Acute myeloid leukemia ( AML ) is a cancer of the myeloid line of blood cells, characterized by rapid growth of abnormal cells that accumulate in the bone marrow and blood and interfere with normal blood cells. Symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and an increased risk of infection. Sometimes spread may occur in the brain, skin, or gums. As acute leukemia, AML develops rapidly and is usually fatal within weeks or months if left untreated.
Risk factors include smoking, chemotherapy or previous radiation therapy, myelodysplastic syndrome, and exposure to benzene chemistry. The underlying mechanism involves the replacement of normal bone marrow with leukemia cells, which results in a decrease in red blood cells, platelets, and normal white blood cells. Diagnosis is generally based on bone marrow aspiration and specific blood tests. AML has several subtypes; for treatments and results that may vary.
AML is usually initially treated with chemotherapy aimed at stimulating forgiveness. People can then proceed to receive additional chemotherapy, radiation therapy, or stem cell transplantation. Specific genetic mutations present in cancer cells can guide therapy, and determine how long the person will survive. Arsenic trioxide can be tried in cases of relapse after ordinary treatments.
AML affects about one million people globally by 2015 and resulted in 147,000 deaths. This is most common in older adults. Men are more affected than women. AML can be cured in about 35% of people under 60 years and 10% over 60 years. Older people who are not well enough to receive intensive chemotherapy have typical survival for 5-10 months. It accounts for about 1.8% of cancer deaths in the United States.
Video Acute myeloid leukemia
Signs and symptoms
Most of the signs and symptoms of AML are caused by the replacement of normal blood cells with leukemia cells. Lack of normal white blood cell production makes people more susceptible to infection; while leukemia cells themselves originate from white blood cell precursors, they have no capacity against infection. Reduced number of red blood cells (anemia) can cause fatigue, pallor, and shortness of breath. Lack of platelets can cause easy bruising or bleeding with mild trauma.
Early signs of AML are often blurred and non-specific, and may be similar to influenza or other common ailments. Some common symptoms include fever, fatigue, weight loss or loss of appetite, shortness of breath, anemia, easy bruising or bleeding, petechiae (flat, pin-head-sized spots under the skin caused by bleeding), bone and joint pain , and persistent or frequent infections.
Splenic enlargement can occur in AML, but it is usually mild and asymptomatic. Swollen lymph nodes are rare in AML, in contrast to acute lymphoblastic leukemia. The skin is involved about 10% of the time in the form of leukemia cutis. Rarely, Sweet syndrome, paraneoplastic inflammation of the skin, can occur with AML.
Some people with AML may experience swelling of the gums due to infiltration of leukemia cells into the gum tissue. Rarely, the first sign of leukemia may be the development of a dense leukemia mass or a tumor outside the bone marrow, called chloroma. Occasionally, a person may show no symptoms, and leukemia can be discovered incidentally during routine blood tests.
Maps Acute myeloid leukemia
Risk factors
A number of risk factors for developing AML have been identified, including: other blood disorders, chemical exposure, ionizing radiation, and genetics.
Other blood disorders
Preleukemic blood disorders, such as myelodysplastic syndrome (MDS) or myeloproliferative disease (MPS), may evolve into AML; the exact risk depends on the type of MDS/MPS. The presence of asymptomatic clonal hematopoiesis also increases the risk of transformation to AML to 0.5-1.0% per year.
Chemical exposure
Exposure to anticancer chemotherapy, especially alkylating agents, may increase the risk of further AML development. The risk is highest about three to five years after chemotherapy. Other chemotherapeutic agents, especially epipodophyllotoxins and anthracyclines, have also been associated with treatment-related leukemia, which is often associated with specific chromosome abnormalities in leukemia cells.
Occupational chemical exposure to benzene and other aromatic organic solvents is controversial as a cause of AML. Benzene and many of its derivatives are known to be carcinogenic in vitro . While some studies have shown an association between occupational exposure to benzene and an increased risk of AML, others have suggested the risks that arise, if any, are few.
Radiation
High amounts of ionizing radiation exposure can increase the risk of AML. The victims of the Hiroshima and Nagasaki atom bombs experienced an increase in AML, as did radiologists who were exposed to high-level X-rays before the adoption of modern radiation-safety practices. People treated with ionizing radiation after treatment for prostate cancer, non-Hodgkin's lymphoma, lung cancer, and breast cancer have the highest chance of obtaining AML, but this increased risk returns to the background risk observed in the general population after 12 years.
