Childhood Leukemia – Causes, Symptoms, Treatment

Childhood Leukemia is a leukemia that occurs in a child and is a type of childhood cancer. Childhood leukemia is the most common childhood cancer, accounting for 29% of cancers in children aged 0–14 in 2018.[1] There are multiple forms of leukemia that occur in children, the most common being acute lymphoblastic leukemia (ALL) followed by acute myeloid leukemia (AML).[2] Survival rates vary depending on the type of leukemia but may be as high as 90% in ALL.[3]

Types of Childhood Leukemia

Leukemia is usually described either as “acute”, which grows quickly, or “chronic”, which grows slowly. The vast majority of childhood leukemia is acute, and chronic leukemias are more common in adults than in children. Acute leukemias typically develop and worsen quickly (over periods of days to weeks). Chronic leukemias develop over a slower period of time (months), but are more difficult to treat than acute leukemias.[2][5] The following are some of the main types of leukemia that occur in children.

Acute lymphoblastic

The most common form childhood leukemia is acute lymphocytic (or lymphoblastic) leukemia (ALL), which makes up 75-80% of childhood leukemia diagnoses.[7][2] ALL is a form of leukemia that affects lymphocytes, a type of white blood cells which fights infection. When a patient has ALL, the bone marrow makes too many immature white blood cells and they do not mature correctly. These white blood cells also do not work correctly to fight infection. The white blood cells over-produce, crowding the other blood cells in the bone marrow.[5][3]

Acute myelogenous

Another type of acute leukemia is acute myelogenous leukemia (AML). AML accounts for most of the remaining cases of leukemia in children, comprising about 20% of childhood leukemia.[7] AML is cancer of the blood in which too many myeloblasts (immature white blood cells) are produced in the bone marrow. The marrow continues to produce abnormal cells that crowd the other blood cells and do not work properly to fight infection.[4]

Acute promyelocytic

Acute promyelocytic leukemia (APL) is a specific type of AML. In this leukemia promyelocytes are produced and build up in the bone marrow. A specific chromosome translocation (a type of genetic change) is found in patients with APL. Genes on chromosome 15 change places with genes on chromosome 17. This genetic change prevents the promyelocytes from maturing properly.[4]

Chronic myelogenous

Chronic myelogenous leukemia (CML) is a chronic leukemia that develops slowly, over months to years. CML is rare in children, but does occur.[7] CML patients have too many immature white blood cells being produced, and the cells crowd the other healthy blood cells. A chromosome translocation occurs in patients with CML. Part of chromosome 9 breaks off and attaches itself to chromosome 22, facilitating exchange of genetic material between chromosomes 9 and 22. The rearrangement of the chromosomes changes the positions and functions of certain genes, which causes uncontrolled cell growth.[4]

Chronic lymphocytic leukemia (CLL) is another form of chronic leukemia, but is extremely rare in children.[2]

Juvenile myelomonocytic

Juvenile myelomonocytic leukemia (JMML) is a form of leukemia in which myelomonocytic cells are overproduced. It is sometimes considered a myeloproliferative neoplasm. It is rare and most commonly occurs in children under the age of four. In JMML, the myelomonocytic cells produced by the bone marrow and invade the spleen, lungs, and intestines.[8][9]

or

Types of leukemia in children

There are different types of leukemia, which are based mainly on:

  • If the leukemia is acute (fast growing) or chronic (slower growing)
  • If the leukemia starts in myeloid cells or lymphoid cells

Knowing the specific type of leukemia a child has can help doctors better predict each child’s prognosis (outlook) and select the best treatment.

Acute leukemias

Most childhood leukemias are acute. These leukemias can progress quickly, and typically need to be treated right away. The main types of acute leukemia are:

  • Acute lymphocytic (lymphoblastic) leukemia (ALL): About 3 out of 4 childhood leukemias are ALL. These leukemias start in early forms of white blood cells called lymphocytes.
  • Acute myeloid leukemia (AML): This type of leukemia, also called acute myelogenous leukemia, acute myelocytic leukemia, or acute non-lymphocytic leukemia, accounts for most of the remaining cases of childhood leukemia. AML starts from the myeloid cells that normally form white blood cells (other than lymphocytes), red blood cells, or platelets.

