Chronic myelogenous leukemia overview
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: James Nasr[2]
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Overview
Chronic myelogenous leukemia (CML) is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which proliferation of precursor and mature granulocytes (neutrophils, eosinophils, and basophils) occurs. It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. Chronic myelogenous leukemia is caused by a mutation in BCR-ABL gene. The most potent risk factor in the development of chronic myelogenous leukemia is ionizing radiation.Chronic myelogenous leukemia may be classified into five phases: chronic phase, accelerated phase, blast crisis, relapsed or recurrent CML and refractory disease. Historically, it has been treated with chemotherapy, interferon, bone marrow transplantation, and targeted therapies.
Historical Perspective
In the 1840s, the first cases of chronic myelogenous leukemia (splenomegaly with high leukocyte count) was reported in France, Germany, and Scotland. In 1960, the association of Philadelphia chromosome with the pathogenesis of chronic myelogenous leukemia was first discovered. In 1973, (9;22) translocation was first discovered. Definition of the breakpoint cluster region (BCR) on chromosome 22 was first reported in 1984 and the demonstration of the BCR-ABL transcript in CML was first discovered in 1985. CML was previously classified into five subtypes. This has been replaced with a newer model, where it was classified into three phases. In 2022, the World Health Organisation eliminated one of these phases, leaving two remaining categories. From 1980 on wards allogeneic stem cell transplantation (SCT) became the treatment of choice for eligible patients. In 1998, the era of tyrosine kinase inhibitors (TKI) began. TKIs have drastically changed the therapeutic landscape of CML, converting it from a fatal leukemia to a chronic, highly manageable disease.
Classification
Chronic myelogenous leukemia (CML) may into two phases: CML-chronic phase (CML-CP), CML-blastic phase (CML-BP). A third phase, CML-accelerated phase (CML-AP), is also widely recognised, however removed by the World Health Organisation (WHO) in 2022. Some studies still indicate the importance of this phase due to its distinct prognosis and treatment regiment from CML-CP and CML-BP.
Pathophysiology
Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent bone marrow stem cells. The hallmark of CML is the formation of the Philadelphia chromosome resulting from the reciprocal t(9;22)(q34;q11.2), resulting in a derivative 9q+ and a small 22q-, results in a BCR-ABL fusion gene and production of a BCR-ABL fusion protein. The gene product of the BCR-ABL gene constitutively activates numerous downstream targets including c-myc, Akt and Jun, all of which cause uncontrolled proliferation and survival of CML cells.
Causes
Chronic myelogenous leukemia is caused by: First, an abnormal chromosome develops: In people with chronic myelogenous leukemia, the Philadelphia chromosome, named for the city where it was discovered, is present in the blood cells of >95 percent of people. Second, the abnormal chromosome creates a new gene: The Philadelphia chromosome creates a new gene called BCR-ABL. it contains instructions that tell the abnormal blood cell to produce too much of a protein called tyrosine kinase that promotes cancer by allowing certain blood cells to grow out of control. Third, the new gene allows too many diseased blood cells: When the bone marrow functions normally, it produces immature cells in a controlled way. These cells then specialize into the various types of blood cells that circulate in the body. In chronic myelogenous leukemia, this process doesn't work correctly and the tyrosine kinase caused by the BCR/ABL gene causes too many white blood cells. These diseased white blood cells build up in huge numbers, crowding out healthy blood cells and damaging the bone marrow.
Differentiating Chronic myelogenous leukemia from other Diseases
Chronic myelogenous leukemia must be differentiated from:leukemoid reaction, chronic neutrophilic leukemia, and acute myeloid leukemia. Definitive distinction is established by detection of the BCR::ABL1 fusion gene.
Epidemiology and Demographics
The incidence of chronic myeloid leukemia was estimated to be 1–2 cases per 100,000 individuals worldwide. The peak age for the CML is 50 to 55 and some series report a median age of up to 67 years. Incidence in CML increases by age, at least up to 75–80 years and in children, is a very rare disease. Males are more commonly affected with CML than females. The male-to-female ratio varying between 1.2 and 1.7 in different studies. The gender difference in incidence is less prominent in younger people.
Risk Factors
The most potent risk factor in the development of chronic myelogenous leukemia is ionizing radiation; for example, increased rates of CML were seen in people exposed to the atomic bombings of Hiroshima and Nagasaki.
Screening
According to the American Cancer Society, screening for chronic myelogenous leukemia is not recommended.
