Introduction: Who Should Undergo Diagnostics

Many people with chronic myeloid leukaemia do not experience noticeable symptoms in the early stages of the disease. In fact, it is quite common for the condition to be detected during a routine blood test performed for an entirely different reason.^[1] This happens because CML develops very slowly, and you can have the condition for years before any warning signs appear.^[2]

When symptoms do occur, they tend to be mild at first and gradually become more noticeable over time. You should consider seeing your doctor if you experience persistent symptoms that worry you, such as feeling unusually tired or weak for no clear reason, unexplained weight loss, or drenching night sweats that soak through your bedclothes.^[1] Other symptoms that might prompt a visit include fever without an obvious cause, shortness of breath during normal activities, or a feeling of fullness or discomfort in the upper left part of your abdomen, where your spleen is located.^[2]

Sometimes people notice they feel full after eating only a small amount of food, or they may experience bone pain or excessive sweating during sleep. A few people develop blurry vision caused by bleeding in the back of the eye.^[1] If you have any of these symptoms that persist for more than a few weeks, it is advisable to seek medical attention. Your general practitioner will examine you and decide whether you need blood tests or a referral to a specialist.^[3]

Classic Diagnostic Methods

Diagnosing chronic myeloid leukaemia involves a series of tests that build upon each other. The process usually begins with a physical examination and a detailed medical history, followed by increasingly specialized tests to confirm the diagnosis and understand the specific characteristics of the disease.

Physical Examination

When you visit your healthcare provider with concerns about possible CML, they will start by examining you and checking your vital signs, including your pulse and blood pressure. During the physical exam, your doctor will feel your lymph nodes to check if they are swollen, and will carefully examine your abdomen, particularly the area on your left side where your spleen is located.^[16]

An enlarged spleen, called splenomegaly, is the most common physical finding in people with CML at the time of diagnosis. The spleen may be only slightly enlarged, or in some cases, it can become quite large and fill much of the abdomen, causing pain or a feeling of fullness.^[12] In about one in ten patients, however, the spleen is neither enlarged enough to feel during examination nor visible on scans.^[12]

Blood Tests

If your doctor suspects CML based on your symptoms or physical examination, they will order blood tests. A complete blood count, often called a CBC, is typically the first test performed. This test measures the numbers of different types of cells in your blood, including red blood cells, white blood cells, and platelets.^[16]

In people with chronic myeloid leukaemia, the CBC often shows an unusually high number of white blood cells. The disease causes an increased number of white blood cells in the blood because abnormal cells in the bone marrow are dividing and multiplying without proper control.^[1] Along with the high white blood cell count, you may have fewer red blood cells, leading to a condition called anaemia, but you might have more platelets than normal and abnormal white blood cells circulating in your bloodstream.^[2]

Beyond the CBC, your doctor may order additional blood tests to check how well your organs are functioning. These blood chemistry tests measure different substances in the blood, including proteins, fats, sugars, and enzymes, to determine if any organs are not working as they should.^[8]

Bone Marrow Tests

To confirm a diagnosis of CML, your doctor will need to examine your bone marrow directly. Bone marrow is the spongy tissue inside your bones where blood cells are made. Two types of bone marrow tests are commonly performed together: bone marrow aspiration and bone marrow biopsy.^[16]

During bone marrow aspiration, your healthcare professional uses a thin needle to remove a small amount of the liquid part of the bone marrow. In a bone marrow biopsy, a needle removes a small piece of solid bone tissue along with the enclosed marrow.^[1] These samples are typically taken from the back of your hip bone, an area called the pelvis. The samples are then sent to a laboratory where specialists examine them under a microscope to look for abnormal cells.

In CML, the bone marrow examination will reveal an increased number of certain types of white blood cells at various stages of development. The percentage of blast cells, which are immature white blood cells, is particularly important because this number helps doctors determine what phase of CML you have.^[7]

Genetic and Chromosome Tests

One of the most important aspects of diagnosing CML involves looking for a specific genetic abnormality. Most people with chronic myeloid leukaemia have a gene mutation called the Philadelphia chromosome.^[1] This chromosome gets its name because researchers in Philadelphia discovered it, not because it is inherited or passed down from parents to children. The Philadelphia chromosome develops during a person’s lifetime as an acquired mutation.^[10]

The Philadelphia chromosome results from a swap of genetic material between two chromosomes in your body—specifically, chromosomes 9 and 22. A piece of chromosome 9 breaks off and attaches to chromosome 22, while a piece of chromosome 22 moves to chromosome 9. This creates a shortened chromosome 22, which is the Philadelphia chromosome.^[5] The rearrangement causes two genes, called ABL1 and BCR, to join together and form a new combined gene called BCR-ABL.^[2]

This BCR-ABL gene produces an abnormal protein that acts like a broken switch, constantly telling your bone marrow cells to grow and divide when they should not. The protein is a type of enzyme called tyrosine kinase, which normally helps control cell growth by turning on and off at appropriate times. In CML, however, the abnormal tyrosine kinase enzyme does not have an “off” switch, so cells keep multiplying uncontrollably.^[2]

Specialized tests are used to detect the Philadelphia chromosome or the BCR-ABL gene in your blood or bone marrow samples. These tests include fluorescence in situ hybridization, often shortened to FISH, and a technique called reverse transcriptase-polymerase chain reaction, or PCR for short.^[16] More than 90 to 95 percent of people with CML will test positive for the Philadelphia chromosome using these methods.^[7]

Some people have variant forms of the chromosome change that involve additional chromosomes beyond chromosomes 9 and 22, or have a hidden form that can only be detected with the specialized FISH or PCR tests rather than standard chromosome analysis.^[7] Testing for the Philadelphia chromosome is essential not only for diagnosing CML but also for distinguishing it from other types of leukaemia that may look similar.

