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1438 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1439

95 percent of patients with classic morphologic findings, which leads per year in persons younger than 20 years to a rate of approximately
to an overtly foreshortened long arm of one of the pair of chromosome 10.0 per 100,000 in octogenarians (Fig. 89–1). Although CML occurs
22 (i.e., 22,22q−), referred to as the Philadelphia (Ph) chromosome. A in children and adolescents, less than 10 percent of all cases occur in
rearrangement of the breakpoint cluster region gene (BCR) on the long persons between 1 and 20 years old. CML represents approximately
arm of chromosome 22 defines this form of CML and is present even in 3 percent of all childhood leukemias. Multiple occurrences of CML in
the 10 percent of patients without an overt 22q abnormality by Giemsa families are rare. There is no concordance of the disease between iden-
chromosome banding. The natural history of the disease is to undergo tical twins. There is no analytical epidemiologic evidence for a familial
clonal evolution into an accelerated phase and/or a rapidly progressive predisposition to CML in Swedish databases. There is some evidence
19
blast phase, an acute leukemia, highly refractory to therapy, which had that overweightness and obesity can increase the incidence of CML. 20
been a frequent event prior to the introduction of tyrosine kinase inhib-
itors (TKIs) in 2001.
In 1845, Bennett in Scotland and Virchow in Germany described ETIOLOGY AND PATHOGENESIS
2
1
patients with splenic enlargement, severe anemia, and enormous con-
centrations of leukocytes in their blood at autopsy. Bennett initially ENVIRONMENTAL LEUKEMOGENS
favored an extreme pyemia as the explanation, but Virchow argued Exposure to very high doses of ionizing radiation can increase the
against suppuration as a cause. Additional cases were reported by occurrence of CML above the expected frequency in comparable popu-
4
Craige and others, and in 1847 Virchow introduced the designation lations. Three major populations—the Japanese exposed to the radiation
3
weisses Blut and leukämie (leukemia). In 1878, Neumann proposed released by the atomic bomb detonations at Nagasaki and Hiroshima,
5
21
that the marrow not only was the site of normal blood cell production, British patients with ankylosing spondylitis treated with spine irradia-
but also was the site from which leukemia originated and used the term tion, and women with uterine cervical carcinoma who received radi-
22
myelogene (myelogenous) leukemia. Subsequent observations amplified ation therapy —had a frequency of CML (as well as acute leukemia)
23
the clinical and laboratory features of the disease, but few fundamen- significantly above the frequency expected in comparable unexposed
6
tal insights were gained until the discovery by Nowell and Hungerford, groups. The median latent period was approximately 4 years in irradi-
who reported in 1960 that two patients with the disease had an apparent ated spondylitics, among whom approximately 20 percent of the leuke-
loss of the long arm of chromosome 21 or 22, an abnormality that was mia cases were CML; 9 years in the uterine cervical cancer patients, of
quickly confirmed and designated the Ph chromosome. Advanced whom approximately 30 percent had CML; and 11 years in the Japanese
7–9
7
cytogenetic techniques confirmed that it was chromosome 22. This survivors of the atomic bombs, of whom approximately 30 percent of
observation led to a new approach to diagnosis, a marker to study the the leukemia patients had CML. Chemical leukemogens, such as ben-
24
pathogenesis of the disease, and a focus for future studies of the molec- zene and alkylating agents, are not causative agents of CML, presumably
ular pathology of the disease. The availability of banding techniques because of their inability to induce the specific chromosome transloca-
to define the fine structure of chromosomes 10,11 led to the discovery by tion required to cause the disease. 25–27
Rowley that the apparent lost chromosomal material on chromosome
12
22 was part of a reciprocal translocation between chromosomes 9 and 22.
The discovery that the cellular oncogene ABL1 on chromosome 9 and ORIGIN FROM A MUTANT HEMATOPOIETIC
a segment of chromosome 22, the BCR, fuse as a result of the translo- STEM CELL
cation provided a basis for the study of the molecular cause of the dis-
ease. 13,14 The appreciation that the fusion gene encoded a constitutively CML results from the malignant transformation of a single hematopoi-
active tyrosine kinase (BCR-ABL1) that was capable of inducing the etic stem cell. The disease is acquired (somatic mutation), given that the
disease in mice established the fusion gene product as the proximate identical twin of patients with CML and the offspring of mothers with
28
cause of the malignant transformation. The search for, identification of, the disease neither carry the Ph chromosome nor develop the disease.
and clinical development of a small molecule inhibitor of the mutant The origin of CML from a single hematopoietic stem cell is supported
tyrosine kinase provided a specific agent, imatinib mesylate, with which by the following lines of evidence:
15
to inhibit the molecule that incites the disease. Several more potent 1. Involvement of erythropoiesis, neutrophilopoiesis, eosinophilo-
congeners have also been synthesized (see “Etiology and Pathogenesis” poiesis, basophilopoiesis, monocytopoiesis, and thrombopoiesis in
below). Thomas and colleagues established that allogeneic hematopoi- chronic phase CML. 29
16
etic stem cell transplantation could cure the disease. An engaging 2. Presence of the Ph chromosome (22q−) in erythroblasts; neu-
monograph on the discoveries and the scientists involved from the trophilic, eosinophilic, and basophilic granulocytes; macrophages;
identification of the Ph chromosome to the development of imatinib and megakaryocytes. 30
has been published. 17 3. Presence of a single glucose-6-phosphate dehydrogenase isoenzyme
in red cells, neutrophils, eosinophils, basophils, monocytes, and
EPIDEMIOLOGY platelets, but not in fibroblasts or other somatic cells in women with
CML who are heterozygotes for isoenzymes A and B. 31–33
CML accounts for approximately 15 percent of all cases of leukemia, 4. Presence of the Ph translocation only on a structurally anomalous
or approximately 6500 new cases in the United States in 2015. The chromosome 9 or 22 of each chromosome pair in every cell analyzed
age-adjusted incidence rate in the United States is approximately 2.3 in occasional patients with a structurally dissimilar 9 or 22 chromo-
per 100,000 persons for men and approximately 1.2 per 100,000 per- some within the pair. 34–36
sons for women. The incidence around the world varies by a factor of 5. Presence of the Ph chromosome in one, but not the other, cell lin-
approximately twofold. The lowest incidence is in Sweden and China eage of patients who are a mosaic for sex chromosomes, as in Turner
37
(approximately 0.7 per 100,000 persons), and the highest incidence is in syndrome (45X/46XX) and Klinefelter syndrome (46XY/47XXY). 38
Switzerland and the United States (approximately 1.5 per 100,000 per- 6. Molecular studies showing variation in the breakpoint of chromo-
sons). The age-specific incidence rate for CML in the United States some 22 among different patients with CML but precisely the same
18
increases logarithmically with age, from approximately 0.2 per 100,000 breakpoint among cells within a single patient with CML. 39,40

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