Chronic Lymphocytic Leukemia
- Author: Muhammad A Mir, MD, FACP; Chief Editor: Emmanuel C Besa, MD more...
Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes (see the image below). It is the most common form of leukemia found in adults in Western countries. Some patients die rapidly, within 2-3 years of diagnosis, because of complications from CLL, but most patients live 5-10 years.
See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, to help detect chronic leukemias and determine the specific type present. See also Chronic Lymphocytic Leukemia (CLL) Guidelines
Signs and symptoms
Patients with CLL present with a wide range of symptoms and signs. Onset is insidious, and it is not unusual for CLL to be discovered incidentally after a blood cell count is performed for another reason; 25-50% of patients will be asymptomatic at time of presentation.
Symptoms include the following:
Enlarged lymph nodes, liver, or spleen
Loss of appetite or early satiety
Abnormal bruising (late-stage symptom)
See Clinical Presentation for more detail.
Patients with CLL have a higher-than-normal white blood cell count, which is determined by complete blood count (CBC). Peripheral blood flow cytometry is the most valuable test to confirm a diagnosis of CLL. Other tests that may be helpful for diagnosis include bone marrow biopsy and ultrasonography of the liver and spleen. Immunoglobulin testing may be indicated for patients developing repeated infections.
Two staging systems are used for CLL.
The Rai-Sawitsky staging system categorizes patients into low-, intermediate-, and high-risk groups, as follows:
Low risk (formerly stage 0) – Lymphocytosis in the blood and marrow only (25% of presenting population) 
Intermediate risk (formerly stages I and II) – Lymphocytosis with enlarged nodes in any site or splenomegaly or hepatomegaly (50% of presentation)
High risk (formerly stages III and IV) – Lymphocytosis with disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100 x 10 9/L) (25% of all patients)
The Binet staging system categorizes patients according to the number of lymph node groups involved, as follows:
Stage A – Hemoglobin greater than or equal to 10 g/dL, platelets greater than or equal to 100 × 10 9/L, and fewer than 3 lymph node areas involved.
Stage B – Hemoglobin and platelet levels as in stage A and three or more lymph node areas involved
Stage C – Hemoglobin less than 10 g/dL or platelets less than 100 × 10 9/L, or both
See Workup for more detail.
Patients with early-stage CLL are not treated with chemotherapy until they become symptomatic or display evidence of rapid progression of disease. Early initiation of chemotherapy has failed to show benefit in CLL and may even increase mortality.
When chemotherapy is initiated, the nucleoside analogue fludarabine is the most commonly used first-line therapy in CLL. Combination regimens have shown improved response rates in several clinical trials and include the following:
Fludarabine, cyclophosphamide, and rituximab (FCR) [3, 4]
Pentostatin, cyclophosphamide, and rituximab (PCR)
Fludarabine, cyclophosphamide, and mitoxantrone (FCM)
Cyclophosphamide, vincristine, and prednisone (CVP)
Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)
Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. It is the most common form of leukemia found in adults in Western countries. (See the histologic sample in the image below.)
Onset is insidious, and it is not unusual for CLL to be discovered incidentally after a blood cell count is performed for another reason. Enlarged lymph nodes are the most common presenting symptom, but patients may present with a wide range of symptoms and signs. (See Presentation.)
Chemotherapy is not needed in CLL until patients become symptomatic or display evidence of rapid progression of disease. A variety of chemotherapy regimens are used in CLL. These may include nucleoside analogues, alkylating agents, and biologics, often in combination. Allogeneic stem cell transplantation is the only known curative therapy. (See Treatment.)
The cells of origin in most patients with CLL are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells. Morphologically, in the peripheral blood, these cells resemble mature lymphocytes.
CLL B-lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20dim, CD21, and CD23 monoclonal antibodies. In addition, they express CD5, which is more typically found on T cells. Because normal CD5+ B cells are present in the mantle zone of lymphoid follicles, B-cell CLL is most likely a malignancy of a mantle zone–based subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies.
CLL B-lymphocytes express extremely low levels of surface membrane immunoglobulin, most often immunoglobulin M (IgM) or IgM/IgD and IgD. Additionally, they also express extremely low levels of a single immunoglobulin light chain (kappa or lambda).
An abnormal karyotype is observed in the majority of patients with CLL. The most common abnormality is deletion of 13q, which occurs in more than 50% of patients. Individuals showing 13q14 abnormalities have a relatively benign disease that usually manifests as stable or slowly progressive isolated lymphocytosis.