Genetics
Hereditary risk for AML appears to be present. Some cases of AML developing in the family at a higher level than expected by chance have been reported. Some congenital conditions may increase the risk of leukemia; the most common is probably Down's syndrome, which is associated with an increase of 10 to 18 times the risk of AML. In the second example, disabling mutations in either of the two parental genes GATA2 leads to a reduction, ie haploinsufficiency, at the cellular product level of genes, GATA2 transcription factor, and thus becomes a rare autosomal dominant genetic disease, GATA2 deficiency. The disease is associated with a series of highly variable disorders including very high risks of developing AML. The specific genetic disorders that cause AML usually vary between those who develop the disease as a child versus an adult. However, AML-induced GATA2 deficiency may first appear in children or adults.
Diagnosis
The first clue to an AML diagnosis is usually an abnormal result in a complete blood count. While the excess of abnormal white blood cells (leukocytosis) is a common finding with leukemia, and leukemia explosion is sometimes seen, AML may also present with an isolated decline in platelets, red blood cells, or even with low white blood cell counts. leukopenia). While the diagnosis of suspected AML can be performed by peripheral blood smear examination when there is leukemia leakage circulation, definitive diagnosis usually requires adequate bone marrow aspiration and biopsy and excludes pernicious anemia (vitamin B12 deficiency), folic acid. deficiency and copper deficiency.
Marrow or blood is examined under a light microscope, as well as flow cytometry, to diagnose the presence of leukemia, to differentiate AML from other leukemia types (eg acute lymphoblastic leukemia - ALL), and to classify subtypes of disease. Marrow or blood samples are usually also tested for chromosomal abnormalities with routine cytogenetics or fluorescent hybridization in situ. Genetic studies can also be performed to look for specific mutations in genes such as FLT3 , nucleophosmin, and KIT , which may affect the outcome of the disease.
Cytochemical stains on blood and bone marrow streaks are helpful in AML differences from ALL, and in the subclassification of AML. The combination of Sudanese myeloperoxidase or black stains and nonspecific esterase dyes will provide the desired information in most cases. The black reaction of myeloperoxidase or Sudan is most useful in establishing the identity of AML and distinguish it from ALL. Non-specific esterase stains are used to identify monocytic components in AML and to differentiate poorly differentiated monoblastic leukemia from ALL.
Diagnosis and classification of AML can be challenging, and should be performed by a qualified hematologist or hematologist. In the immediate case, the presence of certain morphological features (such as Auer rods) or certain flow cytometry results may differentiate AML from other leukemia; However, in the absence of such features, the diagnosis may be more difficult.
The two most common classification schemata used for AML are the older French-American-English (FAB) system and the newer World Health Organization (WHO) system. According to the widely used WHO criteria, the diagnosis of AML is established by showing the involvement of more than 20% of blood and/or bone marrow by leukemic myeloblasts, except in the three best forms of prognosis of acute myeloid leukemia with recurrent genetic disorders (t (8; 21) inv (16), and t (15; 17)) in which the presence of a genetic disorder is diagnostic regardless of explosion percentage. The French-American-British (FAB) classification is slightly tighter, requiring a 30% percentage explosion in the bone marrow (BM) or peripheral blood (PB) for the diagnosis of AML. AML should be carefully distinguished from "preleukemic" conditions such as myelodysplastic or myeloproliferative syndromes, which are treated differently.
Because acute promyelocytic leukemia (APL) has the highest brackets and requires a unique form of treatment, it is important to immediately establish or exclude the diagnosis of this leukemia subtype. Fluorescent in situ hybridization performed on blood or bone marrow is often used for this purpose, as it is easy to identify the translocated chromosome [t (15; 17) (q22; q12);] that characterize APL. There is also a need to detect the presence of the molecular PML/RARA fusion protein, which is the oncogenic product of the translocation.
World Health Organization
The WHO 2008 classification for acute myeloid leukemia tries to be more clinically useful and results in more meaningful prognosis information than the FAB criteria. Each WHO category contains many descriptive subcategories that appeal to hematologists and oncologists; However, much of the significant clinical information in the WHO scheme is communicated through categorization into one of the subtypes listed below.
WHO AML subtypes are:
Acute leukemia of the ambiguous lineage (also known as a mixture of biphenotypic acute phenotype or leukemia) occurs when leukemia cells can not be classified as myeloid or lymphoid cells, or where both types of cells are present.
