Diagnosis and Phases of Chronic Myelogenous Leukemia (CML)

CML Diagnosis

It's worth highlighting that most individuals with chronic myeloid leukemia do not experience any noticeable symptoms at the time of their diagnosis. In fact, it is entirely possible to visit a healthcare professional for an unrelated blood test or an entirely different health issue and discover an abnormal white blood cell count, which may prompt your doctor to consider the possibility of CML.

To establish an official diagnosis of CML, medical professionals employ various tests to analyze both your blood and bone marrow. These samples are subsequently examined by a pathologist and a hematopathologist, who specialize in the study of blood and bone marrow disorders.

Complete Blood Count (CBC) with Differential

This test will provide current red blood cell counts, white blood cell counts, platelet counts and hemoglobin levels within red blood cells. The differential analysis will specifically categorize the various types of white blood cells. People with CML often have a dramatically high white blood cell count, a decreased red blood cell count and either an increase or decrease in the platelet count (depending on the severity of their CML).

Peripheral Blood Smear

A peripheral blood smear is a testing technique doctors use to examine your red and white blood cells as well as your platelets to gauge your blood health. This test shows the immature granulocytes as well as basophils and eosinophils, which are important effector cells in human allergic diseases and are indicative of inflammation. The mature granulocytes have decreased apoptosis (programmed cell death) resulting in a build-up of long-lived cells with low or absent enzymes, resulting in a low score.

Bone Marrow Aspiration and Biopsy

Your doctor will perform a thorough evaluation of your bone marrow to assess its overall health and functionality with a bone marrow biopsy and aspiration. Aspiration is the extraction of bone marrow fluid using a syringe, while a bone marrow trephine biopsy involves the removal of a thin, 1-2 cm piece of bone within the marrow in one piece. Typically, these procedures are carried out together and provide the same diagnostic information to the physician. However, there are distinctions between the two.

A bone marrow biopsy offers insights into the internal structure of the bone marrow within the bone, while aspiration merely collects a sample of bone marrow cells. The biopsy is typically taken from either the hip bone, and the aspiration is typically taken from the breastbone. A sedative is administered before these procedures. During aspiration, a needle is inserted through the skin and into the bone, which may result in a pulling sensation. Conversely, the biopsy employs a slightly larger needle and may cause some discomfort, though it is typically short-term.

Genetic Tests

Chronic myeloid leukemia is characterized by the presence of a genetic anomaly known as the Philadelphia chromosome. Within the body's cells, DNA serves as the blueprint that defines their functions. In CML, a unique genetic event occurs where specific segments of chromosome 9 and chromosome 22 engage in a reciprocal translocation, with a piece of chromosome 9 and 22 switching places and attaching.

This genetic exchange results in chromosome 9 becoming elongated and chromosome 22 becoming shortened, giving rise to the Philadelphia chromosome (Ph). This alteration in the structure and positioning of chromosomes leads to the creation of a novel gene called BCR-ABL, which produces a protein known as tyrosine kinase. Tyrosine kinase, in turn, sets off an uncontrolled proliferation of white blood cells.

Consequently, there is an excessive accumulation of diseased and dysfunctional white blood cells, outnumbering their healthy counterparts in the bloodstream. This genetic abnormality is a hallmark of CML and is integral to its diagnosis and treatment considerations.

Cytogenetic Testing

A cytogenetic analysis or karyotyping is a test in which special stains are applied to the bone marrow and then the cells are observed to detect any abnormalities in chromosomal structure.

It is used to identify the presence of the Philadelphia (Ph) chromosome, which shows up in more than 90% of all CML cases.

Fluorescent in Situ Hybridization (FISH)

Fluorescence in Situ Hybridization (FISH) is a laboratory test used to examine genes and chromosomes in cells and considered to be more effective than cytogenetic testing. Using fluorescent staining, the dye only attaches to specific genes or parts of chromosomes. The purpose of this test is to identify the BCR-ABL gene, the novel gene that’s created due to the reciprocal translocation giving rise to the Philadelphia chromosome. Oftentimes, cryogenic analysis doesn’t pick up on the Ph chromosome therefore FISH is a better testing method.

