Chronic lymphocytic leukemia (chronic lymphocytic leukemia)

Being the most frequent type of leukemia in the West, chronic lymphocytic leukemia is manifested by mature abnormal neoplastic lymphocytes with an abnormally long lifespan. In the bone marrow, spleen and lymph nodes there is leukemia infiltration.

Symptoms of the disease may be absent or include lymphadenopathy, splenomegaly, hepatomegaly and nonspecific symptoms due to anemia (fatigue, malaise). The diagnosis is based on the study of the smear of peripheral blood and bone marrow aspirate. Treatment does not begin until the symptoms of the disease develop, and its purpose is to prolong life and reduce the symptoms of the disease. The therapy includes chlorambucil or fludarabine, prednisolone, cyclophosphamide and / or doxorubicin. Monoclonal antibodies such as alemtuzumab and rituximab are increasingly being used. Palliative radiotherapy is used for patients in whom lymphadenopathy or splenomegaly disrupts the function of other organs.

The incidence of chronic lymphocytic leukemia increases with age; 75% of all cases are diagnosed in patients older than 60 years. This disease occurs 2 times more often in men. Although the cause of the disease is unknown, in some cases there is a family history of the disease. Chronic lymphocytic leukemia is rare in Japan and China, and the incidence does not seem to increase in expatriates in the US, suggesting a genetic factor. Chronic lymphocytic leukemia is widespread among Jews from Eastern Europe.

[1], [2], [3], [4], [5]

Pathophysiology of chronic lymphocytic leukemia

Approximately 98% of cases are malignant transformation of CD4 ⁺ B cells with the initial accumulation of lymphocytes in the bone marrow and their subsequent spread to the lymph nodes, other lymphoid tissues, eventually leading to splenomegaly and hepatomegaly. With the progression of the disease, abnormal hematopoiesis leads to the development of anemia, neutropenia, thrombocytopenia and a decrease in the synthesis of immunoglobulins. Many patients develop hypogammaglobulinemia and impaired antibody production, which may be due to an increase in the activity of T suppressors. Patients with an increased predisposition to autoimmune diseases, for example autoimmune hemolytic anemia (usually Coombs-positive) or thrombocytopenia, and a slightly increased risk of other oncological diseases.

In 2-3% of cases, the T-cell type of clonal expansion develops, and even in this group several subtypes differ (for example, large granular lymphocytes with cytopenia). In addition, chronic lymphocytic leukemia includes other chronic leukemoid pathologies: prolymphocytic leukemia, leukemia phase of cutaneous T-cell lymphoma (Cesari syndrome), hairy cell leukemia and lymphomatous leukemia (leukemic changes in common malignant lymphoma). Differentiation of these subtypes from typical chronic lympholeukemia usually presents no difficulties.

Symptoms of chronic lymphocytic leukemia

The onset of the disease is usually asymptomatic; chronic lymphocytic leukemia is often diagnosed accidentally when performing a routine blood test or examining asymptomatic lymphadenopathy. Specific symptoms are usually absent, patients complain of weakness, lack of appetite, weight loss, dyspnoea with exercise, feeling of filling the stomach (with enlarged spleen). Usually, generalized lymphadenopathy, mild or moderate hepatomegaly and splenomegaly are found on examination. With the progression of the disease, pallor appears due to the development of anemia. Infiltration of the skin, maculopapular or diffuse nature, manifests itself usually with T-cell chronic lymphocytic leukemia. Hypogammaglobulinemia and granulocytopenia in the late stages of chronic lymphocytic leukemia can predispose to the development of bacterial, viral or fungal infections, especially pneumonia. Herpes zoster often develops , the spread of which is usually dermatomic.

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 (necessary for I-IV stages)
Stage I	Plus enlarged lymph nodes
II stage	Plus hepatomegaly or splenomegaly
III stage	Plus anemia with hemoglobin <110 g / l
IV stage	Plus thrombocytopenia with a platelet count of <100,000 / μL

Binet

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

The affected areas: cervical, axillary, inguinal, liver, spleen, lymph nodes.

