 = Acute myeloid leukemia = 
 
 Acute myeloid leukemia ( AML ) , also known as acute <unk> leukemia or acute <unk> leukemia ( <unk> ) , is a cancer of the myeloid line of blood cells , characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells . AML is the most common acute leukemia affecting adults , and its incidence increases with age . Although AML is a relatively rare disease , accounting for roughly 1 @.@ 2 % of cancer deaths in the United States , its incidence is expected to increase as the population ages . 
 The symptoms of AML are caused by replacement of normal bone marrow with leukemic cells , which causes a drop in red blood cells , platelets , and normal white blood cells . These symptoms include fatigue , shortness of breath , easy bruising and bleeding , and increased risk of infection . Several risk factors and chromosomal abnormalities have been identified , but the specific cause is not clear . As an acute leukemia , AML progresses rapidly and is typically fatal within weeks or months if left untreated . 
 AML has several subtypes ; treatment and prognosis vary among subtypes . AML is cured in 35 – 40 % of people less than 60 years old and 5 – 15 % more than 60 years old . Older people who are not able to withstand intensive chemotherapy have an average survival of 5 – 10 months . 
 AML is treated initially with chemotherapy aimed at inducing a remission ; people may go on to receive additional chemotherapy or a <unk> stem cell transplant . Recent research into the genetics of AML has resulted in the availability of tests that can predict which drug or drugs may work best for a particular person , as well as how long that person is likely to survive . The treatment and prognosis of AML differ from those of chronic <unk> leukemia ( <unk> ) in part because the cellular differentiation is not the same ; AML involves higher percentages of <unk> and undifferentiated cells , including more blasts ( <unk> , <unk> , and <unk> ) . 
 
 = = Signs and symptoms = = 
 
 Most signs and symptoms of AML are caused by the replacement of normal blood cells with leukemic cells . A lack of normal white blood cell production makes people more susceptible to infections ; while the leukemic cells themselves are derived from white blood cell precursors , they have no infection @-@ fighting capacity . A drop in red blood cell count ( anemia ) can cause fatigue , <unk> , and shortness of breath . A lack of platelets can lead to easy bruising or bleeding with minor trauma . 
 The early signs of AML are often vague and nonspecific , and may be similar to those of influenza or other common illnesses . Some <unk> symptoms include fever , fatigue , weight loss or loss of appetite , shortness of breath , anemia , easy bruising or bleeding , <unk> ( flat , pin @-@ head sized spots under the skin caused by bleeding ) , bone and joint pain , and persistent or frequent infections . 
 <unk> of the spleen may occur in AML , but it is typically mild and <unk> . <unk> node swelling is rare in AML , in contrast to acute <unk> leukemia . The skin is involved about 10 % of the time in the form of leukemia <unk> . Rarely , Sweet 's syndrome , a <unk> inflammation of the skin , can occur with AML . 
 Some people with AML may experience swelling of the <unk> because of infiltration of leukemic cells into the gum tissue . Rarely , the first sign of leukemia may be the development of a solid leukemic mass or tumor outside of the bone marrow , called a <unk> . Occasionally , a person may show no symptoms , and the leukemia may be discovered incidentally during a routine blood test . 
 
 = = Risk factors = = 
 
 A number of risk factors for developing AML have been identified , including : other blood disorders , chemical exposures , ionizing radiation , and genetics . 
 
 = = = <unk> = = = 
 
 " <unk> " blood disorders , such as myelodysplastic syndrome ( MDS ) or myeloproliferative disease ( <unk> ) , can evolve into AML ; the exact risk depends on the type of MDS / <unk> . 
 
 = = = Chemical exposure = = = 
 
 Exposure to <unk> chemotherapy , in particular <unk> agents , can increase the risk of subsequently developing AML . The risk is highest about three to five years after chemotherapy . Other chemotherapy agents , specifically <unk> and <unk> , have also been associated with treatment @-@ related leukemias , which are often associated with specific chromosomal abnormalities in the leukemic cells . 
 Occupational chemical exposure to benzene and other <unk> organic <unk> is controversial as a cause of AML . <unk> and many of its derivatives are known to be carcinogenic in vitro . While some studies have suggested a link between occupational exposure to benzene and increased risk of AML , others have suggested the attributable risk , if any , is slight . 
 
 = = = Radiation = = = 
 
 High amounts of ionizing radiation exposure can increase the risk of AML . <unk> of the atomic bombings of <unk> and <unk> had an increased rate of AML , as did <unk> exposed to high levels of X @-@ rays prior to the adoption of modern radiation safety practices . People treated with ionizing radiation after treatment for prostate cancer , non @-@ Hodgkin lymphoma , lung cancer and breast cancer have the highest chance of acquiring AML , but this increased risk returns to the background risk observed in the general population after 12 years . 
 
