小说答题模板Acute Myeloid Leukemia:Epidemiology and Etiology
Barbara Deschler,MD
Michael Lübbert,MD,PhD
Department of Hematology/Oncology,University of Freiburg,Freiburg,Germany.Acute myeloid leukemias(AMLs)are infrequent,yet highly malignant neoplasms responsible for a large number of cancer-related deaths.The incidence has been near stable over the last years.It continuously shows2peaks in occurrence in early childhood and later adulthood.With an incidence of3.7per100,000per-sons and an age-dependent mortality of2.7to nearly18per100,000persons, there is a rising awareness in the Western world of AML’s special attributes result-ing from an ever-aging population.To objectively describe epidemiologic data on this patient population,recent publications were evaluated to make transparent the current trends and facts.A review of the literature is prented,reflecting highlights of current rearch with respect to AML etiology.To estimate outcome and discuss informed treatment decisions with AML patients of different age groups and different biologic risk categories,it is mandatory to consider that the outcome results reported in clinical trials were until now heavily biad toward younger patients,whereas the overall dismal prognosis docume
耸立拼音nted in popula-tion-bad studies most likely reflects the exclusion of older patients from aggres-sive treatment.The etiology for most cas of AML is unclear,but a growing knowledge concerning leukemogenenic agents within chemotherapy regimens for other malignancies is already available.This includes specific associations of the most frequent balanced translocations in AML,including the‘‘good-risk’’abnormal-ities comprid by the core binding factor ,AML with the translocation (8;21)and inversion of chromosome16,and acute promyelocytic leukemia with the translocation(15;17)).In contrast to the genetic alterations,epigenetic lesions, e.g.,promoter silencing by hypermethylation of the p15/INK4b and other genes, are increasingly recognized as important in the pathogenesis of AML.Cancer 2006;107:2099–107.Ó2006American Cancer Society.
KEYWORDS:acute myeloid leukemia,epidemiology,etiology,survival.
A cute leukemias are rare dias,but have a disproportionally
large effect on cancer survival statistics.1Acute myeloid leuke-mia(AML)is the most common type of leukemia in adults,yet con-tinues to have the lowest survival rate of all leukemias.Although rates have improved remarkably in the younger age group,the prog-nosis in older patients continues to be very poor.2,3
Incidence
The American Cancer Society estimates that31,500individuals in the U.S.will be diagnod with1form of leukemia annually. Approximately21,500patients will die of their dia.4,5Although the incidence of acute leukemias accounts for<3%of all cancers, the dias constitute the leading cau of death due to cancer in children and persons age<39years.4–6
AML accounts for approximately25%of all leukemias in adults in the Western world,and therefore is the most frequent form of
写书法的好处Address for reprints:Barbara Deschler,MD,
Department of Hematology/Oncology,University
of Freiburg,Hugstetterstr.55,D-79106Freiburg,
Germany;Fax:(011)49761-270-3690;E-mail:
deschler@mm11.ukl.uni-freiburg.de
Received July7,2006;revision received July31,
电脑怎么打根号2006;accepted August3,2006.
ª2006American Cancer Society
DOI10.1002/cncr.22233
Published online3October2006in Wiley InterScience(www.).
2099
leukemia.4,7Worldwide,the incidence of AML is highest in the U.S.,Australia,and western Europe.8The age-adjusted incidence rate of AML in the U.S.in the years 1975–2003was approximately 3.4per 100,000persons (¼2.5per 100,000persons when age-adjusted to the world standard population).9The American Cancer Society estimates that 11,930men and women (6350men and 5580women)in the U.S.will be diagnod with AML in 2006.10
Age
Leukemia is the most common cancer diagnosis in children age <15years,with an overall incidence of 4.3per 100,000persons in the U.S.9However,in this age group acute lymphocytic leukemia (ALL)is
狮子天秤ap-proximately 5times more common than AML,thereby accounting for approximately 76%of all childhood leukemia diagnos.Converly,AML compris only 15%to 20%of cas in patients age 15years.11The peak incidence rate occurs in the first year of life and then decreas steadily up to the age of 4years,at which point it remains relatively constant throughout the years of childhood and early adulthood.12
AML is therefore primarily a dia of later adulthood.The distribution of the proportion of pre-valent cas of all leukemias in the U.K.shows that 42.8%of patients are age >65years.Patients newly diagnod with AML have a median age of 65years.13AML is rarely diagnod before the age of 40years;thereafter,the incidence increas progres-sively with age.From 2000to 2003,the U.S.inci-dence rate in people age <65years was only 1.8per 100,000persons,whereas the incidence rate in people age !65years was 17per 100,000persons (Fig.1).9As shown in Figure 1,a slight decrea in the incidence of AML in patients age >85years in the U.S.population rais the question of whether a lack of published data regarding this phenomenon prents an artifact due to underdiagnod AML cas in the oldest old.
