Which of the following is the most specific laboratory test to diagnose chronic myelogenous leukemia?

Practice Essentials

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 accounts for 20% of all leukemias affecting adults. See the image below.

See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, to help detect chronic leukemias and determine the specific type present.

Signs and symptoms

The clinical manifestations of CML are insidious, changing somewhat as the disease progresses through its 3 phases (chronic, accelerated, and blast). Patients in the chronic phase may be asymptomatic or may display any of the following signs and symptoms:

• Fatigue, weight loss, loss of energy, decreased exercise tolerance

• Low-grade fever and excessive sweating from hypermetabolism

• Elevated white blood cell (WBC) count or splenomegaly on routine assessment

• Early satiety and decreased food intake from encroachment on stomach by enlarged spleen

• Left upper quadrant abdominal pain from spleen infarction

• Hepatomegaly

The following are signs and symptoms of progressive disease:

• Bleeding, petechiae, and ecchymoses during the accelerated phase

• Bone pain and fever in the blast phase

• Increasing anemia, thrombocytopenia, basophilia, and a rapidly enlarging spleen in blast crisis

See Presentation for more detail.

Diagnosis

The diagnosis of CML is based on the following:

• Histopathologic findings in the peripheral blood

• Philadelphia chromosome (Ph2) in bone marrow cells

The workup for CML consists of the following:

• CBC with differential

• Peripheral blood smear

• Bone marrow analysis

Blood count and peripheral smear findings

• Total WBC count 20,000-60,000 cells/μL, with mildly increased basophils and eosinophils

• Mild to moderate anemia, usually normochromic and normocytic

• Platelet counts low, normal, or increased

• Leukocyte alkaline phosphatase stains very low to absent in most cells

• Leukoerythroblastosis, with circulating immature cells from the bone marrow

• Early myeloid cells (eg, myeloblasts, myelocytes, metamyelocytes, nucleated red blood cells)

Bone marrow findings

• Ph2 (a reciprocal translocation of chromosomal material between chromosomes 9 and 22)

• BCR/ABL mutation

• Hypercellularity, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells

• Megakaryocytes are prominent and may be increased

• Mild fibrosis in the reticulin stain

See Workup for more detail.

Management

Goals of treatment of CML include the following:

• Hematologic remission (normal CBC and physical examination [ie, no organomegaly])

• Cytogenetic remission (normal chromosome returns with 0% Ph2-positive cells)

• Molecular remission (negative polymerase chain reaction [PCR] result for BCR/ABL mRNA

Tyrosine kinase inhibitors for CML

• Imatinib mesylate (Gleevec): For chronic, accelerated, and blastic phases; standard treatment of choice

• Dasatinib (Sprycel): For chronic phase

• Nilotinib (Tasigna): For chronic phase

• Bosutinib (Bosulif): For chronic, accelerated, and blast phases

• Ponatinib (Iclusig): For chronic or blast phase T315I-positive cases, or in appropriate patients in whom no other TKI therapy is tolerated or indicated

• Asciminib (Scemblix): For chronic phase T3151-positive cases or in chronic phase patients previously treated with 2 or more TKIs

Other medications for CML

• Interferon-alfa: Former first-line agent; now combined with newer drugs for refractory cases

• Hydroxyurea (Hydrea): Myelosuppressive agent for inducing hematologic remission

• Busulfan: Myelosuppressive agent for inducing hematologic remission

• Omacetaxine (Synribo): Protein translation inhibitor indicated for chronic- or accelerated-phase CML with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors

Allogeneic bone marrow transplantation (BMT) or stem cell transplantation

• Only proven cure for CML

• Ideally performed in the chronic phase

• Candidate patients should be offered the procedure if they have a matched or single–antigen-mismatched related donor available

• Overall survival for allogeneic BMT with matched unrelated donors ranges from 31% to 43% for patients younger than 30 years and from 14% to 27% for older patients

• Currently relegated to patients who do not achieve molecular remissions or show resistance to imatinib and failure of second-generation tyrosine kinase inhibitors (eg, dasatinib)

• Patients with minimal residual disease after transplantation require interferon maintenance therapy or donor lymphocyte infusion

Supportive treatment

• Leukapheresis for white blood cell counts greater than 300,000 cells/µL

• Splenectomy for severe or painful splenomegaly

See Treatment and Medication for more detail.

