Chronic myelogenous leukemia

Chronic myeloid leukemia (chronic granulocytic leukemia, chronic myelogenous leukemia, chronic myeloid leukemia) develops when as a result of malignant transformation and clonal myeloproliferation of pluripotent stem cells significant hyperproduction of immature granulocytes begins.

The disease is initially asymptomatic. The progression of chronic myelogenous leukemia occurs secretly with a nonspecific, "benign" stage of the disease (malaise, lack of appetite, weight loss), gradually shifting into an accelerated phase and an overbearing crisis with more severe symptoms of the disease, such as splenomegaly, pallor, bleeding, a tendency to subcutaneous hemorrhages, fever , lymphadenopathy and skin changes. To establish the diagnosis it is necessary to study the smear of peripheral blood, aspirate the bone marrow and determine the Philadelphia chromosome. The use of imatinib significantly improved the response to the treatment and survival of patients. The ability of imatinib to cause a cure is being studied. Also used for treatment are myelosuppressive drugs (eg, hydroxyurea), stem cell transplantation, interferon a.

Chronic myelogenous leukemia accounts for approximately 15% of all leukemias in adults. It occurs at any age, but rarely develops to 10 years, the median age at the time of diagnosis is 45-55 years. It is equally common in men and women.

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Pathophysiology of chronic myelogenous leukemia

Most cases of chronic myelogenous leukemia seem to be induced by a translocation known as the Philadelphia chromosome, which is found in 95% of patients. It is a reciprocal translocation of t (9; 22) in which a part of the chromosome 9 containing the on-gen c-abl is translocated to the chromosome 22 and is connected to the BCR gene. The combined ABL-BCR gene plays an important role in the pathogenesis of chronic myelogenous leukemia and leads to the production of a specific tyrosine kinase. Chronic myeloleukemia arises from an overgrowth of granulocytes by an abnormal pluripotent hematopoietic cell, first in the bone marrow and then extramedullary (for example, in the liver and spleen). Although granulocyte production dominates, the neoplastic clone includes both erythrocytes, megakaryocytes, monocytes and even some T and B lymphocytes. Normal stem cells are preserved and can be active after the drug has been depressed by a clone of chronic myelogenous leukemia.

Chronic myelogenous leukemia initially manifests as an inactive, chronic phase, which can last from several months to several years. In some cases, then the accelerating phase develops, manifesting a lack of the effect of therapy, an increase in anemia and progressive thrombocytopenia, followed by a terminal phase, blast crisis, when blastic tumor cells develop in extramedullary zones (eg, bones, central nervous system, lymph nodes, skin ). Progression of the disease, as in acute leukemia, leads to a rapid development of complications, including sepsis and hemorrhages. In some patients, the chronic phase directly passes into the blast crisis phase.

Symptoms of chronic myelogenous leukemia

Disease initially often occurs secretly with the gradual development of nonspecific symptoms (for example, fatigue, weakness, anorexia, weight loss, fever, night sweats, a feeling of fullness in the abdomen), which can help start the examination. For the onset of the disease, pallor, bleeding, easily formed subcutaneous hemorrhages and lymphadenopathy are not common, but moderate or severe splenomegaly is widespread (occurs in 60-70% of patients). With the progression of the disease, splenomegaly may increase, pallor and bleeding appear. Fever, noticeable lymphadenopathy and skin rash are formidable harbingers.

Diagnosis of chronic myelogenous leukemia

Chronic myelogenous leukemia is often diagnosed on the basis of a general clinical blood test, conducted randomly or when examined for splenomegaly. The level of granulocytes is elevated, usually less than 50,000 / μL in asymptomatic patients, and 200,000-1,000,000 / μL in patients with manifestations of disease symptoms; the number of platelets is normal or slightly elevated; the level of hemoglobin is usually more than 100 g / l.

A peripheral blood smear can help in the differential diagnosis of chronic myelogenous leukemia from leukocytosis of another etiology. With chronic myelogenous leukemia in the smear, mostly immature granulocytes, absolute eosinophilia and basophilia, although in patients with a white blood cell count of less than 50,000 / μL, the amount of immature granulocytes may be small. Leukocytosis in patients with myelofibrosis is usually accompanied by the presence of erythrocyte nuclei, drop-shaped erythrocytes, anemia and thrombocytopenia. Leukemoid myeloid reactions caused by cancer or infections are seldom accompanied by absolute eosinophilia and basophilia.