 = = = <unk> = = = 
 
 A hereditary risk for AML appears to exist . Multiple cases of AML developing in a family at a rate higher than predicted by chance alone have been reported . Several congenital conditions may increase the risk of leukemia ; the most common is probably Down syndrome , which is associated with a <unk> to 18 @-@ fold increase in the risk of AML . 
 
 = = Diagnosis = = 
 
 The first clue to a diagnosis of AML is typically an abnormal result on a complete blood count . While an excess of abnormal white blood cells ( <unk> ) is a common finding , and leukemic blasts are sometimes seen , AML can also present with isolated decreases in platelets , red blood cells , or even with a low white blood cell count ( <unk> ) . While a <unk> diagnosis of AML can be made by examination of the peripheral blood smear when there are circulating leukemic blasts , a definitive diagnosis usually requires an adequate bone marrow aspiration and <unk> . 
 <unk> or blood is examined under light microscopy , as well as flow <unk> , to <unk> the presence of leukemia , to differentiate AML from other types of leukemia ( e.g. acute <unk> leukemia - ALL ) , and to classify the subtype of disease . A sample of marrow or blood is typically also tested for chromosomal abnormalities by routine cytogenetics or fluorescent in situ <unk> . Genetic studies may also be performed to look for specific mutations in genes such as FLT3 , <unk> , and KIT , which may influence the outcome of the disease . 
 <unk> stains on blood and bone marrow <unk> are helpful in the distinction of AML from ALL , and in <unk> of AML . The combination of a <unk> or Sudan black stain and a nonspecific esterase stain will provide the desired information in most cases . The <unk> or Sudan black reactions are most useful in establishing the identity of AML and distinguishing it from ALL . The nonspecific esterase stain is used to identify a <unk> component in <unk> and to distinguish a poorly differentiated <unk> leukemia from ALL . 
 The diagnosis and classification of AML can be challenging , and should be performed by a qualified <unk> or <unk> . In straightforward cases , the presence of certain <unk> features ( such as <unk> rods ) or specific flow <unk> results can distinguish AML from other leukemias ; however , in the absence of such features , diagnosis may be more difficult . 
 The two most commonly used classification <unk> for AML are the older French @-@ American @-@ British ( FAB ) system and the newer World Health Organization ( WHO ) system . According to the widely used WHO criteria , the diagnosis of AML is established by demonstrating involvement of more than 20 % of the blood and / or bone marrow by leukemic <unk> , except in the three best prognosis forms of AML with recurrent genetic abnormalities ( t ( 8 ; 21 ) , <unk> ( 16 ) , and t ( 15 ; 17 ) ) in which the presence of the genetic <unk> is diagnostic irrespective of blast percent . The French – American – British ( FAB ) classification is a bit more stringent , requiring a blast percentage of at least 30 % in bone marrow ( <unk> ) or peripheral blood ( <unk> ) for the diagnosis of AML . AML must be carefully differentiated from " <unk> " conditions such as myelodysplastic or myeloproliferative <unk> , which are treated differently . 
 Because acute promyelocytic leukemia ( APL ) has the highest <unk> and requires a unique form of treatment , it is important to quickly establish or exclude the diagnosis of this subtype of leukemia . <unk> in situ <unk> performed on blood or bone marrow is often used for this purpose , as it readily identifies the chromosomal translocation [ t ( 15 ; 17 ) ( <unk> ; <unk> ) ; ] that <unk> APL . There is also a need to <unk> detect the presence of PML / <unk> fusion protein , which is an <unk> product of that translocation . 
 
 = = = World Health Organization = = = 
 
 The WHO 2008 classification of acute myeloid leukemia attempts to be more clinically useful and to produce more meaningful prognostic information than the FAB criteria . Each of the WHO categories contains numerous descriptive <unk> of interest to the <unk> and <unk> ; however , most of the clinically significant information in the WHO <unk> is communicated via categorization into one of the subtypes listed below . 
 The WHO subtypes of AML are : 
 Acute leukemias of ambiguous lineage ( also known as mixed phenotype or <unk> acute leukemia ) occur when the leukemic cells can not be classified as either myeloid or <unk> cells , or where both types of cells are present . 
 
