Philadelphia Positive Chronic Myeloid Leukaemia

Philadelphia chromosome-positive chronic myeloid leukaemia is a rare blood cancer that occurs when pieces of two chromosomes swap places, creating an abnormal chromosome that changes how white blood cells grow in the bone marrow.

Table of contents

• What is Philadelphia chromosome-positive chronic myeloid leukaemia?
• Understanding the Philadelphia chromosome
• Phases of the disease
• Symptoms
• Causes and risk factors
• Diagnosis
• Treatment
• Prognosis and survival

What is Philadelphia chromosome-positive chronic myeloid leukaemia?

Chronic myeloid leukaemia (CML) is a rare type of blood cancer affecting the bone marrow at the center of the bones. The bone marrow is the soft, spongy tissue where blood cells are made. CML is a slowly progressing blood and bone marrow disease that usually occurs during or after middle age and rarely occurs in children^[1][2].

Chronic myeloid leukaemia makes up about 20 percent of all cases of adult leukaemia. About 9,000 people in the United States are diagnosed with CML each year^[1][4]. The term “chronic” means this cancer tends to progress more slowly than severe forms of leukaemia. The term “myeloid” refers to the type of cells affected by this cancer^[2].

• Bone marrow
• Blood
• Spleen

When someone has CML, the body makes too many abnormal white blood cells. These abnormal cells are made in the bone marrow and can get into the bloodstream and circulate around the body. They do not develop properly and so do not work normally. For example, they don’t give protection from infection that they should. There are too many of these abnormal white blood cells, and they might stop the bone marrow producing enough healthy blood cells. They can also build up in the lymph nodes and spleen and cause swelling^[3].

Understanding the Philadelphia chromosome

Humans have 23 pairs of chromosomes, which contain DNA information for all the genes in the body’s cells. The chromosomes and information within them tell the cells how to grow and multiply. Sometimes during cell copying, the cells may make a mistake when copying their information to form a new cell^[1].

The Philadelphia chromosome is one of these mistakes. It occurs when pieces of two different chromosomes swap places. This happens with parts of chromosomes 9 and 22, which break away and change places to make an abnormal chromosome 22 — the Philadelphia chromosome^[1][6].

The Philadelphia chromosome occurs in 90 percent of people with CML. When the Philadelphia chromosome is present in CML, the person has Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML)^[1].

Ph+ CML creates an abnormal gene called BCR-ABL. This gene produces an abnormal protein in the bone marrow called tyrosine kinase. This protein can activate the bone marrow, causing it to make too many immature white blood cells^[1][4].

Normally, the body creates and uses immature white blood cells in a controlled way. However, with Ph+ CML, these immature white blood cells grow out of control. These cells can also contain the Philadelphia chromosome, which means the copies of these cells will also include it. These cells may be called leukemic white blood cells, which start to duplicate, build up in the bone marrow, and travel through the body via the bloodstream^[1].

Over time, these abnormal cells may take the space of healthy white and red blood cells and platelets, leading to a person experiencing physical symptoms^[1].

The Philadelphia chromosome is not passed from parent to child. It happens during a person’s lifetime. The cause is unknown^[6][7].

Phases of the disease

Unlike other types of cancers which occur in stages, doctors classify CML into phases. These phases refer to the spread and acceleration of the disease^[1][7].

Chronic phase: The abnormal cells are in the person’s blood, bone marrow, and spleen but are still developing slowly. Most people (approximately 90 percent) are diagnosed in chronic-phase CML. In this phase, differentiated cells persist, although they often show increasing morphological abnormalities^[1][4][8].

Accelerated phase: Patients with accelerated-phase CML show signs of progression without meeting the criteria for blast crisis. Signs include progressive splenomegaly, increased leukocytosis and/or thrombocytosis, and progressive anemia. The patient experiences increased anemia, thrombocytopenia, and marrow fibrosis^[8][12].

Blast phase (or blast crisis): This phase is a sudden increase in blast cells (immature blood cells) in the bone marrow and blood. The disease suddenly begins to develop more quickly. Additional signs include thrombocytopenia, increasing and painful splenomegaly or hepatomegaly, fever, bone pain, and development of destructive bone lesions. Approximately 90 percent of patients are diagnosed in CP-CML, but CML can progress to accelerated phase or blast phase, which are fast-growing and hard to treat^[1][3][4][8].

Transition between the chronic, accelerated, and blastic phases may occur gradually over one year or more, or it may occur abruptly^[8][12].

Symptoms

Chronic myeloid leukaemia often doesn’t cause symptoms in the early stages. It might be detected during a blood test. Sometimes CML does not cause any symptoms at all^[2][6][7].

When symptoms do occur, they may include^[2][6][7]:

• Feeling very tired or weak (fatigue)
• Weight loss without trying
• Fever
• Drenching night sweats (excessive sweating during sleep)
• Frequent infections
• Loss of appetite
• Pain or a feeling of fullness below the ribs on the left side
• Bone pain
• Bleeding easily
• Blurry vision caused by bleeding in the back of the eye

Although CML may present without symptoms, an enlarged spleen (splenomegaly) is the most common finding during physical examination at the time of diagnosis. The spleen may be enormous, filling most of the abdomen, causing pain or a feeling of fullness and presenting a significant clinical problem, or it may be only minimally enlarged. In about 10 percent of patients, the spleen is neither palpable nor enlarged on imaging^[8][12].

Causes and risk factors

The exact cause of CML is not fully understood. It is hard to predict who will get CML. However, there are a few factors that could raise a person’s risk^[7][12]:

• Age: Risk increases with age. CML typically affects older adults and rarely occurs in children, though it can occur at any age^[2][7].
• Gender: CML is slightly more common in men^[7].
• Radiation exposure: Exposure to high-dose ionizing radiation or being accidentally exposed to very high levels of radiation^[7][12].