The level of alkaline phosphatase in chronic myelogenous leukemia is usually low and increased in leukemoid reactions. The bone marrow examination should be performed to assess the karyotype, cellularity (as a rule, increased) and the degree of myelofibrosis expression.

The diagnosis is confirmed when a Ph-chromosome is found in a cytogenetic or molecular assay, although it is absent in 5% of patients.

During the acceleration phase, anemia and thrombocytopenia usually develop. The level of basophils may increase and the maturation of granulocytes may be impaired. The proportion of immature cells and the level of alkaline phosphatase of leukocytes is increasing. In the bone marrow may develop myelofibrosis, and with microscopy may be noted sideroblasts. Evolution of the neoplastic clone may be accompanied by the development of new abnormal karyotypes, often an additional chromosome 8 or isochromosome 17 is identified.

Further progression may lead to the development of blast crisis with the appearance of myeloblasts (in 60% of patients), lymphoblasts (30%) and megakaryoblasts (10%). In 80% of patients, additional chromosomal abnormalities are detected.

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Treatment of chronic myelogenous leukemia

With the exception of some cases in which stem cell transplantation has been successfully used, treatment does not lead to recovery, but survival may be prolonged with imatinib treatment.

Imatinib inhibits the specific tyrosine kinase synthesized by the BCR-ABL gene. The drug is highly effective in achieving complete clinical and cytogenetic remission in Ph-positive chronic myelogenous leukemia and superior in efficiency to other regimens (eg, interferon ± cytosine arabinoside). Imatinib also excels other types of therapy during the acceleration and blast crisis phase. Combinations of chemotherapy with imatinib with blast crisis are characterized by a higher response than each approach to treatment alone. Treatment has excellent tolerability. The high level of the duration of complete remission with imatinib therapy makes it possible to hope for the possibility of curing this disease.

Older regimens of chemotherapy are used to treat BCR-ABL-negative patients with relapse after treatment with imatinib and patients with violent crisis. The main drugs are busulfan, hydroxyurea and interferon. The hydroxyurea therapy is easiest to control, and it is characterized by only a small number of side effects. The initial dose is usually 500 to 1000 mg orally 2 times a day. Control of a general clinical blood test is performed every 1 or 2 weeks with appropriate dose adjustment. Busulfan often causes unpredictable general myelosuppression, interferon causes an influenza-like syndrome, often poorly tolerated by patients. The main advantage of these drugs is the reduction of splenomegaly and adenopathy and control of the tumor burden, leading to a decrease in the likelihood of developing massive tumor lysis and gout. None of these drugs increases the median survival time by more than 1 year compared with untreated patients. Thus, reducing the symptoms of the disease is the main goal of therapy, and treatment is not continued in the presence of severe toxicity.

Although spleen irradiation is rarely used, this method can be useful in cases of refractory chronic myelogenous leukemia or in terminal stages of the disease in patients with severe splenomegaly. The total dose usually ranges from 6 to 10 Gy with a fractionation of 0.25 to 2 Gy / day. Treatment should begin with very low doses and be carefully monitored for the level of white blood cells. Efficiency is usually low.

Splenectomy can alleviate abdominal discomfort, reduce thrombocytopenia, and reduce the need for blood transfusions in cases where splenomegaly can not be controlled by chemotherapy or radiotherapy. Splenectomy plays an important role in the chronic phase of chronic myelogenous leukemia.

Prognosis for chronic myelogenous leukemia

Before imatinib, 5 to 10% of patients died within 2 years of diagnosis; 10-15% of patients died every year. The median duration of life ranged from 4 to 7 years. Most patients die during blast crisis or during the acceleration phase. Median survival after blast crisis development is from 3 to 6 months, but may increase to 12 months when remission is achieved.

With Ph-negative chronic myeloleukemia and chronic myelomonocytic leukemia, a less favorable prognosis than with Ph-positive chronic myelogenous leukemia. According to clinical features, they are similar to myelodysplastic syndrome.