Chronic Myeloid Leukemia (CML) occurs when the bone marrow makes too many white blood cells relative to the other components of the blood. Only about 10% of leukemias are CML. In CML, a genetic change takes place in a blood forming stem cell; also called a hematopoietic stem cell (HSC). Everyone is born with a few tens of thousands of HSCs that are the source for all of the red blood cells, platelets, and white blood cells that people make throughout their life. In CML, the genetic change, called a mutation, in HSCs connects two genes together, or fused, to yield a new mutated gene that makes the HSCs turn into CML cells. The abnormal gene fusion is called BCR-ABL and it causes HSCs to yield many more white blood cells than are needed by the body. The production of too many white blood cells is called leukemia (Greek: leukos meaning white, h/aima referring to blood). Leukemia cells expand and divide, building up in the bone marrow and then entering the bloodstream. Typically, CML is a slow-growing leukemia, however, it can also change into a fast-growing acute leukemia. If it changes, it becomes more difficult to treat.
Factors that increase the risk of CML are older age, being male, and radiation exposure, such as radiation therapy used to treat certain types of cancer. Common signs and symptoms of CML include easy bleeding, fatigue, fever, weight loss, pain or fullness below the ribs on the left side, pale skin, and sweating excessively during sleep. Some patients have no symptoms, and CML comes to medical attention after routine blood testing.
The ABL portion of BCR-ABL is a signaling protein called a “tyrosine kinase” and when the ABL gene is fused to BCR, yielding BCR-ABL, the ABL tyrosine kinase is always “on” signaling to cells to increase in number. Targeted drugs that block the abnormal signals from the BCR-ABL are called “tyrosine kinase inhibitors” or “TKIs”. While all patients are unique, TKIs are extremely effective for many patients. For example, imatinib and other drugs that target the BCR-ABL protein (dasatinib, nilotinib, bosutinib, posatinib) can eliminate almost all of the CML cells in the body. Indeed, for most patients these drugs are so effective that the CML cells can only be detected by a very sensitive molecular technique called “polymerase chain reaction” or “PCR”.
Although most patients with CML do very well, some patients have CML that becomes more aggressive (so called accelerated phase) or even converts to an acute leukemia (called “blast phase”). Sometimes, patients first come to medical attention already with accelerated or blastic CML. Accelerated and blastic CML are much more difficult to treat than “chronic phase” CML. TKIs do not work as well or for as long in accelerated phase CML and often, patients with blastic CML are treated with strong chemotherapy. Hematopoietic stem cell transplantation is often considered for patients with accelerated or blastic CML. Studies are being conducted to determine whether new drugs or combinations of drugs may provide better clinical outcomes. This is an active area of research.
All of the below tyrosine kinase inhibitors (TKIs) have very specific activity in CML. In general, worldwide the most frequently used drug is imatinib because it has the least side effects. If patients become resistant or intolerant to imatinib, dasatinib or nilotinib are used most often. In patients with a BCR-ABC T315I mutation, Ponatinib is used.