eMedicine Specialties > Hematology > Stem Cells and Disorders

Chronic Myelogenous Leukemia

Author: Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Coauthor(s): Ulrich Josef Woermann, MD, Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland
Contributor Information and Disclosures

Updated: Mar 16, 2010

Introduction

Background

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Leukemia.

Pathophysiology

Chronic myelogenous leukemia (CML) is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9; t(9;22). The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph) chromosome after the city of discovery.

This translocation relocates an oncogene called abl from the long arm of chromosome 9 to the long arm of chromosome 22 in the BCR region. The resulting BCR/ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the chronic myelogenous leukemia (CML) phenotype through processes that are not yet fully understood.^{1,2,3,4,5,6,7,8}

The presence of BCR/ABL rearrangement is the hallmark of chronic myelogenous leukemia (CML), although this rearrangement has also been described in other diseases. It is considered diagnostic when present in a patient with clinical manifestations of CML.

Frequency

United States

Chronic myelogenous leukemia (CML) accounts for 20% of all leukemias affecting adults. It typically affects middle-aged individuals. Although uncommon, the disease also occurs in younger individuals.

International

Increased incidence of chronic myelogenous leukemia (CML) was reported among individuals exposed to radiation in Nagasaki and Hiroshima after the dropping of the atomic bomb.

Mortality/Morbidity

Generally, 3 phases of chronic myelogenous leukemia (CML) are recognized. The general course of the disease is characterized by an eventual evolution to a refractory form of acute myelogenous or, occasionally, lymphoblastic leukemia. The median survival of patients using older forms of therapy is 3-5 years.

• Most patients with chronic myelogenous leukemia (CML) present in the chronic phase, characterized by splenomegaly and leukocytosis (see image below) with generally few symptoms.
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    Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. In addition, basophilia, eosinophilia, and thrombocytosis can be seen. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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    Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. In addition, basophilia, eosinophilia, and thrombocytosis can be seen. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

• This phase is easily controlled by medication. The major goal of treatment during this phase is to control symptoms and complications resulting from anemia, thrombocytopenia, leukocytosis, and splenomegaly. Newer forms of therapy aim at delaying the onset of the accelerated or blastic phase.
• After an average of 3-5 years, chronic myelogenous leukemia (CML) usually evolves into the blast crisis, which is marked by an increase in the bone marrow or peripheral blood blast count or by the development of soft-tissue or skin leukemic infiltrates. Typical symptoms are due to increasing anemia, thrombocytopenia, basophilia, a rapidly enlarging spleen, and failure of the usual medications to control leukocytosis and splenomegaly. The manifestations of blast crisis are similar to those of acute leukemia. Treatment results are unsatisfactory, and most patients succumb to the disease once this phase develops.
• In approximately two thirds of cases, the blasts are myeloid. However, in the remaining one third of patients, the blasts exhibit a lymphoid phenotype, further evidence of the stem cell nature of the original disease. Additional chromosomal abnormalities are usually found at the time of blast crisis, including additional Ph chromosomes or other translocations.
• In many patients, an accelerated phase occurs 3-6 months before the diagnosis of blast crisis. Clinical features in this phase are intermediate between the chronic phase and blast crisis.

Age

• In general, chronic myelogenous leukemia (CML) occurs in the fourth and fifth decades of life.
• Younger patients aged 20-29 years may be affected and may present with a more aggressive form, such as in accelerated phase or blast crisis.
• Uncommonly, chronic myelogenous leukemia (CML) may appear as a disease of new onset in elderly individuals.