 = = = French @-@ American @-@ British = = = 
 
 The French @-@ American @-@ British ( FAB ) classification system divides AML into eight subtypes , <unk> through to <unk> , based on the type of cell from which the leukemia developed and its degree of maturity . This is done by examining the appearance of the malignant cells with light microscopy and / or by using cytogenetics to characterize any underlying chromosomal abnormalities . The subtypes have varying <unk> and responses to therapy . Although the WHO classification ( see above ) may be more useful , the FAB system is still widely used . 
 Eight FAB subtypes were proposed in 1976 . 
 The <unk> subtypes of AML also include rare types not included in the FAB system , such as acute <unk> leukemia , which was proposed as a ninth subtype , M8 , in 1999 . 
 
 = = <unk> = = 
 
 The malignant cell in AML is the myeloblast . In normal <unk> , the myeloblast is an immature precursor of myeloid white blood cells ; a normal myeloblast will gradually mature into a mature white blood cell . In AML , though , a single myeloblast <unk> genetic changes which " freeze " the cell in its immature state and prevent differentiation . Such a <unk> alone does not cause leukemia ; however , when such a " differentiation arrest " is combined with other mutations which disrupt genes controlling proliferation , the result is the uncontrolled growth of an immature clone of cells , leading to the clinical entity of AML . 
 Much of the diversity and <unk> of AML stems is because leukemic transformation can occur at a number of different steps along the differentiation pathway . Modern classification schemes for AML recognize the characteristics and behavior of the leukemic cell ( and the leukemia ) may depend on the stage at which differentiation was halted . 
 Specific cytogenetic abnormalities can be found in many people with AML ; the types of chromosomal abnormalities often have prognostic significance . The chromosomal <unk> encode abnormal fusion proteins , usually transcription factors whose altered properties may cause the " differentiation arrest " . For example , in acute promyelocytic leukemia , the t ( 15 ; 17 ) translocation produces a PML @-@ <unk> fusion protein which binds to the <unk> acid receptor element in the <unk> of several myeloid @-@ specific genes and inhibits myeloid differentiation . 
 The clinical signs and symptoms of AML result from the growth of leukemic clone cells , which tends to displace or interfere with the development of normal blood cells in the bone marrow . This leads to <unk> , anemia , and <unk> . The symptoms of AML are , in turn , often due to the low numbers of these normal blood elements . In rare cases , people with AML can develop a <unk> , or solid tumor of leukemic cells outside the bone marrow , which can cause various symptoms depending on its location . 
 An important <unk> mechanism of <unk> in AML is the epigenetic induction of <unk> by genetic mutations that alter the function of epigenetic enzymes , such as the DNA <unk> <unk> and the metabolic enzymes <unk> and <unk> , which lead to the generation of a novel <unk> , D @-@ 2 @-@ <unk> , which inhibits the activity of epigenetic enzymes such as <unk> . The hypothesis is that such epigenetic mutations lead to the <unk> of tumor <unk> genes and / or the activation of proto @-@ <unk> . 
 
 = = Treatment = = 
 
 First @-@ line treatment of AML consists primarily of chemotherapy , and is divided into two phases : induction and postremission ( or consolidation ) therapy . The goal of induction therapy is to achieve a complete remission by reducing the number of leukemic cells to an undetectable level ; the goal of consolidation therapy is to eliminate any residual undetectable disease and achieve a cure . <unk> stem cell transplantation is usually considered if induction chemotherapy fails or after a person <unk> , although transplantation is also sometimes used as front @-@ line therapy for people with high @-@ risk disease . Efforts to use <unk> kinase inhibitors in AML continue . 
 
 = = = <unk> = = = 
 
 All FAB subtypes except M3 are usually given induction chemotherapy with cytarabine ( ara @-@ C ) and an anthracycline ( most often <unk> ) . This induction chemotherapy regimen is known as " 7 + 3 " ( or " 3 + 7 " ) , because the cytarabine is given as a continuous IV infusion for seven consecutive days while the anthracycline is given for three consecutive days as an IV push . Up to 70 % of people with AML will achieve a remission with this protocol . Other alternative induction <unk> , including high @-@ dose cytarabine alone , <unk> @-@ like <unk> or <unk> agents , may also be used . Because of the toxic effects of therapy , including <unk> and an increased risk of infection , induction chemotherapy may not be offered to the very elderly , and the options may include less intense chemotherapy or <unk> care . 
 The M3 subtype of AML , also known as acute promyelocytic leukemia ( APL ) , is almost universally treated with the drug all @-@ trans @-@ <unk> acid ( <unk> ) in addition to induction chemotherapy , usually an anthracycline . Care must be taken to prevent disseminated <unk> <unk> ( <unk> ) , complicating the treatment of APL when the <unk> release the contents of their granules into the peripheral circulation . APL is eminently <unk> , with well @-@ documented treatment protocols . 
 The goal of the induction phase is to reach a complete remission . Complete remission does not mean the disease has been cured ; rather , it signifies no disease can be detected with 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 length of remission depends on the prognostic features of the original leukemia . In general , all <unk> will fail without additional consolidation therapy . 
 