Polymerase Chain Reaction (PCR)

Quantitative polymerase chain reaction (qPCR) is the most sensitive test used to detect and measure the quantity of BCR-ABL gene in blood or bone marrow samples. This test can be conducted using either blood or bone marrow samples. PCR is more sensitive than karyotyping and is adept at detecting even trace amounts of BCR-ABL, although initial levels are typically high at diagnosis. PCR testing is instrumental in establishing the baseline level of BCR-ABL, which serves as a reference point for subsequent assessments of a patient's response to treatment.

A rising PCR level may signal inadequate treatment response or the need to stop treatment. If you are in the chronic phase with little to no symptoms, this test is best performed before any treatment is administered. If you are receiving treatment, PCR levels will drop significantly, indicating a strong response to treatment.

Computed Tomography (CT) Scan

A CT scan takes pictures of the inside of the body using X-rays from different angles which are then combined together to create a very detailed 3D image to see abnormalities. A contrast medium (dye) injected into the patient is used to heighten the quality of the image. The CT offers a look into how the CML is affecting other parts of the body such as the size of the spleen, which is often significantly enlarged in CML patients.

Magnetic Resonance Imaging (MRI)

MRI’s are used to find cancer in the body. It provides cross-sectional images of the inside of your body from many different angles to see if the cancer is spreading and serves as a tool to plan the cancer treatment. Getting an MRI scan is painless, but as this is a machine that uses a very large and powerful magnet, it is crucial to inform your doctor of any metal you may have in your body.

Ultrasound

Ultrasounds are used to look for tumors in certain areas of the body that don't show up on X-rays. It generates images called sonograms by emitting high-frequency sound waves that penetrate your body. As these sound waves interact with organs and tissues, they produce echoes that are transformed into live images depicting the structure and motion of organs, and it can even visualize blood flow within blood vessels.

These images are displayed on a computer screen for review. This is a great tool to differentiate between fluid filled cysts and solid tumors because of their echo patterns. This is a quick and safe way to get plenty of information about the patient’s health without exposing them to harmful radiation.

Simulation Test

A scan may be performed to inspect your brain and spinal cord for any signs that the CML has spread to this area.

CML Phases

Chronic Phase

This is the most stable phase in chronic myeloid leukemia, but it develops slowly. Most people in this phase do not exhibit many symptoms, if at all. Although the chronic phase is characterized by less than 10% blasts in the blood, without effective treatment it can progress to the accelerated or blast phases.

Accelerated Phase

The accelerated phase is marked by 10-19% blast cells in the bloodstream. However, it lacks a precise, well-defined description. It serves as a transitional stage between the chronic and blast phases, and in some instances, these cells exhibit fresh cytogenetic alterations in addition to the Philadelphia chromosome. This occurs due to added DNA damage and mutations in the CML cells. This phase is marked by more symptoms such as persistent fatigue, dramatic weight loss and a swollen spleen accompanied by a sensation of fullness.

Blast Crisis

The blast phase, also called the acute phase or blast crisis, is when the leukemia transforms into acute myeloid leukemia (AML). In such cases, the bone marrow is filled with blast cells resulting in more blast cells around the circulatory system and possibly even spreading to other organs. This phase is accompanied by a more serious prognosis, leaving patients much more vulnerable to infections.

The accurate diagnosis of chronic myeloid leukemia is a multifaceted process that involves various tests and examinations. It's important to note that many individuals with CML may not exhibit noticeable symptoms at first, making early detection through routine blood tests crucial. Medical professionals employ a range of diagnostic tools and simulation tests to determine the extent and progression of the disease. Understanding the phases of CML, from chronic to blast crisis, is essential for proper treatment planning. Early diagnosis and monitoring are key to effectively managing CML and improving patients' prognosis and quality of life.