Today, patients with CML take imatinib or other drugs that work in a similar way (nilotinib and dasatinib), and in most cases, the disease seems to disappear and often stays in remission for many years. Imatinib was the first true therapy targeted to a specific gene mutation that affects the cells that develop into white blood cells and other blood cells. Nilotinib and Dasatinib followed as additional options for patients. If the first therapy that a patient takes stops working or the patient has severe side effects, their doctor will prescribe a different product. A different product may work better or have less severe side effects.
That mutation, known as the Philadelphia chromosome, was discovered decades ago. Researchers used innovative new technology to discover a substance that would block the abnormal activity of the mutated gene--and a whole approach to cancer treatment was born. Today targeted therapies are used to treat many kinds of cancer.
How is CML different from other forms of leukemia?
All leukemias are cancers of the blood or the bone marrow, the substance inside our bones that forms blood cells, and are characterized by the growth of too many of a specific types of blood cells. In the case of CML, these cells are called granulocytes. CML is one of four major types of leukemia. It is called chronic because it usually progresses slowly over a period of months or years.
There are approximately 5,150 new cases of CML diagnosed each year, accounting for 15% of all leukemias. The majority of cases are in people over the age of 55. CML is very rare in children and younger people. CML is a rare disease. The only known risk factor is exposure to high levels of radiation but most people who have that kind of exposure do not develop CML. It does not run in families.
Researchers have discovered a specific mutation that appears to be directly linked to CML, called BCR/ABL. This abnormal, or mutated gene is formed when parts of two of our chromosomes switch places with each other, known as a translocation. In CML, this translocation, or exchange of genetic material takes place between chromosomes 9 and 22. The shorter chromosome known as the Philadelphia chromosome (PH) is the hallmark of CML and is found in 95-100% of CML patients. CML is often referred to as PH+ CML. The ABR/ABL gene is found on the Philadelphia chromosome. It results in the over production of a specific type of protein called tyrosine kinase.
The protein causes too many granulocytes, a type of white blood cell, to be formed. In addition to there being too many granulocytes, they are abnormal, immature in appearance and the way they function in blood and bone marrow. In CML, this happens very slowly, but as the abnormal white cells accumulate, they crowd out normal cells and weaken the body's ability to fight infection.
Many people don't have any signs or symptoms of CML. It is not unusual for it to be discovered when a person has blood work or laboratory tests for some other reason. When people do experience symptoms, they can include
Sometimes people will realize after the blood test reveals the leukemia that they have been experiencing these symptoms for a period of time but had not thought they were significant or attributed them to other causes or conditions. These are also symptoms of other conditions, both cancerous and non-cancerous.
If a blood test comes back with abnormal results or your doctor suspects you may have CML, you will need a variety of tests to confirm the diagnosis and determine the phase of your disease. CML has three phases which are explained below. These tests involve a complete medical history and physical examination which includes an assessment on the size of your spleen.
Your spleen is part of your body's circulatory system. It plays a number of important roles in making, storing and breaking down blood cells. It is common for the spleen to become enlarged when people have leukemia.
You will also need additional blood tests. These include basic tests such as CBC, complete blood counts and more sophisticated analyses of the cell's chromosomes, known as cytogenetics and molecular testing. Almost everyone with CML has the Philadelphia chromosome or the BCR/ABL gene, so this is an important indicator for this disease. It can be used either to confirm the diagnosis or, if the gene is not present, to indicate another kind of leukemia. An additional, highly sensitive test determines the levels of BCR/ABL in the blood and marrow. This is called molecular or PCR testing for polymerase chain reaction test.
In many cases, it is not possible to do the full analysis using blood obtained from blood from outside the bone, known as peripheral blood. It may be necessary to obtain a blood sample from the bone marrow through an aspiration and/or a biopsy. These procedures are done together and involve withdrawing bone marrow in both a semi-liquid and solid state using a needle. The marrow is then sent to the pathologist for examination. In addition to testing for the presence of the PH chromosome and BCR/ABL protein, the pathologist will count the number or immature, abnormal white cells, known as blasts that are found in the specimen.
These tests are critical to making an accurate diagnosis, but they are also important in tracking the response to treatment. Doctors use the results as the basis to measure pre and post treatment blood counts, blood chemistry, the presence of the PH chromosome and the BCR/ABL protein.
You may also have imaging tests, such as CT scans or ultrasound examinations to determine if the cancer is affecting other parts of your body. This is often used to look at the size of the spleen in patients with CML.
CML has three phases: chronic, accelerated and blast. Knowing the phase of CML is important to planning treatment.
Chronic phase: This is the earliest phase of CML, the one in which many people do not experience symptoms or have only mild symptoms such as a feeling of tiredness or fullness. Their bodies are still able to fight infection. In medical terms, people in the chronic phase has less than 5% blasts or immature leukemia cells. About 90% of patients are diagnosed in the chronic phase which can last for several years.
Accelerated phase: In this phase, the cancer becomes more aggressive. There are now more than 5% but fewer than 30% blasts. The spleen typically becomes enlarged. New chromosome changes, or genetic mutations appear in the cells. People often develop symptoms during this phase including unexplained fevers.
Blast phase: This is the final, life threatening phase for CML. Patients have more than 30% blasts in their peripheral blood and bone marrow, and often become very ill with fever, weight loss, loss of energy and appetite and other problems. The blast phase is very much like what people experience when they have acute leukemia. Without effective treatment, all CML patients will progress from the chronic to the accelerated to the blast phase of their disease.
