Causes and Risk Factors of Leukemia

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radiation is one of the risk factors for leukemia
Can exposure to radiation cause leukemia?. Credit: © Maggie Dziadkiewicz | Dreamstime.com

While the exact causes of leukemia are unknown, several known, as well as possible causes and risk factors for the disease have been identified. Known risk factors vary with the different types of leukemia but include radiation (from atomic bomb exposures to medical radiation), exposures to chemicals such as benzene and pesticides, previous chemotherapy, some infections, and certain genetic conditions.

A few of the possible risk factors that have been studied include Splenda (sucralose), electromagnetic fields such as high voltage power lines, coffee, and radon. Chronic leukemia is much more common in older adults, and though acute leukemia is often thought of as being a childhood cancer, acute myeloid leukemia is actually much more common in adults. For unknown reasons, men are more likely than women to develop the four major types of leukemia.

We aren't certain exactly what causes leukemia, but a series of mutations in genes that control the growth of the cell leads to uncontrolled growth of these cells in the bone marrow. Risk factors for the disease can be broken down into those that are fairly well substantiated, and those that may possibly raise risk, but the relationship is still uncertain at this time.

Known and Probable Risk Factors

There are several risk factors for the development of leukemia that have been documented in a number of studies.

A risk factor is something that is associated with an increased risk of developing leukemia but does not necessarily cause the disease. Some of these include:

Age

Age as a risk factor for leukemia varies widely with the type of leukemia. Together, acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML) account for 30 percent of childhood cancers.

While many people consider these diseases childhood cancers, AML is actually much more common in adults (the average age at diagnosis is 68) and around 40 percent of cases of ALL are in adults. When ALL is diagnosed in childhood, it is most common in children under the age of 5 years. Chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML) are much more common in older adults, and are very uncommon in people under the age of 40.

Gender

The primary types of leukemia (AML, ALL, CML, and CLL) are slightly more common in males than females, but the reasons for this are unknown.

Birth Weight

Children who have high birth weights (weight at birth greater than 8.9 pounds or 4000 grams) have a greater risk of developing ALL.

Ethnicity

Racial differences in incidence differ between the types of leukemia. ALL has the highest incidence in Hispanic whites, followed by non-Hispanic whites and Asian and Pacific Islanders, with the lowest incidence in blacks. CLL is more common in non-Hispanic whites, followed by blacks, with the lowest incidence in Hispanics and Asian and Pacific Islanders. AML is similar among people of different ethnic backgrounds during childhood, but in adults is more common in non-Hispanic whites.

CML is most common in non-Hispanic whites followed by blacks and then Hispanics, with the lowest incidence in Asian and Pacific Islanders.

Radiation

Some types of radiation are a known risk factor for leukemia, and others are only possible risk factors. There are two primary types of radiation:

  • Non-ionizing radiation: This type of radiation is fairly weak, and includes the type that is emitted from a cell phone or computer terminal. While some concerns have been raised, such as the concern about brain tumor risk and cell phones, the risk is considered relatively small.
  • Ionizing radiation: In contrast, ionizing radiation has been linked to leukemia. This type of radiation has much more energy, enough to break certain chemical bonds, remove electrons from atoms, and damage DNA in cells.

    There are a number of different ways in which ionizing radiation has been associated with leukemia. These include:

    • Atomic bomb radiation: Survivors of the Hiroshima and Nagasaki atomic bombings had a significantly increased risk of developing leukemia.
    • Nuclear accidents: Survivors of the 1986 Chernobyl nuclear reactor disaster had an increased risk of leukemia two to five years after the meltdown. Those who were highly exposed had twice the risk of developing leukemia as those not exposed.
    • Medical diagnostic radiation: Ionizing radiation was found to be carcinogenic (or cancer-causing) only a few years after X-rays were discovered, and concern has been raised in recent years over the danger of too much medical radiation, particularly in children. The risk varies, with imaging tests such as CT scans, bone scans, and PET scans involving much more radiation than plain x-rays. (MRI scans use magnets and do not involve exposure to radiation)
    • Medical therapeutic radiation: Radiation therapy for cancer can increase the risk of developing leukemia (especially AML), with the risk highest in the period five years to nine years after radiation. The risk varies with the site of radiation as well as the dose used.
    • Radioactive iodine therapy: Receiving radioactive iodine therapy as a treatment for hyperthyroidism or thyroid cancer is associated with an increased risk of leukemia, with the risk of AML being 80 percent higher than for those who didn't receive this therapy. The risk is even higher for CML, with those exposed having a risk 3.5 times higher than average.
    • Air and space travel: Air flight, especially over the far north, involves exposure to cosmic radiation, but this amount of ionizing radiation is relatively small. The leukemia risk from space travel due to galactic cosmic rays, however, is a subject of great interest among those looking at travel to places such as Mars in the future.
    • Radioactive materials: Uranium mining as an occupation increases the risk of leukemia. There has also been concern about exposure to radioactive material in tobacco products, which pick up these materials in the soil where they are grown.
    • Radon: Radon is an odorless, colorless gas that is released by the normal decay of uranium in the soil beneath our homes in our homes. Radon is the second leading cause of lung cancer after smoking. The association of radon with leukemia is relatively recent, and came about because areas that have a higher incidence of CML (the north and central states) have higher radon levels.