 = = = <unk> = = = 
 
 Even after complete remission is achieved , leukemic cells likely remain in numbers too small to be detected with current diagnostic techniques . If no further postremission or consolidation therapy is given , almost all people with AML will eventually relapse . Therefore , more therapy is necessary to eliminate <unk> disease and prevent relapse — that is , to achieve a cure . 
 The specific type of postremission therapy is <unk> based on a person 's prognostic factors ( see above ) and general health . For good @-@ prognosis leukemias ( i.e. <unk> ( 16 ) , t ( 8 ; 21 ) , and t ( 15 ; 17 ) ) , people will typically undergo an additional three to five courses of intensive chemotherapy , known as consolidation chemotherapy . For people at high risk of relapse ( e.g. those with high @-@ risk cytogenetics , underlying MDS , or therapy @-@ related AML ) , <unk> stem cell transplantation is usually recommended if the person is able to tolerate a transplant and has a suitable donor . The best postremission therapy for intermediate @-@ risk AML ( normal cytogenetics or cytogenetic changes not falling into good @-@ risk or high @-@ risk groups ) is less clear and depends on the specific situation , including the age and overall health of the person , the person 's values , and whether a suitable stem cell donor is available . 
 For people who are not eligible for a stem cell transplant , <unk> with a combination of <unk> <unk> ( <unk> ) and <unk> 2 ( <unk> ) after the completion of consolidation has been shown to reduce the absolute relapse risk by 14 % , translating to a 50 % increase in the likelihood of maintained remission . 
 
 = = = <unk> AML = = = 
 
 For people with relapsed AML , the only proven potentially <unk> therapy is a <unk> stem cell transplant , if one has not already been performed . In 2000 , the <unk> antibody @-@ linked <unk> agent <unk> <unk> ( <unk> ) was approved in the United States for people aged more than 60 years with relapsed AML who are not candidates for high @-@ dose chemotherapy . This drug was voluntarily withdrawn from the market by its manufacturer , <unk> in 2010 . 
 Since treatment options for relapsed AML are so limited , <unk> care or enrolment in a clinical trial may be offered . 
 For relapsed acute promyelocytic leukemia ( APL ) , arsenic trioxide is approved by the US FDA . Like <unk> , arsenic trioxide does not work with other subtypes of AML . 
 
 = = <unk> = = 
 
 Acute myeloid leukemia is a <unk> disease ; the chance of cure for a specific person depends on a number of prognostic factors . 
 
 = = = <unk> = = = 
 
 The single most important prognostic factor in AML is cytogenetics , or the chromosomal structure of the leukemic cell . Certain cytogenetic abnormalities are associated with very good outcomes ( for example , the ( 15 ; 17 ) translocation in acute promyelocytic leukemia ) . About half of people with AML have " normal " cytogenetics ; they fall into an intermediate risk group . A number of other cytogenetic abnormalities are known to associate with a poor prognosis and a high risk of relapse after treatment . 
 The first publication to address cytogenetics and prognosis was the <unk> trial of 1998 : 
 Later , the Southwest <unk> Group and Eastern Cooperative <unk> Group and , later still , Cancer and Leukemia Group B published other , mostly overlapping lists of cytogenetics <unk> in leukemia . 
 
 = = = <unk> syndrome = = = 
 
 AML which arises from a pre @-@ existing myelodysplastic syndrome ( MDS ) or myeloproliferative disease ( so @-@ called secondary AML ) has a worse prognosis , as does treatment @-@ related AML arising after chemotherapy for another previous <unk> . Both of these entities are associated with a high rate of unfavorable cytogenetic abnormalities . 
 
 = = = Other prognostic markers = = = 
 
 In some studies , age > 60 years and elevated <unk> <unk> level were also associated with poorer outcomes . As with most forms of cancer , performance status ( i.e. the general physical condition and activity level of the person ) plays a major role in prognosis as well . 
 
