Best Practice & Research Clinical Haematology RSS feed: Current Issue. In practical paperback format, each 200 page topic-based issue of Best Practice & Research Clinical Haematology will provide a comprehensive review of current clinical practice and thinking within the specialty of haematology. All chapters are commissioned and written by an international team of practising clinicians with the Guest Editors for each issue drawn from a pool of renowned experts and opinion leaders. Reference is made to: • the latest original research • Cochrane Reviews • audits and confidential enquiries • national and international conferences • national and international guidelines • personal communications All chapters take the form of practical, evidence-based reviews that seek to address key clinical issues of diagnosis, treatment and patient management. Each issue follows a problem-orientated approach that focuses on the key questions to be addressed, clearly defining what is known and not known. Management will be described in practical terms so that it can be applied to the individual patient. Boxed and bulleted Learning Objectives and Practice Points are features within each chapter and will highlight the core and essential knowledge that will help the physician to provide the best care to their patients. The series' objective is to provide a continuous update for the busy clinician and researcher.http://www.bprch.com/?rss=yesElsevier Inc.en © 2010 Published by Elsevier Inc. All rights reserved. Best Practice & Research Clinical Haematology1521-6926231March 2010 © 2010 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.bprch.com/article/PIIS1521692610000228/abstract?rss=yesEditorial Board / Aims & Scope10.1016/S1521-6926(10)00022-8Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-0iiiiiihttp://www.bprch.com/article/PIIS1521692610000113/abstract?rss=yesOur understanding of chronic lymphocytic leukaemia (CLL) has undergone dramatic changes over the past 20 years. This issue of Best Practice & Research in Clinical Hematology gathers a large panel of internationally recognised experts who not only review recent advances in biology, diagnosis, prognostication and treatment of chronic lymphocytic leukaemia but also offer their personal points of view on how further advances in this disease should be pursued.PrefaceEmili Montserrat10.1016/j.beha.2010.03.001Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-012http://www.bprch.com/article/PIIS1521692610000022/abstract?rss=yesThe diagnosis of chronic lymphocytic leukaemia (CLL) is based on clinical and laboratory features. Morphology and immunophenotype are the initial diagnostic investigations. In atypical cases, these tests should be complemented with molecular genetics and/or histology to exclude other B-cell disorders of small lymphocytes. Morphologically, CLL can be classified into typical and atypical. Immunophenotyping is the only method that can establish or confirm the diagnosis as CLL lymphocytes have a distinct immunophenotypic signature. A scoring system compounding the results with a set of markers allows firming up the diagnosis. Other immunological markers such as CD38 and ZAP-70 have an important prognostic impact. Fluorescence in situ hybridization (FISH) analysis, chiefly by detecting 17p (TP53 locus) and 11q (ATM) deletions and mutational status of the IgVH gene, also provides prognostic information and may determine the type of therapy. In atypical CLL, histology and/or molecular genetics may be required to exclude other B-cell disorders.Diagnostic issues in chronic lymphocytic leukaemia (CLL)Estella Matutes, Ayoma Attygalle, Andrew Wotherspoon, Daniel Catovsky10.1016/j.beha.2010.01.001Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-0320http://www.bprch.com/article/PIIS1521692609001066/abstract?rss=yesChronic lymphocytic leukaemia (CLL) is characterised by accumulation of CD5+ monoclonal B cells in primary and secondary lymphoid tissues. Genetic defects and stimuli originating from the microenvironment concur to the selection and expansion of the malignant clone. Several lines of evidence, including molecular and functional analysis of the monoclonal immunoglobulin, support the hypothesis that stimulation through the B-cell receptor affects life and death of leukaemic cells. The microenvironment also has a critical role in the survival and accumulation of leukaemic cells within lymphoid organs where signals delivered from the surrounding cells are likely crucial in inducing proliferation. Nevertheless, several major biological issues still remain to be solved including regulation of the balance between proliferation and survival of leukaemic cells and the links between emerging gene abnormalities and microenvironment. In this