Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder of the primitive hematopoietic stem cell and is characterized by the presence of the Philadelphia (Ph1) chromosome. This abnormal chromosome results from reciprocal translocation involving the long arms of chromosome 9 and 22, t(9;22)(q34;q11).

Incidence

One per 100,000 for persons younger than 20 years and 1-3% of all childhood leukemia. One hundred cases of CML are diagnosed in the United States per year.

Table 13-19. WHO Classification of Chronic Myeloproliferative Diseases

Chronic myelogenous leukemia (Ph chromosome, t[9;22] [q34;q11], BCR/ABL positive) Chronic neutrophilic leukemia

Chronic eosinophilic leukemia (and the hypereosinophilic syndrome) Polycythemia vera

Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis) Essential thrombocythemia

Chronic myeloproliferative disease, unclassifiable

From Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-302, with permission.

Clinical Phases Chronic Phase

Blood or bone marrow contains less than 5% leukemic blasts. Clinically stable for several years.

Signs and symptoms

Nonspecific complaints: fever, night sweats, abdominal pain, bone pain Symptoms resulting from hyperviscosity: Neurologic dysfunction: headache, strokes Visual disturbances: retinal hemorrhages, papilledema Priapism Hepatomegaly, splenomegaly Pallor.

Laboratory Findings Hematologic findings

Mild normocytic, normochromic anemia

Leukocytosis with shift to left characterized by sequential orderly maturation of myeloid series in all stages starting from myeloblasts to segmented neu-trophils

Increased absolute eosinophil and basophil counts Thrombocytosis

Decreased leukocyte alkaline phosphatase score Deterioration of neutrophil function progressively

Bone marrow examination: hypercellularity, myelogenous bulge with sequential order maturation, increased eosinophilic and basophilic series, increased megakaryocytes. There may be myelofibrosis. Gaucher-like cells or sea-blue histi-ocytes may be present. Cytogenetics: presence of Ph1 chromosome.

Blood chemistry

Elevation of lactic dehydrogenase, uric acid, vitamin B12, and transcobalamin 1 levels.

Accelerated Phase

Poorly defined intermediate phase characterized by increasing blood and bone marrow leukemic blasts (10-19%) and cytopenias

Dyspoiesis, rising basophil count, progressive myelofibrosis, or refractoriness to therapy Clonal karyotypic evolution.

Signs and symptoms

Fever, night sweats, weight loss.

Table 13-20 lists the WHO criteria for diagnosis of the accelerated phase of CML.

Blast Phase

Table 13-20 lists WHO criteria for diagnosis of the blast phase of CML.

Blasts greater than 20% in blood or bone marrow; or extramedullary or intramedullary clusters of blasts. Myeloid blast crisis: most common type of blast crisis (80%); may be myeloblastic or myelomonocytic. Associated karyotypic evolution: duplication of Ph1 chromosome, trisomies of 8, 19, or 21 chromosomes, i(17q), t(7;11), acute myelogenous leukemia specific rearrangements, for example, t(15;17). Lymphoid blast crisis: less common type of blast crisis (15-20%), more often B lineage than T. Associated karyotypic evolution: duplication of Ph1 chromosome, trisomy 21, inv(7), t(14;14).

Multilineage blast crisis: mixed myelocytic, erythrocytic, megakaryoblastic, and lym-phocytic. Blasts may coexpress antigens of different lineage or two distinct populations of blasts may be present (uniclonal with bilineages).

Erythrocytic blast crisis: rare in pure form.

Megakaryoblastic blast crisis: rare in pure form, associated with inv(3)(q21;q26) or t(3)(q21;q26). Mast cell crisis: extremely rare.

Signs and symptoms:

Pallor, easy bruisability, pruritis, urticaria, bone pain.

Table 13-20. WHO Criteria for Diagnosis of Accelerated and Blast Phases of CML

Accelerated phase

Diagnose if one or more of the following is present:

Blasts 10-19% of peripheral blood white cells or bone marrow cells Peripheral blood basophils at least 20%

Persistent thrombocytopenia (<100 x 109/L) unrelated to therapy, or persistent thrombocytosis (>1000 x 109/L) unresponsive to therapy Increasing spleen size and increasing WBC count unresponsive to therapy Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase CML)

Megakaryocytic proliferation in sizable sheets and clusters, associated with marked reticulin or collagen fibrosis, and/or severe granulocytic dysplasia, should be considered suggestive of accelerated phase. They often occur simultaneously with one or more of the other features listed.

Blast phase

Diagnose if one or more of the following is present:

Blasts 20% or more of peripheral blood white cells or bone marrow cells

Extramedullary blast proliferation

Large foci or clusters of blasts in bone marrow biopsy

From Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-302, with permission.

Biology of CML

Molecularly targeted therapies have revolutionized cancer therapeutics and are much more selective in their actions than traditional chemotherapy agents. CML is a disease that exemplifies how the discoveries in molecular biology have helped design molecularly targeted therapies.

Figure 13-3 depicts the Ph1 chromosome, the molecular genetic studies of which have revealed that the ABL (Abelson) segment from chromosome 9 is translocated to chromosome 22 at its major breakpoint cluster region (BCR) and thus forms a novel fusion gene termed the BCR-ABL. The BCR-ABL fusion gene usually makes an oncoprotein having a 210-kDa molecular weight. The following are some of the functional domains of BCR-ABL oncoprotein:

Domain

Location Function

Oligomerization domain BCR Y177 BCR

Serine-threonine kinase BCR Y kinase (SH1) ABL

Actin binding domain ABL

Activation of ABL kinase.

Y177 regulates the Ras and P13K pathways through recruitment of GRB2-SOS and GAB2-P13K. These pathways are important for transformation and proliferation.

Activation of signal transduction proteins.

Constitutive tyrosine kinase activity that is responsible for phosphorylation of signal and adaptor proteins and plays a central role in leukemogenesis.

Interference with adhesion.

Ph 22q-

Chromosome 22 in chronic myeloid leukemia

Ph 22q-

Chromosome 22 in chronic myeloid leukemia

Downstream signal transduction

Constitutively active ABL-tyrosine kinase with autophosphorylation which creates binding sites for SH2 domains of other proteins

Downstream signal transduction

Constitutively active ABL-tyrosine kinase with autophosphorylation which creates binding sites for SH2 domains of other proteins

Transformation r Proliferation Inhibition of apoptosis

Was this article helpful?

0 0

Post a comment