Determining the Phase of CML

Once CML is confirmed, doctors need to determine which phase of the disease you have. Chronic myeloid leukaemia progresses through different phases based on how much the disease has developed. Most systems describe three phases: chronic phase, accelerated phase, and blast phase (also called blast crisis).^[6]

The phase is determined by counting the number of blast cells in your blood and bone marrow, along with looking at other factors such as the size of your spleen, your symptoms, and your blood cell counts.^[8] Most people are diagnosed during the chronic phase, when the disease is progressing slowly and is most treatable. The chronic phase can be kept under control for many years with proper treatment.^[14]

Knowing what phase you are in helps your doctor decide on the best treatment approach and gives information about what to expect. The phase can change over time if the disease progresses, which is why ongoing monitoring with blood tests and sometimes bone marrow tests is necessary even after diagnosis.

Diagnostics for Clinical Trial Qualification

Clinical trials are research studies that test new treatments or ways of using existing treatments for chronic myeloid leukaemia. If you are considering participating in a clinical trial, you will need to undergo specific tests and evaluations to determine whether you are eligible to enroll. These tests serve two purposes: they ensure that the trial is safe for you, and they help researchers gather standardized information about all participants.

Baseline Testing Requirements

Before you can join a clinical trial for CML, researchers need to establish a baseline understanding of your health and disease status. This typically includes all the standard diagnostic tests used to confirm CML and determine its characteristics. You will need recent blood tests showing your complete blood count and blood chemistry panel, as well as bone marrow test results confirming the presence of CML.^[12]

Documentation of the Philadelphia chromosome or BCR-ABL gene is almost always required for clinical trials testing CML treatments, since this genetic change is what defines the disease and is the target of most CML therapies.^[5] The testing must typically be done within a certain timeframe before enrollment, often within the past few weeks or months, to ensure the information is current.

Phase and Risk Assessment

Clinical trials often have specific criteria regarding what phase of CML participants must have. Some trials are designed only for people in the chronic phase, while others may focus on accelerated or blast phase disease. Your doctors will need to document which phase you are in using the standard criteria based on blast cell percentages and other disease features.^[12]

Additionally, researchers may assess your risk category, which takes into account factors such as your age, spleen size, blood cell counts, and the percentage of blast cells. These factors help predict how your disease might progress and whether you fall into a low-risk, intermediate-risk, or high-risk group.^[6] Clinical trials may specifically recruit participants from certain risk categories to test whether new treatments work better in particular groups.

Organ Function Testing

To ensure your safety during a clinical trial, researchers need to know that your vital organs are functioning well enough to handle the study treatment. This typically involves blood tests to check your liver and kidney function, as many cancer treatments are processed by these organs.^[16] Your heart function may also be evaluated using tests such as an electrocardiogram or echocardiogram, particularly if the trial involves drugs that can affect the heart.

Molecular Response Monitoring

Many clinical trials for CML focus on measuring how well treatment reduces the number of leukaemia cells in your body. This is assessed through a concept called molecular response, which is measured using PCR tests that count how many of your cells still carry the BCR-ABL gene.^[11]

When you first start treatment in a clinical trial, you will have a baseline PCR test. Then, at regular intervals—usually every three months—you will have follow-up PCR tests to see if the number of CML cells is decreasing. A good molecular response means fewer and fewer cells contain the abnormal gene over time.^[11] Different levels of molecular response have specific names, such as early molecular response, major molecular response, and deep molecular response, each representing a greater reduction in disease burden.

Clinical trials often define success based on achieving certain molecular response milestones within specific timeframes. For example, a trial might measure what percentage of participants achieve a major molecular response within 12 months of starting the study treatment. These standardized measures allow researchers to compare different treatments fairly and determine which approaches work best.

Additional Genetic Testing

Some clinical trials may require additional genetic or molecular tests beyond the standard Philadelphia chromosome detection. These might include tests to look for additional chromosome abnormalities or specific mutations within the BCR-ABL gene that could affect how well certain treatments work.^[7] Such detailed genetic information helps researchers understand why some people respond better to treatment than others and can guide the development of more personalized therapies in the future.

Performance Status Evaluation

Clinical trials typically assess your general health and ability to carry out daily activities using what is called a performance status score. This evaluation helps determine whether you are well enough to participate in the study and whether you can handle the demands of the trial treatment and visit schedule. Your performance status takes into account factors such as whether you can work, care for yourself, and how much time you spend in bed or resting during the day.

The combination of all these diagnostic tests and assessments creates a comprehensive picture of your health and disease status. This information not only determines whether you qualify for a particular clinical trial but also provides crucial baseline data that researchers will use to measure the effects of the treatment being studied. By carefully selecting participants who meet specific criteria, clinical trials can more accurately determine whether new treatments are safe and effective for people with CML.