context, mouse models are helpful tools in understanding disease mechanisms and in evaluating the efficacy of novel therapeutic agents.An overview of chronic lymphocytic leukaemia biologyM.T.S. Bertilaccio, C. Scielzo, M. Muzio, F. Caligaris-Cappio10.1016/j.beha.2009.12.005Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-02132http://www.bprch.com/article/PIIS1521692610000095/abstract?rss=yesB cell-type chronic lymphocytic leukaemia (CLL) has long been considered a disease of resting lymphocytes. However, cell surface and intracellular phenotypes suggest that most CLL cells are activated cells, although only a small subset progresses beyond the G1 stage of the cell cycle. In addition, traditional teaching says that CLL cells divide rarely, and therefore the build-up of leukaemic cells is due to an inherent defect in cell death. However, in vivo labelling of CLL cells indicates a much more active rate of cell birth than originally estimated, suggesting that CLL is a dynamic disease.Here we review the observations that have led to these altered views of the activation state and proliferative capacities of CLL cells and also provide our interpretation of these observations in light of their potential impact on patients.Chronic lymphocytic leukaemia: a disease of activated monoclonal B cellsRajendra N. Damle, Carlo Calissano, Nicholas Chiorazzi10.1016/j.beha.2010.02.001Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-03345http://www.bprch.com/article/PIIS1521692610000058/abstract?rss=yesPatients with B-chronic lymphocytic leukaemia /small lymphocytic lymphoma (CLL) have a 5–10% risk of developing autoimmune complications, which primarily cause cytopaenia. These autoimmune cytopaenias can occur at any stage of CLL and do not have independent prognostic significance. The most common autoimmune complication is autoimmune haemolytic anaemia with a lower frequency of immune thrombocytopaenia and pure red blood cell aplasia and only rarely, autoimmune granulocytopaenia (AIG). Autoimmune cytopaenia should always be considered in the differential diagnosis of cytopaenia in patients with CLL. Patients with CLL can also have more than one form of autoimmune cytopaenia, which can occur together with bone-marrow failure. Treatment is usually effective but rarely curative for autoimmune cytopaenia complicating CLL. Optimal therapy will depend on a timely and accurate diagnosis of autoimmune cytopaenia and should be individualised according to the severity of the cytopaenia and the presence or absence of concomitant progressive CLL requiring therapy.Autoimmune Complications in Chronic Lymphocytic Leukaemia (CLL)Clive S. Zent, Neil E. Kay10.1016/j.beha.2010.01.004Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-04759http://www.bprch.com/article/PIIS1521692610000101/abstract?rss=yesMonoclonal B-lymphocytosis (MBL) is defined as the presence of a population of monoclonal B-cells, usually with a chronic lymphocytic leukaemia (CLL) phenotype, which comprise fewer than 5000 cells per μl with no evidence of tissue involvement. Over the past few years, MBL has been clearly defined and differentiated from CLL so that individuals with MBL are no longer inappropriately labelled as suffering from leukaemia. In this review, we will describe the entity of MBL and summarise the evidence that underlies the current theory on the pathophysiology of the disorder, the relationship with CLL and the probability of developing progressive disease requiring treatment. 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.Clinical and diagnostic implications of monoclonal B-cell lymphocytosisAndy C. Rawstron, Peter Hillmen10.1016/j.beha.2010.02.002Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-06169http://www.bprch.com/article/PIIS1521692609001042/abstract?rss=yesMany prognostic factors have been identified in chronic lymphocytic leukaemia (CLL). Based on the assessment of B cell receptor (BCR) structure and function, a subdivision into subtypes is possible (e.g., immunoglobulin heavy chain variable gene segment (IGHV) unmutated and mutated, V3-21 usage) with distinct biological and clinical characteristics. Recurrent genomic aberrations (i.e., 11q and 17p deletion) and gene mutations (i.e., TP53 and ATM) help to define biological and clinical subgroups. In addition, serum markers (e.g., thymidine kinase (TK) and ß2-microglobulin (ß2-MG)), cellular markers (e.g., CD38 and ZAP70) and clinical staging have an impact on outcome in CLL. The biological characterisation of CLL has not only led to progress in outcome prediction but also has begun to be translated into novel treatment strategies. Nonetheless, most factors associated with prognosis have not been thoroughly interrogated for their predictive value in the light of different