Chronic myeloleukemia

Chronic myelogenous 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. Progression of chronic myelogenous leukemia is latent with a non-specific, "benign" stage of the disease (malaise, loss of appetite, weight loss), gradually moving into the acceleration phase and a crisis with more pronounced symptoms of the disease, such as splenomegaly, pallor, bleeding, tendency to subcutaneous hemorrhages, fever, lymphadenopathy and skin changes. To establish a diagnosis, it is necessary to examine a peripheral blood smear, bone marrow aspirate and determine the Philadelphia chromosome. The use of imatinib has significantly improved the response to treatment and survival of patients. The ability of imatinib to cause a cure is currently being studied. Myelosuppressive drugs (eg, hydroxyurea), stem cell transplantation, interferon a are also used for treatment.

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

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Pathophysiology of chronic myelogenous leukemia

Most cases of chronic myeloid leukemia are apparently induced by a translocation known as the Philadelphia chromosome, which is found in 95% of patients. It is a reciprocal translocation t(9;22), in which a portion of chromosome 9 containing the c-abl oncogene is translocated to chromosome 22 and fused with the BCR gene. The fused ABL-BCR gene plays an important role in the pathogenesis of chronic myeloid leukemia and results in the production of a specific tyrosine kinase. Chronic myeloid leukemia arises from the hyperproduction of granulocytes by an abnormal pluripotent hematopoietic cell, initially in the bone marrow and then extramedullary (eg, liver, spleen). Although granulocyte production predominates, the neoplastic clone also includes erythrocytes, megakaryocytes, monocytes, and even some T- and B-lymphocytes. Normal stem cells are preserved and may be active after drug inhibition of the chronic myelogenous leukemia clone.

Chronic myelogenous leukemia initially manifests itself as an inactive, chronic phase that can last from several months to several years. In some cases, an acceleration phase then develops, manifested by the lack of effect of therapy, increasing anemia and progressive thrombocytopenia, followed by a terminal phase, blast crisis, when blast tumor cells develop in extramedullary areas (e.g., bones, central nervous system, lymph nodes, skin). Disease progression, as in acute leukemia, leads to the rapid development of complications, including sepsis and hemorrhage. In some patients, the chronic phase directly passes into the blast crisis phase.

Symptoms of Chronic Myeloid Leukemia

The disease is often insidious at first, with a gradual development of nonspecific symptoms (e.g., fatigue, weakness, anorexia, weight loss, fever, night sweats, abdominal fullness), which may prompt investigation. Pallor, bleeding, easy subcutaneous hemorrhages, and lymphadenopathy are not typical at the onset of the disease, but moderate to severe splenomegaly is common (occurring in 60-70% of patients). As the disease progresses, splenomegaly may increase, pallor and bleeding may occur. Fever, noticeable lymphadenopathy, and skin rash are ominous precursors.

Diagnosis of chronic myelogenous leukemia

Chronic myelogenous leukemia is often diagnosed on the basis of a complete blood count obtained incidentally or during investigation of splenomegaly. The granulocyte count is elevated, usually less than 50,000/μL in asymptomatic patients and 200,000-1,000,000/μL in symptomatic patients; the platelet count is normal or slightly elevated; the hemoglobin level is usually greater than 100 g/L.

A peripheral blood smear may help differentiate chronic myeloid leukemia from leukocytosis of other etiologies. In chronic myeloid leukemia, the smear shows predominantly immature granulocytes, absolute eosinophilia, and basophilia, although in patients with a leukocyte count of less than 50,000/μl, the number of immature granulocytes may be small. Leukocytosis in patients with myelofibrosis is usually accompanied by the presence of nucleated red blood cells, teardrop-shaped red blood cells, anemia, and thrombocytopenia. Leukemoid myeloid reactions caused by cancer or infections are rarely accompanied by absolute eosinophilia and basophilia.

Alkaline phosphatase levels are usually low in chronic myeloid leukemia and elevated in leukemoid reactions. Bone marrow examination should be performed to assess karyotype, cellularity (usually elevated), and the extent of myelofibrosis.

The diagnosis is confirmed by detection of the Ph chromosome by cytogenetic or molecular analysis, although it is absent in 5% of patients.

During the acceleration phase, anemia and thrombocytopenia usually develop. Basophil levels may increase and granulocyte maturation may be impaired. The proportion of immature cells and the level of leukocyte alkaline phosphatase increase. Myelofibrosis may develop in the bone marrow and sideroblasts may be seen on microscopy. 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%). Additional chromosomal abnormalities are detected in 80% of patients.

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Treatment of chronic myelogenous leukemia

Except in some cases where stem cell transplantation is successful, treatment is not curative, but survival may be prolonged with imatinib.

Imatinib inhibits a 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 is superior in efficacy to other regimens (eg, interferon ± cytosine arabinoside). Imatinib is also superior to other types of therapy in the acceleration phase and blast crisis. Combinations of chemotherapy with imatinib in blast crisis are characterized by a higher response than each treatment approach alone. The treatment is excellently tolerated. The high level of duration of complete remission with imatinib therapy allows us to hope for the possibility of curing this disease.

Older chemotherapy regimens are used to treat BCR-ABL-negative patients who relapsed after imatinib treatment and patients with power crisis. The mainstays of therapy are busulfan, hydroxyurea, and interferon. Hydroxyurea therapy is the easiest to monitor and has few side effects. The initial dose is usually 500 to 1000 mg orally twice daily. Complete blood counts are monitored every 1 or 2 weeks and the dose is adjusted accordingly. Busulfan often causes unpredictable systemic myelosuppression, and interferon causes a flu-like syndrome that is often poorly tolerated by patients. The main advantages of these drugs are the reduction of splenomegaly and adenopathy and control of tumor burden, leading to a decrease in the likelihood of massive tumor lysis and gout. None of these drugs increases median survival beyond 1 year compared with untreated patients. Thus, symptom relief is the primary goal of therapy, and treatment is not continued in the presence of significant toxicity.

Although splenic irradiation is rarely used, it may be useful in cases of refractory chronic myeloid leukemia or in terminal stages of the disease in patients with severe splenomegaly. The total dose usually ranges from 6 to 10 Gy, divided into fractions of 0.25 to 2 Gy/day. Treatment should be started with very low doses and carefully monitored by white blood cell counts. Efficacy is usually low.

Splenectomy can relieve abdominal discomfort, reduce thrombocytopenia, and decrease the need for blood transfusions when splenomegaly cannot be controlled by chemotherapy or radiation therapy. Splenectomy plays an important role in the chronic phase of chronic myeloid leukemia.

Prognosis for chronic myelogenous leukemia

Before imatinib, 5 to 10% of patients died within 2 years of diagnosis; 10 to 15% of patients died each subsequent year. The median survival was 4 to 7 years. Most patients die during blast crisis or the acceleration phase. The median survival after blast crisis is 3 to 6 months, but can increase to 12 months when remission is achieved.

Ph-negative chronic myeloid leukemia and chronic myelomonocytic leukemia have a less favorable prognosis than Ph-positive chronic myeloid leukemia. Their clinical features are similar to myelodysplastic syndrome.