complement, and represents a potential therapeutic strategy in PNH...

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..Currently, no external quality assessment (EQA) programme or reference material is available for whole-blood PNH testing (red cells and leucocytes) by flow cytometry...

..001). Eculizumab dramatically alters the natural course of PNH, reducing symptoms and disease complications as well as improving survival to a similar level to that of the general population...

..Together, these data suggest a high prevalence of haemolysis-associated NO scavenging, Doppler-estimated systolic pulmonary hypertension, and depressed right ventricular function in patients with PNH...

..These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function...

..The successful application of fludarabine plus alemtuzumab, or fludarabine in combination with other cytotoxic agents, as preparative regimens for stem cell transplantation techniques is also covered...

..It is not a curative therapy but has a great benefit on those with this rare debilitating condition...

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..Large PNH granulocyte clones are predictive of venous thrombosis, although the exact cut-off for clone size is still to be determined. Primary prophylaxis with warfarin in PNH prevents thrombosis with acceptable risks...

..In addition, we will evaluate the importance of further clinical investigations, in particular, the relevance of screening for MBL and undertaking bone marrow investigations according to the clinical setting and B-cell phenotype...

..With protocols in place for dose escalation, for dose postponement in the event of cytopenia, and for anti-infective prophylaxis, alemtuzumab can be used effectively and safely in high-risk B-CLL patients...

..Gene therapy remains a tantalising possibility, although a greater understanding of the pathophysiology of PNH is required, as well as advances in gene therapy techniques, before such an approach can be seriously considered...

..The results suggest continuous re-entry into the cell cycle as no distinct stem cell pool was detectable...

..MRD analysis in the peripheral blood also may be used during therapy to predict eventual response and potentially to guide therapy to achieve the optimal outcome...

..Alemtuzumab induced significant responses in these patients with clinical benefit in the majority and with acceptable toxicity in a high-risk group...

..A growing list of clinical manifestations attributed to hemoglobin release in a variety of acquired and iatrogenic hemolytic disorders suggests that hemolysis and hemoglobinemia should be considered as a novel mechanism of human disease...

..The implications of these findings for monoclonal antibody therapy in WM are discussed...

..The combination of rituximab with other agents is also being investigated, and these ongoing trials will help define the role of rituximab in CLL...

..To test whether eradication of minimal residual disease (MRD) in B-cell chronic lymphocytic leukemia (CLL) by alemtuzumab is associated with a prolongation of treatment-free and overall survival...

..Infectious complications are the most important toxicity seen and are related to the depletion of normal lymphocytes. The clinical efficacy in combination with both fludarabine and rituximab is under investigation...

..In conclusion, DAT status at the time of initiation of therapy provides a new prognostic indicator, although FC may protect against AHA. This trial was registered at http://isrctn.org as no. 58585610...

..This trial is registered at http://clinicaltrials.gov as NCT00130000...

..Because high response rates and few complications are observed in previously untreated patients, the use of alemtuzumab earlier in therapy may provide optimum benefit to patients...

..Complete morphologic bone marrow responses were seen in 3 patients, including eradication of disease measured by sensitive flow cytometry in 2. Campath-1H combined with fludarabine is a highly promising novel therapy for refractory CLL...

..32 (rs11083846, PRKD2; P = 3.96 x 10(-9)). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL...

..The detection of CLL-phenotype cells provides a surrogate marker of carrier status, potentially facilitating gene identification through mapping in families and direct analysis of isolated CLL-phenotype cells...

..Subcutaneous alemtuzumab is more convenient and better tolerated but may be associated with some patients forming anti-alemtuzumab antibodies, particularly those patients who were previously untreated...

..The data suggest that inherited factors increase the susceptibility to both indolent and aggressive CLL, and they provide unbiased demonstration that the age of onset in CLL families is younger than in the general population...

..Future studies of MBL should be directed towards determining its relationship to clinical disease, particularly in individuals from families with a genetic predisposition to developing CLL...

..The data suggest that myeloma plasma cells are unlikely to be depleted by alemtuzumab in most patients...

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..Pending the outcome of such trials, treatment decisions outside the context of a clinical trial still should be based on guidelines established by the most recent National Cancer Institute-sponsored Working Group...

..8%-6.6%) of IgH somatic hypermutation. The monoclonal CLL phenotype cells present in otherwise healthy individuals may represent a very early stage of indolent CLL and should be useful in elucidating the mechanisms of leukemogenesis...