Clinical

History

• The clinical manifestations of chronic myelogenous leukemia (CML) are insidious and are often discovered incidentally when an elevated white blood cell (WBC) count is revealed by a routine blood count or when an enlarged spleen is revealed during a general physical examination.
• Nonspecific symptoms of tiredness, fatigue, and weight loss may occur long after the onset of the disease. Loss of energy and decreased exercise tolerance may occur during the chronic phase after several months.
• Patients often have symptoms related to enlargement of the spleen, liver, or both.
  • The large spleen may encroach on the stomach and cause early satiety and decreased food intake. Left upper quadrant abdominal pain described as "gripping" may occur from spleen infarction. The enlarged spleen may also be associated with a hypermetabolic state, fever, weight loss, and chronic fatigue.
  • The enlarged liver may contribute to the patient's weight loss.
• Some patients with chronic myelogenous leukemia (CML) may have low-grade fever and excessive sweating related to hypermetabolism.
• The disease has 3 clinical phases, and chronic myelogenous leukemia (CML) follows a typical course of an initial chronic phase, during which the disease process is easily controlled; followed by a transitional and unstable course (accelerated phase); and, finally, a more aggressive course (blast crisis), which is usually fatal.
  • Most patients are diagnosed while still in the chronic phase. The WBC count is usually controlled with medication (hematologic remission). This phase varies in duration depending on the maintenance therapy used. It usually lasts 2-3 years with hydroxyurea (Hydrea) or busulfan therapy, but the chronic phase has lasted for longer than 9.5 years in patients who respond well to interferon alfa therapy. Furthermore, the addition of imatinib mesylate in recent years has dramatically improved the duration of hematologic and, indeed, cytogenetic remissions.
  • Some patients with chronic myelogenous leukemia (CML) progress to a transitional or accelerated phase, which may last for several months. The survival of patients diagnosed in this phase is 1-1.5 years. This phase is characterized by poor control of the blood counts with myelosuppressive medication and the appearance of peripheral blast cells (>15%), promyelocytes (>30%), basophils (>20%), and platelet counts less than 100,000 cells/μL unrelated to therapy. Promyelocytes and basophils are shown in the image below.
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      Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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      Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

  • Usually, the doses of the medications need to be increased. Splenomegaly may not be controllable by medications, and anemia can worsen. Bone pain and fever, as well as an increase in bone marrow fibrosis, are harbingers of the last phase. Thus, signs of transformation or accelerated phase in patients with chronic myelogenous leukemia are poor control of blood counts with myelosuppression or interferon, increasing blast cells in peripheral blood with basophilia and thrombocytopenia not related to therapy, new cytogenetic abnormalities, and increasing splenomegaly and myelofibrosis.
  • Acute phase, or blast crisis, is similar to acute leukemia, and survival is 3-6 months at this stage. Bone marrow and peripheral blood blasts of 30% or more are characteristic. Skin or tissue infiltration also defines blast crisis. Cytogenetic evidence of another Ph-positive clone (double) or clonal evolution (other cytogenetic abnormalities such as trisomy 8, 9, 19, or 21, isochromosome 17, or deletion of Y chromosome) is usually present.
• In some patients who present in the accelerated, or acute, leukemia phase of the disease (skipping the chronic phase), bleeding, petechiae, and ecchymoses may be the prominent symptoms. In these situations, fever is usually associated with infections.

Physical

• Splenomegaly is the most common physical finding in patients with chronic myelogenous leukemia (CML).
  • In more than 50% of the patients with CML, the spleen extends more than 5 cm below the left costal margin at time of discovery.
  • The size of the spleen correlates with the peripheral blood granulocyte counts (see image below), with the largest spleens being observed in patients with high WBC counts.
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      Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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      Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

  • A very large spleen is usually a harbinger of the transformation into an acute blast crisis form of the disease.
• Hepatomegaly also occurs, although less commonly than splenomegaly. Hepatomegaly is usually part of the extramedullary hematopoiesis occurring in the spleen.
• Physical findings of leukostasis and hyperviscosity can occur in some patients, with extraordinary elevation of their WBC counts, exceeding 300,000-600,000 cells/μL. Upon funduscopy, the retina may show papilledema, venous obstruction, and hemorrhages.

Causes

• The initiating factor of CML is still unknown, but exposure to irradiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki.
• Other agents, such as benzene, are possible causes.

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