French-American-English
The French-American-British (FAB) classification system divides AML into eight subtypes, M0 through M7, based on the type of cell from which leukemia develops and its maturity level. This is done by examining the appearance of malignant cells by light microscopy and/or by using cytogenetics to characterize the underlying chromosome abnormalities. Subtypes have a variety of prognosis and response to therapy. Although the WHO classification (see above) may be more useful, FAB systems are still widely used.
Six FAB subtypes (M1 through M6) were originally proposed in 1976, although later revisions added M7 in 1985 and M0 in 1987.
The subtypes of AML morphology also include rare species not included in the FAB system, such as acute basophilic leukemia, proposed as the ninth subtype, M8, in 1999.
Pathophysiology
Malignant cells in AML are myeloblast. In normal hematopoiesis, myeloblasts are precursors of immature myeloid blood cells; normal myeloblasts will gradually mature into mature white blood cells. In AML, though, single myeloblasts accumulate genetic changes that "freeze" cells in an immature state and prevent differentiation. Such mutations alone do not cause leukemia; However, when this "capture of differentiation" is combined with other mutations that interfere with the gene that controls proliferation, the result is the uncontrolled growth of immature cell imitations, leading to the clinical entity AML.
Most of the diversity and heterogeneity of AML is because leukemia transformation can occur in a number of different steps along the differentiation pathway. The modern classification scheme for AML recognizes that the characteristics and behavior of leukemia (and leukemia) cells can depend on the stage at which differentiation is stopped.
Specific cytogenetic abnormalities can be found in many people with AML; this type of chromosomal abnormality often has a prognostic significance. Translocation of chromosomes encodes abnormal fusion proteins, usually transcription factors whose altered properties can lead to "arrest of differentiation". For example, in acute promyelocytic leukemia, t (15; 17) translocation produces PML-RAR? a fusion protein that binds to the retinoic acid receptor element in the promoter of some myeloid-specific genes and inhibits myeloid differentiation.
Clinical signs and symptoms of AML result from leukemia clonal cell growth, which tend to replace or interfere with the development of normal blood cells in the bone marrow. It causes neutropenia, anemia, and thrombocytopenia. The symptoms of AML, in turn, are often caused by the low amount of these normal blood elements. In rare cases, people with AML may develop chloroma, or a solid tumor of leukemia cells outside the bone marrow, which can cause various symptoms depending on its location.
An important pathophysiological mechanism of leukemogenesis in AML is the induction of epigenetic dedifferentiation by genetic mutations that alter the function of epigenetic enzymes, such as T22 DNA demetilase and metabolic enzymes IDH1 and IDH2, leading to novel generation of oncometabolite, D -2-hydroxyglutarate , which inhibits the activity of epigenetic enzymes such as TET2. The hypothesis is that the epigenetic mutation leads to the silencing of tumor suppressor genes and/or activation of proto-oncogenes.
Treatment
The first-line treatment of AML consists primarily of chemotherapy, and is divided into two phases: induction and postremission therapy (or consolidation). The purpose of induction therapy is to achieve complete remission by reducing the number of leukemia cells to undetectable levels; the purpose of consolidation therapy is to eliminate the undetected diseases that are left and achieve healing. Hematopoietic stem cell transplantation is usually considered if induction chemotherapy fails or after a person relaps, although transplantation is sometimes also used as front-line therapy for people with high-risk illness. Efforts to use tyrosine kinase inhibitors in AML continue.
Induction
All FAB subtypes except M3 are usually given induction chemotherapy with cytarabine (fig-C) and anthracycline (most often daunorubicin). This induction chemotherapy regimen is known as "7 3" (or "3 7"), since cytarabine is given as a continuous IV infusion for seven consecutive days while anthracycline is given for three consecutive days as an IV boost. Up to 70% of people with AML will achieve remission with this protocol. Other alternative induction regimens, including high doses of cytarabine alone, a similar regimen of FLAG or an investigative agent, may also be used. Because of the toxic effects of therapy, including myelosuppression and increased risk of infection, induction chemotherapy may not be offered to older people, and the choice may include less intense chemotherapy or palliative care.
The M3 subtype of AML, also known as acute promyelocytic leukemia (APL), is almost universally treated with all-other drug-secretinoic acid (ATRA) in addition to induction chemotherapy, usually anthracycline. Care should be taken to prevent disseminated intravascular coagulation (DIC), complicating APL treatment when promyelocytes release their granular content into the peripheral circulation. APL is markedly curable, with well-documented treatment protocols.
