Page 1209 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 67

CHRONIC MYELOID LEUKEMIA

Ravi Bhatia

Chronic myeloid leukemia (CML) is a hematopoietic malignancy significantly increased risk for leukemia. High-dose irradiation of
originating from transformation of a primitive hematopoietic cell. myeloid cell lines in vitro induces the expression of BCR-ABL tran-
Without treatment, CML progresses from an initial chronic phase scripts indistinguishable from those that characterize CML. The
(CP), characterized by marrow hyperplasia and increased numbers of BCR-ABL gene can be detected at low levels in a proportion of
circulating differentiated myeloid cells, to more advanced phases of healthy individuals using a very sensitive polymerase chain reaction
disease (accelerated phase [AP] and blast crisis [BC]) marked by a (PCR) assay. These findings suggest that the fusion gene develops
block in differentiation, accumulation of blasts, and depletion of relatively frequently in hematopoietic cells, but only infrequently
normal hematopoietic cells, especially white blood cells (WBCs) and leads to leukemia development. The mechanism by which the Ph
platelets. CML was the first malignant disease found to be consistently chromosome is first formed and the time required for progression to
associated with a specific cytogenetic abnormality, the Philadelphia overt disease are unknown.
chromosome (Ph), resulting in the formation of the BCR-ABL fusion
oncogene. Study of the BCR-ABL gene has not only led to sensitive
methods to detect residual disease and predict outcome, but has also PATHOPHYSIOLOGY
yielded highly effective “targeted” therapies aimed at inhibiting
abnormal tyrosine kinase activity resulting from the BCR-ABL fusion CML is generally believed to develop from transformation of a primi-
oncogene. In addition, CML was one of the first diseases demon- tive hematopoietic stem cell (HSC) by the BCR-ABL fusion gene.
strated to be curable by hematopoietic cell transplantation (HCT). The progeny of transformed HSCs have a proliferative advantage over
Thus, CML has become the model for “tailored” therapy, in which normal hematopoietic cells, thus allowing the Ph-positive clone to
various treatments can be escalated on the basis of molecular response. gradually displace residual normal hematopoiesis. The translocation
is found in cells of myeloid, erythroid, megakaryocytic, and
B-lymphoid origin, consistent with a HSC origin of the disease.
ETIOLOGY/EPIDEMIOLOGY/GENETICS Hematopoietic expansion in patients with CP disease primarily
involves an increase in myeloid cell mass, related to an expansion of
CML was recognized as a distinct entity, associated with massive mature cells, as well as increased numbers of precursor and progenitor
splenomegaly and leukocytosis without other explanations, in the cells. In CP, the leukemic cells are minimally invasive and are primar-
mid-1800s. The modern history of CML was initiated by Nowell and ily located in hematopoietic tissues including the blood, bone marrow,
Hungerford in 1960. They used newly developed techniques to spleen, and liver. The proliferative advantage of the malignant clone
detect a small chromosome in metaphase preparations of marrow cells may be related to enhanced responsiveness to hematopoietic growth
from CML patients. This abnormal chromosome was the first con- factors and/or reduced response to inhibitory factors. CML progeni-
sistent chromosomal abnormality in human malignancies and was tors also demonstrate altered adhesion to marrow stromal cells and
termed the Philadelphia chromosome after the city of its discovery. extracellular matrix. Altered microenvironmental interactions may
Rowley showed that the Philadelphia chromosome resulted from a contribute to another feature of CML, which is abnormal progenitor
translocation between chromosomes 9 and 22 [t(9;22)(q34;q11)] trafficking with increased numbers of circulating progenitors and
(Fig. 67.1). The genes involved in this translocation were cloned in extramedullary hematopoiesis. Several observations indicate that
the 1980s, and the t(9;22) translocation was shown to result from although the Ph-positive clone displaces normal hematopoiesis, it
the fusion of the breakpoint cluster region (BCR) gene on chromo- does not destroy residual normal stem cells. For example, Ph-negative
some 22 to the Abelson leukemia virus (ABL) gene on chromosome progenitors can be seen after cultures of CML cells in vitro are
9, with formation of the BCR-ABL fusion oncogene. This oncogene selected on the basis of cell surface phenotype, and can be identified
codes for a constitutively active cytoplasmic tyrosine kinase, which is in the blood after high-dose chemotherapy. As described later in the
the principal cause of the CP of CML. Until the 1970s, CML was Therapy section, treatment with agents such as interferon (IFN) or
regarded as an incurable and inevitably lethal disorder. It was then TKIs can result in restoration of Ph-negative hematopoiesis in CML
recognized that selected patients can be cured by allogeneic HCT. patients.
However, transplantation therapy for CML is limited by donor avail- The BCR-ABL gene originates from a chromosomal translocation
ability and the risk for life-threatening toxicity. More recently, ima- that results in the fusion of the ABL gene on chromosome 9 and the
tinib mesylate and other tyrosine kinase inhibitors (TKIs), which BCR gene on chromosome 22. The translocation is related to a break
specifically block the enzymatic action of the abnormal tyrosine in ABL upstream of exon a2 and in the major breakpoint cluster
kinase coded by the fusion oncogene, have resulted in a high rate of region of the BCR gene. This leads to juxtaposition of a 5′ portion
remission and improved survival in CML patients. of BCR and a 3′ portion of ABL on a shortened chromosome 22 (the
CML is the most common of the myeloproliferative diseases and derivative 22q-, or Ph). The resulting messenger RNA (mRNA)
represents 15% to 20% of all new leukemia cases. The annual inci- usually contains one of two BCR-ABL junctions, designated e13a2
dence of CML is 1 to 1.5 cases per 100,000 population per year. The (formerly b2a2) and e14a2 (or b3a2). Both BCR-ABL mRNA mol-
median age at diagnosis is 67 years and the incidence sharply rises ecules are translated into a 210-kD fusion protein, referred to as
with age. The disease occurs slightly more often in men than in p210BCR-ABL. Rarely, other variant breakpoints and fusions can give
women. CML may occur in children, but only approximately 10% rise to full-length, functionally oncogenic BCR-ABL proteins,
of cases occur in individuals between 5 and 20 years of age, represent- notably p190BCR-ABL (associated with an e1a2 mRNA junction)
ing only 3% of all childhood leukemias. Concordance of disease is and p230BCR-ABL (associated with an e19a2 mRNA junction). Of
not observed between identical twins. Persons exposed to high-dose patients with CML who have a normal-appearing karyotype, one-
irradiation, including survivors of atomic bombing, have a third have a cytogenetically occult BCR-ABL gene, usually located on

1055