Chronic Leukemias

Accumulation of neoplastic, mature lymphoid or mature myeloid cells in the blood, which usually progresses far more slowly than that in acute leukemia.

If the neoplastic cells are of the lymphoid type, the disease is called chronic lymphocytic leukemia (CLL); if they are of the myeloid type, it is called chronic myelocytic (myeloid, myelogenous) leukemia (CML). In > 95% of cases, CLL involves the neoplastic proliferation of B cells.

CLL, primarily a disease of the elderly, is the most common leukemia in Western society, accounting for 25 to 40% of all leukemias. The incidence is about 4/100,000 for all ages and about 80/100,000 for persons > 80. About 90% of all patients are > 50, with the majority > 60. Men are affected twice as often as women. CML usually occurs in persons in their 30s and 40s and is rare in the elderly.

Etiology and Pathophysiology

A genetic component seems to be involved in CLL, because the illness is more common in certain families. Some of these families have immunologic abnormalities. Chronic viral infections (eg, with Epstein-Barr virus) have also been suggested as a possible cause. Ionizing radiation plays no part in the etiology of CLL.

In > 95% of CLL cases, the neoplastic proliferation involves lymphocytes of B-cell origin; in the remaining cases, the proliferation involves lymphocytes of T-cell origin. Cells appear morphologically mature but have receptors for mouse erythrocytes, human leukocyte antigen (HLA)-DR, and small amounts of surface immunoglobulin, suggesting some degree of immaturity. Trisomy 12 has been identified in about 25% of cases. Monoclonal lymphocytes accumulate in the peripheral blood, bone marrow, lymphoid tissues, and sometimes other organs. Infiltration of the bone marrow may eventually result in pancytopenia. Deficiency of normal B cells often leads to bacterial infection. Transformation to a diffuse large cell lymphoma (Richter's syndrome) or to acute prolymphocytic leukemia may occur as a terminal event.

In CLL, the anemia and thrombocytopenia may result from marrow replacement, hypersplenism, or suppressor mechanisms such as antiplatelet antibodies.

Symptoms and Signs

Presentation varies greatly. More than 25% of patients are asymptomatic; the disease is diagnosed during routine physical examination or by blood count. The most common initial symptoms are fatigue, malaise, and decreased exercise tolerance. In many elderly patients, an exacerbation of coronary artery disease or cerebrovascular disease is the initial manifestation.

Splenomegaly is clinically detectable in 50% of patients at presentation; it can cause abdominal pain or early satiety. Lymphadenopathy commonly occurs in the cervical, axillary, and supraclavicular areas. Inguinal adenopathy is rare. Hepatomegaly may develop as the disease progresses. Jaundice usually suggests hemolysis, although biliary obstruction can result from periportal lymph node enlargement. Lymphocytic infiltration can occur in any organ. In the late stages, ecchymoses and petechiae may result from thrombocytopenia.

Fever is usually secondary to bacterial infection, which is the most common complication of CLL, particularly affecting the lungs and urinary tract. Gram-positive cocci, gram-negative bacilli, fungi, Listeria, and Pneumocystis carinii are the most common causative organisms. Fever, in the late stages, may indicate the development of acute prolymphocytic leukemia or aggressive lymphoma. Clinically significant hyperviscosity (which may result in skin and mucosal bleeding, visual disturbances, headache, and other changing neurologic manifestations) is rare, occurring only when the WBC count is >= 800,000/µL.

T-cell CLL usually is a more aggressive disorder than B-cell CLL, with massive splenomegaly, marked neutropenia, skin infiltration, modest bone marrow infiltration, and a rapid clinical course leading to death in about 50% of these patients. However, some cases have an indolent course. There is a high concurrence with rheumatoid arthritis.

Diagnosis

The diagnosis of CLL requires demonstration of sustained lymphocytosis and bone marrow lymphocyte infiltration in the absence of other causes. The absolute lymphocyte count is generally > 4800/µL, commonly > 15,000/µL. The cells appear mature and tend to smudge when the blood smear is prepared.