therapeutic approaches. With a growing number of agents acting on specific biological targets and being used in different clinical situations, the future is likely to bring the identification of predictive factors in CLL.Moving from prognostic to predictive factors in chronic lymphocytic leukaemia (CLL)Thorsten Zenz, Stefan Fröhling, Daniel Mertens, Hartmut Döhner, Stephan Stilgenbauer10.1016/j.beha.2009.12.003Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-07184http://www.bprch.com/article/PIIS1521692609001030/abstract?rss=yesRapid progress has been achieved recently in the management of chronic lymphocytic leukaemia (CLL). New insights into the molecular pathology of CLL have generated a plethora of biological markers that predict the prognosis and influence therapeutic decisions. Moreover, fludarabine, bendamustine and two monoclonal antibodies, alemtuzumab and rituximab, have been approved by European and/or American regulatory agencies. Additional monoclonal antibodies targeting CD20, CD23, CD37, CD38 or CD40, as well as drugs designed to interfere with proteins regulating the cell cycle, apoptotic machinery or leukaemic microenvironment (e.g., flavopiridol, oblimersen, ABT-263 or lenalidomide) are investigated in clinical trials. An increased experience with reduced-intensity allogeneic progenitor cell transplantation allows offering this option to physically fit patients. This review attempts to summarise the current use of these different modalities in CLL therapy.Therapy of chronic lymphocytic leukaemiaMichael Hallek10.1016/j.beha.2009.12.002Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-08596http://www.bprch.com/article/PIIS152169261000006X/abstract?rss=yesAmong chronic lymphocytic leukaemia (CLL) patients who require therapy, their response to therapy is the most important prognostic factor, with a better response predicting longer progression-free and overall survival. In this context, patients who achieve minimal residual disease (MRD)-negative status have better prognosis than those with inferior response to therapy, including those with MRD-positive complete response (CR). MRD can be assessed by either allele-specific polymerase chain reaction (PCR) or four-colour cytofluorometry. Importantly, methods to determine MRD in CLL have been standardised. Nevertheless, MRD status should not be used as a goal of therapy outside clinical studies. This is because the issue of the benefits of achieving MRD-negative status in patients with CLL requires further investigation in large controlled trials, in which patients should be stratified according to not only clinical variables but also biological parameters such as cytogenetics, IGHV mutations or ZAP-70 expression.Is MRD eradication a desirable goal in CLL?Carol Moreno, Matthias Ritgen, Andy Rawstron10.1016/j.beha.2010.01.005Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-097107http://www.bprch.com/article/PIIS1521692609001029/abstract?rss=yesThere is no clear consensus regarding the optimal management of chronic lymphocytic leukaemia. Many patients are diagnosed at an advanced age and will die with chronic lymphocytic leukaemia, but of other unrelated causes. A significant minority are diagnosed at an earlier age, or with more aggressive disease, and despite chemotherapy, are likely to die of chronic lymphocytic leukaemia. The infusion of autologous or allogeneic haemopoietic stem cells, following a variety of conditioning regimes, offers the possibility of longer remissions or even cure. We explore the key questions facing clinicians in this field: Who is it best to transplant? When is it best to transplant? How is it best to transplant?Stem cell transplantation in chronic lymphocytic leukaemia – steering a safe course over shifting sandsSimon Hallam, John G. Gribben10.1016/j.beha.2009.12.001Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-0109119http://www.bprch.com/article/PIIS1521692610000083/abstract?rss=yesThe nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathway is constitutively active in a variety of cancers, including chronic lymphocytic leukaemia (CLL). The importance of this signalling pathway identifies it as a prime therapeutic target; however, the complexity and potential side effects of inhibiting NF-κB have thus far made the clinical use of NF-κB inhibitors a relatively unexplored resource in this disease. This article discusses the role of NF-κB in CLL as a common crossroad for pathways promoting drug resistance in CLL. We provide the background on how this pathway contributes to both spontaneous and drug-induced apoptosis. Potential new avenues to regulate this pathway in CLL are also discussed.Signalling to drug resistance in CLLErin Hertlein, John