Rarely, acute leukemias can have features of both ALL and AML. These are called mixed lineage leukemia, acute undifferentiated leukemias, or mixed phenotype acute leukemias (MPALs). In children, they are generally treated like ALL and usually respond to treatment like ALL.

Chronic leukemias

Chronic leukemias are rare in children. These leukemias tend to grow more slowly than acute leukemias, but they are also harder to cure. Chronic leukemias can be divided into 2 main types:

  • Chronic myeloid leukemia (CML): Also called chronic myelogenous leukemia, CML is rare in children. Treatment is similar to that used for adults . For more detailed information on CML,
  • Chronic lymphocytic leukemia (CLL): This leukemia is extremely rare in children. For more information on CLL.

Causes of Childhood Leukemia

The exact cause of most cases of childhood leukemia is not known.[10] Most children with leukemia do not have any known risk factors.[10]

  • One hypothesis is that childhood acute lymphoblastic leukemia (ALL) is caused by a two-step process, starting with a prenatal genetic mutation and then exposure to infections[11] While this theory is possible, there is not enough evidence in patients currently to either support or refute the relationship between infection and developing ALL[12]
  • There is evidence linking maternal alcohol consumption to AML development in children.[13] Indoor insecticide exposure has also been linked to the development of childhood leukemias.[14] High levels of coffee consumption during pregnancy (2-3 cups/day or greater) have been linked to childhood leukemia as well.[15]
  • It has also been suggested that allergies are linked to the development of childhood leukemia but this is not supported by current evidence.[16]
Kids have a greater chance of developing leukemia if they have:
  • an identical twin who had leukemia at a young age
  • a non-identical twin or other siblings with leukemia
  • had radiation therapy or chemotherapy for other types of cancer
  • taken medicines to suppress their immune system after an organ transplant
  • a genetic health problem, such as:
    • Li-Fraumeni syndrome
    • Down syndrome
    • Klinefelter syndrome
    • neurofibromatosis
    • ataxia telangectasia
    • Fanconi anemia

Childhood leukemia risk factors

There’s no known way to prevent leukemia, but there are several risk factors that may increase a person’s chance of developing the disease. These include having one of several genetic disorders, including:

  • Ataxia-telangiectasia
  • Bloom syndrome
  • Diamond-Blackfan anemia
  • Down syndrome
  • Fanconi anemia
  • Klinefelter syndrome
  • Li-Fraumeni syndrome
  • Neurofibromatosis
  • Schwachman-Diamond syndrome
  • Trisomy 8
  • Severe congenital neutropenia (also called Kostmann syndrome)
  • Having a sibling with the disease;
  • Exposure to x-rays, alcohol, or cigarette smoke before birth
  • Exposure to high levels of radiation or certain chemicals, including benzene, which is used in oil refineries, chemical plants, and other industries.

Symptoms of Childhood Leukemia

Most initial symptoms of leukemia are related to problems with the bone-marrow function. There are a variety of symptoms that children may experience. The symptoms tend to appear quickly in acute leukemia and slowly over time in chronic leukemia.[1] Symptoms in the different types of childhood leukemia include:

  • feelings of fatigue or weakness
  • repetitive infections or fever
  • bone and joint pain
  • refusing to walk, which likely results from bone pain or fatigue
  • easy bleeding or bruising (including petechiae)
  • increased paleness of skin
  • abdominal pain or fullness, which may cause shortness of breath or loss of appetite
  • swollen lymph nodes under the arms, in the groin, chest and neck.
  • enlarged spleen or liver
  • weight loss[5][6]
  • rash[4]
  • Infections
  • Fever
  • Loss of appetite
  • Tiredness
  • Easy bruising or bleeding
  • Swollen lymph nodes
  • Night sweats
  • Shortness of breath
  • Pain in the bones or joints

Diagnosis of Childhood Leukemia

Childhood leukemia is diagnosed in a variety of ways. The diagnostic procedures confirm if there is leukemia present, the extent of the leukemia (how far it has spread), and the type of leukemia. The diagnostic procedures are similar for the different types of leukemias:

  • A bone marrow aspiration and biopsy – to look for and collect leukemia cells. In aspiration, a fluid sample is removed from the marrow. In biopsy, bone marrow cells are removed. Usually both procedures are performed at the same time and used together to help with diagnosis.
  • Tests called immunophenotyping and cytogenetic analysis – are performed on the cells to further determine the type and subtype of leukemia.
  • A complete blood count – which is a measurement of size, number, and maturity of different blood cells in blood.
  • Blood tests may include blood chemistry – evaluation of liver and kidney functions, and genetic studies.
  • A spinal tap – a special needle is placed into the lower back into the spinal canal, which is the area around the spinal cord. Cerebral spinal fluid is fluid that bathes the child’s brain and spinal cord. A small amount of cerebral spinal fluid is sent for testing to determine if leukemia cells are present.[5][17]

Treatment of Childhood Leukemia

Treatment for childhood leukemia is based on a number of factors, including the type of leukemia, characteristics of the leukemia, prognostic characteristics (children with worse prognostic characteristics receive more aggressive therapy, see Prognosis section), response to therapy, and extent of the disease at diagnosis. Treatment is typically managed by a team of health care professionals, consisting of pediatric oncologists, social workers, pediatric nurse specialists, and pediatricians among others.[5][4]

While the exact treatment plan is determined by the type of leukemia and factors listed above, there are five types of therapies that are generally used to treat all childhood leukemias. Four of these are standard treatment and one is in clinical trials. The four specific types of treatments that are traditionally used are Chemotherapy, Stem cell transplant, Radiation therapy and Targeted therapy.[3][4][5][18] Immunotherapy is another type of therapy that is currently in clinical trials.[3][5][4]

Chemotherapy – is a treatment that uses chemicals to interfere with the cancer cells ability to grow and reproduce. Chemotherapy can be used alone or in combination with other therapies. Chemotherapy can be given either as a pill to swallow orally, an injection into the fat or muscle, through an IV directly into the bloodstream or directly into the spinal column.[5][4][19][20]

Stem cell transplant – is a process in which the blood-forming cells that are abnormal (like leukemia cells) or that were destroyed by chemotherapy are replaced with healthy new blood-forming cells. A stem-cell transplant can help the human body produce more healthy white blood cells, red blood cells, or platelets. It also reduces the risk of life-threatening conditions such as anemia, or hemorrhage. Stem cell transplants can be done by obtaining cells from the bone marrow, blood or umbilical cord blood. Stem cell transplants can use the cells from one’s self, called an autologous stem cell transplant or they can use cells from another person, known as an allogeneic stem cell transplant. The type used in childhood leukemia is typically allogenic. The donors used must be a match to the child getting the transplant by a marker called HLA[18][21]

Radiation therapy – uses various types of radiation to kill cancer cells.

Targeted therapy – is the use of medication to specifically kill the cancerous cells. The medication is able to leave healthy normal cells alone while it targets cancer.[18] These include tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and proteasome inhibitors.[4][5]

Immunotherapy – is a type of therapy that uses the child’s own immune system to fight cancer. This therapy is currently in clinical trials.[3][22]

ALL

Treatment for childhood ALL consists of three phases: Induction, Consolidation/Intensification, and Maintenance.[18]

  • Induction is intended to kill the large majority of the cancer cells. It typically lasts for 4–6 weeks and uses chemotherapy and glucocorticoids.[3] After induction, the goal is to put cancer into remission. Remission means that cancer is no longer detected in the bone marrow or blood and that normal cells have returned to the bone marrow.[5] However, remission does not mean that the cancer is cured. It is thought there are still cancer cells that are hiding in the body, so more treatment is needed to kill them.[23]
  • Consolidation/Intensification is used to kill any remaining cells that have the potential to become cancerous.[18] It consists of more chemotherapy and lasts for a few months.[3]
  • Maintenance is a lower-intensity chemotherapy regimen that used to kill any more remaining cells in the bone marrow that could regrow into cancer cells and cause leukemia to come back. It lasts for 18–30 months.[3][5]

Immunotherapy, radiation therapy, stem cell transplant, and targeted therapies may also be used in the treatment of ALL. This will depend on the extent of ALL, the characteristics of the ALL and if it has recurred (come back after initial treatment).[3][23][22]

