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CHAPTER 88 leukemic blast cells in the blood and marrow. The diagnosis of the myelog-

ACUTE MYELOGENOUS enous form of acute leukemia is confirmed specifically by identification of
myeloperoxidase activity in blast cells or by identifying characteristic cluster
LEUKEMIA of differentiation (CD) antigens on the blast cells (e.g., CD13, CD33). Because
the leukemic stem cell is capable of imperfect differentiation and maturation,
the clone may contain cells that have the morphologic or immunophenotypic
features of erythroblasts, megakaryocytes, monocytes, eosinophils, or, rarely,
Jane L. Liesveld and Marshall A. Lichtman basophils or mast cells, in addition to myeloblasts or promyelocytes. When
one cell line is sufficiently dominant, the leukemia may be referred to by that
lineage: for example, acute erythroid, acute megakaryocytic, acute monocytic
SUMMARY leukemia, and so on. Certain cytogenetic alterations are more frequent; these
abnormalities include t(8;21), t(15;17), inversion 16 or t(16;16), trisomy 8,
Acute myelogenous leukemia (AML) is the result of a sequence of somatic and deletions of all or part of chromosome 5 or 7. A translocation involving
mutations in a primitive multipotential hematopoietic cell. Exposure to chromosome 17 at the site of the retinoic acid receptor–α (RAR-α) gene is
radiation, chronic exposure to high doses of benzene, and chronic inhalation uniquely associated with acute promyelocytic leukemia. AML usually is treated
of tobacco smoke increase the incidence of the disease. Obesity has been with cytarabine and an anthracycline antibiotic, although other drugs may be
found to be an endogenous risk factor. A small but increasing proportion of added or substituted in poor-prognosis, older, refractory, or relapsed patients.
cases develop after a patient with lymphoma, a nonhematologic cancer, or The exception to this approach is the treatment of acute promyelocytic leu-
an autoimmune disorder is exposed to intensive chemotherapy, especially kemia with all-trans-retinoic acid, arsenic trioxide, and sometimes an anthra-
with alkylating agents or topoisomerase II inhibitors. The mutant (leukemic) cycline antibiotic. High-dose chemotherapy and either autologous stem cell
hematopoietic cell acquires the features of a leukemic stem cell capable of infusion or allogeneic hematopoietic stem cell transplantation may be used in
self-renewal and desultory differentiation and maturation. It gains a growth an effort to treat relapse or patients at high risk to relapse after chemotherapy
and survival advantage in relationship to the normal polyclonal pool of treatment. The probability of remission in acute myelogenous leukemia ranges
hematopoietic stem cells. As the progeny of this mutant, now leukemic, multi- from approximately 80 percent in children to less than 25 percent in octoge-
potential cell proliferates to form approximately 10 to 100 billion or more cells, narians. The probability for cure decreases from approximately 50 percent in
normal hematopoiesis is inhibited, and normal red cell, neutrophil, and plate- children to virtually zero in octogenarians.
let blood levels fall. The resultant anemia leads to weakness, exertional limita-
tions, and pallor; the thrombocytopenia to spontaneous hemorrhage, usually
in the skin and mucous membranes; and the neutropenia and monocytopenia
to poor wound healing and minor infections. Severe infection usually does not
occur at diagnosis, but often does if the disease progresses because of lack of DEFINITION AND HISTORY
treatment or if chemotherapy intensifies the decrease of blood neutrophil and
monocyte levels. The diagnosis is made by measurement of blood cell counts Acute myelogenous leukemia (AML) is a clonal, malignant disease
and examination of blood and marrow cells and is based on identification of of hematopoietic tissues that is characterized by (1) accumulation
of abnormal (leukemic) blast cells, principally in the marrow, and
(2) impaired production of normal blood cells. Thus, the leukemic cell
infiltration in marrow is accompanied, nearly invariably, by anemia and
thrombocytopenia. The absolute neutrophil count may be low or nor-
mal, depending on the total white cell count.
Acronyms and Abbreviations: ALL, acute lymphocytic leukemia; AML, acute The first well-documented case of acute leukemia is attributed to
myelogenous leukemia; APL, acute promyelocytic leukemia; ATRA, all-trans retin- Friedreich, but Ebstein was the first to use the term acute leukämie
1
2
oic acid; CBF, core binding factor; CD, cluster of differentiation; ceAML, clonally in 1889. This work led to the general appreciation of the clinical dis-
evolved acute myelogenous leukemia; CEBPA, CCAAT-enhancer binding protein A; tinctions between AML and chronic myelogenous leukemia (CML). In
3
CML, chronic myelogenous leukemia; CNL, chronic neutrophilic leukemia; DNMT, 1878, Neumann, who proposed that marrow was the site of blood cell
4
DNA methyltransferase; FAB, French-American-British classification; FISH, fluores- production, first suggested that leukemia originated in the marrow and
cence in situ hybridization; FLT, Fms-like tyrosine kinase; G-CSF, granulocyte colony- used the term myelogene (myelogenous) leukemia. The availability of
stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; GVHD, polychromatic stains, as a result of the work of Ehrlich, the description
5
graft-versus-host disease; HLA, human leukocyte antigen; HSC, hematopoietic stem of the myeloblast and myelocyte by Naegeli, and the earliest apprecia-
6
cell; IDH, isocitrate dehydrogenase; ITD, internal tandem duplication; MDR, multidrug tion of the common origin of red cells and leukocytes by Hirschfield
7
resistance; MDS, myelodysplastic syndrome; NPM1, nucleophosmin-1 mutation; OS, laid the foundation for our current understanding of the disease.
overall survival; PAS, periodic acid–Schiff; PCR, polymerase chain reaction; P-gp, Although Theodor Boveri proposed a critical role for chromo-
permeability glycoprotein; ppm, parts per million; PTD, partial tandem duplication; somal abnormalities in the development of cancer in 1914, a series of
RAR, retinoic acid receptor; RT, reverse transcriptase; RUNX, runt-related transcription technical developments in the 1950s was needed to permit informed
factor; SAHA, suberoylanilide hydroxamic acid; t, translocation; TdT, terminal deoxy- examination of the chromosomes of human cancer cells. Thereafter, the
nucleotidyl transferase; TET, ten-eleven translocation; TKD, tyrosine kinase domain; discovery that a G group chromosome consistently had a foreshortened
TMD, transient myeloproliferative disease; TNF, tumor necrosis factor; VEGF, vascular long arm in the cells of patients with CML (Philadelphia chromosome)
endothelial growth factor; WBC, white blood cell; WHO, World Health Organization; supported the concept that chromosome abnormalities may be specif-
WT, Wilms tumor. ically linked to a cancer phenotype. This finding was followed by the
introduction of banding of chromosomes, which enhanced the specific

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