Background

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 three 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, 2] 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.)

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 (Ph2) chromosome after the city of discovery. (See the image below.)

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. [3, 4, 5, 6, 7, 8, 9, 10, 2]

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.

Epidemiology

The American Cancer Society (ACS) estimates that 8860 new cases of CML will be diagnosed in 2022, 5120 in males and 3740 in females. The ACS estimates that 1220 deaths from CML will occur in 2022, 670 in males and 550 in females. [11] Incidence and mortality rates for CML did not change significantly over 2009–2019; based on 2015–2019 data, the age-adjusted rate of new cases was 1.9 per 100,000 population per year, and the death rate was 0.3 per 100,000 population per year. [12]

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. The 5-year survival rate has more than doubled, from 31% in the early 1990s to 70.4% for patients diagnosed from 2012 to 2018. [11, 12] The improvement has resulted from earlier diagnosis, improved therapy with targeted drugs 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)

The three 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%

Since the advent of the Sokal score, two other CML prognostic scores have been developed: the Hasford score in the 1990s and the EUTOS (European Treatment and Outcome Study) score in the 2000s. Like the Sokal score, the Hasford formula categorizes patients into low-, intermediate- and high-risk groups; the EUTOS score differentiates only between high-risk and low-risk groups. The Hansford score, which also incorporates peripheral blood eosinophils and basophils as a percentage of total leukocytes, may be more accurate at discriminating between low-risk and intermediate-risk CML, and so may be useful in predicting molecular response to initial TKI treatment of patients with chronic-phase CML. [13]

Online calculators of these scores are available. See the Sokal Score for CML and Calculation of Relative Risk of CML Patients.

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: blast phase at diagnosis

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

• Older age

• Symptomatic presentation

• Poor performance status

• African-American descent

• Hepatomegaly

• Splenomegaly

• Negative Philadelphia 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

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. In a study of 832 patients who received imatinib for treatment of CML and were in complete cytogenetic remission after 2 years, survival was not statistically significantly different from that of the general population. [14]  Another study of long-term outcome of treatment with imatinib, with median follow-up of 10.9 years, reported overall survival of 83.3% with a complete cytogenetic response rate of 82.8%. [15]

Patients who develop blast crisis, which has manifestations similar to those of acute leukemia, have a very poor prognosis. Treatment results are unsatisfactory, and most of these patients succumb to the disease. Survival is 3-6 months.

A study by Wang et al addressed the prognostic impact of specific additional chromosomal abnormalities (ACAs) in CML. The concurrent presence of two or more ACAs conferred inferior survival. In patients with a single chromosomal change at the time of ACA emergence, the following three were associated with a relatively good prognosis [16] :

• Trisomy 8

• -Y

• An extra copy of Philadelphia chromosome

In contrast, the following three ACAs were associated with a relatively poor prognosis:

• i(17)(q10)

• -7/7q (-7/del7q)

• 3q26.2 rearrangements

Patient Education

Current patient education information on CML is available on the American Cancer Society and National Cancer Institute Web sites. For additional patient education information, see Leukemia.

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Author

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, 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 Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Chief Editor

Sara J Grethlein, MD, MBA, FACP Executive Medical Director and Medical Oncologist, Swedish Cancer Institute

Sara J Grethlein, MD, MBA, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Women's Association, American Society of Clinical Oncology, American Society of Hematology, Gold Humanism Honor Society, Leukemia and Lymphoma Society

Disclosure: Nothing to disclose.

Additional Contributors

Acknowledgements

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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