Page 1041 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 59

CLINICAL MANIFESTATIONS AND TREATMENT OF ACUTE

MYELOID LEUKEMIA

Stefan Faderl and Hagop M. Kantarjian

INTRODUCTION to 1 in 278 [female]). Based on Surveillance, Epidemiology, and
End Results (SEER) data from 2005 to 2009, small differences in
Acute myeloid leukemia (AML) is a clonal disorder of hematopoietic frequency also exist by race; AML is more common in whites than
stem or progenitor cells causing a differentiation block and unregu- other ethnic groups (http://seer.cancer.gov). According to one study
lated proliferation of hematopoietic cells in the marrow, blood, and of 27,525 patients with AML, based on the SEER database from
in some cases extramedullary sites. The consequences of this malig- 1999 to 2008, African–Americans and Hispanics had a 12% and
nant transformation include marrow failure, profound immune 6% increased hazard of death, respectively. This unfavorable hazard
deficiencies, and not infrequently manifestations of a systemic inflam- rate pertained despite the higher rate in these two ethnic groups of
matory response of varying severity. The high malignant potential of AML with translocations t(8;21) and t(15;17), both associated with
AML with rapid progression, universally fatal outcome if left unat- a better outcome.
tended to, and challenging clinical course and management continue Several studies have suggested associations between leukemia
to attract a high level of interest. diagnosis and season of the year. One study looking at this asso-
Knowledge of the pathobiologic aspects of AML as it relates to ciation found December and January as the two months with the
origin of blast cells, their biologic behavior, sensitivity to therapeutic highest number of new diagnoses, particularly for patients older
interventions, and their interactions with and interdependence on the than 65 years and men. Observations such as these raise interest-
microenvironment is growing. Extensive application of whole-genome ing questions about the role of infectious agents in the etiology
sequencing has identified numerous gene mutations and molecular of AML.
footprints in AML, highlighting the heterogeneity of AML, devising
better tools for prognosis, and identifying abnormal cellular and
signaling pathways as central to the development of the leukemic PATHOBIOLOGY
phenotype against which novel targeted therapies are increasingly
being developed. Molecular genetic analysis has greatly contributed to a better under-
Progress in basic, translational, and clinical research is cutting standing of the pathobiology that underlies the initiation and evolu-
inroads into decade-old management paradigms. Although standard tion of AML. AML is characterized by a relatively well-defined set of a
induction therapy for most patients with AML has not changed much small number of recurrent mutations. A series of transforming events
in four decades and remains rooted in cytarabine/anthracycline (e.g., mutational processes intrinsic to the particular cell, exposure to
combinations, newer studies are addressing a variety of questions: external mutagens, genotoxic treatment of unrelated malignancies)
higher doses of cytarabine and/or anthracyclines during induction leads to the development of preleukemic stem cells. Through the
therapy, incorporation of novel drugs into existing chemotherapy aggregate action of a network of mutated genes, these cells are charac-
backbones, separate approaches to core-binding factor (CBF) leuke- terized by impaired self-renewal properties, blocks in differentiation,
mias, chemotherapy-free treatment of most patients with acute pro- limited capacity to undergo apoptosis, and altered signaling and
myelocytic leukemias (APL), alternative ways of treating AML in metabolic pathways. Frequently, a given type of mutation is not
older patients, the expanding role of epigenetic therapies, and a sufficient to elicit the full leukemogenic phenotype and a second set
steadily increasing armamentarium of small-molecule targeted thera- of mutations is necessary for the fully transformed leukemic stem
pies in AML salvage. New drugs allow old concepts such as mainte- cells to develop. The transformation of immature hematopoietic cells
nance therapy to be revisited. More extended application of that arises out of genetic changes in hematopoietic stem and more
measurements of minimal residual disease (MRD) may have the same committed progenitor cells is thus considered a stepwise process
helpful impact in AML as it proved to have in other forms of acute in which genes of complementary mutation classes act together.
leukemias. A major challenge for the future lies in the ability to This view gave rise to the two-hit model of leukemogenesis. In this
effectively incorporate and utilize the vast amount of generated data model, two separate classes of mutations are operative: mutations
in the most effective way to extend to patients with AML the benefit that activate signal induction pathways and lead to uninhibited pro-
of the exploits of research. liferation and survival; and mutations that affect transcription factors
or other transcription elements that cause impaired hematopoietic
differentiation and aberrant acquisition of self-renewal properties.
EPIDEMIOLOGY Whereas mutations between these two groups easily coexist, muta-
tions within one class are typically mutually exclusive. Since the initial
In 2014, 18,860 new cases of patients with AML were diagnosed in publication of this model in 2002, whole-genome sequencing has
the United States and an estimated 10,460 patients with AML died identified many more gene mutations involved in AML pathobiology.
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from it. The age-adjusted incidence rate of AML is 3.6/100,000 Although most of these more recently described genes do not neatly
population. However, with a median age at diagnosis of 66 years, fit into one or the other mutation classes, the principle of syner-
incidence rates are as high as >15/100,000 in the older age group, gistic activity in the process of malignant transformation remains
and about 70% of all diagnoses of AML are in patients over 55 years nevertheless valid.
of age. This is important as older patients have more comorbidities, Once compromised by a set of genetic mutations and in the
respond less well to chemotherapy than younger patients, and carry context of propitious interactions with the microenvironment,
the worst prognosis of any age group. AML is slightly more frequent leukemic cells may quickly accrue additional abnormalities (on a
in men than women (lifetime risk of acquiring AML: 1 in 227 [male] genetic or epigenetic level), and a new level of genomic instability

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