Genes & Cancer
2(2) 95 –107
© The Author(s) 2011
Reprints and permission:
Acute myeloid leukemia (AML) is a clonal hematopoietic
disorder resulting from genetic alterations in normal hema-
topoietic stem cells. These alterations disrupt normal dif-
ferentiation and/or cause excessive proliferation of
abnormal immature leukemic cells known as blasts. As the
disease progresses, blast cells accumulate in the bone mar-
row, blood, and organs and interfere with the production of
normal blood cells. This leads to fatal infection, bleeding,
or organ infiltration in the absence of treatment within
1 year of diagnosis.1-3 AML is characterized by more than
20% blasts in bone marrow. AML can arise de novo or sec-
ondarily either due to the progression of other diseases or
due to treatment with cytotoxic agents (referred to as
therapy-related AML). Up to 10% to 15% of patients with
AML develop the disorder after treatment with cytotoxic
chemotherapy (usually for a solid cancer). There are 2 main
types of therapy-related AML. The “classic” alkylating-
agent type has a latency period of 5 to 7 years and is often
associated with abnormalities of chromosomes 5 and/or 7.4
Exposure to agents, such as etoposide and teniposide, that
inhibit the DNA repair enzyme topoisomerase II is associated
with secondary AML with a shorter latency period, usually 1
to 3 years, with rearrangements at chromosome 11q23.5
Drugs, such as chloramphenicol, phenylbutazone, chloro-
quine, and methoxypsoralen, can induce marrow damage
that may later evolve into AML. Secondary AML may also
occur because of progression of myelodysplastic syndrome
(MDS) or chronic bone marrow stem cell disorders, such as
polycythemia vera, chronic myeloid leukemia, primary
thrombocytosis, or paroxysmal nocturnal hemoglobin-
uria.6,7 Secondary AML has a particularly poor prognosis
and is not considered to be curable, with the exception of
secondary acute promyelocytic leukemia (APL).8 This is
largely due to the high percentage of secondary AML asso-
ciated with multidrug resistance (MDR) mechanisms: up to
70% of secondary AML patients show overexpression of
P-glycoprotein (Pgp) or other MDR mechanisms.9
The genetic changes in leukemic blasts make them inef-
fective at generating mature red blood cells, neutrophils,
monocytes, and platelets. In addition, these AML blasts
also inhibit normal blasts from differentiating into mature
progeny. Inhibition does not result from “crowding out” of
normal blasts; rather, inhibition may be mediated by vari-
ous chemokines produced by AML blasts.10 AML pro-
gresses rapidly and is typically fatal within weeks or months
if left untreated. The most common cause of death in AML
is bone marrow failure, and the principal sign of marrow
failure is infection. Potential fatal organ infiltration, most
Onconova Therapeutics Inc., Pennington, NJ, USA
C. Chandra Kumar, Onconova Therapeutics Inc., 73 Route 31 North,
Pennington, NJ 08534
Genetic Abnormalities and Challenges in
the Treatment of Acute Myeloid Leukemia
C. Chandra Kumar
Submitted 01-Feb-2011; accepted 17-Mar-2011
Acute myeloid leukemia (AML) is a hematopoietic disorder in which there are too many immature blood-forming cells accumulating in the bone marrow
and interfering with the production of normal blood cells. It has long been recognized that AML is a clinically heterogeneous disease characterized by a
multitude of chromosomal abnormalities and gene mutations, which translate to marked differences in responses and survival following chemotherapy.
The cytogenetic and molecular genetic aberrations associated with AML are not mutually exclusive and often coexist in the leukemic cells. AML is a
disease of the elderly, with a mean age of diagnosis of 70 years. Adverse cytogenetic abnormalities increase with age, and within each cytogenetic group,
prognosis with standard treatment worsens with age. In the past 20 years, there has been little improvement in chemotherapeutic regimens and hence
the overall survival for patients with AML. A huge unmet need exists for efficacious targeted therapies for elderly patients that are less toxic than available
chemotherapy regimens. The multitude of chromosomal and genetic abnormalities makes the treatment of AML a challenging prospect. A detailed
understanding of the molecular changes associated with the chromosomal and genetic abnormalities in AML is likely to provide a rationale for therapy
design and biomarker development. This review summarizes the variety of cytogenetic and genetic changes observed in AML and gives an overview of
the clinical status of new drugs in development.
acute myeloid leukemia, genetic abnormalities, new drugs
Genes & Cancer / vol 2 no 2 (2011)
commonly involving the lung and the brain, becomes more
likely as the disease progresses.
