Chronic lympholeukemia (chronic lymphocytic leukemia)

The most common type of leukemia in the West, chronic lymphocytic leukemia is characterized by mature, abnormal neoplastic lymphocytes with an abnormally long lifespan. Leukemic infiltration is seen in the bone marrow, spleen, and lymph nodes.

Symptoms may be absent or include lymphadenopathy, splenomegaly, hepatomegaly, and nonspecific symptoms due to anemia (fatigue, malaise). Diagnosis is based on peripheral blood smear and bone marrow aspirate. Treatment is not started until symptoms develop and is aimed at prolonging survival and reducing symptoms. Therapy includes chlorambucil or fludarabine, prednisolone, cyclophosphamide, and/or doxorubicin. Monoclonal antibodies such as alemtuzumab and rituximab are increasingly used. Palliative radiation therapy is used for patients whose lymphadenopathy or splenomegaly impairs the function of other organs.

The incidence of chronic lymphocytic leukemia increases with age; 75% of all cases are diagnosed in patients over 60 years of age. The disease is twice as common in men. Although the cause of the disease is unknown, there is a family history of the disease in some cases. Chronic lymphocytic leukemia is rare in Japan and China, and the incidence does not appear to be increased in expatriates in the United States, suggesting a genetic factor. Chronic lymphocytic leukemia is common among Jews from Eastern Europe.

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Pathophysiology of chronic lymphocytic leukemia

In approximately 98% of cases, malignant transformation of CD4 ⁺ B cells occurs with initial accumulation of lymphocytes in the bone marrow and subsequent dissemination to the lymph nodes and other lymphoid tissues, eventually leading to splenomegaly and hepatomegaly. As the disease progresses, abnormal hematopoiesis leads to the development of anemia, neutropenia, thrombocytopenia, and decreased immunoglobulin synthesis. Many patients develop hypogammaglobulinemia and impaired antibody formation, possibly due to increased activity of T-suppressors. Patients have an increased predisposition to autoimmune diseases, such as autoimmune hemolytic anemia (usually Coombs-positive) or thrombocytopenia, and a slightly increased risk of developing other oncological diseases.

In 2-3% of cases, the T-cell type of clonal expansion develops, and even within this group, several subtypes are distinguished (for example, large granular lymphocytes with cytopenia). In addition, chronic lymphocytic leukemia includes other chronic leukemoid pathologies: prolymphocytic leukemia, leukemic phase of cutaneous T-cell lymphoma (Sezary syndrome), hairy cell leukemia, and lymphomatous leukemia (leukemic changes in widespread malignant lymphoma). Differentiation of these subtypes from typical chronic lymphocytic leukemia is usually not difficult.

Symptoms of Chronic Lymphocytic Leukemia

The onset of the disease is usually asymptomatic; chronic lymphocytic leukemia is often diagnosed incidentally during routine blood tests or examination of asymptomatic lymphadenopathy. Specific symptoms are usually absent, patients complain of weakness, loss of appetite, weight loss, shortness of breath on exertion, a feeling of fullness in the stomach (with an enlarged spleen). Generalized lymphadenopathy, mild to moderate hepatomegaly and splenomegaly are usually detected during examination. As the disease progresses, pallor occurs due to the development of anemia. Infiltration of the skin, maculopapular or diffuse, is usually seen in T-cell chronic lymphocytic leukemia. Hypogammaglobulinemia and granulocytopenia in the late stages of chronic lymphocytic leukemia may predispose to the development of bacterial, viral or fungal infections, especially pneumonia. Herpes zoster often develops, the distribution of which is usually dermatomal.

Clinical staging of chronic lymphocytic leukemia

Classification and stage

Description

Rai

Stage 0	Absolute lymphocytosis in the blood > 10,000/μl and 30% in the bone marrow (required for stages I-IV)
Stage I	Plus enlarged lymph nodes
Stage II	Plus hepatomegaly or splenomegaly
Stage III	Plus anemia with hemoglobin < 110 g/l
Stage IV	Plus thrombocytopenia with platelet count <100,000/µL

Binet

Stage A	Absolute lymphocytosis in blood > 10,000/μl and 30% in bone marrow; hemoglobin 100 g/l, platelets > 100,000/μl, < 2 involved lesions
Stage B	As for stage A, but 3-5 involved lesions
Stage C	As for stage A or B, but platelets < 100,000/µL

Affected areas: neck, armpits, inguinal, liver, spleen, lymph nodes.