Bad on the documented frequent progression of myelodysplastic syndromes (MDS)to AML,an incread incidence of MDS with age appears to partly explain both the high incidence and poor pro
gnosis of AML in the elderly.Becau an increas-ing blast count in MDS leads to higher mortality without reaching the definition of AML,a distinction between the 2entities of myeloid disorders may be primarily mantic.The common AML subtype in the elderly shares characteristics with AML that fol-lows MDS,Fanconi anemia,and alkylating agent chemotherapy,and occurs in an estimated 10%to 15%of AML in younger patients.It has been referred to as MDS-related AML and is characterized by com-mon cytogenetic abnormalities shared with MDS,and frequent multilineage dysplastic morphology in residual hematopoietic precursors.By contrast,AML with genotypes typical of younger patients,true de novo AML,has an approximately flat incidence throughout life,also in progressive age groups.Approximately 5%of elderly patients with AML are estimated to belong to the true de novo AML group,which is consistent with the incidence in younger patients.14
An incread incidence of unfavorable cytogenet-ics contributes to poor outcome in patients age >56years,and,within each cytogenetic risk group,treat-ment outcome deteriorates with age.15,16
Although incidence rates for AML have been reported to be nearly stable over time among the dif-ferent age groups,there was a slight increa noted among the oldest group.17
Gender and Ethnicity
The incidence of AML varies with gender and race.In the Surveillance,Epidemiology,and End Result (SEER)databa for children ages 1to 4years there was an incidence rate of 0.8per 100,000persons for boys and for girls.In the first few years of life,the incidence of AML in whites is 3-fold higher than in blacks;however,blacks have slightly higher rates of AML among children age !3years.12
AML in adults has a slight male predominance in most countries.In 2000–2003,the age-adjusted incidence rate of AML in the U.S.was 3.7per 100,000for both xes,4.6per 100,000for males,and 3.0per 100,000for females.The incidence rate of U.S.males is substantially higher than the incidence rates reported for males in all other countries.18
In the U.S.in 2000,AML was more common in blacks than in whites.However,during 2000to 2003,the incidence of AML for blacks (3.2per 100,000per-sons)was lower than for whites (3.8per 100,000per-sons).
9
FIGURE 1.Age-specific incidence of acute myeloid leukemia in the U.S.,
2000À2003.Source:Surveillance,Epidemiology,and End Results program.
2100CANCER November 1,2006/Volume 107/Number 9
Mortality
Untreated AML is a uniformly fatal dia.Although it is possible to support patients for a certain period (median survival,11–20weeks),19,20they ultimately die of the leading complications associated with bone marrow ,infection and hemorrhage). Most patients ek medical attention for symptoms related to anemia,infection,or bleeding,and tho patients typically require immediate therapeutic in-tervention.Other patients are not candidates for cy-totoxic therapy,mainly becau of older age and/or poor performance status or other active vere medi-cal comorbidities that complicate their care.In such ttings,a supportive strategy may be most appropri-
ate.21Firm stratification criteria for decision-making in this tting are not uniformly established.
