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.
Chronic myelogenous leukemia. 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.
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:
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Fatigue, weight loss, loss of energy, decreased exercise tolerance
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Low-grade fever and excessive sweating from hypermetabolism
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Elevated white blood cell (WBC) count or splenomegaly on routine assessment
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Early satiety and decreased food intake from encroachment on stomach by enlarged spleen
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Left upper quadrant abdominal pain from spleen infarction
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Hepatomegaly
The following are signs and symptoms of progressive disease:
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Bleeding, petechiae, and ecchymoses during the accelerated phase
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Bone pain and fever in the blast phase
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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:
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Histopathologic findings in the peripheral blood
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Philadelphia chromosome (Ph1) in bone marrow cells
The workup for CML consists of the following:
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CBC with differential
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Peripheral blood smear
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Bone marrow analysis
Blood count and peripheral smear findings
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Total WBC count 20,000-60,000 cells/μL, with mildly increased basophils and eosinophils
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Mild to moderate anemia, usually normochromic and normocytic
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Platelet counts low, normal, or increased
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Leukocyte alkaline phosphatase stains very low to absent in most cells
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Leukoerythroblastosis, with circulating immature cells from the bone marrow
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Early myeloid cells (eg, myeloblasts, myelocytes, metamyelocytes, nucleated red blood cells)
Bone marrow findings
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Ph1 (a reciprocal translocation of chromosomal material between chromosomes 9 and 22)
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BCR-ABL mutation
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Hypercellularity, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells
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Megakaryocytes are prominent and may be increased
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Mild fibrosis in the reticulin stain
See Workup for more detail.
Management
Goals of treatment of CML include the following:
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Hematologic remission (normal CBC and physical examination [ie, no organomegaly])
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Cytogenetic remission (normal chromosome returns with 0% Ph1-positive cells)
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Molecular remission (negative polymerase chain reaction [PCR] result for BCR-ABL mRNA
Tyrosine kinase inhibitors (TKIs) for CML
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Imatinib (Gleevec): For Ph+ chronic, accelerated, and blastic phases
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Dasatinib (Sprycel): For newly diagnosed chronic phase, and chronic, accelerated, or myeloid or lymphoid blast phase with resistance or intolerance to prior therapy including imatinib
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Nilotinib (Tasigna): For newly diagnosed chronic phase, and chronic or accelerated phase with resistance to or intolerance of prior therapy that included imatinib
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Bosutinib (Bosulif): For newly diagnosed chronic phase, and chronic, accelerated, or blast phase with resistance to or intolerance of prior therapy that included imatinib
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Ponatinib (Iclusig): For chronic phase patients with resistance or intolerance to at least 2 prior kinase inhibitors, for accelerated or blast phase patients in whom no other TKI therapy is tolerated or indicated, and for BCR-ABL T315I–positive chronic, acclerated, or blast phase CML
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Asciminib (Scemblix): For chronic phase cases that are BCR-ABL T315I positive or that were previously treated with 2 or more TKIs
Other medications for CML
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Interferon-alfa: Former first-line agent; now combined with newer drugs for refractory cases
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Hydroxyurea (Hydrea): Myelosuppressive agent for inducing hematologic remission
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Busulfan: Myelosuppressive agent for inducing hematologic remission
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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
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Only proven cure for CML
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Ideally performed in the chronic phase
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Candidate patients should be offered the procedure if they have a matched or single–antigen-mismatched related donor available
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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
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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)
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Patients with minimal residual disease after transplantation require interferon maintenance therapy or donor lymphocyte infusion
Supportive treatment
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Leukapheresis for white blood cell counts greater than 300,000 cells/µL
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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, tyrosine kinase inhibitors (TKIs), starting with the first-generation TKI imatinib, have become the agents of choice in CML. They are playing increasingly important roles in inducing complete remission, which can allow cessation of therapy and excellent response if disease returns. TKIs are slowly replacing allogeneic hematopoietic stem cell transplantation as a 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 (Ph1) chromosome after the city of discovery. (See the image below.)
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.
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 8930 new cases of CML will be diagnosed in 2023, 5190 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 2016–2020 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 70.6% for patients diagnosed from 2013 to 2019. [11, 12] The improvement has resulted from earlier diagnosis, therapy with targeted drugs and hematopoietic stem cell transplantation (HSCT), and better supportive care.