AML

Childhood AML is more challenging cancer to treat than childhood ALL. Childhood AML treatment usually consists of higher dose chemotherapy given over a shorter period of time compared to ALL treatment. Due to this shorter and more intense treatment, side effects are also more intense. These children are therefore treated in treatment centers or hospitals where they will stay for a longer period of their treatment.[24][25] Treatment for AML consists of 2 phases: Induction and Consolidation. There is no maintenance phase of therapy in AML as it was not shown to lower the chances of cancer coming back.[26]

  • Induction is aimed at killing leukemia in the blood and bone marrow. Its goal is to put cancer into remission. Treatments used in induction therapy for childhood AML may include chemotherapy, targeted therapy, radiation therapy, stem cell transplant, or other treatments as part of a clinical trial. The exact treatment will vary depending on the characteristics of the child and cancer.
  • Consolidation begins after remission is obtained and is aimed at killing any remaining cancer cells. It will again vary depending on specifics about the patient and cancer. It typically will consist of chemotherapy followed by a stem cell transplant.

In addition to these treatments, there are also clinical trials of immunotherapy and targeted therapy for AML.[4][24][25][26] The APL type of AML is also treated with all-trans retinoic acid or arsenic trioxide therapy in addition to what is listed above.[4]

Other childhood leukemias

JMML is typically treated by chemotherapy followed by a stem cell transplant.[9][8] CML is typically treated with targeted therapy and possibly a stem cell transplant if it comes back or does not respond to the targeted therapy at first.[4]

ALL

The 5-year survival rate for children and adolescents under the age of 15 years diagnosed with ALL was 91.8% in the USA between 2007 and 2013. The survival rate for children under the age of 5 years with ALL was 94% during the same time period.[29]

Prognostic factors in ALL

  • Age at diagnosis – Children between the ages of 1–9 years with B-cell ALL (a specific type of ALL) have better cure rates than children less than 1 year old or over 10 years old. This does not seem to matter in T-cell ALL (another specific type of ALL).
  • White blood cell count at diagnosis – Children with very high white blood cell counts at diagnosis are higher risk patients than those with lower counts.
  • Specific type of ALL
  • Spread to other organs (such as the brain, spinal cord, and testicles) signifies worse prognosis
  • Chromosome changes: Patients whose leukemia cells have more chromosomes are more likely to be cured. Different chromosome translocations are also associated with different prognoses.
  • Initial treatment response: Children who respond to treatment quickly initially have a better prognosis.[5][28]

AML

The survival rate for children under the age of 15 years with AML was 66.4% in the USA between 2007 and 2013. This is lower than the rates for ALL.[29]

Prognostic factors for AML:

  • Age at diagnosis – Children under 2 years old may have a better prognosis than older children. However, how strong this link is is unclear.
  • White blood cell count at diagnosis – Children with lower white blood cell counts tend to have a better prognosis. Children with Down Syndrome and AML typically have a good prognosis.
  • The specific type of AML – APL generally is a good prognosis. Specific chromosome changes affect prognosis.
  • AML that started because of treatment for different cancer usually has a poorer prognosis.
  • Response to treatment – As with ALL, patients whose disease responds faster to treatment tend to have a better prognosis.
  • Children who are a normal weight usually have a better prognosis than those who are overweight or underweight.[4][17][28]

After effects

As treatments for childhood leukemias have gotten better, there are more children surviving and living into adulthood. These survivors are at risk for long term after-effects of treatment. The specific risks depend on the type of therapy that was given and the type of cancer the child had.[30]

The older aggressive treatment regimens with cranial irradiation and higher doses of anthracyclines (such as doxorubicin) caused an increased risk of solid tumors, heart failure, growth retardation, and cognitive defects.[31] In types of childhood leukemias with good cure rates (mainly ALL), efforts are continually made to decrease the amount of toxicity caused by chemotherapy and other treatments.[3]