    Previous Chemotherapy

    While the benefits of chemotherapy usually far outweigh the risks, some chemotherapy drugs can predispose a person to leukemia later on. This is true even for the drugs commonly used for early-stage breast cancer. For most of these drugs, the risk begins to increase 2 years after treatment, and peaks between 5 years and 10 years after treatment. 

    Acute myeloid leukemia (AML) is the form of leukemia most often associated with chemotherapy, but ALL has also been linked. Examples of drugs associated with leukemia include Cytoxan (cyclophosphamide), Leukeran (chlorambucil), VePesid (etoposide), Vumon (teniposide), Gleostine, CeeNu, and CCNSB (lomustine), Gliadel and BiCNU (carmustine), Myleran (busulfan), Mustargen (mechlorethamine), and  Novantrone (mitoxantrone).

    Drugs such as Adriamycin (doxorubicin) and other anthracyclines, Platinol (cisplatin) and other platinum drugs, and bleomycin have been associated with leukemia but less commonly than the drugs mentioned earlier.

    Medical conditions

    Some medical conditions are associated with an elevated risk of developing leukemia. Myelodysplastic syndromes are disorders of the bone marrow that have been referred to as "preleukemia" and carry a significant risk of developing into AML (up to 30 percent). Other conditions such as essential thrombocytopenia, primary myelofibrosis, and polycythemia vera also carry an increased risk. People who are immunosuppressed, such as those who take immunosuppressive medications due to an organ transplant, have a significantly increased risk of developing leukemia.

    Associations have been noted between leukemia in adults and medical conditions such as inflammatory bowel disease (ulcerative colitis and Crohn's disease), rheumatoid arthritis, systemic lupus erythematosus (lupus), celiac disease, and pernicious anemia, among others. A large 2012 study looking into these associations, however, did not find a link between most of these conditions and leukemia. The study did find an increased risk of AML in people with ulcerative colitis and CML in people with peptic ulcer disease. (Genetic syndromes associated with leukemia are discussed below.)

    Home and Occupational Exposures

    There are a number of exposures that have been associated with leukemia, though the risk varies with the different types of the disease. Some of the substances have been linked clearly in many studies, while others are still uncertain. Some of these include:

    • Benzene: Benzene is a known carcinogen that is present in a number of materials, such as some paints, solvents, plastics, pesticides, detergents, and unleaded gasoline. Benzene is also a byproduct of the combustion of coal. Benzene in tobacco smoke is thought to be one of the reasons why smoking is strongly linked to AML. Maternal and childhood exposure to paint at home is associated with an elevated risk of ALL. Home use of petroleum solvents is associated with an increased risk of childhood AML. 
    • Home pesticide exposures: Pesticide exposure during pregnancy and childhood appears to be associated with an increased risk of leukemia according to several studies.
    • Contaminated drinking water: An increased risk of leukemia was found among those at a U.S. Marine Corp base camp in North Carolina that was contaminated by a solvent between 1950 and 1985.
    • Formaldehyde: Medical workers and embalmers have an increased risk of leukemia (myeloid leukemias). When people think of formaldehyde, a lab or embalming fluid may come to mind, but many people are exposed to formaldehyde through the "off-gassing" of formaldehyde from pressed wood products (such as particleboard, plywood, and fiberboard). Formaldehyde exposure such as this is considered to be a known carcinogen, but it's not clear what level of exposure (amount or duration) might be a problem. Other sources of formaldehyde include some glues and adhesives, some insulation materials, and some paper product coatings. Like benzene, formaldehyde is also found in tobacco smoke.

    Noting that the incidence of childhood leukemia has been increasing in California, studies are in progress looking at environmental exposures that may be associated with this risk.

    Infections

    Infection with the Human T-Cell Leukemia Virus (HTLV-1) increases the risk of leukemia. The virus is a retrovirus (similar to HIV), and infects the type of white blood cells known as T lymphocytes or T cells. HTLV-1 is spread in a way similar to HIV and can be transmitted through blood transfusions, through sexual contact, by sharing needles among IV drug abusers, and from a mother to a child during delivery or through breastfeeding.

    HTLV-1 is relatively common in the U.S., but is found in the Caribbean (especially Haiti and Jamaica), Japan, central and west Africa, and Middle East (especially Iran). It's thought that between 1 percent and 4 percent of people who are exposed to the virus will develop leukemia, and the most common age of onset is between 30 and 50.

