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 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]
CML is a neoplastic disease of the hematopoietic stem cells. Its incidence is 2 per 100 000/year. The peak age for the disease is 50 to 55 (e1). The Philadelphia chromosome (e2), the product of a translocation of chromosomes 9 and 22 (e3), is characteristic of CML. The resulting fusion protein acts as an active kinase. Kinase inhibitors such as imatinib block the activity of bcr-abl (e4, e5). CML is one of the few malignant diseases triggered by a single oncogene (bcr-abl) (e6, e7). This is the reason for the excellent efficacy of molecularly targeted CML therapy. Diagnosis requires evidence of bcr-abl translocation via cytogenetics, polymerase chain reactions (PCRs) or Western blot tests. CML is usually diagnosed in the initial, chronic phase (CP), which if left untreated advances to an accelerated phase (AP) after three to five years, and finally a blast crisis (BC). Leukocytosis of more than 100 000/µL with continuous left shift leading to myeloblasts or promyelocytes and splenomegaly are characteristic of the chronic phase. The features of the accelerated phase are as follows:
- Increased numbers of blast cells in the blood or bone marrow
- Increased or decreased platelet count
- Increased numbers of basophils in the peripheral blood or
- Other chromosome anomalies (e8).
The blast crisis, with increased blast cell numbers (=20%) in the blood or bone marrow, matches the clinical picture of acute leukemia. Monitoring of CML during therapy includes measuring bcr-abl levels in the blood and bone marrow, as well as blood counts. This is why three separate levels of response are distinguished.PMID:20221270
CML can be classified into three disease phases: chronic phase (CP), accelerated phase (AP), and blast phase (BP). PMID:24729196
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 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
[7]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.
26434969/22054730
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 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
Chronic myelogenous leukemia (CML) occurs in all age groups, but most commonly in the middle-aged and elderly. Chronic myelogenous leukemia affects slightly more men than women. chronic myelogenous leukemia represents about 15–20% of all cases of adult leukemia in Western populations.[8] In 2011, the age-adjusted incidence of chronic myelogenous leukemia was 1.81 per 100,000 persons in the United States.[9]
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. Other risk factors include formaldehyde, obesity, and smoking.[6][10]
Screening
According to the American Cancer Society, screening for chronic myelogenous leukemia is not recommended.[2]
Natural History, Complications and Prognosis
If left untreated, majority of patients with chronic myelogenous leukemia may progress to develop fever, night sweats, and fatigue. Common complications of chronic myelogenous leukemia include bleeding and anemia. Prognosis is generally poor, and the 5-year survival rate of patients with chronic myelogenous leukemia is approximately 59.9%.[9][1]
Diagnosis
Staging
Chronic myelogenous leukemia may be classified according to the clinical characteristics and laboratory findings into three subtypes: chronic phase, accelerated phase, and blast crisis. [10][11]
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.[10]
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.
Laboratory Findings
Laboratory findings consistent with the diagnosis of chronic myelogenous leukemia include leukocytosis, thrombocytopenia, and anemia.[10]
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.[10]
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.[10]
Brain MRI
Brain MRI may be helpful in the detection of brain metastasis in patients with chronic myelogenous leukemia.[10]
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.[10]
Other Diagnostic Studies
Other diagnostic studies for chronic myelogenous leukemia include bone marrow aspiration and biopsy, lumbar puncture, and lymph node biopsy.[10]
Treatment
Medical Therapy
Medical therapies for chronic myelogenous leukemia 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.[1]
Surgery
Surgical intervention is recommended for the management of chronic myelogenous leukemia in case of splenectomy.[10]
Primary Prevention
There are no primary preventive measures available for chronic myelogenous leukemia.[2]
Secondary Prevention
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.
- ↑ 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.
- ↑ 9.0 9.1 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.
- ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 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.