The Philadelphia chromosome is not passed from parent to child. It is not inherited and is not caused by anything a person did or did not do^[6][7].

Diagnosis

Tests and procedures used to diagnose chronic myeloid leukaemia include a combination of physical examination, medical history, and specialized tests^[7][12][13].

Physical examination: The health care provider examines the patient and checks vital signs such as pulse and blood pressure. The provider also feels lymph nodes, spleen and abdomen for swelling^[13].

Blood tests: A sample of blood is drawn using a needle and sent to a lab for a complete blood count (CBC). A CBC checks the number of different types of cells in the blood. Chronic myeloid leukaemia often causes a very high number of white blood cells. Blood tests also can measure organ function. Blood chemistry tests measure different substances in the blood, including electrolytes, fats, proteins, glucose (sugar), and enzymes^[7][13].

Bone marrow tests: Bone marrow biopsy and bone marrow aspiration are used to collect bone marrow samples for testing. Bone marrow has a solid and a liquid part. In a bone marrow biopsy, a needle is used to collect a small amount of the solid tissue. In a bone marrow aspiration, a needle is used to draw a sample of the fluid. The samples are typically taken from the hip bone and sent to a lab for testing^[7][13].

Tests to look for the Philadelphia chromosome: Specialized tests are used to analyze blood or bone marrow samples for the presence of the Philadelphia chromosome or the BCR-ABL gene. These tests may include fluorescence in situ hybridization analysis. Using peripheral blood, molecular techniques can detect the presence of the chromosome 9;22 translocation^[8][13].

If CML is diagnosed, additional tests such as imaging tests may be performed to see whether the cancer has spread^[7].

Treatment

With five BCR-ABL tyrosine kinase inhibitors approved in the United States for the treatment of chronic-phase CML, it is generally thought to be a manageable disease. Advances in treatment have improved the prognosis of people with chronic myeloid leukaemia. Most people can achieve remission and live for many years after diagnosis^[2][4].

Tyrosine kinase inhibitors (TKIs): These are the main treatment for CML. TKIs are medicines that target the abnormal BCR-ABL protein. When TKIs are taken correctly as prescribed (called compliance), CML has a favourable prognosis. Imatinib remains the most prescribed therapy for CML worldwide and the TKI of choice as frontline therapy for many clinicians, despite it being the least potent TKI and most prone to resistance and progression^[4][11][16].

Second-generation TKIs are more potent than imatinib and induce a more rapid and deeper molecular response overall. They are also more effective at preventing resistance and disease progression. However, the higher potency of second- and third-generation TKI has always been linked to greater toxicity, which has limited the advantage of these drugs over imatinib^[11].

Asciminib is a newer type of treatment called a STAMP (specifically targeting the ABL myristoyl pocket) inhibitor. It is the first STAMP inhibitor and binds to a different part of the BCR-ABL protein than other TKIs. Its specificity minimizes off-target toxicity. After a decade of clinical trials, both in patients with resistance and intolerance to two or more TKI and more recently in the frontline setting, asciminib is fulfilling its early promise of a more rapid and reliable pathway to long-term disease control with minimal toxicity^[11].

Most people with CML will need to learn to live with taking daily medicines and the side effects. They will need regular blood tests and hospital visits. Many people face uncertainty and worry about how well treatment is working and what will happen next. With time and support, many people manage to adjust to life with CML^[14].

Many people worry about whether the treatment will work. The fortunate few go on to achieve treatment-free remission, but even in these 20 to 30 percent of patients, treatment-free remission is only successful after many years of TKI therapy^[11].

Prognosis and survival

Prognosis and survival depend on many factors. Only a doctor familiar with a person’s medical history, type of cancer, phase, characteristics of the cancer, treatments chosen and response to treatment can put all of this information together with survival statistics to arrive at a prognosis^[16].

The outlook for CML patients is mixed. Most will achieve good disease control and can expect a near-normal survival, but many experience significant side effects and toxicities which impact quality of life. Around 10 to 20 percent have poor responses to several lines of therapy. Even with available CML treatments, approximately 30 percent of patients do not survive five years. This sobering statistic points to areas where improved care is needed^[4][11].

Prognostic factors that influence prognosis include^[16]:

• Taking medicine correctly: When TKIs are taken as prescribed, CML has a favourable prognosis.
• Age: People who are older than 60 years of age have a less favourable prognosis than people younger than 60.
• Phase: CML that is in the accelerated or blast phase at the time of diagnosis has a less favourable prognosis than CML that is diagnosed in the chronic phase.
• Philadelphia chromosome presence: Ph-positive CML has a more favourable prognosis than Ph-negative CML.
• Additional chromosome abnormalities: These genetic changes increase the risk that CML will progress or stop responding to treatment.
• Enlarged spleen: If the spleen is larger than normal at diagnosis, the prognosis is less favourable.
• Platelet count: Having a very low or a very high platelet count at diagnosis is a less favourable prognostic factor.

Many people with CML are diagnosed in the chronic phase. Their disease is low risk and treatable. Doctors might tell these patients that they can expect to have the same length of life as people without CML. However, some people are diagnosed in the accelerated or blast phase. Unfortunately it can be harder to control this stage of CML^[14].

Chronic cancers like CML will always be part of a person’s life. It is different from some other types of cancer that go away when treatment ends. Although some people can eventually stop treatment, for many people there isn’t an end to the treatment or tests. With time and support, many people manage to adjust to life with CML^[14].