C. Byrd10.1016/j.beha.2010.01.007Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-0121131http://www.bprch.com/article/PIIS1521692610000071/abstract?rss=yesThe availability of safe and effective monoclonal antibodies has revolutionised the treatment strategies for patients with chronic lymphocytic leukaemia (CLL). Alemtuzumab, the first antibody approved for these patients, induces responses in one-third of relapsed and refractory patients, and in more than 80% when used as initial therapy. Rituximab, while exhibiting modest single-agent activity, improves the response rate when added to standard chemotherapy and may even prolong patient survival. The most recent antibody to be approved by regulatory agencies is ofatumumab, a new anti-CD20 antibody, with efficacy in patients whose disease is refractory to both fludarabine and alemtuzumab. Other antibodies or related molecules in development are directed at antigens, such as CD20, CD23 and CD37. Through rational combinations with chemotherapy and other biologic agents, the outcome for patients with CLL will further improve.Monoclonal antibody therapy of chronic lymphocytic leukaemiaBruce D. Cheson10.1016/j.beha.2010.01.006Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-0133143http://www.bprch.com/article/PIIS1521692609001054/abstract?rss=yesInfectious complications continue to be a major cause of morbidity and mortality in patients with chronic lymphocytic leukaemia (CLL). The pathogenesis of infections in these patients is multifactorial, related to inherent immune defects and therapy-related immunosuppression. Hypogammaglobulinaemia is an important predisposing factor for infection in all patients. The use of the purine analogues such as fludarabine, and monoclonal antibodies such as rituximab and alemtuzumab, has introduced a new spectrum of infectious complications caused by pathogens such as Pneumocystis, Listeria, mycobacteria, herpesviruses Candida and Aspergillus, related to the cellular immune suppression induced by these agents. This review focusses on the pathogenesis and risk factors for infections in patients with CLL, the spectrum of infectious complications and preventive approaches to infection in these patients, using antimicrobial and immunoglobulin prophylaxis and vaccination strategies.Infectious complications of chronic lymphocytic leukaemia: pathogenesis, spectrum of infection, preventive approachesVicki A. Morrison10.1016/j.beha.2009.12.004Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-0145153http://www.bprch.com/article/PIIS1521692610000046/abstract?rss=yesChronic lymphocytic leukaemia (CLL) is characterised by the dependence on the overexpression of anti-apoptotic proteins to maintain their survival. Based on this biological context, a strategy for CLL therapy was proposed using inhibitors of transcription and translation to transiently reduce the short-lived survival proteins and induce cell death. This includes inhibitors of the cyclin-dependent kinases required for the activation of RNA polymerase II, as well as homoharringtonine and silvestrol, the natural compounds that inhibit translation. As their actions are independent of p53 or ataxia telangiectasia mutated (ATM) function, agents that act by such mechanisms are promising to overcome resistance to current CLL therapy. Further, the combination of inhibitors of transcription and translation, together with other approaches that interfere with the function of anti-apoptotic proteins, may initiate synergistic killing in CLL.Strategy to induce apoptosis and circumvent resistance in chronic lymphocytic leukaemiaRong Chen, William Plunkett10.1016/j.beha.2010.01.003Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-0155166http://www.bprch.com/article/PIIS1521692610000034/abstract?rss=yesThe authors who have contributed to this monograph are highly experienced and recognised experts in chronic lymphocytic leukaemia (CLL). These authors have provided from their respective points of view, an authoritative summary of the progress that has been made in CLL. Thus, the task assigned to me is to answer the question, ‘Where do we go from here?’, which is particularly formidable. It requires me to let my own imagination take over and try to look into the future. Dr. Emili Montserrat has agreed to let me speculate as to where the future research in this disease might lead us and to do this without being required to cite any references.Where do we go from here?Kanti R. Rai10.1016/j.beha.2010.01.002Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-0167168http://www.bprch.com/article/PIIS1521692610000265/abstract?rss=yesKeyword Index10.1016/S1521-6926(10)00026-5Best Practice & Research Clinical Haematology 23, 1 (2010)2010-03-01Best Practice & Research Clinical Haematology2010-03-01231S1521-6926(10)X0002-0I1I1