The purpose of the induction phase is to achieve a complete remission. Complete remission does not mean the disease has healed; on the contrary, it denotes no disease that can be detected by available diagnostic methods. Complete remission is obtained in about 50% -75% of newly diagnosed adults, although this may vary based on the prognostic factors described above. The duration of remission depends on the prognosis feature of the original leukemia. In general, all remissions will fail without additional consolidation therapy.
Consolidation
Even after complete remission is achieved, leukemia cells may remain too small to be detected with current diagnostic techniques. If no postremisi or further consolidation therapy is given, almost everyone with AML will eventually recur. Therefore, more therapy is needed to eliminate undetected disease and prevent recurrence - that is, to achieve healing.
The specific type of post-termination therapy is individualized based on one's prognostic factors (see above) and general health. For good-prognosis leukemia (ie, inv (16), t (8,21), and t (15,17)), people will typically undergo an additional three to five intensive chemotherapy programs, known as consolidated chemotherapy. For people at high risk of relapse (eg those with high-risk cytogenetics, underlying MDS, or AML-associated therapy), allogeneic stem cell transplantation is usually recommended if the person is able to tolerate the transplant and have a suitable donor. The best postoperative therapy for moderate risk AML (normal cytogenetics or cytogenetic changes not falling into high-risk or high-risk groups) is less clear and depends on the specific situation, including the age and overall health of the person, the values ​​of the person, and whether the donor appropriate stem cells are available.
For people not eligible for stem cell transplantation, immunotherapy with a combination of histamine dihydrochloride (Ceplene) and interleukin 2 (Proleukin) after completion of consolidation has been shown to reduce the risk of absolute recurrence by 14%, which translates to a 50% increase in the likelihood of remission being maintained.
Relapsed AML
For people with AML relapse, the only potentially proven healing therapy is hematopoietic stem cell transplantation, if a person has never been done. In 2000, the cytotoxic agent of the monoclonal antibody gemtuzumab ozogamicin (Mylotarg) was approved in the United States for people over 60 years of age with recurrent AML who were not candidates for high-dose chemotherapy. This drug was withdrawn voluntarily from the market by its manufacturer, Pfizer in 2010.
Because treatment options for relapse AML are very limited, palliative care or enrollment in clinical trials may be offered.
For acute relapse of promyelocytic leukemia (APL), arsenic trioxide is approved by the US FDA. Like ATRA, arsenic trioxide does not work with other subtypes of AML.
Prognosis
Acute myeloid leukemia is a curable disease; the chances of healing for a particular person depend on a number of prognostic factors.
Cytogenetics
The most important prognostic factor in AML is cytogenetics, or the chromosomal structure of leukemia cells. Cytogenetic abnormalities are associated with excellent results (eg, translocation (15; 17) in acute promyelocytic leukemia). About half of people with AML have "normal" cytogenetics; they belong to the medium risk group. A number of other cytogenetic disorders are known to be associated with a poor prognosis and a high risk of relapse after treatment.
The first publication discussing cytogenetics and prognosis was a 1998 MRC trial:
Then, the Southwest Oncology Group and the Eastern Cooperative Oncology Group and, later on, Cancer and Leukemia Group B published another overlapping list of the overlapping of cytogenetic prognostication in leukemia.
Myelodysplastic Syndrome
AML emerging from previously existing myelodysplastic syndrome (MDS) or myeloproliferative disease (called secondary AML) has a worse prognosis, as does AML-associated treatment after chemotherapy for previous malignancies. Both of these entities are associated with high levels of cytogenetic abnormality.
Other prognostic markers
In some studies, age & gt; 60 years and elevated levels of lactate dehydrogenase are also associated with worse outcomes. Like most forms of cancer, performance status (ie general physical condition and level of activity of the person) plays a major role in the prognosis as well.
The five-year survival rate is about 25% overall. Age plays an important role: 40% of people under the age of 60, but only 10% of those on it, live five years after diagnosis.
Genotype
A large number of molecular changes are being studied for their prognostic impact in AML. However, only FLT3-ITD , NPM1 , CEBPA and c-KIT are currently included in the international risk stratification that validated schema. This is expected to increase rapidly in the near future. FLT3 internal tandem duplication (ITD) has been shown to provide a worse prognosis in AML with normal cytogenetics. Some of the FLT3 inhibitors have undergone clinical trials, with mixed results. Two other mutations - NPM1 and bialar CEBPA are associated with improved results, especially in people with normal cytogenetics and are used in current risk stratification algorithms.
