Chronic lymphocytic leukemia (CLL) is common hematologic disease in Western societies with over 15,000 patients were diagnosed annually [1], but is very rare in Asian cohorts as well as Korea. The molecular diagnostic tools and variable understanding of the pathobiology of the disease have facilitated characterization of variations in the disease’s clinical course, resulting in better risk stratification [2]. Consequently more precise targeting of therapy is possible, and the rapid evolution of treatment strategies for CLL and development of new drugs warrant a closer look into CLL. In consideration that the course of CLL typically has medical problems related to chronic infection, immunosuppressive status, autoimmune complication and surveillance of secondary malignancies, long-term relationship between medical practitioners and patients is need to solve those problems. Also, in Korea, the incidence of CLL has been gradually increased too and it is not the orphan disease any more in recent years, so we have plan to describe the generalized review about CLL, to intend to bring attention to take a profound interest in the field of CLL for the Korean medical doctors and researchers.

There are significant geographical variations in the incidence of CLL. CLL is the most common adult B-cell leukemia of elderly patients in the Western world, but is less common among people of African or Asian origin [1]. Although the exact cellular origin of CLL remains a matter of controversy [2], approximately half of all CLL cases have unmutated IgV genes (uCLL). The remaining cases carry somatically mutated IgV genes (mCLL) [3]. This distinction is of biological interest and clinical relevance because uCLL is more aggressive, with a significantly shorter time from diagnosis to initial treatment [4].

Identification of the cellular origin of CLL is essential to elucidating the pathobiology of a tumor. Only then can the full natural course of the disease be revealed. It is also important to understand the dysregulation of gene expression and cellular functions [5]. The cellular origin of CLL as uCLL and mCLL is delineated by the absence or presence of IgV genes, respectively, from memory B-cells in a post-germinal center. However, based on a recent report on specific IgV gene rearrangements, a derivative of uCLL (CD5+, CD27-CD38^low) from conventional naive B-cells was proposed. mCLL (CD5+CD27+IgM+B-cell lymphoma [Bcl] 6_mutIgVH_mut) derives from a distinct, previously unrecognized B-cell subset from postgerminal centers [6].

According to the crude incidence rate of non-Hodgkin lymphoma and the ratio of CLL in lymphoma, the crude incidence rate per 100,000 individuals was 0.11. In Korea, 56 patients are newly diagnosed with CLL annually. The crude prevalence rate of CLL is 0.61 per 100,000. In total, 306 patients had prevalent CLL from the National Cancer Incidence Database (KNCI DB) in Korea (Table 1) [7]. The population of Korean patients have been limited, but according to a few reported data of single center, Korean patients diagnosed with CLL have more atypical immunophenotype with high frequencies of FMC7+ and strong presentation with CD22+ and more aggressive than that in Western populations [8,9]. And also considering an increasing incidence rate, and improvements in treatment, the incidence and prevalence rates are expected to be relatively high.

Conventional metaphase cytogenetic techniques are difficult in CLL due to the very low proliferative activity of leukemia cells in vitro. Therefore, interphase cytogenetic analysis with fluorescence in situ hybridization (FISH) is the standard method to detect chromosomal abnormalities that may have prognostic significance. Cytogenetic abnormalities that can be detected by FISH are present in approximately 80% of patients with previously untreated CLL. In a German study, the most common abnormality was del(13q) (55%), followed by del(11q) (18%), trisomy 12 (16%), and del(17p) (7%) [10]. In the 2014 National Comprehensive Cancer Network guidelines, CLL was classified into three risk groups by FISH, with del(17p) as TP53 gene found to be the strongest predictor for poor prognosis (Tables 2 and 3) [9,11-18]. In contrast with the results of Western societies, trisomy 12 was more common abnormality, followed by del(13q14), del(11q22), and del(17p13) in Korean CLL data [9].

CLL is usually asymptomatic and found during a routine blood test. However, some patients consult a physician because of painless swelling of the lymph nodes, often in the cervical area, which spontaneously enlarge and shrink but do not disappear. CLL is usually first suspected through the presence of lymphocytosis. According to the 1996 International Workshop on CLL update of the National Cancer Institute guidelines for CLL diagnosis and treatment, an absolute B lymphocyte count in the peripheral blood of ≥ 5,000/µL (5 × 10⁹/L) sustained for longer than 3 months must be observed [19]. In the current system, patients with an absolute lymphocyte count less than 5,000/µL (5 × 10⁹/L) are usually diagnosed with monoclonal B-cell lymphocytosis rather than CLL if they do not have palpably enlarged lymph nodes, spleen, and/or liver [20]. Immunophenotyping, usually by flow cytometry, is a key component to the diagnosis of CLL [21]. Major immunophenotypic analyses of CLL show the expression of B cell-associated antigens, including CD19, CD20 (usually weak), and CD23, with characteristic expression of CD5, a common T-cell antigen [19]. In addition, the κ or λ light chain restriction pattern and surface IgM and IgD expressions are decreased. Immunohistochemistry of lymph node biopsies show that they were positive for CD5, CD20, and CD23, and negative for CD3, CD10, and cyclin D1 (Table 4). Because of CD5 expression in CLL, mantle cell lymphoma may mimic CLL. However, neoplastic cells from mantle cell lymphoma stain strongly for cyclin D1 and surface membrane immunoglobulin, have a t(11;14) chromosomal abnormality, and are CD23-negative. In contrast, malignant cells in CLL are cyclin D1-negative and often CD23-positive [22].

The two staging systems for CLL are the Binet staging system, proposed in 1981 (Table 5) [23], and the Rai staging system, suggested in 1975 (Table 6) [24]. The Binet staging system is used more frequently.

CLL patients in the high-risk group include those who are refractory to fludarabine chemotherapy, who fail to achieve a response or show disease progression within 24 months of rituximab-based combination chemotherapy, or who have a TP53 mutation or del(17p). These high-risk patients have less than 36 months of overall survival after chemotherapy. We routinely performed FISH to detect chromosomal aberrations that are strong poor prognostic markers (Table 7). The identification of new genetic lesions in CLL has prompted the development of a comprehensive and dynamic prognostic algorithm. This algorithm considers gene mutations, chromosomal abnormalities, and their changes during recent clonal evolution (Table 8) [25]. However, this model requires both additional verification and a solution to its high cost.

CLL is an extremely heterogeneous disease and most patients have early stage disease at the time of diagnosis. Therapy is indicated for patients with “active disease,” as manifested by an advanced stage, high tumor burden, disease-related “B” symptoms, or repeated infections [26,27].

In Korea, although there are small numbers of patients diagnosed with CLL, the incidence of CLL is gradually increasing. This increase appears to be related with the rapid aging of society and the westernization of Korean lifestyles.

As the rapid evolution of treatment strategies for CLL and development of new drugs warrant a closer look into CLL, Korean medical doctors and researchers should take a profound interest in the field of CLL.