Chapter 47: The Chronic Myelogenous Leukemias

INTRODUCTION

• BCR-ABL-positive chronic myelogenous leukemia (CML) results from a somatic mutation in a pluripotential lymphohematopoietic cell.

• CML is characterized by granulocytic leukocytosis, granulocytic immaturity, basophilia, anemia, and often thrombocytosis in the blood, intense leukemic granulocytic precursor expansion in the marrow, and splenomegaly.

• The natural history of the disease is to evolve into an accelerated phase in which cytopenias develop and response to chronic phase therapy is lost; it often terminates in acute leukemia.

ETIOLOGY

• Exposure to high-dose ionizing radiation increases the incidence of CML, with a mode of increased incidence that ranges from 4 to 11 years in different exposed populations.

PATHOGENESIS

Genetic Abnormality

• CML is the result of an acquired genetic abnormality that induces a malignant transformation of a single pluripotential lymphohematopoietic cell.

• The proximate cause is a translocation between chromosome 9 and 22 [t(9;22)]. This alteration juxtaposes a portion of the ABL protooncogene from chromosome 9 to a portion of the BCR gene on chromosome 22.

• The resulting gene fusion, BCR-ABL, creates an oncogene that encodes an elongated protein tyrosine phosphokinase (usually p210) that is constitutively expressed. This mutant protein disrupts cell signal pathways and results in the malignant transformation.

• The genetic alteration is present in erythroid, neutrophilic, eosinophilic, basophilic, monocytic, megakaryocytic, and marrow B- and T-lymphocytic cells, consistent with its origin in a pluripotential cell.

• The Philadelphia (Ph) chromosome specifically refers to chromosome 22 with a shortened long arm and is evident by light microscopy of cell metaphase preparations in approximately 90 percent of cases. Fluorescence in situ hybridization (FISH) can identify the fusion BCR-ABL gene in approximately 95 percent of cases.

Hematopoietic Abnormalities

• There is a marked expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation resulting in an inexorable increase in white cell count.

• Megakaryocytopoiesis is often expanded. Erythropoiesis is usually moderately deficient.

• Function of the neutrophils and platelets is nearly normal; infection and bleeding are not a feature of the chronic phase.

EPIDEMIOLOGY

• CML accounts for approximately 15 percent of all cases of leukemia and approximately 3 percent of childhood leukemias.

• Males are affected at approximately 1.5 times the rate of females.

• The age-specific incidence rate increases exponentially from late teen age (0.2 cases/100,000) to octogenarians (10 cases/100,000).

• Familial occurrence is vanishingly rare, and there is no concordance in identical twins.

• Neither chemical agents, including benzene, cytotoxic drugs, nor combusted tobacco smoke have a causal relationship with CML.

CLINICAL FEATURES

• Approximately 30 percent of patients are asymptomatic at the time of diagnosis. The disease is discovered coincidentally when an elevated white count is noted at a medical evaluation.

• Symptoms are gradual in onset and may include easy fatigability, malaise, anorexia, abdominal discomfort and early satiety, weight ...