The investigators are investigating the clinical significance of the C-KIT mutation in AML. This is common, and potentially, clinically relevant due to the availability of tyrosine kinase inhibitors, such as imatinib and sunitinib which can block pharmacologically c-KIT activity. It is expected that additional markers (eg, RUNX1 , ASXL1 , and TP53 ) consistently associated with inferior outcomes will soon be included in this recommendation. The importance of other mutated gene prognostics (eg, DNMT3A , IDH1 , IDH2 ) is less clear.
Expectations of healing
Drug levels in clinical trials ranged from 20-45%; although clinical trials often involve only younger people and those who are able to tolerate aggressive therapy. The overall healing rate for everyone with AML (including the elderly and those who can not tolerate aggressive therapy) is likely to be lower. Cure rates for promyelocytic leukemia can be as high as 98%.
Relapse
Relapse is common, and the prognosis is poor. Long-term survival after recurrence is so rare that the only known case has been submitted to the Catholic Church as evidence of a miracle attributed to Marie-Marguerite d'Youville.
Epidemiology
Acute myeloid leukemia is a relatively rare cancer. There are about 10,500 new cases each year in the United States, and the incidence rate remained stable from 1995 to 2005. AML accounts for 1.2% of all cancer deaths in the United States.
AML incidence increases with age; the median age at diagnosis was 63 years. AML accounts for about 90% of all acute leukemia in adults, but rarely occurs in children. The level of AML associated therapy (ie, AML caused by previous chemotherapy) increases; Current therapy-related diseases account for about 10-20% of all AML cases. AML is slightly more common in men, with a male-to-female ratio of 1.3: 1.
There are several geographical variations in AML events. In adults, the highest rates are seen in North America, Europe, and Oceania, while AML adults are rare in Asia and Latin America. In contrast, childhood AML is less common in North America and India than in other parts of Asia. These differences may be due to population genetics, environmental factors, or a combination of the two.
AML accounts for 34% of all leukemia cases in the UK, and about 2,900 people are diagnosed with the disease in 2011.
History
The first published description of a leukemia case in medical literature dated 1827, when French physician Alfred-Armand-Louis-Marie Velpeau described a 63-year-old flower seller who developed a disease characterized by fever, weakness, urinary stones, and substantial. enlarged liver and spleen. Velpeau notes that this person's blood has a consistency "like porridge", and speculates the appearance of the blood because of the white cells. In 1845, a number of people who died with enlarged spleen and changes in "the color and consistency of their blood" were reported by a pathologist based in Edinburgh J.H. Bennett; he used the term "leucocythemia" to describe this pathological condition.
The term "leukemia" was coined by Rudolf Virchow, a famous German pathologist, in 1856. As a pioneer in the use of light microscopy in pathology, Virchow was the first to describe the abnormal excess of white blood cells in people with clinical conditions. syndrome described by Velpeau and Bennett. Because Virchow is unsure about the etiology of excess white blood cells, he uses the pure term "leukemia" (Greek: "white blood") to refer to his condition.
Further progress in the understanding of acute myeloid leukemia occurs rapidly with the development of new technologies. In 1877, Paul Ehrlich developed a technique of blood film staining that allowed him to describe in detail normal and abnormal white blood cells. Wilhelm Ebstein introduced the term "acute leukemia" in 1889 to distinguish rapid and fatal progressive leukemia from slower chronic leukemia. The term "myeloid" was coined by Franz Ernst Christian Neumann in 1869, as he was the first person to recognize white blood cells made in bone marrow (Greek: Ã,Âμ ?????, myelos = (bone) marrow) as opposed to the spleen. The technique of bone marrow examination to diagnose leukemia was first described in 1879 by Mosler. Finally, in 1900, myeloblast, which is a malignant cell in AML, is characterized by Otto Naegeli, who divides leukemia into myeloid and lymphocytic.
In 2008, AML became the first cancer genome to be fully sequenced. DNA is extracted from leukemia cells compared with unaffected skin. Leukemia cells contain mutations acquired in some genes previously unrelated to the disease.
Pregnancy
Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women. How it works depends mainly on the type of leukemia. Acute leukemia usually requires rapid and aggressive treatment, although there is a significant risk of loss of pregnancy and birth, especially if chemotherapy is given during the first trimester progressively progresses.
References
External links
- Acute myeloid leukemia in Curlie (based on DMOZ)
- GeneReviews/NIH/NCBI/UW entered in Familial Acute Myeloid Leukemia (AML) with CEBPA Mutation
- PDQ statement on AML for health professionals at National Cancer Institute
Source of the article : Wikipedia
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