By MedHelp Editors
Chronic myelogenous leukemia, or CML, is a type of slow-progressing cancer of the white blood cells. CML starts in the bone marrow where white blood cells are produced. White blood cells are part of the immune system and help to fight off infection.
CML is almost always associated with a chromosomal abnormality called the Philadelphia chromosome. The Philadelphia chromosome produces a protein called BCR-ABL which causes too many stem cells to develop into white blood cells. Unlike other blood cells, these new, diseased white blood cells don't die off, instead they accumulate in the body. Eventually these diseased cells crowd out other healthy blood cells and damage the bone marrow, spleen, liver and blood, and then spread to other parts of the body.
CML is highly treatable when detected in the first phase of the disease, call the chronic phase. There is no cure for CML. But targeted therapy drugs such as imatinib (Gleevec), dasatinib (Sprycel) and nilotinib (Tasigna) are highly successful in putting the disease into remission for an indefinite period of time.
CML occurs when something goes wrong in the genes of the blood cells, but doctors aren't sure what initially triggers CML to develop. About 90 percent of patients with CML have developed an abnormal chromosome in their blood cells called the Philadelphia chromosome. Doctors aren't sure what causes this abnormal chromosome.
"This chromosomal abnormality probably happens in people all the time and is recognized as an abnormality and deleted," says Matt Kalaycio, MD, director of the Chronic Leukemia and Myeloma Program at the Cleveland Clinic. "But for whatever reason, in some people, it happens and it stays."
High doses of radiation, such as those from cancer treatment, may lead to the development of CML. However, most people who receive radiation treatment for cancer do not develop CML and most people with CML have not been exposed to high doses of radiation. Dental and medical x-rays have not been linked to CML.
Named after the city in which it was discovered, the Philadelphia chromosome is a chromosome that develops because of an abnormality in the cells. It is formed when a section of chromosome 9 switches places with a section of chromosome 22, creating an extra-long chromosome 9 and an extra-short chromosome 22. The extra-long chromosome 22 is the Philadelphia chromosome.
The Philadelphia chromosome produces a new gene called BCR-ABL (BCR comes from the original chromosome 22 and ABL comes from the original chromosome 9). The BCR-ABL gene instructs the blood cells to produce too much of a certain enzyme called tyrosine kinase. Tyrosine kinase causes blood stem cells (which are different from embryonic stem cells) to produce too many white blood cells. These new white blood cells are not like normal cells in that they grow out of control and do not die as they should. This crowds out healthy blood cells, leading to damage to the bone marrow. Eventually the diseased blood cells infect other areas of the body.
No, CML is not hereditary, meaning it cannot be passed from parent to child. The Philadelphia chromosome is limited to cells in the blood. "Blood cells are not passed from mother to fetus," says Dr. Kalaycio.
CML is rare, affecting one to two out of every 100,000 people, most often middle-aged adults, and makes up 7 - 20 percent of total leukemia cases. CML rarely occurs in children. The National Cancer Institute estimated that just over 5,000 new cases of CML were diagnosed in 2009, and that approximately 22,500 people are living with CML in the United States.
Though scientists aren't exactly sure, time, in terms of advanced age, probably explains why CML occurs more often in adults than children. Because CML is caused by a chromosomal abnormality, the probability that an abnormality will occur increases each time the genes replicate, explains Dr. Kalaycio. An adult's genes have replicated millions of more times than a child's genes and therefore have a higher likelihood of developing the abnormality.
Because CML often does not cause any symptoms in the early stage of the disease, "the most common way a person who is later diagnosed with CML comes to attention is by a routine complete blood count done for some unrelated reason, for example, through a routine physical or preoperative testing," says Dr. Kalaycio.
When symptoms do present, they tend to be general, flu-like symptoms such as:
- Night sweats
- Weight loss
- Bone pain
- Pain on the left side of the abdomen
- Feeling full quickly or inability to eat large amounts of food (caused by an enlarged spleen)
Most often a blood test or a bone marrow test is used to test for and diagnose CML. A bone marrow test requires that a small sample of bone marrow be removed for testing. This is done by either a bone marrow biopsy or bone marrow aspiration procedure. Often a bone marrow biopsy and bone marrow aspiration are performed at the same time.
Because it is currently unknown what causes CML, presently there are no known ways to prevent chronic myelogenous leukemia.
Chronic myelogenous leukemia has three distinct phases:
Currently, chronic phase CML is almost always treated with imatinib (Gleevec). Gleevec, which was approved in 2001 as front-line treatment for CML, is a type of drug called a tyrosine kinase inhibitor and works by blocking the tyrosine kinase enzyme which produces the disease white blood cells (blast cells). The 8-year survival rate for Gleevec is 85 percent, meaning that the disease is in remission for 85 percent of people who have been taking Gleevec since the drug was first approved. About 15 to 20 percent of people with chronic phase CML are not able to take Gleevec either because they don't respond to treatment or they cannot tolerate the side effects, according to Dr. Kalaycio.