In B-cell CLL, the number of T cells and B cells increases, but the malignant B cells increase preferentially, accounting for 40 to 90% of all lymphocytes. They are of monoclonal origin and express the surface immunoglobulins of one light chain class. The usual surface immunoglobulin is IgM; less commonly, it is IgD. The ratio of helper (CD4) to suppressor (CD8) T cells is reversed because of an increased number of suppressor cells. This reversal may account for the development of pure RBC aplasia, which occurs in a few patients.

In T-cell CLL, CD4 or CD8 cells predominate over B cells. T-cell CLL is characterized by lymphocytes that form rosettes with sheep RBCs. The lymphocytes often exhibit cytoplasmic azurophilic granules. The malignant cell may have a more convoluted nucleus and is usually of CD4 immunophenotype. CD8 T-cell CLL is rare and usually presents with marked anemia and neutropenia disproportionate to the extent of bone marrow and organ involvement.

In either type, the RBC morphologic characteristics are usually normal. Anemia occurs in 10 to 20% of patients and is usually normochromic and normocytic. The Coombs' test reveals IgG coating of RBCs in about 20% of patients; however, an autoimmune hemolytic anemia occurs only 8% of the time. Thrombocytopenia occurs in 10 to 20% of patients. Bone marrow morphologic examination shows interstitial or nodular infiltration in the early stages of disease and diffuse infiltration in the advanced stages.

In about 5% of patients, the immunoglobulin found on the cell surface is also found in the serum as a monoclonal protein. Hypogammaglobulinemia or agammaglobulinemia is found in 50 to 75% of patients.

Prognosis

The 5-year survival rate is only about 50%; however, 25 to 30% of patients with CLL live 10 years or more. Patients with CLL have at least a fourfold risk of developing a second malignancy.

Two common approaches to staging are the Rai, which is primarily based on hematologic changes, and the Binet, based on extent of disease (see Table 73-1). Using the Binet classification, patients in stage A, with <= 2 involved sites, usually survive > 7 years. Patients in stage B, with 3 to 5 involved sites (possibly including the cervical, axillary, supraclavicular, and inguinal lymph nodes as well as the liver and spleen), usually survive < 5 years. Patients in stage C have anemia (Hb < 10 g/dL) or thrombocytopenia (platelets < 100,000/µL) and usually survive < 2 years. Generally, the disease progresses in a stepwise pattern from less severe to more severe.

Other unfavorable prognostic signs include diffuse replacement of bone marrow, trisomy 12 plus other abnormal chromosomes, and surface IgM rather than IgD.

Treatment

Treatment is outlined for the Binet stages.

Stage A patients and stage B patients usually do not require treatment, because the complications of chemotherapy (eg, infection, development of acute nonlymphocytic leukemia) may be more deleterious than the disease itself. However, stage B patients are treated as described for stage C patients if they are troubled by progressive, disabling constitutional symptoms clearly attributable to the leukemia.

For stage C patients, chlorambucil is the most commonly used agent. It induces responses in 50 to 80% of patients and complete remission in 10 to 20%. Chlorambucil may be given orally at a daily dosage of 0.08 to 0.2 mg/kg or for 1 day every 4 weeks at 0.4 mg/kg as a single dose. The dosage is tapered as the WBC count falls and is discontinued when the lymphocyte count falls below 20,000/µL. Prednisone 0.8 mg/kg/day is often used concomitantly and may improve the response rate. Corticosteroids alone are used only in patients with autoimmune hemolytic anemia or thrombocytopenia. Some patients may benefit from the newer agents fludarabine or pentostatin. Certain combination chemotherapy regimens, such as cyclophosphamide, doxorubicin, vincristine, and prednisone, may be useful in advanced stages.

Radiation therapy is used to reduce locally bulky disease, vital organ compromise, or painful bone lesions. Patients with refractory CLL may benefit from repeated leukapheresis, which lowers the WBC count, reduces organomegaly, and reduces cytopenia.

When transformation to either an acute prolymphocytic leukemia or an aggressive lymphoma occurs, response to chemotherapy or radiation is generally poor.

End-of-Life Issues

Although elderly patients often live with chronic leukemia for years or decades, it is still likely to cause death. As the disease advances, patients should be helped through preparations for death, and their wishes regarding terminal care should be documented.