Chronic Myelogenous Leukemia 

  • Author: Emmanuel C Besa, MD; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP   more...
 
Updated: Dec 14, 2011
 

Background

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, 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.

CML is one of the few cancers known to be caused by a single, specific genetic mutation. More than 90% of cases result from a cytogenetic aberration known as the Philadelphia chromosome (see Pathophysiology).

CML progresses through 3 phases: chronic, accelerated, and blast. In the chronic phase of disease, mature cells proliferate; in the accelerated phase, additional cytogenetic abnormalities occur; in the blast phase, immature cells rapidly proliferate.[1] Approximately 85% of patients are diagnosed in the chronic phase and then progress to the accelerated and blast phases after 3-5 years. The diagnosis of CML is based on the histopathologic findings in the peripheral blood and the Philadelphia chromosome in bone marrow cells (see Workup).

CML accounts for 20% of all leukemias affecting adults. It typically affects middle-aged individuals. Uncommonly, the disease occurs in younger individuals. Younger patients may present with a more aggressive form of CML, such as in accelerated phase or blast crisis. Uncommonly, CML may appear as a disease of new onset in elderly individuals.

The goals of treatment are to achieve hematologic, cytogenetic, and molecular remission. Although a variety of medications have been used in CML, including myelosuppressive agents and interferon alfa, the tyrosine kinase inhibitor imatinib mesylate is currently the agent of choice, and other drugs in this category are playing increasingly important roles. However, allogeneic bone marrow transplantation is currently the only proven cure for CML. (See Treatment.)

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Pathophysiology

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 (Ph1) chromosome after the city of discovery. (See the image below.)

The Philadelphia chromosome, which is a diagnosticThe Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows). Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine.

This translocation relocates an oncogene called ABL from the long arm of chromosome 9 to a specific breakpoint cluster region (BCR) in the long arm of chromosome 22. The ABL oncogene encodes a tyrosine protein kinase. 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 CML phenotype, through processes that are not yet fully understood.[2, 3, 4, 5, 6, 7, 8, 9, 10, 1]

The presence of BCR/ABL rearrangement is the hallmark of 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.

The initiating factor of CML is still unknown, but exposure to ionizing radiation 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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Prognosis

Historically, the median survival of patients with CML was 3-5 years from the time of diagnosis. Currently, patients with CML have a median survival of 5 or more years and a 5-year survival rate of 50-60%. The improvement has resulted from earlier diagnosis, improved therapy with interferon and bone marrow transplantation, and better supportive care.

As treatment improved, the need to stage patients according to their prognoses became necessary to justify procedures with high morbidity and mortality, such as bone marrow transplantation.

Staging of patients is based on several analyses using multiple variate analysis between the association of pretreatment host and leukemic cell characteristics and corresponding survival rates. The findings from these studies classify patients into the following groups:

  • Good risk (average survival of 5-6 years)
  • Intermediate risk (average survival of 3-4 years)
  • Poor risk (average survival of 2 years)

One widely used prognostic index, the Sokal score, is calculated for patients aged 5-84 years by the following equation:

Hazard ratio = exp 0.0116 (age - 43) + 0 .0345 (spleen size [cm below costal margin] - 7.5 cm) + 0.188 [(platelet count/700)2 - 0.563] + 0.0887 (% blasts in blood - 2.1)

Online calculators for the Sokal score are available.

The 3 categories of the Sokal score are as follows:

  1. Low risk: score < 0.8
  2. Intermediate risk: score 0.8-1.2
  3. High risk: score > 1.2

The Sokal score correlates with the likelihood of achieving complete cytogenetic response, as follows:

  • Low-risk patients: 91%
  • Intermediate-risk patients: 84%
  • High-risk patients: 69%

A combined prognostic model, incorporating previous models such as the Sokal score, has been devised using the number of poor-prognosis characteristics. Stages in this model are as follows:

  • Stage 1: 0 or 1 characteristic
  • Stage 2: 2 characteristics
  • Stage 3: 3 or more characteristics
  • Stage 4: diagnosis at blast phase

Poor-prognosis characteristics include the following clinical and laboratory factors:

  • Older age
  • Symptomatic presentation
  • Poor performance status
  • African American descent
  • Hepatomegaly
  • Splenomegaly
  • Negative Ph chromosome or BCR/ABL
  • Anemia
  • Thrombocytopenia
  • Thrombocytosis
  • Decreased megakaryocytes
  • Basophilia
  • Myelofibrosis (increased reticulin or collagen)

The following therapy-associated factors may indicate a poor prognosis in patients with CML:

  • Longer time to hematologic remission with myelosuppression therapy
  • Short duration of remission
  • High total dose of hydroxyurea or busulfan
  • Poor suppression of Ph-positive cells by chemotherapy or interferon alfa therapy

A German study of 139 low-risk patients with CML, according to the Sokal score, indicated that new therapeutic agents have brought improvement in survival. Median survival according to treatment used was as follows:

  • Busulfan: 6 years (50 patients)
  • Hydroxyurea: 6.5 years (55 patients)
  • Interferon alfa: approximately 9.5 years (34 patients)

Some patients with molecular remissions from interferon alfa may be cured, but this can only be established over time.

The tyrosine kinase inhibitor imatinib has replaced interferon as a first-line therapy, as it is associated with a higher response rate and better tolerance of adverse effects. Long-term follow-up of patients who received imatinib in the treatment of CML and achieved a complete cytogenic response 2 years after the start of treatment demonstrated that their survival was not statistically significantly different from that of the general population.[11]

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. Acute phase, or blast crisis, is similar to acute leukemia, and survival is 3-6 months at this stage.

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Contributor Information and Disclosures
Author

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Coauthor(s)

Ulrich Josef Woermann, MD  Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland

Disclosure: Nothing to disclose.

Chief Editor

Koyamangalath Krishnan, MD, FRCP, FACP  Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, James H Quillen College of Medicine at East Tennessee State University

Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians

Disclosure: Nothing to disclose.

Additional Contributors

Bruce Buehler, MD Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

Maurie Markman, MD Vice President for Medical Oncology Services, National Director for Medical Oncology, Cancer Treatment Centers of America

Maurie Markman, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, and American Society of Hematology

Disclosure: Eli Lilly Honoraria Speaking and teaching; Genentech Consulting fee Consulting; Cellgene Consulting fee Consulting; Hana Pharmaceuticals Consulting fee Consulting; Boehringer Ingelheim Consulting fee Consulting; Ortho Biotech Consulting fee Consulting; Morphotech Consulting; Amgen Consulting fee Consulting

Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Clarence Sarkodee-Adoo, MD Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program

Disclosure: Takeda Millenium Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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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.
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.
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.
Bone marrow film at 400X magnification demonstrates clear dominance of granulopoiesis. The number of eosinophils and megakaryocytes is increased. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows). Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine.
Fluorescence in situ hybridization using unique-sequence, double-fusion DNA probes for bcr (22q11.2) in red and c-abl (9q34) gene regions in green. The abnormal bcr/abl fusion present in Philadelphia chromosome–positive cells is in yellow (right panel) compared with a control (left panel). Courtesy of Emmanuel C. Besa, MD.
 
 
 
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