    Smoking

    Adding to the list of cancers caused by smoking, tobacco use is associated with a significantly increased risk of AML. At the current time, it's thought that around 20 percent of AML cases are linked to smoking. There is some evidence that leukemia in children may be linked with parent's smoking, and mothers exposed to secondhand smoke appear to have a slightly elevated risk of developing ALL.

    Alcohol

    While alcohol consumption is linked with a number of cancers, a 2014 study found no association between alcohol use and the four major types of leukemia. There has been a link noted, however, between maternal alcohol consumption during pregnancy and AML in children born to these mothers. 

    Possible Risk Factors

    In addition to probable risk factors for leukemia, there are several risk factors that are being evaluated for their association with leukemia. Some possible risk factors include:

    Western Diet

    With many types of leukemia, especially acute leukemia in children, there appears to be little association with dietary practices. In CLL, however, the most common type of leukemia in adults in the U.S., diet may play a role. A  2018 study in Spain found that those who ate a Western diet were 63 percent more likely to develop CLL than those who consumed a Prudent diet or Mediterranean diet.

    Sucralose (Splenda)

    There has been controversy surrounding a possible connection between the artificial sweetener Splenda and cancer. Splenda was approved in 1999 and is currently present in thousands of products worldwide. Despite a multitude of reassuring studies prior to its approval, a 2016 Italian study on mice found that mice who were exposed to Splenda throughout their lives (beginning in-utero), had a significantly increased risk of developing leukemia. It's important to note that this was an animal study, and the doses were equivalent to an adult consuming 4 times the average amount of Splenda every single day. That said, with the popularity of Splenda as a sugar substitute, it's thought that young children could easily exceed the FDA's acceptable daily intake of 5 mg/kg daily.

    Electromagnetic Fields (Power Lines)

    Since 1979, when a study found an increased risk of leukemia in children who lived near high voltage power lines, a number of studies have looked at the possible association with mixed results; some showing an increased risk with high levels of exposure, and others showing little, if any, effect. Three analyses that have compared results of studies to date (totaling 31 studies in all) found that high exposures (0.3 uT or higher) were associated with a 1.4 to 2.0 times increased risk of leukemia. This level of exposure, however, is not common. In these studies, only 0.5 to 3.0 percent of children had an exposure equal to or exceeding 0.3 uT.

    Radon

    At the current time there is a possibility that radon in homes, a form of radiation mentioned above, may increase the risk of chronic lymphocytic leukemia (CLL). Radon is a well-known carcinogen, and it's thought that roughly 27,000 people die from radon-induced lung cancer each year in the United States. 

    Radon is an odorless, colorless gas, that is produced by the normal breakdown of uranium found in the soil and rocks beneath homes. Elevated levels have been found in all 50 states, and the only way to know if you are at risk is to do radon testing. A 2016 study found that the areas in the United States where CLL is most common, are also the regions to known to have the highest radon levels (northern and central states). While the association between radon and leukemia is uncertain, some researchers propose that radon could lead to leukemia in a way similar to how it increases lung cancer risk.

    Coffee and Tea

    Coffee and tea have both been looked at with regard to the risk of leukemia, and the studies have been mixed; some showing an increased risk with more consumption, and others, showing a potential protective effect instead (a reduced risk of leukemia). Since people metabolize coffee and tea in different ways (fast metabolizers vs slow metabolizers), it could be that the effects vary between different people.

    Sedentary Lifestyle

    While some studies have found no association between level of physical activity and leukemia, a 2016 study found that people who engaged in more "leisure physical activity" were around 20 percent less likely to develop myeloid leukemias than those who were less active.

    Genetics

    The role of family history and genetics varies between the different types of leukemia.

    ALL does not appear to run in families, with the exception being that an identical twin has an increased risk of developing ALL if his or her identical twin developed the disease before one year of age. In contrast, family history plays an important role in CLL. People who have a first-degree family member who has had CLL (parent, sibling, or child) have over twice the risk of developing the disease themselves. While the risk of ALL does not appear to be familial (with the exception of a twin), there are certain genetic syndromes that are associated with an increased risk (see below).

    A family history of AML in first-degree relatives increases risk, but the age at diagnosis is important. Siblings of children with AML have a risk up to four times higher of developing the disease, with the risk in identical twins being around 20 percent. In contrast, children who have a parent who has adult-onset leukemia do not appear to be at a higher risk. Family history doesn't appear to play a significant role in the development of CML.

    Genetic conditions and syndromes that are associated with an increased risk of some types of leukemia include:

    • Down syndrome (trisomy 21): People with Down syndrome have roughly a 20 percent increased risk of developing leukemia (AML and ALL). The incidence is highest in children under the age of 5 years.
    • Klinefelter's syndrome (XXY)
    • Fanconi anemia
    • Li-Fraumeni syndrome
    • Neurofibromatosis
    • Ataxia telangiectasia
    • Bloom syndrome
    • Wiskott Aldrich syndrome
    • Schwachman-Diamond syndrome
    • Blackfan-Diamond syndrome
    • Kostmann syndrome
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