Chronic Lymphocytic Leukemia

Author: Dr Frederick Appelbaum Fred Hutchinson Cancer Research Center Seattle 2008-07-28

Chronic Lymphocytic Leukemia (CLL) is among the most common forms of leukemia, with approximately 10,200 new cases diagnosed in the United States in 2006. The incidence of CLL increases with age and the disease is uncommon in patients less than age 50.

Biology and Classification  

Chronic Lymphocytic Leukemia develops when an alteration occurs in a lymphocyte or lymphocyte precursor resulting in its increased proliferation and prolonged survival.  As opposed to AML or ALL, the malignant cells in CLL appear mature and closely resemble normal lymphocytes. The problem is that with time too many malignant lymphocytes accumulate, crowding out normal cells in the marrow and causing enlargement of the liver, spleen and lymph nodes. 
Cases of CLL can be categorized according to the immunophenotype of the leukemic cell, cytogenetics and other molecular markers. Most cases of CLL are of B cell origin, but occasional cases more closely resemble normal T cells.  The leukemic cells in some cases express the surface protein CD38, a finding associated with a more aggressive disease course.  Cytogenetic abnormalities are found in the chromosomes of the majority of CLL cases. Loss of material from chromosome 13 is the most common finding and is associated with slower disease progression, while abnormalities involving 11q or 17p are associated with more rapid disease progression.  A particular gene, ZAP-70, is overexpressed in some cases of CLL, and this finding has been associated with a poorer prognosis. In the course of normal B cell development, the immunoglobulin heavy chain gene is rearranged. In about 50% of cases of CLL, the immunoglobulin heavy chain gene is not be rearranged in the leukemia cell, suggesting that the leukemia arose in a more immature cell. These cases have a somewhat more aggressive disease course than seen in the 50% of CLL cases where the immunoglobulin heavy chain has been rearranged.
CLL is staged using either the Rai or the Binet system.  The Rai system is more commonly used in the United States and is made up of 5 stages, based on the number of cells in the peripheral blood, the involvement of lymph nodes and spleen and residual marrow function (See Table 3). Overall prognosis depends on both the stage of disease, but also the immunophenotypic, cytogenetic and molecular markers noted above.  

Table 3    RAI Classification Staging for CLL 

 

Stage	Feature	Median Survival (years)
0	Lymphocytosis only	>12
I	Lymphadenopathy	8.5
II	Splenomegaly	6
III	Anemia*	1.5
IV	Thrombocytopenia*	1.5

* The anemia or thrombocytopenia cannot be immune-mediated

Causes

There are no known environmental risk factors for CLL.  Unlike the other forms of leukemia, neither prior chemotherapy nor radiation exposure appears to increase the incidence of CLL.  There are ethnic differences.  CLL is more common in Ashkenazi Jews of Eastern European ancestry and is much less common in Asian countries.  There is an increased incidence of the disease in families where a prior relative has been diagnosed with the disease.

Signs and Symptoms

In many patients, the diagnosis of CLL is made incidentally when an increased lymphocyte count is noted during a routine examination.  In these asymptomatic patients, there are often no abnormal findings on physical examination, although in about 50% of cases enlargement of the lymph nodes or liver and spleen is found.  In other cases, patients see their physicians because of weakness and fatigue, swollen lymph nodes or spleen, repeated infections, or unintended weight loss. 

Diagnosis of CLL

The diagnosis of CLL requires a sustained increase in mature appearing lymphocytes in the peripheral blood of more than 5000/mm³. Immunophenotyping, cytogenetic, and molecular analysis of the peripheral blood cells helps confirm the diagnosis and provides prognostic information. The finding of an abnormal immunophenotype with a population of B cell markers plus the CD5 antigen helps confirm the diagnosis. Cytogenetic or FISH testing often reveals abnormalities of chromosomes 13, 11, 17 or others. The bone marrow is usually infiltrated with greater than 30% lymphocytes. 

Therapy of CLL

Following the diagnosis of CLL, a first decision is whether to initiate therapy or simply observe the patient.  CLL can take years to progress, and so if patients are asymptomatic, a “watch and wait” approach is sometimes taken.  Often physicians will observe the patient for several months to determine the rate of increase in the peripheral blood lymphocyte count.  If the rate of increase is very slow, than continued watchful waiting is reasonable.  If, however, the peripheral lymphocyte count increases more rapidly, then active therapy may be pursued.  Disease markers, including CD38, ZAP 70, immunoglobulin heavy chain status and cytogenetics are also considered in making the decision to treat or just observe the asymptomatic patient.
A number of different therapies are available for the treatment of CLL.  In the 1980s and 1990s, single agent chlorambucil was the most commonly used treatment.  Randomized trials showed that response rates were higher using fludarabine than chlorambucil. [14]  Subsequently, several trials have found that certain combinations of therapy, such as fludarabine plus cyclophosphamide, or fludarabine plus rituximab, gave higher response rates than fludarabine alone. [15, 16]  Today, in the United States, the most commonly used combinations are fludarabine plus rituximab, or fludarabine plus rituximab plus cyclophosphamide.  These combinations are usually given for four to six cycles.  With such therapy, 35-40% of patients will achieve a complete response and 80-90% will have a partial or complete response.  Following the completion of therapy, patients are generally observed until the disease grows back to a degree requiring further therapy.  The average duration of progression-free survival with modern therapies is in excess of three years, but varies considerably depending on the individual’s disease-specific risk factor. 
The choice of treatment for recurrent CLL depends on a large number of factors.  If the duration of first response was in excess of 18 months, patients will usually respond to retreatment with a fludarabine-containing regimen, similar to that used for initial therapy.  If the duration of first remission was short, alternative therapies are usually considered.  Alemtuzumab, an antibody against the CD52 antigen, is approved for the treatment of recurrent CLL. 
Patients with less aggressive CLL can live for many years with their disease.  However, with time, the disease can become less sensitive to available therapies.  Progressive CLL may cause anemia by crowding out normal red cell production, resulting in a need for red cell transfusions.  In other cases, the abnormal lymphocytes can destroy normal red cells resulting in a hemolytic anemia that requires therapy with prednisone or a similar steroid. Recurrent infections can become a problem because of drops in normal immunoglobulin producing cells.  Thus, some patients may benefit from infusions of immunoglobulin. Splenic enlargement may cause pain in the left-upper quadrant requiring splenectomy.  In some cases, the abnormal lymphocytes may change in their characteristics and begin to grow rapidly as masses in the lymph nodes, similar to a lymphoma.  This change is called “Richter’s transformation” and usually is treated using chemotherapeutic agents similar to those used to treat non-Hodgkin lymphoma.
Although current standard chemotherapies can extend the life of patients with CLL for many years, none are able to cure the disease. The only curative therapy is allogeneic hematopoietic cell transplantation. Because of the toxicities of transplantation, its use is usually reserved for younger, healthier patients with high risk disease who have failed first line conventional therapy.  With the development of reduced intensity transplant regimens, this approach is now being tested in patients in the 60s and 70s.