  • Secondary cancers – Survivors who received treatment for childhood leukemia are at risk for developing a secondary cancer later in life. The risk of acquiring a second cancer is weighed against the benefit of receiving therapy for life-threatening leukemia.[30]
  • Neurological – Survivors of ALL are at risk for various neurocognitive and neuropsychological issues that affect their quality of life.[3][30] These include issues with attention span, vision, processing speed, memory, growth failure, malnutrition, obesity, reduced fertility, psychiatric problems.[32] All of the latent effects listed impact patients.[33]
  • Growth and development – Some childhood leukemia treatments, notably stem cell transplants, can stunt growth. Growth hormone is sometimes given to help with this.[30] Fertility may be affected in both boys and girls who receive leukemia treatment.[30][34]
  • Bone problems – Bone problems or damage may result from glucocorticoids.[30]
  • Emotional – Childhood leukemia is a very taxing disease, on the caregiver and the child. Some emotional issues that survivors have reported include: depression, anxiety, post-traumatic stress disorder, difficulties with interpersonal relationships, poor body image, and schizophrenia among other issues. However, it is unclear if the rates of mental and emotional problems are higher in childhood leukemia survivors than the general population.[35] Regardless, some children may have emotional or psychological issues that may be addressed by doctors, other care team members, parents, and friends.[36]

ENVIRONMENTAL RISK FACTORS FOR CHILDHOOD LEUKEMIA

Exposure Science in Studies of Childhood Leukemia Risk

As mentioned earlier, childhood leukemia is the most common form of pediatric cancer; but, for the purposes of epidemiological study, it is a rare disease. As such, the vast majority of epidemiological investigations into the causes of childhood leukemia are forced to employ a case-control study design. In many instances, case-control studies of childhood leukemia are designed to assess children’s exposure to disease risk factors retrospectively. That is, a child is first diagnosed with leukemia, then s/he is enrolled in the case-control study, and only afterwards can investigators begin to assess the agents to which s/he has been exposed. This design imposes limitations on the epidemiologist, as etiologically relevant specimens – biological and environmental – are not necessarily available for collection by the time the child is under study. As discussed above, childhood leukemia can be initiated during the prenatal period, but most cases are not diagnosed until the child is between two to four years old. This leaves a long time interval between the first windows of susceptibility to leukemogenic agents and the time period when investigators can start measuring a child’s exposure to those agents. To overcome these challenges, childhood leukemia investigators have employed a variety of strategies to assess children’s exposures to potentially carcinogenic agents.

Using Parent Interviews To Assess Children’s Exposures to Chemicals

One simple way to circumvent the need for the collection of biological or environmental samples during etiologically relevant time periods is to interview participating parents to obtain information about their child’s history of exposure to specific agents. Such interviews can be used to pinpoint historical exposures during critical windows of a child’s development (e.g., the second trimester of pregnancy), they can be wide-ranging in scope, and they can be especially effective in assessing parents’ conscious behaviors (e.g., smoking habits, residential pesticide use, occupational histories). On the other hand, interview-based exposure assessments have inherent limitations; they are imprecise measures of chemical exposure, they provide little information about any of a child’s exposures that go unrecognized by the parents, and they are potentially subject to recall and reporting biases if parents of case and control children remember or report their children’s exposures in different ways. In practice, though, reproducibility studies have suggested that, for some of the environmental exposures that are of interest in childhood leukemia research — ionizing radiation,– pesticides, and smoking – there is minimal evidence of differential recall between cases and controls.

Estimating Ambient Environmental Exposures Using Geographic Information Systems

An alternative strategy for assessing a child’s history of environmental exposures is to estimate ambient pollution using Geographic Information Systems (GIS) and geospatial modeling and to use these estimates of ambient conditions as surrogates for the child’s total exposure to chemicals. Many governing bodies record a child’s home address on the birth certificate and this information can be obtained for research purposes contingent on appropriate ethical review and approval. Exposure models based on GIS data and geocoded birth addresses could provide useful information about children’s exposure to chemicals at the time of birth and, potentially, throughout the prenatal period as well (if participating mothers did not change residence during pregnancy). Moreover, complete residential histories can be obtained from parents via interview, which allows for a more comprehensive model of a child’s historic exposures to ambient chemicals. Agricultural pesticide application,, traffic-related air pollution, and electromagnetic fields have been estimated using GIS in the context of epidemiological studies of childhood leukemia. One limitation of using estimates of ambient pollution as surrogates for total exposures is the inability to account for chemical exposures that occur indoors. This is a substantial drawback, because children tend to spend the vast majority of their time indoors, there are distinct chemical sources indoors, and chemical exposures tend to be higher indoors than outdoors.,