After long-term increas or mostly level trends that date from the1930s,death rates for all leuke-mias were reportedly decreasing in the1990s in the U.S.and Europe.6,22From2000to2003,the U.S.age-adjusted mortality rate of AML was2.7per100,000 persons.As is the ca with incidence,the mortality associated with AML varies with age,gender,and race.Mortality rates in the U.S.appear to increa with age becau the age-adjusted mortality rate shows its peak at17.6per100,000persons in people ages80to84years.
The mortality rate for males is higher than that for females,with the U.S.age-adjusted mortality rate at3.5per100,000for males and2.2per100,000for females(2000–2003).AML mortality is greater in whites than in blacks.The U.S.age-adjusted mortal-ity rate was2.7per100,000for whites and2.2per 100,000for blacks in the year2000.It is estimated that approximately7,800adults will die annually of AML in the U.S.7,10,23
Early Survivorship
A comprehensive report on the total leukemia inci-dence and survival in the vered the period 1973to1990.24Here,overall survival rates for all leu-kemia patients improved only slightly when compar-ing the periods1974to1976and1983to1989,but were consistently higher in whites compared
with blacks,with little gender difference noted.When ana-lyzing survival rates in more detail,it was found that in comparing the period1974to1983with1984to 1993,overall survival rates improved notably among all races/age groups age<45years.However,for blacks age!45years there was little improvement in overall survival.In particular,for blacks age>65 years,survival rates for leukemia were decreasing, which was not obrved in earlier data.17To our knowledge,the reasons for the gender and racial
differences obrved in all subtypes of leukemia remain unclear.
The overall U.S.survival rate associated with AML from1996to2002was21.7%.10Figure2depicts 5-year survival rates stratified by age.The5-year relative survival rate was highest for tho who were younger and female.In AML,however,as oppod to the entire group of leukemias,blacks had a slightly better5-year survival rate than whites(21.5%vs.
19.8%).
A recent study reported that the5-year survival rate of tho age55years was23%,whereas the corresponding rate for tho age>55years was11%. Survival rates have incread in the last decade among this younger group(from9%in the1980s to 35%in the1990s),but have not changed in the olde
r group,who therefore po the biggest challenge for achieving a therapeutic success.9
In a large recent Italian population-bad study (n¼1005),the median survival of patients age>60 years with AML who were treated with either sup-portive or aggressive therapy was5months and7 months,respectively.In patients age>70years,the median survival was4months,which was,notably, regardless of the type of therapeutic effort.20Age has further been shown to be inverly associated with1) referral to a treatment center25and/or inclusion into a clinical trial26;2)tolerance to induction treatment (early death or death during the immediate postche-motherapy pha)27;and3)the ability to achieve remission.In older patients(age>60years),standard induction therapy achieves complete remission in only30%to50%of treated individuals.28
Most rates of dia-free survival reported in major clinical studies are above the ,4-year survival rates of up to42%),29yet they too demon-strate quite variable results.The differences in survival results noted among various trials using similar chem-otherapy can possibly be explained by the prevalence of negative prognostic characteristics within a
study FIGURE2.Age associated with5-year relative survival in patients with acute myeloid leukemia in the U.S.,1996À2002.Source:Surveillance,Epi-demiology,and End Results program.
Epidemiology and Etiology of AML/Deschler and Lübbert2101
population.30To understand clinical features and out-comes of that significant number of patients not meet-ing inclusion criteria for clinical studies,population-bad evaluations have found increasing attention. Some results concerning age distribution,treatment decisions,remission rates,and survival in AML do demonstrate significant differences in some of the large clinical investigations.In1report,of a total of 170AML patients,55%were treated outside a study protocol.26Nonstudy patients differed significantly from patients included in clinical trials with respect to
age and performance status at the time of clinical pre-ntation,comorbidity,and type of AML.Patients who participated in a clinical trial had a median age of46 years(range,16–73years),whereas tho not included were significantly older(median age of63years;range, 21–83years).Survival was significantly better in patients treated in a clinical protocol(median overall survival of15months vs. 3.4months).For survival results in population-bad studies,e Table 1.An increa in median survival may possibly,at least partly,be explained by improved supportive care over the past decades.
