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Haematological Malignancies New Developments in Chronic Lymphocytic Leukaemia Diagnosis Julio Delgado, Rodrigo Santacruz, Tycho Baumann, and Emili Montserrat Department of Hematology, Institute of Hematology and Oncology, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain Abstract Chronic lymphocytic leukaemia (CLL) is the most prevalent leukaemia in the developed world, with a remarkable racial and sex diversity. The diagnosis of CLL is based on the presence in blood of more than 5,000 monoclonal B cells/µl, with a distinctive immunophenotype (CD5+, SmIg dim , CD20 dim , CD19, CD23), which persists for more than 3 months. Newer monoclonal antibodies, such as anti-CD43, anti-CD200 or anti-ROR1, may provide further information in differentiating CLL from other chronic lymphoproliferative disorders. CLL lacks a specific genetic signature regarding chromosomic aberrations, but in cases of uncertain diagnosis molecular genetics including fluorescent in situ hybridisation may be useful. Next-generation sequencing techniques are unfolding the molecular heterogeneity of CLL. Keywords Chronic lymphocytic leukaemia, small lymphocytic lymphoma, Richter's Syndrome, inmunophenotyping, prognosis, monoclonal B-cell lymphocytosis Disclosure: The authors have no conflicts of interest to declare. Received: 14 June 2013 Accepted: 27 July 2013 Citation: European Oncology & Haematology, 2013;9(2):114–8 Correspondence: Emili Montserrat, Department of Hematology, Institute of Hematology and Oncology, Hospital Clínic, IDIBAPS, University of Barcelona, C/ Villarroel, 170, 08036 Barcelona, Spain. E: emontse@clinic.ub.es Chronic lymphoproliferative disorders (CLPD) comprise several disorders that arise from a monoclonal proliferation of mature B or T cells. Among these entities, there are many that frequently involve the blood and are usually detected in routine blood analyses, the most frequent being chronic lymphocytic leukaemia (CLL). Before the advent of immunophenotyping, most CPLD were diagnosed as CLL, but advances in the morphological evaluation of peripheral blood and lymphoid tissues, immunohistochemistry, flow cytometry and molecular genetics have facilitated their differential diagnosis. Moreover, these new techniques are allowing to identify distinct clinico-biologic forms of CLL. 1–3 Epidemiology CLL is the most prevalent form of leukaemia. In the US it is estimated that approximately 16,000 cases/year are diagnosed with CLL. The age- adjusted incidence rate is 4.2 cases per 100,000 per year, with a clear difference between men (5.8 cases/year) and women (3.0 cases/year). 4 In Europe, the incidence rate is similar (4.9 cases/year), with a similar sex distribution (5.9 for males and 4.0 for females). 5 The incidence of CLL dramatically increases with age, reaching >20 cases/year in individuals older than 70, and even >30 cases/year in patients aged 80 or older. On the contrary, CLL is infrequent in persons under the age of 40 (0.2 cases/year). 4 One of the most notorious epidemiological characteristics of CLL is its racial diversity. Within the US, the incidence rate is highest in Caucasian males (6.2 cases/year) and females (3.2 cases/year) compared with African Americans (4.3 and 2.0 cases/year for males and females, respectively), while Asian Americans and Pacific Islanders had the lowest incidence (1.3 and 0.7 cases/year for males and females, respectively). 4 Incidence rates are even lower in the Far East, and countries such as Japan have an age-adjusted incidence of 0.48 cases/year, which is even lower than that of mantle-cell lymphoma (MCL) in that region. 6 114 Furthermore, the clinical outcome of patients with CLL is also different across various ethnic groups. In the US, African American patients with CLL present at a younger age and with more frequent advanced disease, extranodal involvement and B symptoms compared with Caucasian patients. Consequently, African American patients had a significantly shorter event-free and overall survival, an effect that was found to be independent from other prognostic factors in a multivariable analysis. 7 By contrast, in a recent series or Japanese patients, most cases had favourable prognostic markers and an excellent clinical outcome. 8 It is important to note, however, that rather than diversity in the characteristics of the disease, these differences could reflect disparities in access to medical care. 7 Diagnosis The hallmark of the disease is an increased white blood cell count with a high percentage of small, mature-looking lymphocytes. In patients diagnosed on routine analysis, anaemia is found in less than 10 % of the patients. Importantly, anaemia is not always due to the infiltration of the bone marrow by the disease; other causes such as autoimmunity, iron, folic acid or vitamin B12 deficiency may account for the presence of anaemia and should be discarded when these comorbidities are under consideration. 9,10 Likewise, a marked thrombocytopenia (e.g. <20,000/ µl) should raise the possibility of an immune origin, particularly in the absence of anaemia. Hypogammaglobulinaemia is frequent (30  % of patients) and tends to worsen over the course of the disease. 11 Serum immunofixation can demonstrate an M component (usually of the immunoglobulin M [IgM] type) in around 10–15 % of patients. A positive direct antiglobulin test is observed in around 5  % of the patients at the time of diagnosis, with clinically apparent autoimmune haemolytic anaemia being less frequent. 12 The lymph nodes show involvement by © Touc h ME d ic a l ME d ia 2013