The outlook is even more favorable for patients with CML in the chronic phase who receive TKI therapy, because these agents often prevent progression to accelerated and blast crisis. For example, in the IRIS trial of the first TKI, imatinib, the estimated overall survival of patients who received imatinib as initial therapy was 89% at five years; only an estimated 7% of patients progressed to accelerated-phase CML or blast crisis. [13] The second-generation TKIs dasatinib, nilotinib, and bosutinib have proved significantly more effective than imatinib, [14, 15, 16] and the third-generation TKIs ponatinib and asciminib provide a second-line option for cases resistant to other therapies. [17, 18]
In the accelerated phase, survival rates vary widely according to treatment. If the patient responds well to TKIs, rates are nearly as good as for those in the chronic phase. Overall, survival rates for those in the blast crisis phase hover below 20%. [12] The best chance for survival involves using drugs to get the disease back into the chronic phase and then try HSCT. A retrospective review reported five-year overall survival (OS) of 34% in patients treated with combination therapy that included a TKI and intensive chemotherapy or a hypomethylating agent; five 5-year OS in patients who proceeded to transplantation was 58%.{ref73
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.
Risk stratification
As treatment of CML has improved, the need to stage patients according to their prognoses became necessary to justify procedures with high morbidity and mortality, such as HSCT. 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:
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Good risk (average survival of 5-6 years)
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Intermediate risk (average survival of 3-4 years)
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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:
- Low risk: score < 0.8
- Intermediate risk: score 0.8-1.2
- High risk: score > 1.2
The Sokal score correlates with the likelihood of achieving complete cytogenetic response, as follows:
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Low-risk patients: 91%
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Intermediate-risk patients: 84%
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High-risk patients: 69%
Since the advent of the Sokal score, 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 Hasford 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 chronic-phase CML. [19]
Online calculators of these scores are available. See the Sokal Score for CML, Calculation of Relative Risk of CML Patients, and EUTOS Score for Chronic Myelogenous Leukemia (CML).
Currently, most patients with CML die from causes other than leukemia while still in remission. For that reason, another risk score, the EUTOS Long Term Survival (ELTS) score has been developed to predict the probability of dying from CML. The ELTS score, based on TKI-treated patients and validated for patients older than 18 years, uses the same criteria as the Sokal score but assigns different values, particularly for age. The score is calculated using the following formula [20] :
0.0025 × (age/10)3 + 0.0615 × spleen size + 0.1052 × peripheral blood blasts + 0.4104 × (platelet count/1000)–0.5
The EUTOS ELTS score categories are as follows:
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Low risk: < 1.5680
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Intermediate risk:1.5680–2.2185
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High-risk: > 2.2185
An online calculator is available. See The EUTOS long-term survival (ELTS) score.
Additional chromosomal abnormalities
A study by Wang et al addressed the prognostic impact of specific additional chromosomal abnormalities (ACAs) in CML. [21] In patients with a single chromosomal change, the following three ACAs were associated with a relatively good prognosis when they emerged during the chronic phase or at the time of CML diagnosis:
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Trisomy 8
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-Y
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An extra copy of Philadelphia chromosome (+Ph)
However, if trisomy 8 was accompanied by one or more of those other ACAs, patients had a poorer prognosis.
The following three ACAs were associated with a relatively poor prognosis, regardless of the disease phase at the time of emergence:
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i(17)(q10)
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-7/7q (-7/del7q)
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3q26.2 rearrangements
A study by Hehlmann et al of ACAs in patients in chronic phase CML concluded that although the prognosis with trisomy 8 alone was clearly better than with trisomy 8 accompanied by further abnormalities, it was still worse than with low-risk ACA. [22] In addition, these authors identified the following ACAs as conferring high risk:
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+Ph
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i(17q)
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+17
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+19 +21
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3q26
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11q23
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-7
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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Chronic myelogenous leukemia. 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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Chronic myelogenous leukemia. 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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Chronic myelogenous leukemia. 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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Chronic myelogenous leukemia. 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.
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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.
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Chronic myelogenous leukemia. 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.
Tables
Mutation |
Tyrosine kinase inhibitor |
T3151 |
Ponatinib |
F317L/V/I/C, T315A |
Nilotinib, bosutinib, or ponatinib |
V299L |
Nilotinib or ponatinib |
Y253H, E255V/K, F359V/I/C |
Dasatinib, bosutinib, or ponatinib |