Diagnosis of chronic lymphocytic leukemia

Chronic lymphatic leukemia is confirmed in the study of the smear of peripheral blood and bone marrow; The criteria for diagnosis are long-term absolute peripheral blood lymphocytosis (> 5000 / μL) and an increase in the number of lymphocytes in the bone marrow (> 30%). Differential diagnosis is made using immunophenotyping. Other diagnostic signs are hypogammaglobulinemia (<15% of cases), there is less increase in the level of lactate dehydrogenase. In 10% of cases, moderate anemia (usually immuno-hemolytic) and / or thrombocytopenia is noted. In 2-4% of cases on the surface of leukemia cells can be present monoclonal immunoglobulin serum.

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

[6], [7], [8]

Treatment of chronic lymphocytic leukemia

Specific therapy includes chemotherapy, glucocorticoids, monoclonal antibodies and radiotherapy. These remedies can alleviate the symptoms of the disease, but the increase in the survival rate of patients with their use is not proven. Excessive treatment is more dangerous than insufficient therapy.

Chemotherapy

Chemotherapy is prescribed in response to the development of the symptoms of the disease, including general symptoms (fever, night sweats, severe weakness, weight loss), significant hepatomegaly, splenomegaly and / or lymphadenopathy; lymphocytosis more than 100 000 / mkl; infection, accompanied by anemia, neutropenia and / or thrombocytopenia. Alkylating drugs, especially chlorambucil as monotherapy or in combination with glucocorticoids, have long been the basis of treatment of B-cell chronic lymphocytic leukemia, but fludarabine is a more effective drug. The periods of remission with its use are longer than with the treatment with other medications, although no increase in the survival time of patients has been detected. With hairy cell leukemia, the high efficacy of interferon a, deoxycomoformin and 2-chlorodeoxyadenosine has been demonstrated. Patients with prolymphocytic leukemia and lymphomatous leukemia usually need combined chemotherapy regimens, and they often only have a partial response to therapy.

[9], [10], [11], [12], [13], [14]

Glucocorticoid therapy

Immuno-hemolytic anemia and thrombocytopenia are indications for glucocorticoid therapy. The use of prednisolone 1 mg / kg orally once a day in patients with advanced chronic lymphocytic leukemia sometimes leads to an astonishing rapid improvement, although the duration of the effect is often small. Metabolic complications and an increase in the frequency and severity of infections require precautions with prolonged use of prednisolone. The use of 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 proportion of the partial response at standard doses in patients with chronic lymphocytic leukemia is 10-15%. In previously untreated patients, the response rate was 75% with complete remission in 20% of patients. The response rate for alemtuzumab in previously treated patients refractory to fludarabine is 75%, and in previously untreated patients, 75-80%. Problems associated with immunosuppression are more common with the use of alemtuzumab than rituximab. Rituximab is used in combination with fludarabine or with fludarabine and cyclophosphamide; these combinations significantly increase the frequency of achieving complete remissions in both previously received and untreated patients. At present, alemtuzumab in combination with rituximab and chemotherapy is used to treat a minimal residual disease, which leads to effective removal of bone marrow infiltration by leukemia cells. When alemtuzumab is used, reactivation of cytomegalovirus and other opportunistic infections occurs.

Radiation therapy

For a short-term relief of the symptoms of the disease, lymphadenopathy, the liver and the spleen can be treated with local radiotherapy. Sometimes it is effective to conduct total body irradiation in small doses.

Prognosis for chronic lymphocytic leukemia

The median lifespan of patients with B-cell chronic lymphocytic leukemia or its complications is approximately 7-10 years. Survival without treatment in patients with stage 0 and II at the time of diagnosis is 5 to 20 years. Patients with stage III or IV die within 3-4 years from the time of diagnosis. Progression with the development of bone marrow deficiency is usually accompanied with a short life expectancy. In patients with chronic lymphocytic leukemia, there is a high probability of developing secondary cancers, especially skin cancer.

Despite the progression of chronic lymphocytic leukemia, in some patients clinical symptomatology is absent for several years; treatment is not indicated until the disease progresses or its symptoms develop. Cure, as a rule, is unattainable and treatment provides relief of symptoms and prolongation of the patient's life. Supportive therapy includes transfusion of erythrocyte mass or the use of erythropoietin in anemia; transfusion of thrombocytes with bleeding due to thrombocytopenia; antimicrobials for bacterial, fungal or viral infections. Since neutropenia and agammaglobulinemia reduce the body's defense against bacteria, antibiotic therapy must be bactericidal. In patients with hypogammaglobulinemia and recurrent or refractory infections or with a prophylactic goal in the development of more than two severe infections within 6 months, the need for therapeutic infusions of immunoglobulin should be considered.