Natural History, Complications and Prognosis
If left untreated, majority of patients with chronic myelogenous leukemia may progress from a chronic phase where differentiation is reasonably well-maintained to blast or acute phase (BP) where differentiation is lost. The progression to BP occurs at a median of 3–5 years from diagnosis in untreated patients. Some complications of chronic myelogenous leukemia include fatigue, excess bleeding, enlarged spleen, and infection. Prognosis is generally poor, and the 5-year survival rate of patients with chronic myelogenous leukemia is approximately 59.9%. Targeted therapy with small molecule tyrosine kinase inhibitors (TKIs) dramatically alter the natural history of the disease, improving 10-year overall survival (OS) from 20 to 80–90%.
Diagnosis
Staging:
Chronic myelogenous leukemia may be classified according to the clinical characteristics and laboratory findings into five phases: Chronic phase, accelerated phase, blast crisis, relapsed or recurrent CML, and refractory disease. The earliest phase is the chronic phase and generally has the best response to treatment. The accelerated phase is a transitional phase and blastic phase is a aggressive phase that becomes life-threatening. Relapsed CML means that the number of blast cells in the blood and bone marrow increase after remission and finally, refractory disease means the leukemia did not respond to treatment.
History and Symptoms:
Up to 50% of patients with CML are asymptomatic and clinical features, when present, are generally nonspecific. Common symptoms of CML include: Fatigue, Weight loss, Fever, malaise, easy satiety, left upper quadrant fullness, and Pain. Less common symptoms of CML include: Bleeding, thrombosis, gouty arthritis, symptoms of hyperviscosity including priapism, retinal hemorrhages, and upper gastrointestinal ulceration and bleeding, Dyspnea, drowsiness, loss of coordination, confusion due to sludging in the pulmonary or cerebral vessels, headaches, Bone pain, arthralgias, and Splenic infarction
Physical Examination
Patients with chronic myelogenous leukemia are usually well-appearing. Physical examination of patients with chronic myelogenous leukemia is usually remarkable for following: Skin bruising, fever, splenomegaly, and lymphadenopathy.
Laboratory Findings
Laboratory findings consistent with the diagnosis of chronic myelogenous leukemia in CBC include: thrombocytosis and/or marked leukocytosis (median of 100,000/µL) with a left shift, blasts usually number <2%, absolute basophilia is nearly universal, absolute eosinophilia, monocytosis and normal or elevated platelet count; thrombocytopenia suggests an alternative diagnosis or the presence of advanced stage. Elevated uric acid levels and elevated histamine levels due to basophilia are other laboratory findings.
Chest X-Ray
Chest x-ray may be helpful in the diagnosis of chronic myelogenous leukemia. Findings on chest x-ray suggestive of chronic myelogenous leukemia include enlarged mediastinal lymph nodes, enlarged thymus gland, and pneumonia.
CT
Abdominal and chest CT scan may be helpful in the diagnosis of chronic myelogenous leukemia. Findings on CT scan suggestive of chronic myelogenous leukemia include enlarged lymph nodes.
Brain MRI
Brain MRI may be helpful in the detection of brain metastasis in patients with chronic myelogenous leukemia.
Abdominal Ultrasound
Abdominal ultrasound may be helpful in the diagnosis of chronic myelogenous leukemia. Findings on abdominal ultrasound suggestive of chronic myelogenous leukemia include enlarged lymph nodes and splenomegaly.
Other Diagnostic Studies
Other diagnostic studies for chronic myelogenous leukemia include bone marrow aspiration and biopsy, lumbar puncture, and lymph node biopsy. Genomic PCR, Southern blot assay, Reverse transcriptase PCR, Northern blot analysis, Western blot analysis or immunoprecipitation can be helpful in the diagnosis of chronic myelogenous leukemia; the gold standard diagnostic test in chronic myelogenous leukemia is cytogenetic analysis.
Treatment
Medical Therapy
Medical therapies for chronic myelogenous leukemia (CML) include chemotherapy, stem cell transplant , and/or biological therapy. With improved understanding of the nature of the BCR-ABL protein and its action as a tyrosine kinase, targeted therapies have been developed (the first of which was imatinib mesylate) which specifically inhibit the activity of the BCR-ABL protein. These tyrosine kinase inhibitors can induce complete remissions in chronic myelogenous leukemia, confirming the central importance of BCR-ABL as the cause of chronic myelogenous leukemia.
Surgery
Surgery is not the first-line treatment option for patients with chronic myelogenous leukemia. Splenectomy is usually reserved for patients with enlarged spleen and it has no role in curing CML.
Primary Prevention
There are no primary preventive measures available for chronic myelogenous leukemia.
Secondary Prevention
There are no secondary preventive measures available for chronic myelogenous leukemia.