Late Survivorship
The incidence of and risk factors for the develop-ment of late quelae of treatment in patients who survived for>10years(median,15years)after a di-agnosis of childhood AML was evaluated at St.Jude Children’s Rearch Hospital.31Growth abnormalities were the most common late effects in adulthood (51%).Depending on the treatment modality(chem-otherapy only,combined chemoradiotherapy,or com-bined chemoradiotherapy with concutive bone marrow transplantation),endocrine abnormalities, cataracts,cardiac abnormalities,academic difficul-ties,and condary malignancies resulted in14%to 51%of cas.In addition to physical late effects,psy-chosocial complications were obrved.Some treat-ment modalities are more likely than others to produce certain long-term complications:Radiation more frequently than chemotherapy results in growth and neuroendocrine abnormalities and developmen-tal delay32;total body irradiation,for example,preced-ing allogeneic bone marrow transplantation has been shown to significantly impair growth in children33; and corticosteroids and immobilization are suspected to lead to osteopenia and osteoporosis.34Frequently occurring cardiovascular dia in survivors of AML may be due in part to the administration of cardio-toxic medication,but also to posttreatment obesity.32 Patients that survive AML and treatment have also been monitored in a long-term follow-up at the Uni-versity of Te
xas M.D.Anderson Cancer Center.35Some very relevant conclusions have been drawn in this report.Only10%of all1892patients entered the potentially cured cohort,which was defined as the patient population in complete remission after a fol-low-up of3years.Tho patients in the potentially cured cohort were likely to be able to return to work, suggesting that the major threat to patients with newly diagnod AML is the dia and not the treatment. Etiology
The development of AML has been associated with veral risk factors,as summarized in Table2.Gener-ally,known risk factors account for only a small number of obrved cas.36The include age,ante-cedent hematologic dia,and genetic disorders;as well as exposures to virus as well as radiation, chemical,or other occupational hazards and previ-ous chemotherapy.11,37,38
Leukemogenesis is a multistep process that re-quires the susceptibility of a hematopoietic progenitor
TABLE1
Selected Population-Bad Studies of Myeloid Neoplasias in Various Populations:Survival Regardless of Treatment Strategy
Population Median age,
years
Median survival,
weeks Reference
Northern Sweden63725 Northern England71889 Italy692820TABLE2
Selected Risk Factors Associated With Acute Myeloid Leukemia Genetic disorders Down syndrome
Klinefelter syndrome
Patau syndrome
Ataxia telangiectasia
Shwachman syndrome
Kostman syndrome
Neurofibromatosis
Fanconi anemia
Li-Fraumeni syndrome Physical and chemical exposures Benzene
Drugs such as pipobroman
Pesticides
Cigarette smoking
写给对象的小作文
走向成熟Embalming fluids
Herbicides
Radiation exposure Nontherapeutic,therapeutic
radiation Chemotherapy Alkylating agents
Topoisomera-II inhibitors
Anthracyclines
Taxanes
趣味字谜2102CANCER November1,2006/Volume107/Number9
cell to inductive agents at multiple stages.The differ-ent subtypes of AML may have distinct causal me-chanisms,suggesting a functional link between a particular molecular abnormality or mutation and the causal agent.39Most cas of AML ari de novo with-out objectifiable leukemogenic exposure.
Genetics
Genetic factors
Among children,genetic disorders and constitutional genetic defects are important risk factors associated with AML(Table1).38Children with Down syndrome have a10-fold to20-fold incread likelihood of devel-oping acute leukemia.40Other inherited dias asso-ciated with AML include Klinefelter syndrome,Li-Fraumeni syndrome,41Fanconi anemia,and neurofi-bromatosis.11A recent study found that other risk fac-tors for developing AML in children include race/ ethnicity,the father’s age at time of conception,and time since the mother’s last live birth.42Specifically, Asian/Pacific Islan
der children had a higher risk than non-Hispanic white infants;children born to fathers age>35years,compared with tho ages20to34 years,also were found to have an incread risk;and a longer time since the last live birth(at least7years) resulted in an elevated risk of children developing AML.
