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Chronic Myelogenous Leukemia:Pathophysiology and Etiology

Last updated on May 12, 2023


Leukemias are cancers of the hematopoietic (blood-producing) system. The word leukemia derives from the Latin word for white blood and refers to the proliferation of white blood cells (leukocytes) in people with this disease.

The hematopoietic cascade: development of mature blood cells from pluripotent stem cells.

Chronic Myelogenous Leukemia:Pathophysiology and EtiologyMature blood cells (red cells, white cells, and platelets) are normally produced in the bone marrow from primitive hematopoietic stem cells. (FIGURE. The hematopoietic cascade: development of mature blood cells from pluripotent stem cells shows the different lineages of blood cells and the stages involved in their maturation.)

The blood cells mature and differentiate through a sequence of steps involving a series of complex — and incompletely understood — interactions with growth factors, cytokines, and other cells in the bone marrow. Once mature, the blood cells leave the bone marrow and enter the general circulation, where they have a limited life span.

Leukemia occurs when a genetic mutation arises in a single cell that interferes with the normal maturation and differentiation of developing leukocytes. These changes produce “immortal” white blood cells, in which the mechanisms of programmed cell death (apoptosis) are inactivated. The white blood cells proliferate without limitation, eventually replacing normal bone marrow cells and entering the peripheral bloodstream.

Unlike acute leukemias (which have a sudden onset, progress rapidly, and, if untreated, can be fatal in as little as two months from the onset of symptoms), chronic leukemias are indolent. They have an insidious onset, progress slowly, and can remain asymptomatic and require no treatment for months or years.

Leukemia is a heterogeneous disease; in other words, the leukemic mutations may affect any stage of hematopoietic differentiation, and the type of leukemia can be characterized by the type of affected cell. If the mutations affect the maturation of lymphoid cells, lymphoid leukemias result (e.g., chronic lymphocytic leukemia, acute lymphocytic leukemia); maturation arrest in myeloid differentiation results in myeloid leukemias (e.g., chronic myelogenous leukemia, acute myelogenous leukemia).

In chronic myelogenous leukemia, maturation arrest in myeloid differentiation is caused by a genetic mutation that results in increasing numbers of circulating myeloid cells: neutrophils, basophils, and eosinophils, collectively known as granulocytes (which are themselves a type of leukocyte). The main function of granulocytes is to fight infection by bacteria and fungi. Granulocytes also regulate allergic reactions. In the chronic phase of the disease, these cells are functionally mature and the initial clinical features of the disease are a result of high levels of these granulocytes.

Among patients who are symptomatic at presentation, symptoms of chronic myelogenous leukemia include fatigue, weight loss, fever, night sweats, bruising, aches in bones and joints, and swollen lymph nodes. Other patients are diagnosed following a routine blood test. Table 1 lists laboratory features characteristic of chronic myelogenous leukemia.

TABLE. Laboratory Features Characteristic of Chronic Myelogenous Leukemia

Diagnostic Modality Features Characteristic of chronic myelogenous leukemia
Blood count • Presence of leukocytosis (white blood count usually >25,000 per mm3).
• Elevated basophils and granulocytes (particularly myelocytes).  Promyelocytes and  myeloblasts present  in small numbers unless patient has presented during blast crisis.

• Erythrocyte and platelet counts may also be increased.

• Mild anemia is present in 50% of cases at presentation.

• Platelet count is abnormally high in 30-50% of cases.

Blood smear • Morphology of white and red cells is normal.
• Platelet morphology is usually normal but giant platelets may be present.
Bone marrow biopsy • Marrow is hypercellular; an increase in the number of myeloid white blood cells occurs, particularly early myeloid forms.
Cytogenetic/molecular analysis • Presence   of   Philadelphia  chromosome/BCR-/4BL   fusion gene.

In addition to increasing the number of circulating granulocytes, chronic myelogenous leukemia affects the maturation of bone marrow stem cells and causes an increase in blasts in the bloodstream and marrow. Blasts cannot carry out the functions of the mature granulocytes, resulting in anemia and increased risk of infection.

Chronic myelogenous leukemia is primarily a disease of adulthood. The median age at diagnosis is 55-60 years; less than 10% of cases occur in people under the age of 20. The disease in children is similar in behavior to that in adults, but the outcome of treatment with progenitor stem-cell transplantation — the only potentially curative therapy for chronic myelogenous leukemia — is better in these younger individuals. Although the median survival is five to seven years (based on patients treated in the pre-imatinib era), the range is wide: some patients die within one year of diagnosis, while others live for more than 15 years. The ratio of chronic myelogenous leukemia cases by sex is 1.4 male cases to 1 female case, but the clinical course is similar in both sexes.


Cytogenetic Changes

Prognostic Factors


Chronic myelogenous leukemia is an acquired rather than an inherited condition; familial cases are rare and little evidence exists linking hereditary factors to chronic myelogenous leukemia. The offspring of patients with chronic myelogenous leukemia do not have a higher incidence of chronic myelogenous leukemia than does the general population, and there is no correlation in monozygotic twins. In the great majority of patients, a causative factor cannot be identified. Nevertheless, it is well known that ionizing radiation is a predisposing factor, as shown by studies of survivors of the Nagasaki and Hiroshima atomic bombs and of patients who have received radiotherapy for conditions such as cervical cancer.

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