Chronic myeloid leukemia (CML) is a rare myeloproliferative neoplasm that is characterized by the presence of the Philadelphia (Ph) chromosome and uninhibited expansion of bone marrow stem cells. The Ph chromosome arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22 (t(9;22)(q34;q11.2), resulting in the BCR-ABL1 fusion gene.1BCR-ABL1 encodes an oncoprotein with constitutive tyrosine kinase activity that promotes growth and replication through downstream pathways, which is the driving factor in the pathogenesis of CML.1
Typical treatment for CML involves life-long use of oral BCR-ABL tyrosine kinase inhibitors (TKI). Currently, 5 TKIs have regulatory approval for treatment of this disease. With the introduction of imatinib in 2001 and the subsequent development of second- (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) TKIs, CML has become a chronic disease with a life-expectancy that is similar to that of the general population. This article reviews the diagnosis of CML and the parameters used for monitoring response to TKI therapy; the selection of initial TKI therapy is reviewed in a separate follow-up article.
According to SEER data estimates, 8430 new cases of CML were diagnosed in the United States in 2018. CML is a disease of older adults, with a median age of 65 years at diagnosis, and there is a slight male predominance. Between 2011 and 2015, the number of new CML cases was 1.8 per 100,000 persons. The median overall survival (OS) in patients with newly diagnosed chronic-phase CML (CP-CML) has not been reached.2 Given the effective treatments available for managing CML, it is estimated that the prevalence of CML in the United States will plateau at 180,000 patients by 2050.3
A 53-year-old woman presents to her primary care physician with complaints of fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. Her past medical history is significant for uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking. On physicial exam her spleen is palpated 8 cm below the left costal margin. A complete blood count (CBC) with differential identifies a total white blood cell (WBC) count of 124,000/μL, with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin is 12.4 g/dL and platelet count is 801 × 103/µL.
- How is the diagnosis of CML made?
The diagnosis of CML is often suspected based on an incidental finding of leukocytosis and, in some cases, thrombocytosis. In many cases, this is an incidental finding on routine blood work, but approximately 50% of patients will present with constitutional symptoms associated with the disease. Characteristic features of the WBC differential include left-shifted maturation with neutrophilia and immature circulating myeloid cells. Basophilia and eosinophilia are often present as well. Splenomegaly is a common sign, present in 50% to 90% of patients at diagnosis. In those patients with symptoms related to CML at diagnosis, the most common presentation includes increasing fatigue, fevers, night sweats, early satiety, and weight loss. The diagnosis is confirmed by cytogenetic studies showing the Ph chromosome abnormality, t(9; 22)(q3.4;q1.1), and/or reverse transcriptase polymerase chain reaction (PCR) showing BCR-ABL1 transcripts.
- What further testing is needed when evaluating a patient for CML?
There are 3 distinct phases of CML: chronic phase (CP), accelerated phase (AP), and blast phase (BP). Bone marrow biopsy and aspiration at diagnosis are mandatory in order to determine the phase of the disease at diagnosis. This distinction is based on the percentage of blasts, promyelocytes, and basophils present as well as the platelet count and presence or absence of extramedullary disease.4 The vast majority of patients at diagnosis have CML that is in the chronic phase. The typical appearance in CP-CML is a hypercellular marrow with granulocytic and occasionally megakaryocytic hyperplasia. In many cases, basophilia and/or eosinophilia are noted as well. Dysplasia is not a typical finding in CML.5 Bone marrow fibrosis can be seen in up to one-third of patients at diagnosis, and may indicate a slightly worse prognosis.6 Although a diagnosis of CML can be made without a bone marrow biopsy, complete staging and prognostication are only possible with information gained from this test, including baseline karyotype and confirmation of CP versus a more advanced phase of CML.