In this context,acute promyelocytic leukemia (APL)has been investigated in detail.Reprenting an example of a unique AML subtype(FAB M3)with a characteristic morphology associated with distinct chromosomal and gene rearrangement aberrations,it has been shown to also have distinct epidemiologic features.For yet unknown reasons,an incread inci-dence of APL has been recognized in adult patients originating in Latin America and in Southern Europe. Of interest,the APL-specific gene rearrangement is different in Latinos,with the majority of breakpoints in the RAR a gene in the PML/RAR a transcript in intron6(called bcr1).It therefore is speculated that this particular breakpoint site may be determined ge-netically.43–45
Acquired genetic abnormalities
Acquired(‘‘somatic’’)clonal chromosomal abnormal-ities are found in50%to80%of AML cas,25,46–49 with rising incidences in patients with condary leu-kemia50or older age.14,51–53
Frequently found abnormalities include loss or deletion of chromosome5,7,Y,and9,translocations such as t(8;21)(q22;q22);t(15;17)(q22;q11),trisomy8 and21,and other abnormalities involving chromo-somes16,9,and11.
Multiple studies have demonstrated the prognos-tic importance of cytogenetic abnormalities in AML,
making this at prent the most important predictor of short-term30,54,55and long-term35outcome:Pa-tients with a good prognosis are tho with func-tional inactivation of the core binding factors(CBFs): AML1and CBF b.The cas include patients with AML and t(8;21)(q22;q22)or inv(16)(p13;q22),2of the most frequent recurrent cytogenetic abnormal-ities in de novo AML in younger patients.56
Poor-risk patients have a loss of all or part of chromosome5or7,translocations involving11q23, or abnormalities of chromosome3.57
A model of a‘‘2-hit-hypothesis’’for the AML phe-notype by so-called Class1and2mutations has been suggested.It describes the cooperativity of activating mutations in FLT3(Fms-like tyrosine kina3) (¼Class1)and gene rearrangements involving hema-topoietic transcription factors(¼Class2).The ex-pression of both class may result in the AML phenotype.FLT3mutations have been associated with
all subtypes of AML,and with the majority of known chromosomal translocations associated with AML.In this hypothesis,FLT3mutations rve as exemplary of Class1mutations that,alone,confer a proliferative and survival advantage to hematopoietic progenitors but do not affect cell differentiation.Further examples of Class1mutations are activating mutations in N-RAS or K-RAS in AML.In contrast,Class2mutations would be exemplified by AML1/ETO,CBF b/SMMHC, PML/RAR a,and MLL-related fusion genes.They appear to impair hematopoietic differentiation,but are not sufficient to cau leukemia when expresd alone.This new hypothesis may have important im-plications for novel treatment ,molec-ular targeting of both FLT-3and fusion proteins).58 Data have been published recently showing that individuals with certain polymorphisms in genes metabolizing carcinogens have an incread risk of developing AML.59NAD(P)H:quinone oxidoreducta 1(NQO1),for example,is a carcinogen-metabolizing enzyme that detoxifies quinones and reduces oxida-tive stress.A polymorphism at nucleotide609of the NQO1complementary DNA results in a lowering of the enzymes’activity.This polymorphic variant is associated with a predisposition to therapy-related AML60and lected cytogenetic subgroups of de novo AML.61
Physical and Chemical Factors
A vast variety of environmental and chemical expo-sures are assumed to be associated with a variab
ly elevated risk of developing AML in adults.Only a limited number of hazards will be mentioned here.