 = = = = <unk> = = = = 
 
 A large number of molecular alterations are under study for their prognostic impact in AML . However , only FLT3 @-@ <unk> , <unk> , <unk> and c @-@ KIT are currently included in <unk> international risk <unk> <unk> . These are expected to increase rapidly in the near future . FLT3 internal tandem <unk> ( <unk> ) have been shown to confer a poorer prognosis in AML with normal cytogenetics . Several FLT3 inhibitors have undergone clinical trials , with mixed results . Two other mutations - <unk> and <unk> <unk> are associated with improved outcomes , especially in people with normal cytogenetics and are used in current risk <unk> algorithms . 
 Researchers are investigating the clinical significance of c @-@ KIT mutations in AML . These are prevalent , and potentially clinically relevant because of the availability of <unk> kinase inhibitors , such as <unk> and <unk> that can block the activity of c @-@ KIT <unk> . It is expected that additional markers ( e.g. , <unk> , <unk> , and <unk> ) that have consistently been associated with an inferior outcome will soon be included in these recommendations . The prognostic importance of other <unk> genes ( e.g. , <unk> , <unk> , <unk> ) is less clear . 
 
 = = = <unk> of cure = = = 
 
 Cure rates in clinical trials have ranged from 20 – 45 % ; although clinical trials often include only younger people and those able to tolerate aggressive <unk> . The overall cure rate for all people with AML ( including the elderly and those unable to tolerate aggressive therapy ) is likely lower . Cure rates for promyelocytic leukemia can be as high as 98 % . 
 
 = = Epidemiology = = 
 
 Acute myeloid leukemia is a relatively rare cancer . There are approximately 10 @,@ 500 new cases each year in the United States , and the incidence rate has remained stable from 1995 through 2005 . AML accounts for 1 @.@ 2 % of all cancer deaths in the United States . 
 The incidence of AML increases with age ; the median age at diagnosis is 63 years . AML accounts for about 90 % of all acute leukemias in adults , but is rare in children . The rate of therapy @-@ related AML ( that is , AML caused by previous chemotherapy ) is rising ; therapy @-@ related disease currently accounts for about 10 – 20 % of all cases of AML . AML is slightly more common in men , with a male @-@ to @-@ female ratio of 1 @.@ 3 : 1 . 
 There is some geographic variation in the incidence of AML . In adults , the highest rates are seen in North America , Europe , and Oceania , while adult AML is rarer 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 . 
 
 = = = UK = = = 
 
 AML accounts for 34 % of all leukaemia cases in the UK , and around 2 @,@ 900 people were diagnosed with the disease in 2011 . 
 
 = = History = = 
 
 The first published description of a case of leukemia in medical literature dates to 1827 , when French physician Alfred @-@ Armand @-@ Louis @-@ Marie Velpeau described a 63 @-@ year @-@ old <unk> who developed an illness characterized by fever , weakness , urinary stones , and substantial enlargement of the liver and spleen . Velpeau noted the blood of this person had a consistency " like <unk> " , and speculated the appearance of the blood was due to white <unk> . In 1845 , a series of people who died with enlarged <unk> and changes in the " colors and <unk> of their blood " was reported by the Edinburgh @-@ based pathologist <unk> Bennett ; he used the term " <unk> " to describe this <unk> condition . 
 The term " leukemia " was coined by Rudolf Virchow , the renowned German pathologist , in 1856 . As a pioneer in the use of the light microscope in pathology , Virchow was the first to describe the abnormal excess of white blood cells in people with the clinical syndrome described by Velpeau and Bennett . As Virchow was uncertain of the <unk> of the white blood cell excess , he used the purely descriptive term " leukemia " ( Greek : " white blood " ) to refer to the condition . 
 Further advances in the understanding of acute myeloid leukemia occurred rapidly with the development of new technology . In 1877 , Paul Ehrlich developed a technique of staining blood films which allowed him to describe in detail normal and abnormal white blood cells . Wilhelm <unk> introduced the term " acute leukemia " in 1889 to differentiate rapidly progressive and fatal leukemias from the more <unk> chronic leukemias . The term " myeloid " was coined by Franz Ernst Christian Neumann in 1869 , as he was the first to recognize white blood cells were made in the bone marrow ( Greek : <unk> , <unk> = ( bone ) marrow ) as opposed to the spleen . The technique of bone marrow examination to <unk> leukemia was first described in 1879 by <unk> . Finally , in 1900 , the myeloblast , which is the malignant cell in AML , was characterized by Otto <unk> , who divided the leukemias into myeloid and <unk> . 
 In 2008 , AML became the first cancer genome to be fully sequenced . DNA extracted from leukemic cells were compared to unaffected skin . The leukemic cells contained acquired mutations in several genes that had not previously been associated with the disease . 
 
 = = <unk> = = 
 
 Leukemia is rarely associated with pregnancy , affecting only about 1 in 10 @,@ 000 pregnant women . How it is handled depends primarily on the type of leukemia . Acute leukemias normally require prompt , aggressive treatment , despite significant risks of pregnancy loss and birth defects , especially if chemotherapy is given during the <unk> sensitive first <unk> . 
 
 