Chronic Lymphocytic Leukemia 

  • Author: Muhammad A Mir, MBBS; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Dec 1, 2011
 

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 the histologic sample in the image below.)

Peripheral smear from a patient with chronic lymphPeripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.

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 Clinical.)

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.)

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Pathophysiology

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.[2] 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).[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 CLL cases.[5]

Investigations have also identified a number of high-risk genetic features and markers, including the following:

  • Germline immunoglobulin variable heavy chain (IgVH)
  • IgVHV3-21 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.

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Etiology

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.[6]

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Epidemiology

United States statistics

More than 17,000 new cases of CLL are reported every year. 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.

International statistics

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.[7]

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Prognosis

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.[8, 9]

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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Proceed to Clinical Presentation
 
 
Contributor Information and Disclosures
Author

Muhammad A Mir, MBBS  Attending Physician, Department of Medicine, Eastern Maine Medical Center

Muhammad A Mir, MBBS is a member of the following medical societies: American College of Physicians and American Society of Hematology

Disclosure: Nothing to disclose.

Coauthor(s)

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

Delong Liu, MD, PhD is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology

Disclosure: Nothing to disclose.

Samir C Patel, MD  Fellow, Department of Hematology and Medical Oncology, Metropolitan Hospital, New York Medical College

Disclosure: Nothing to disclose.

Michael Perry, MD, MS, MACP  Nellie B Smith Chair of Oncology Emeritus, Director, Division of Hematology and Medical Oncology, Deputy Director, Ellis Fischel Cancer Center, University of Missouri-Columbia School of Medicine

Michael Perry, MD, MS, MACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, International Association for the Study of Lung Cancer, and Missouri State Medical Association

Disclosure: Nothing to disclose.

Haleem J Rasool, MD, FACP  Hematologist/Oncologist, Department of Oncology, Franciscan Skemp Healthcare

Haleem J Rasool, MD, FACP is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Clarence Sarkodee-Adoo, MD Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program

Disclosure: Takeda Millenium Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Peripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.
Peripheral smear from a patient with chronic lymphocytic leukemia, large lymphocytic variety. Smudge cells are also observed; smudge cells are the artifacts produced by the lymphocytes damaged during the slide preparation.
 
 
 
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