Chronic myelogenous leukemia overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]
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 mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors is the main finding. It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. Historically, it has been treated with chemotherapy, interferon, bone marrow transplantation, and targeted therapies, which was introduced at the beginning of the 21st century and have radically changed the management of chronic myelogenous leukemia. 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. Chronic myelogenous leukemia may be classified according to the hematologic characteristics and laboratory findings into five subtypes. 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; for example, increased rates of CML were seen in people exposed to the atomic bombings of Hiroshima and Nagasaki. According to the American Cancer Society, screening for chronic myelogenous leukemia is not recommended. Chronic myelogenous leukemia may be classified into five phases: chronic phase, accelerated phase, blast crisis, relapsed or recurrent CML and refractory disease. Chronic myelogenous leukemia must be differentiated from leukemoid reaction, chronic neutrophilic leukemia, and acute myeloid leukemia. Medical therapies for chronic myelogenous leukemia include chemotherapy, stem cell transplant , and/or biological therapy. [1][2][3][4][5][6][7][8]
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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. above
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. From 1980 onwards allogeneic stem cell transplantation (SCT) became the treatment of choice for eligible patients. In 1998, the era of tyrosine kinase inhibitors (TKI) began.17671636/20875546
Classification
[5]Chronic myelogenous leukemia (CML) may be classified according to the hematologic characteristics and laboratory findings into five subtypes: Chronic granulocytic leukaemia (CGL) (95% of all CML), Juvenile CML (extremely rare), Chronic neutrophilic leukaemia (CNL) (extremely rare), Chronic myelomonocytic leukaemia (CMML), Atypical CML (aCML).3332855
Pathophysiology
[9]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.
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Causes
[1]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 90 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 (blood stem 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.[3]
Epidemiology and Demographics
.[10] .[11]The incidence of Chronic Myeloid Leukemia (CML) was estimated to be 1–2 cases per 100,000 individuals worldwide and accounts for 15% of adult leukemias. 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 with an incidence of 0.6–1.2 million children/year. 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.
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Risk Factors
[6][12]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. Other risk factors include older age, being male, formaldehyde, obesity, and smoking.Family history is not a risk factor and The chromosome mutation that leads to chronic myelogenous leukemia is believed to be acquired. PMID:25814090
Screening
According to the American Cancer Society, screening for chronic myelogenous leukemia is not recommended.[2]
Natural History, Complications and Prognosis
[11][1]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%. PMID:23090888 PMID:24337217 PMID:25993200 PMID:26434969
Diagnosis
Staging
[12][13]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.
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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, and left upper quadrant fullness or 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, and confusion due to sludging in the pulmonary or cerebral vessels, are uncommon symptoms. Headaches, bone pain, arthralgias, pain from splenic infarction, and fever are more frequent with CML transformation.PMID:24729196/PMID:26434969.[12]
Physical Examination
Patients with chronic myelogenous leukemia are usually well-appearing. Physical examination of patients with chronic myelogenous leukemia is usually remarkable for skin bruising, fever, splenomegaly, and lymphadenopathy.
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Laboratory Findings
[12]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.
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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.[12]
Abdominal 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.[12]
Brain MRI
Brain MRI may be helpful in the detection of brain metastasis in patients with chronic myelogenous leukemia.[12]
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.[12]
Other Diagnostic Studies
[12]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 (RT) 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.
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Treatment
Medical Therapy
[1]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.
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Surgery
.[12]Surgery for Chronic Myeloid Leukemia - American Cancer Society
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.[2]
Secondary Prevention
There are no secondary preventive measures available for chronic myelogenous leukemia.
References
- ↑ 1.0 1.1 1.2 1.3 National Cancer Institute. Physician Data Query Database 2015.http://www.cancer.gov/types/leukemia/hp/cml-treatment-pdq#section/_19
- ↑ 2.0 2.1 2.2 American Cancer Society.2015.http://www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-detection
- ↑ 3.0 3.1 Gajendra S, Gupta R, Chandgothia M, Kumar L, Gupta R, Chavan SM (2014). "Chronic Neutrophilic Leukemia with V617F JAK2 Mutation". Indian J Hematol Blood Transfus. 30 (2): 139–42. doi:10.1007/s12288-012-0203-6. PMC 4022913. PMID 24839370.
- ↑ Goldman, John M. (2010). "Chronic Myeloid Leukemia: A Historical Perspective". Seminars in Hematology. 47 (4): 302–311. doi:10.1053/j.seminhematol.2010.07.001. ISSN 0037-1963.
- ↑ 5.0 5.1 Shepherd PC, Ganesan TS, Galton DA (1987). "Haematological classification of the chronic myeloid leukaemias". Baillieres Clin Haematol. 1 (4): 887–906. PMID 3332855.
- ↑ 6.0 6.1 Moloney WC (1987). "Radiogenic leukemia revisited". Blood. 70 (4): 905–8. PMID 3477299.
- ↑ von Bubnoff N, Duyster J (February 2010). "Chronic myelogenous leukemia: treatment and monitoring". Dtsch Arztebl Int. 107 (7): 114–21. doi:10.3238/arztebl.2010.0114. PMC 2835925. PMID 20221270.
- ↑ Jabbour E, Kantarjian H (May 2014). "Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management". Am. J. Hematol. 89 (5): 547–56. doi:10.1002/ajh.23691. PMID 24729196.
- ↑ Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet (2007). "Chronic myeloid leukaemia". Lancet. 370 (9584): 342–50. PMID 17662883.
- ↑ Faderl S, Talpaz M, Estrov Z, Kantarjian HM (1999). "Chronic myelogenous leukemia: biology and therapy". Annals of Internal Medicine. 131 (3): 207–219. PMID 10428738.
- ↑ 11.0 11.1 Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER web site, April 2014.
- ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 12.9 Canadian Cancer Society.2015.http://www.cancer.ca/en/cancer-information/cancer-type/leukemia-chronic-myelogenous-cml/staging/?region=ab
- ↑ Vardiman J, Harris N, Brunning R (2002). "The World Health Organization (WHO) classification of the myeloid neoplasms". Blood. 100 (7): 2292–302. PMID 12239137. Retrieved 2007-09-22.