Pesticides

Several studies have suggested that home pesticide exposure before birth and during a child’s early years may increase the risk of childhood leukemia. Indeed, exposure to pesticides is one of the most frequently investigated chemical risk factors for childhood leukemia. A causal link between exposure to pesticides and childhood leukemia is supported by many studies, including the California Childhood Leukemia Study, which demonstrated a relationship between exposure to insecticides – as a general class – and childhood leukemia. Existing studies have generally used interviews with parents to assess children’s exposure to pesticides; as such, no specific pesticide, or class of pesticides, has been implicated as the causal agent underlying these observations.

The Childhood Leukemia International Consortium investigators confirmed the observed association between home pesticide exposure during pregnancy and childhood leukemia using meta-analyses as well. Other investigators have reported similar findings in independent meta-analyses,– generally observing the strongest associations for indoor insecticide use.

Pooled Analyses of Parental Occupational Exposure to Pesticides and Childhood Leukemia

Given the consistently observed association between home pesticide use during early childhood and leukemia risk, a logical extension of this line of research has been to examine the effect of parental occupational exposure to pesticides on childhood leukemia risk. There is evidence that adults exposed to pesticides at work can track these chemicals back to their homes on their shoes, clothing, and skin, potentially exposing their families., Moreover, paternal exposure to pesticides before conception could result in germ cell damage, whereas maternal exposure to pesticides during pregnancy could also expose the fetus to these chemicals. The Childhood Leukemia International Consortium investigators pooled individual parents’ responses to interview questions about job histories and the data were harmonized to a compatible format that characterized parents’ pesticide exposures at work. ALL was associated with paternal exposure to pesticides at work around the time of conception (OR=1.20, 95% CI: 1.06–1.38; N=8,169 fathers of cases and 14,201 fathers of controls), but was not associated with maternal exposure during pregnancy (OR=1.01, 95% CI: 0.78–1.30; N=8,236 case, and 14,850 control mothers). In contrast, AML was associated with maternal exposure to pesticides at work during pregnancy (OR=1.94, 95% CI: 1.19–3.18, N=1,329 case and 12,141 control mothers), but was not associated with paternal exposure around the time of conception (OR=0.91, 95% CI: 0.66–1.24, N=1,231 case and 11,383 control fathers). The modest association between paternal exposure to pesticides around the time of conception and ALL risk in the offspring was more evident in children diagnosed at an older age (5+ years-old) and in children with the T-cell ALL subtype. The Childhood Leukemia International Consortium’s findings of a significant association between maternal exposure to pesticides during pregnancy and AML risk in the offspring is consistent with previous reports.–

GIS-Estimated Ambient Pesticide Levels and Childhood Leukemia

Investigators from the California Childhood Leukemia Study have also evaluated the association between residential proximity to agricultural pesticide applications and childhood ALL. For the families of 213 ALL cases and 268 matched controls, the authors linked residential histories together with agricultural pesticide-use reports from the California Department of Pesticide Regulation, to assess whether living within a half-mile (0.8 km) of pesticide applications was associated with childhood leukemia risk. Elevated ALL risk was associated with lifetime moderate exposure, but not high exposure, to certain physicochemical categories of pesticides, including organophosphates, chlorinated phenols, and triazines, and with pesticides classified as insecticides or fumigants.