AML is the most common acute leukemia affecting adults,
and its incidence increases with age.1 Although the majority
of patients under age 60 years achieve complete remission
(CR) with traditional anthracycline- and cytarabine-based
induction regimens, the long-term survival rates continue to
be poor at approximately 30% to 40%.11-13 The prognosis is
even poorer for those with high-risk AML, such as those
who are older, those who had preceding MDS or myelopro-
liferative disorders, or those with secondary AML from
environmental exposures or prior chemotherapy. In such
cases, CR is achieved in less than 40% of cases, with sur-
vival rates of less than 10%.13 While 60% to 80% of younger
patients achieve CR with standard therapy, only about 20%
to 30% of the overall patient population has long-term dis-
ease-free survival.3 Outcomes are worse for patients aged
60 years or over, with CR rates in the range of 40% to 55%
and poor long-term survival rates.3 Along with age, remis-
sion rates and overall survival depend on a number of other
factors, including cytogenetics, previous bone marrow dis-
orders such as MDS, and comorbidities.3
Epidemiology and Etiology of AML
AML accounts for approximately 25% of all leukemias
diagnosed in adults, and the median age at diagnosis is 67
years.13,14 In the United States, 43,050 new cases of leuke-
mia were reported in the year 2010, of which 12,330 were
new cases of AML. There were 21,840 patients who died in
the year 2010 because of leukemia, of which 8,950 were
attributed to AML.15 The incidence of AML in the <65
years’ age group is 1.8 cases per 100,000 patients, and the
incidence in the >65 years’ age group is 17.9 cases per
100,000 patients.15 The incidence of AML is expected to
increase in the future in line with the aging population, and
along with its precursor myelodysplasia, AML prevalence
appears to be increasing, particularly in the population
older than 60 years of age, and represents the most common
type of acute leukemia in adults. Table 1 shows the inci-
dence and prevalence of AML in the United States and
other developed countries.
Development of AML has been correlated with exposure
to a variety of environmental agents, most likely due to
links between exposure history and cytogenetic abnormali-
ties. Radiation, benzene inhalation, alcohol use, smoking,
dyes, and herbicide and pesticide exposure have all been
implicated as potential risk factors for the development of
AML.16,17 Survivors of the atomic bombs in Japan had an
increased incidence of myeloid leukemias that peaked
approximately 5 to 7 years following exposure.18 Therapeu-
tic radiation also increases AML risk, particularly if given
with alkylating agents such as cyclophosphamide, melpha-
lan, and nitrogen mustard.
Diagnosis and Classification of AML
Demonstration of the accumulation of blasts resulting from
the block in differentiation, characteristic of AML, is the
essential requirement of diagnosis.19 The early signs of
AML include fever, weakness and fatigue, loss of weight
and appetite, and aches and pains in the bones or joints.
Other signs of AML include tiny red spots in the skin, easy
bruising and bleeding, frequent minor infections, and poor
healing of minor cuts. The 2 systems commonly used in the
classification of AML are the French-American-British
(FAB) system and the World Health Organization (WHO)
system. The FAB system is based on morphology and cyto-
chemistry and recognizes 8 subtypes of AML, as shown in
Table 2.20 In 1999, the WHO classification was introduced
to include newer prognostic factors, such as molecular
markers and chromosome translocations, and lowered the
blast minimum criterion to 20%, thus including many cases
classified as high-grade MDS in the FAB system.21 The
WHO classification system identifies 4 AML subgroups: 1)
AML with recurrent genetic abnormalities, 2) AML with
multilineage dysplasia, 3) therapy-related AML and MDS,
and 4) those that do not fall into any of these groups. This
system created a minimum of 17 subclasses of AML, allow-
ing physicians to identify subgroups of patients who might
benefit from specific treatment strategies. Recently, a
revised classification has been published as part of the
fourth edition of the WHO monograph series.22 The aim of
the revision was to incorporate new scientific and clinical
information to refine diagnostic criteria for previously
described neoplasms and to introduce newly recognized
Cytogenetic Abnormalities in AML
AML is characterized by a high degree of heterogeneity
with respect to chromosome abnormalities, gene muta-
tions, and changes in expression of multiple genes and
microRNAs. Cytogenetic abnormalities can be detected in
approximately 50% to 60% of newly diagnosed AML
Table 1. Number of Incidence and Prevalence Cases of Acute
Myeloid Leukemia (AML) in the Major Pharmaceuticals Markets
new AML in 2010
AML in 2010
Note: Incident cases are the new cases diagnosed within a particular
time frame; prevalent cases are all cases present at a particular time.
Prevalence is thus a function of incident cases and duration of disease.
Genes & Cancer / vol 2 no 2 (2011)
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