Chronic lymphocytic leukemia

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Chronic lymphocytic leukemia
Classification & external resources

Peripheral blood smear showing CLL cells
ICD-10	C91.1
ICD-9	204.1

Chronic lymphocytic leukemia (or "chronic lymphoid leukemia"), known for short as CLL, is a type of leukemia in which too many lymphocytes are produced. Although the malignant lymphocytes in CLL may look normal and mature, they are not and these cells may not cope effectively with infection.

CLL is the most common form of leukemia in adults. Men are twice as likely to develop CLL as women. However, the key risk factor is age. Over 75% of new cases are diagnosed in patients over age 50. More than 7,000 new cases of CLL are diagnosed in the U.S. each year.

Contents 1 Subtypes 2 Treatment 3 References 4 External links

[edit] Subtypes

CLL is an abnormal neoplastic proliferation of B cells. The cells accumulate mainly in the bone marrow and blood. CLL is closely related to (and most consider it the same as) a disease called small lymphocytic lymphoma (SLL), a type of non-Hodgkin's lymphoma which presents primarily in the lymph nodes. In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, it is now recognized that these so-called T-cell CLLs are in fact a separate disease group and are currently classified as T cell prolymphocytic leukemias.

The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. This atypical molecular pattern includes the co-expression of cells surface markers CD5 and CD23. In addition, all the CLL cells within one individual are clonal, that is genetically identical. In practice, this is inferred by the detection of only one of the mututally exclusive antibody light chains, kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody producing cells resulting in a mixture of both kappa and lambda expressing cells. The lack of the normal distribution of kappa and lambda producing B cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any B cell malignancy (B cell Non-Hodgkin lymphoma).

Recent publications have indicated that two types of CLL exist based on the maturational state of the cell. This distinction can be discerned by the presence of certain marker molecules such as CD38 and ZAP-70. Their expression correlates with a more immmature cellular state and a more rapid disease course. The cellular DNA also differs between the two groups. The group with the immature cell pattern shows few changes in the DNA in the antibody gene region whereas the mature group contains considerable alterations of the DNA in the antibody gene region. Since assessment of the DNA changes is difficult to perform, most physicians rely on the pattern of marker molecule expression to determine the subtype of CLL.

In addition to the maturational state, the prognosis of patients with CLL is dependent on the genetic changes within the neoplastic cell population. These genetic changes can be identified by fluorescent probes to chromosomal parts using a technique referred to as fluorescent in situ hybridization (FISH). Four main genetic aberrations are recognized in CLL cells that have a major impact on disease behavior. Deletions of part of the short arm of chromosome 17 (del 17p) which target the cell cycle regulating protein p53 are particularly deleterious. Patients with this abnormality have significantly short interval before they require therapy and a shorter survival. This abnormality is found in 5-10% of patients with CLL. Deletions of the long arm on chromosome 11 (del 11q) are also unfavorable although not to the degree seen with del 17p. The abnormality targets the ATM gene and occurs infrequently in CLL (5-10%). An additional chromosome 12 (trisomy 12) is a relatively frequent finding occurring in 20-25% of patients and imparts an intermediate prognosis. Finally, deletion of the long arm of chromosome 13 (del 13q) is the most common abnormality in CLL with roughly 50% of patients with cells containing this defect. These patients have the best prognosis and most will live many years, even decades, without the need for therapy. The gene targeted by this deletion is a segment that likely produces small inhibitory RNA molecules that affect expression of important death inhibiting genes.

Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma. Hairy cell leukemia is also a neoplasm of B lymphocytes but differs significantly from CLL by its morphology under the microscope (hairy cell leukemia cells have delicate, hair-like projections on their surface) and marker molecule expression. All the B cell malignancies of the blood and bone marrow can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow and occasionally lymph node cells by a pathologist with specific training in blood disorders. A sophisticated instrument called a flow cytometer is necessary for cell marker analysis and the detection of genetic problems in the cells may require visualing the DNA changes with fluorescent probes by fluorescent in situ hybridization (FISH).

[edit] Treatment

Whilst generally considered incurable CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years - in some cases for decades. Because of its slow onset, early-stage CLL is generally not treated since it is believed that early CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time.

The decision to start CLL treatment is taken when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life. Clinical "staging systems" such as the Rai 4-stage system and the Binet classification can help to determine when and how to treat the patient.

CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy removal of enlarged spleen) or by radiation therapy ("de-bulking" swollen lymph nodes).

Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. There are dozens of agents used for CLL therapy, and there is considerable research activity studying them individually or in combination with each other. For example, although the purine analogue fludarabine was shown to give superior response rates than chlorambucil as primary therapy,^[1] there is no evidence that early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease. Combination chemotherapy regimens such as fludarabine with cyclophosphamide, FCR (fludarabine, cyclophosphamide and rituximab) and CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) are effective in both newly-diagnosed and relapsed CLL. Allogeneic bone marrow (stem cell) transplantation is rarely used as a first-line treatment for CLL due to its risk.

"Refractory" CLL is a disease that no longer responds favorably to treatment. In this case more aggressive therapies, including bone marrow (stem cell) transplantation, are considered. The monoclonal antibody, alemtuzumab (directed against CD52), may be used in patients with refractory, bone marrow-based disease.^[2] There is increasing interest in the use of reduced intensity allogeneic stem cell transplantion, which offers the prospect of cure for selected patients with a suitable donor.^[3]

Determining when to start treatment and by what means is often difficult; studies have shown there is no survival advantage to treating the disease too early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.

[edit] References

1. ^ Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA (2000). "Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia". N Engl J Med 343 (24): 1750-7. PMID 11114313. 
2. ^ Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR (2002). "Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study". Blood 99 (10): 3554-61. PMID 11986207. 
3. ^ Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J, Deliliers GL, Martino R, Russell N, Van Biezen A, Michallet M, Niederwieser D; Chronic Leukemia Working Party of the EBMT (2003). "Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning". Leukemia 17 (5): 841-8. PMID 12750695. 

[edit] External links

Blogs:

• David Arenson's CLL Diary

Forums:

• CLL Forum - Member supported, moderated, forum-based global community that provides friendly support, information and resources to people living with CLL and their caregivers.
• CLL Canada - Repository of CLL research in laymen's terms.
• UK CLL Support Association - Registered charity that provides UK specific support to patients and caregivers.

Information Resources:

• CLL Topics - Non-profit educational and patient-advocacy organization (excellent resource.)
• CLL Research Consortium - NCI funded program project of leading clinician and scientists trying to cure CLL.

• Leukemia & Lymphoma Society - General CLL information.
• Lymphomation.org - Lymphoma website with a CLL resource page.
• US National Cancer Institute - General information about CLL.

Listservs and Groups:

• ACOR Homepage - Non-profit ACOR (Association of Cancer Online Resources) mailing list. Sign-up and receive email messages from other members of the mailing list.
• CLLResearch - Group dedicated to CLL research and advocacy. Find research papers from various medical journals, CLL news and advocacy information.