Diagnosis of chronic lymphocytic leukemia

Chronic lymphocytic leukemia is confirmed by examination of peripheral blood and bone marrow smears; diagnostic criteria are prolonged absolute lymphocytosis of peripheral blood (> 5000/μl) and an increase in the number of lymphocytes in the bone marrow (> 30%). Differential diagnosis is made using immunophenotyping. Other diagnostic features include hypogammaglobulinemia (< 15% of cases), less commonly an increase in lactate dehydrogenase levels. Moderate anemia (usually immunohemolytic) and/or thrombocytopenia are observed in 10% of cases. In 2-4% of cases, monoclonal serum immunoglobulin may be present on the surface of leukemic cells.

Clinical staging is used for prognosis and treatment. The most common staging systems are the Rai and Binet systems, which are primarily based on hematological changes and lesion volume.

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Treatment of chronic lymphocytic leukemia

Specific therapy includes chemotherapy, glucocorticoids, monoclonal antibodies, and radiation therapy. These agents may relieve symptoms, but have not been shown to improve survival. Overtreatment is more dangerous than undertreatment.

Chemotherapy

Chemotherapy is given in response to the development of disease symptoms, including systemic symptoms (fever, night sweats, severe weakness, weight loss), significant hepatomegaly, splenomegaly and/or lymphadenopathy; lymphocytosis greater than 100,000/μl; infections associated with anemia, neutropenia and/or thrombocytopenia. Alkylating agents, especially chlorambucil alone or in combination with glucocorticoids, have long been the mainstay of treatment for B-cell chronic lymphocytic leukemia, but fludarabine is more effective. It provides longer remission periods than other agents, although no increase in survival has been demonstrated. Interferon a, deoxycoformycin and 2-chlorodeoxyadenosine have been shown to be highly effective in hairy cell leukemia. Patients with prolymphocytic leukemia and lymphomatous leukemia usually require combination chemotherapy regimens and often have only a partial response to therapy.

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Glucocorticoid therapy

Immunohemolytic anemia and thrombocytopenia are indications for glucocorticoid therapy. Prednisolone 1 mg/kg orally once daily in patients with disseminated chronic lymphocytic leukemia sometimes results in dramatic rapid improvement, although the duration of effect is often short. Metabolic complications and an increase in the frequency and severity of infections require precautions with long-term use of prednisolone. Prednisolone with fludarabine increases the risk of infections caused by Pneumocystis jiroveci (formerly P. carinii) and Listeria.

Monoclonal antibody therapy

Rituximab is the first monoclonal antibody successfully used to treat lymphoid malignancies. The partial response rate at standard doses in patients with chronic lymphocytic leukemia is 10-15%. In previously untreated patients, the response rate is 75%, with complete remission in 20%. The response rate with alemtuzumab in previously treated patients refractory to fludarabine is 75%, and in previously untreated patients it is 75-80%. Problems associated with immunosuppression are more common with alemtuzumab than with rituximab. Rituximab is used in combination with fludarabine or with fludarabine and cyclophosphamide; these combinations significantly increase the complete remission rate in both previously treated and treatment-naive patients. Currently, alemtuzumab in combination with rituximab and chemotherapy is used to treat minimal residual disease, which leads to effective elimination of bone marrow infiltration by leukemic cells. Reactivation of cytomegalovirus and other opportunistic infections occurs with the use of alemtuzumab.

Radiation therapy

For short-term relief of disease symptoms, local radiation therapy can be used to treat lymphadenopathy areas, the liver and spleen. Sometimes, low-dose total body irradiation is effective.

Prognosis for chronic lymphocytic leukemia

The median survival time for patients with B-cell chronic lymphocytic leukemia or its complications is approximately 7-10 years. Untreated survival for patients with stage 0 and II at diagnosis ranges from 5 to 20 years. Patients with stage III or IV die within 3-4 years of diagnosis. Progression to bone marrow failure is usually accompanied by a short life expectancy. Patients with chronic lymphocytic leukemia are at high risk of developing secondary cancers, especially skin cancer.

Despite the progression of chronic lymphocytic leukemia, some patients remain asymptomatic for several years; treatment is not indicated until the disease progresses or symptoms develop. A cure is usually unattainable, and treatment aims to relieve symptoms and prolong survival. Supportive care includes red blood cell transfusions or erythropoietin for anemia; platelet transfusions for bleeding due to thrombocytopenia; and antimicrobials for bacterial, fungal, or viral infections. Because neutropenia and agammaglobulinemia reduce host defenses against bacteria, antibiotic therapy should be bactericidal. In patients with hypogammaglobulinemia and recurrent or refractory infections, or prophylactically when more than two severe infections develop within 6 months, therapeutic immunoglobulin infusions should be considered.