The presence of trisomy 12, which is observed in 15% of CLL patients, is associated with atypical morphology and progressive disease. Deletion in the short arm of chromosome 17 has been associated with rapid progression, short remission, and decreased overall survival. 17p13 deletions are associated with loss of function of the tumor suppressor gene p53. Deletions of bands 11q22-q23, observed in 19% of patients, are associated with extensive lymph node involvement, aggressive disease, and shorter survival.
More sensitive techniques have demonstrated abnormalities of chromosome 12. Forty to 50% of patients demonstrate no chromosomal abnormalities on conventional cytogenetic studies. However, 80% of patients will have abnormalities detectable by fluorescence in situ hybridization (FISH). Approximately 2-5% of patients with CLL exhibit a T-cell phenotype.
Studies have demonstrated that the proto-oncogene bcl2 is overexpressed in B-cell CLL. The proto-oncogene bcl2 is a known suppressor of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of bcl-2 protein, genetic translocations that are known to result in the overexpression of bcl2, such as t(14;18), are not found in patients with CLL.
Studies have shown that this upregulation in bcl2 is related to deletions of band 13q14. Two genes, named miRNA15a and miRNA16-1, are located at 13q14 and have been shown to encode not for proteins, but rather for a regulatory RNA called microRNA (miRNA).[6, 7] These miRNA genes belong to a family of highly conserved noncoding genes throughout the genome whose transcripts inhibit gene expression by causing degradation of mRNA or by blocking transcription of mRNA.
Deletions of miRNA15a and miRNA16-1 lead to overexpression of bcl2 through loss of downregulating miRNAs. Genetic analyses have demonstrated deletion or downregulation of these miRNA genes in 70% of CLL cases.
Wang et al studied the CLL genome and discovered splicing factor 3b (SF3B1) mutations affecting pre-mRNA in 15% of sampled cells, similar to the finding of 20% of myelodysplastic syndrome cells that has been described. At some stage, this may offer tempting therapeutic targets.
Investigations have also identified a number of high-risk genetic features and markers, including the following:
Germline immunoglobulin variable heavy chain (IgV H)
IgV H V3-21 gene usage
Increased CD38 expression
Increased Zap70 expression
Elevated serum beta-2-microglobulin levels
Increased serum thymidine kinase activity
Short lymphocyte doubling time (< 6 mo)
Increased serum levels of soluble CD23
These features have been associated with rapid progression, short remission, resistance to treatment, and shortened overall survival in patients with CLL.
Germline IgVH has been shown to indicate a poor prognosis. Studies have shown that these patients also have earlier progression of CLL after treatment with chemotherapy.
Zeta-associated peptide of 70 kilodaltons (Zap70) is a cytoplasmic tyrosine kinase whose expression has been associated with a poor prognosis. Cells with germline IgVH often have an increased expression of Zap70; however, studies have shown discordance rates of 10-20% between IgVH mutational status and Zap70 expression levels.
Elevated levels of Zap70 are believed to decrease the threshold for signaling through bcl2, thereby facilitating the antiapoptotic effects of bcl2.
As in the case of most malignancies, the exact cause of CLL is uncertain. CLL is an acquired disorder, and reports of truly familial cases are exceedingly rare. A meta-analysis of four genome-wide association studies that included 3100 cases of CLL found multiple risk loci. Several of those loci are in close proximity to genes involved in apoptosis, suggesting a plausible underlying biological mechanism.
United States statistics
The American Cancer Society estimates that 18,960 new cases of CLL will be diagnosed in the United States in 2016. The true incidence in the US is unknown and is likely higher, as estimates of CLL incidence come from tumor registries, and many cases are not reported.
Although the incidence of CLL in Western countries is similar to that of the United States, CLL is extremely rare in Asian countries (ie, China, Japan), where it is estimated to comprise only 10% of all leukemias. However, underreporting and incomplete registry may significantly underestimate the true incidence of CLL in these countries.
Race-, sex-, and age-related demographics
The incidence of CLL is higher among whites than blacks. The incidence of CLL is higher in males than in females, with a male-to-female ratio of 1.7:1.
CLL is a disease that primarily affects the elderly, with the median age of presentation being 72 years. Median age is 58 years in familial cases.
The prognosis of patients with CLL varies widely at diagnosis. Some patients die rapidly, within 2-3 years of diagnosis, because of complications from CLL. Most patients live 5-10 years, with an initial course that is relatively benign but followed by a terminal, progressive, and resistant phase lasting 1-2 years. During the later phase, morbidity is considerable, both from the disease and from complications of therapy.[13, 14]
Prognosis depends on the disease stage at diagnosis as well as the presence or absence of high-risk markers (see Pathophysiology).
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