The goal in treatment of chronic phase CML is to kill all cells that have the BCR-ABL cancer gene and bring blood cell levels to a normal range.
In June 2010, the FDA approved the drug nilotinib (Tasigna) to treat newly diagnosed adult patients with chronic phase CML who test positive for the Philadelphia chromosome (Ph+ CP-CML). Recent clinical trials showed that Tasigna works better than Gleevec in as front-line treatment for chronic phase CML. Prior to this new indication, Tasigna has been approved since 2007 to treat adults with chronic phase CML who test positive for the Philadelphia chromosome and do not respond to Gleevec, or for adults with accelerated phase CML.
The drug dasatinib (Sprycel) is also approved by the FDA to treat people who don't respond to Gleevec. A recent study showed that Sprycel also works better than Gleevec as initial treatment for chronic phase CML. These results may lead the FDA to consider an expanded indication for Sprycel, similar to that of Tasigna.
Once a person has started medication treatment for CML, he or she must continue taking the drug(s) for the rest of their life or for as long as they are responding to the treatment.
If drug therapy (including switching drugs) doesn't bring chronic phase CML into remission with 18 months, stem cell transplantation is considered.
Accelerated or blast phase CML may be treated with Gleevec, Tasigna or Sprycel or other types of drugs such as interferon. If a person doesn't respond to medication or he is diagnosed with a T315I mutation (a mutation of the Philadelphia chromosome), stem cell transplantation is considered.
Side effects are different for each type of medication, but generally include nausea, swelling, diarrhea and other symptoms.
When people first start taking CML medication like Gleevec, their blood count must be monitored relatively often to make sure it doesn't get too low.
"The first milestone that we want to see is a complete hematologic remission by three months," says Dr. Kalaycio. "That means that we want the blood count to be normal and the spleen not to be felt. Now that's not what's happening in the bone marrow necessarily, at this stage, it's just in the blood."
Patients who don't achieve that milestone are often switched to another medicine.
"At six months, we want to see some degree of suppression of the Philadelphia chromosome in a bone marrow test," explains Dr. Kalaycio. "It doesn't have to be complete suppression, but it has to be something. We continue to check bone marrow biopsies every six months until the Philadelphia chromosome is no longer present."
Patients who achieve complete cytogenetic remission by six months, meaning that the Philadelphia chromosome is not longer present in a blood or bone marrow test, have a high chance of keeping their CML in remission forever.
"By 18 months of therapy, we need to see no Philadelphia chromosome in a bone marrow test. If it is still present at 18 months, that means therapy hasn't gone as well as we would have liked and we would consider either switching drugs or we consider a stem cell transplant because the pills just simply aren't working that well."
Patients who don't get a complete cytogenic remission by 18 months are unlikely to do so, according to Dr. Kalaycio, and are at increased risk of the disease progressing to accelerated or blast crisis phase.
The current recommendation for women who are on Gleevec is not to become pregnant.
"There are reports of healthy babies being born from patients on Gleevec, but there are also reports of unhealthy babies being born on Gleevec," says Dr. Kalaycio. "So the recommendation is not to do it."
Obviously, that can be difficult news for women who wish to conceive and are on Gleevec. But there are ways to allow for a pregnancy under certain circumstances.
"I would recommend consultation with a leukemia doctor who has experience in working in these situations before just stopping the pill and trying to get pregnant," advises Dr. Kalaycio.
People who have achieved remission of CML with drugs such as Gleevec, should be aware of and on the lookout for two important issues, according to Dr. Kalaycio.
The first issue is medication compliance — you've got to keep taking your medicine for the rest of your life, even if you feel better.
"The biggest problem we have with Gleevec is the person not taking their medicine," says Dr. Kalaycio. "If treatment milestones [like those mentioned above] aren't being met, my first question is, 'Are you taking your medicine?'"
In Dr. Kalaycio's experience, common reasons people who stop taking their medicine include the cost of treatment, that the person feels better and that they think because their disease is in remission they can discontinue treatment.
The second issue is that Gleevec can negatively interact with other drugs, especially some cholesterol-lowering drugs like statins. The toxicity of other drugs can be increased when you're on Gleevec, says Dr. Kalaycio. Be sure to tell every physician who is treating you that you are currerntly taking Gleevec and also inform your leukemia doctor of any new drugs you have been prescribed.
"Unlike other leukemias, there is no immune deficiency in CML, so you don't have to worry about excess risk of infection," says Dr. Kalaycio. With CML, your immune system is perfectly intact and no additional precautions need to be taken to prevent infection, such as wearing a mask in public.
No. CML is not hereditary. So even if your parent has CML, you are not necessarily more likely to develop the disease. And because the disease is relatively rare and does not typically present symptoms in its early phase, screening is unnecessary.