CML should be treated by an oncologist or hematologist experienced in treating this form of cancer. The treatment will depend on the phase of your CML and on your overall health and physical condition. There are now a number of treatment options for CML.
Imatinib was the first successful targeted therapy used to treat CML and it remains a first line treatment for this disease, but there are other drugs that work using the same mechanism to block the development of abnormal white blood cells. These drugs, dasatinib and nilotinib can be used if imatinib begins to lose its effectiveness or if, for some reason, a patient cannot tolerate imatinib or the other drugs that work in the same way that it does. A new agent, bosutinib, was approved to treat chronic, accelerated or blast phase PH positive CML leukemias in adults who cannot take other drugs, or whose disease progressed.
These are often referred to as TKI therapies or kinase inhibitors because they work by blocking or inhibiting the action of an enzyme known as tyrosine kinase. The abnormal BCR/ABL gene results in the production of too much of this enzyme which allows cells to grow and reproduce in an uncontrolled way. Targeted therapies are effective because they are directed at a specific feature the cancer cell requires to grow and survive.
Imatinib is given in a pill form. It does have some side effects but most patients find them mild and are able to tolerate the drug very well. Nearly all patients with chronic phase CML have complete remissions when they begin taking Imatinib. Their blood counts return to normal. Their spleens shrink. In 80-90% of chronic phase patients, the cells containing the abnormal chromosome or gene disappear, which is very important.
Imatinib doesn't cure CML. It most likely will come back if you stop taking Imatinib, but a very high percentage of patients who begin taking Imatinib during the chronic phase remain in remission for years. Some patients from the original clinical trials begun in 1999 are still in complete remission.
Patients taking Imatinib or any of the targeted therapies will be closely monitored every three months to see if the treatment is working. If the targeted therapy is not achieving a complete response, the doctors may change either the dose or the drug, or discuss the possibility of stem cell transplant with you. Some patients have a separate gene mutation that makes TKI targeted therapies ineffective. For this group, stem cell transplantation may be the best option.
A stem cell transplant is a medical procedure in which diseased bone marrow is replaced by highly specialized blood cells called hematopoietic stem cells. These cells are taken from a healthy donor whose cells match the patient's and given to the patient by an infusion. In order to make the stem cell transplant work, it is necessary to destroy the patient's bone marrow first using radiation and chemotherapy.
In the past, when CML was inevitably a fatal disease, stem cell transplants were viewed as first line therapy for patients who were in overall good health. Today, with the success of Imatinib and other targeted therapies, stem cell transplant is used far less frequently. The procedure itself has severe side effects and can even be life threatening. It is, however, the only treatment that has the potential to actually cure CML. For patients who have advanced to the accelerated or blast phase, or are resistant to TKIs, it may be the only effective treatment for their CML.
Studies show that stem cell transplants work best for younger patients, (under age 65), in the chronic phase who have not responded well to targeted therapies. The decision to have a stem cell transplant for CML is a complex one that should be made by you and a team of doctors who are very experienced in treating all phases of CML.
Doctors are able to monitor whether the treatments for CML are working by using three different kinds of tests. These tests allow doctors and patients to check the progress of their treatment. It's important for patients to understand these tests, know their results, make sure that they are monitored on a regular basis. The tests are:
Hematologic Response (HR): These are blood tests that count the number of each kind of blood cell to determine if there are the right numbers of cells in relationship to each other. Hematologic tests also determine whether the numbers of CML cells--abnormal blood cells--have decreased. The goal of a complete hematologic response is to have CML cells decrease to one-tenth of what they were before treatment.
--Time Frame: The goal of treatment is to achieve a complete HR within three months of starting therapy. Patients get hematological testing every 15 days until a complete HR is achieved and then every three months after that.
Cytogenetic Response (CR): This test checks to see if the PH chromosome is still present in the blood and marrow cells. The goal is to have the PH chromosome levels decrease to one-hundredth of what they were before treatment is started.
--Time Frame: The goal is to achieve a complete cytogenetic response within 12 months of starting treatment. Patients are tested every six months for the first year, and then yearly after that.
PCR or Major Molecular Response (MMR): This is a super sensitive test that detects the presence of the abnormal protein, BCR/ABL in the blood and marrow. It can find one cell with BCR/ABL in one million normal cells. The goal of treatment is to reduce BCR/ABL by 1000 times what is was before treatment was started.
--Time Frame: The goal is to achieve a complete MMR within 19 months of starting treatment. Patients are tested every three months after that.
Since CML is a chronic disease, patients will need to have these tests for the rest of their lives. It's a normal part of life for a CML patient to know his or her scores and follow them closely. If the tests indicate that the disease has progressed or the treatment has stopped working, these tests provide a basis for changing the therapy.
CML is a fairly rare form of leukemia which affects primarily people over the age of 55. Little is known about the risk factors for this disease, but doctors do know that it is caused by a specific genetic mutation found in all patients with CML. This mutation provides a target for a special class of drugs known as TKIs that block the production of abnormal white blood cells or blasts that are characteristic of CML. The introduction of targeted therapies has dramatically changed the outlook for CML patients. Many of them have long lasting, complete remissions and live very normal lives--even though they are never actually cured of their CML. The transformation of CML from a fatal disease to truly chronic condition is one of the success stories for cancer research and treatment--and has laid the groundwork for many more targeted treatment for a wide spectrum of cancers.