Exposure to ionizing radiation is linked to AML.62 Among survivors of the atomic bomb explosions in Epidemiology and Etiology of AML/Deschler and Lübbert2103
Japan,an incread incidence of AML was obrved, with a peak at5to7years after exposure.Also,thera-peutic radiation has been found to increa the risk of condary AML.63
Chemotherapeutic agents,such as alkylating agents and topoisomera II inhibitors,have been re-ported to increa the incidence of AML.64,65A number of other substances(therapeutic66and occupational11) have been linked to an incread risk of AML.Chronic exposure to certain chemicals clearly shows an in-cread risk for the development of AML.Benzene is the best studied and most widely ud potentially leu-kemogenic agent.67Persons expod to embalming fluids,ethylene oxides,and herbicides also appear to be at incread risk.Furthermore,smoking has been discusd to be associated with an incread risk of developing AML(particularly of FAB subtype M2), especially in tho persons aged60–75.37
Virus
Virus,particularly RNA retrovirus,have been found to cau many neoplasms in experimental animals, including leukemia.68However,to our knowledge,a clear retroviral cau for acute myeloid leukemia in humans has not been identified to date.An association between the exposure to certain virus and the devel-opment of AML has been suggested.Parvovirus B19 therefore could play a role in the pathogenesis of AML.69To our knowlege,however,it has so far not been demonstrated that simple infection with either an RNA-or DNA-bad virus alone is a cau of acute my-eloid leukemia.
Secondary AML
For most patients with acute leukemia,the cau of the dia is unknown.‘‘The true condary AML’’has been recommended to refer to patients who have a clinical history of prior myelodysplastic syndrome (MDS),myeloproliferative disorder,or exposure to potentially leukemogenic therapies or agents;it is thus a rather broad category.56Greater than90%of condary leukemias are of myeloid origin and have a particularly poor outcome,with a lower incidence of patients achieving a complete remission and a shorter duration of survival than for patients with de novo AML.70–72
Treatment-related condary leukemia was first obrved in survivors of successfully treated Hodgki
n dia,73which extended later to include survivors of ALL74and other dia entities such as multiple myeloma.75
The development of condary AML peaks in the 5to10years after therapy.The distinct pattern of cytogenetic and genetic abnormalities in condary or treatment-related AML is quite remarkable.76It is a subt of10%to20%of patients with AML in whom the dia aris after previous therapy for other malignancies.The risk of therapy-related AML after intensive chemotherapy often is incread100 times or more.77
Specific cytogenetic abnormalities currently rve as the most important factor in distinguishing differ-ences in AML biology,respon to treatment,and prognosis.49The different abnormalities result in gene rearrangements that may reflect the etiology and pathogenesis of the dia.78Treatment-related or condary leukemias are examples in which genetic aberrations provide information regarding its specific etiology.In understanding the mechanisms associated with the development of condary AML,general facts concerning leukemia etiology can been elucidated.
In this context,genetic pathways with different eti-ology and biologic characteristics have been propod for cytogenetic changes that can be related to previous exposure to different chemically w
ell-defined cytostatic agents with a known mechanism of action.79Among tho are alkylating agents:deletions or loss of7q or monosomy7with normal chromosome564,80,81and deletions or loss of5q or monosomy5.82For epipodo-phyllotoxins,balanced translocations to chromosome bands11q23,primarily in children,have been de-scribed.74Topoisomera II inhibitors have been linked to t(8;21),inv(16).83Topoisomera II inhibitors,an-thracyclines,and mitoxantrone,84as well as radio-therapy,85may be associated with therapy-related acute promyelocytic leukemia with t(15;17)and chimeric rearrangements between PML and RARA genes as well as different translocations to chromosome bands11q15 and chimeric rearrangement between the NUP98gene and its partner genes.86Another subgroup includes 10%to15%of all patients with condary AML,with normal karyotype or various chromosome aberrations uncharacteristic of t-AML.79
In the future,many more—as yet unknown genetic and epigenetic changes—may be discovered.To our knowledge to date,methylation of the promoter of p15/IN4b,retinoic acid receptor(RAR)b2,SOCS-1and other genes are frequent abnormalities obrved in a high percentage of patients with AML,87especially in patients with condary AML.88
The obrved changes may po an option for future attempts to decipher epidemiologic and etiologic findings as well as accelerate the development of new treatment strategies.
REFERENCES
1.Jemal A,Siegel R,Ward E,et al.Cancer statistics,2006.CA
Cancer J Clin.2006;56:106–130.
2104CANCER November1,2006/Volume107/Number9
