eMedicine Specialties > Hematology > Stem Cells and Disorders

Chronic Lymphocytic Leukemia

Author: Delong Liu, MD, PhD, Associate Professor of Medicine, Division of Oncology/Hematology, New York Medical College; Chief of Hematology, Phelps Memorial Hospital Center; Director of Non-ablative Allogeneic Stem Cell Transplantation Program, Westchester Medical Center; Editor-in-Chief, Journal of Hematology and Oncology
Coauthor(s): Samir C Patel, MD, Fellow, Department of Hematology and Medical Oncology, Metropolitan Hospital, New York Medical College; Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri/Ellis Fischel Cancer Center; Haleem J Rasool, MD, FACP, Hematologist Oncologist, Department of Oncology, Franciscan Skemp Healthcare
Contributor Information and Disclosures

Updated: Dec 17, 2009

Introduction

Background

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.¹ See histologic sample in the image below.

Pathophysiology

The cells of origin in the majority of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, 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.

B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20, 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 (MZ) of lymphoid follicles, B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is most likely a malignancy of an MZ-based subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies.

B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) cells 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 chronic lymphocytic leukemia (chronic lymphoid leukemia, 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 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 in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). 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 chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) exhibit a T-cell phenotype.

Studies have demonstrated that the protooncogene bcl2 is overexpressed in B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).² The protooncogene 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 chronic lymphocytic leukemia (chronic lymphoid leukemia, 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).^3,4 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 cases of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Investigations have also identified a number of high-risk genetic features and markers that include 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), and 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 chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Germline IgV_H has been shown to indicate a poor prognosis. Studies have shown that these patients also have earlier progression of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) after treatment with chemotherapy. The use of certain IgV _H genes, V3-21, have also been associated with poor prognosis regardless of IgV _H mutational status.

Zeta-associated peptide of 70 kilodaltons (Zap70) is a cytoplasmic tyrosine kinase whose expression has been associated with a poor prognosis. Cells with germline IgV _H often have an increased expression of Zap70; however, studies have shown discordance rates of 10-20% between IgV _H 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. Zap70 function also appears to be dependent on heat shock protein 90 (hsp90), whose inhibition may provide a future therapeutic option.

Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) should also be distinguished from prolymphocytic leukemia, in which more than 65% of the cells are morphologically less mature prolymphocytes.

Frequency

United States

More than 17,000 new cases of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) are reported every year. The true incidence in the US is unknown and is likely higher, as estimates of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) incidence come from tumor registries, and many cases are not reported. One case series had the actual incidence at 38% higher than estimated from tumor registries.

International

Unlike the incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) in Western countries, which is similar to that of the United States, chronic lymphocytic leukemia (chronic lymphoid leukemia, 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 chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) in these countries.

Mortality/Morbidity

• The natural history of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is heterogeneous.
• Some patients die rapidly, within 2-3 years of diagnosis, because of complications from chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).
• The majority of 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.^5,6

Race

The incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is higher among whites compared with blacks.

Sex

The incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is higher in males than in females, with a male-to-female ratio of 1.7:1.

Age

• Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a disease that primarily affects elderly individuals, with the majority of cases reported in individuals older than 55 years. The incidence continues to rise in those older than 55 years.
• However, there are reports that individuals aged 35 years or younger are being diagnosed with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) more frequently.

Clinical

History

Patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) present with a wide range of symptoms and signs at presentation. Onset is insidious, and it is not unusual for chronic lymphocytic leukemia (chronic lymphoid leukemia, 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 and signs of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) may include the following:

• A predisposition to repeated infections such as pneumonia, herpes simplex labialis, and herpes zoster may be noted.
• Enlarged lymph nodes are the most common presenting symptom, seen in 87% of patients symptomatic at time of diagnosis.
• Early satiety and/or abdominal discomfort may be related to an enlarged spleen.
• Mucocutaneous bleeding and/or petechiae may be due to thrombocytopenia.
• Tiredness and fatigue may be present secondary to anemia.
• Fevers, chills, and night sweats and weight loss constitute B symptoms seen in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).
• Ten percent of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) will present with an autoimmune hemolytic anemia.

Physical

• Localized or generalized lymphadenopathy (80-90% of cases)
  • Splenomegaly (30-54% of cases)
  • Hepatomegaly (10-20% of cases)
  • Petechiae
  • Pallor

Causes

• As in the case of most malignancies, the exact cause of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is uncertain.
• The protooncogene bcl2 is known to be overexpressed, which leads to suppression of apoptosis (programmed cell death) in the affected lymphoid cells. In the majority of cases, this appears to be secondary to alterations in the expression of the miRNAs MIRN15a and MIRN16-1.
• Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is an acquired disorder, and reports of truly familial cases are exceedingly rare.⁷

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