Exposure to Herbicides and Childhood Leukemia

Epidemiological studies of childhood leukemia that use environmental or biological samples are relatively scarce. In one such study, investigators from the California Childhood Leukemia Study evaluated the relationship between childhood ALL and herbicide concentrations in settled dust as surrogates of herbicide exposures. The herbicide analysis included 269 ALL cases 0–7 years of age and 333 healthy controls matched on date of birth, sex, and race/ethnicity. Dust samples were collected from carpets using a high-volume small-surface sampler or from participant vacuum cleaners. Concentrations of agricultural or professional herbicides (alachlor, metolachlor, bromoxynil, bromoxynil octanoate, pebulate, butylate, prometryn, simazine, ethalfluralin, and pendimethalin) and residential herbicides (cyanazine, trifluralin, 2-methyl-4-chlorophenoxyacetic acid, mecoprop, 2,4-dichlorophenoxyacetic acid, chlorthal, and dicamba) were used in logistic regression adjusting for age, sex, race/ethnicity, household income, year and season of dust sampling, neighborhood type, and residence type. The risk of childhood ALL was associated with dust levels of chlorthal; compared to homes with a measurement below the analytical limit of detection, odds ratios for the first, second, and third tertiles were 1.49 (95% CI: 0.82–2.72), 1.49 (95% CI: 0.83–2.67), and 1.57 (95% CI: 0.90–2.73), respectively (p-value for linear trend=0.05). No other herbicides were identified as risk factors of childhood ALL. Metayer et al. postulated that 2,3,7,8-tetrachlorodibenzo-p-dioxin – a potent carcinogen and an impurity found in chlorthal – might be the causal agent underlying the observed association.

Limitations of Existing Research on Pesticides and Childhood Leukemia

Previous studies of the relationship between pesticide exposure and childhood leukemia, including pooled analyses conducted by the Childhood Leukemia International Consortium have utilized interviews to assess pesticide exposures to children and their parents. Unfortunately, this study design has precluded investigators from identifying specific chemicals that may be causal agents underlying the observed associations. Findings from the California Childhood Leukemia Study seem to rule out organochlorine pesticides, such as DDT and chlordane, as the culpable pesticides underlying the observed association with childhood leukemia.

Summary of Existing Research on Pesticides and Childhood Leukemia

Pooled analyses of data from studies around the world show a relationship between home pesticide use – especially of insecticides indoors – and the risk of childhood leukemia, which is confirmed by independent systematic reviews and meta-analyses. Pooled analyses of data from the Childhood Leukemia International Consortium demonstrate a relationship between prenatal maternal exposure to pesticides at work and the risk of childhood AML. Likewise, these findings were supported by independent systematic reviews and meta-analyses. Future studies will continue to exam relationships between pesticide exposures and the risk of specific leukemia subtypes and will also identify the specific pesticides which act as causal agents.

Parental Smoking

Parental tobacco use is another suspected risk factor for childhood leukemia that has received a lot of attention from researchers. Cigarettes contain numerous harmful constituents and tobacco use is well known to cause a variety of cancers in adults, including leukemia, via both direct and secondhand means of exposure. Likewise, there is evidence that parental cigarette smoking may also be associated with childhood cancer risk.

Investigators from the California Childhood Leukemia Study, for example, examined the association between parental smoking and childhood leukemia among 281 ALL cases, 46 AML cases, and 416 controls matched on age, sex, maternal race, and Latino ethnicity. Maternal smoking was not associated with an increased risk of either ALL or AML. Paternal preconception smoking was significantly associated with an increased risk of AML (OR=3.84, 95% CI: 1.04–14.17) and marginally associated with an increased risk of ALL (OR=1.32, 95% CI: 0.86–2.04).

Pooled Analyses of Parental Cigarette Smoking and Childhood AML

The Childhood Leukemia International Consortium pooled individual parents’ responses to interview questions about tobacco use from 14 case-control studies, representing 1,300 AML and 15,000 controls. Individual studies ascertained information about parental cigarette smoking at a number of stages of the child’s development with varying degrees of specificity, including maternal smoking during pregnancy and paternal smoking during the three months before conception. The findings from the pooled analyses strengthened the existing evidence of modest associations between paternal cigarette smoking at any time and childhood AML, with dose-response relationships (p<0.05). Maternal smoking during pregnancy was associated with an increased risk of AML for Latino children only.

Meta-analyses of Parental Cigarette Smoking and Childhood ALL

In 2009, a review of studies which evaluated the association between parental smoking and childhood leukemia revealed that 6 of 13 studies which had examined the relationship between paternal smoking and childhood leukemia reported significant positive associations. Subsequently, Liu et al. conducted a meta-analysis, which suggested that childhood ALL was associated with paternal smoking during preconception (OR=1.25, 95% CI: 1.08–1.46) during pregnancy (OR=1.24, 95% CI: 1.07–1.43), and after birth (OR=1.24, 95% CI: 0.96–1.60), with dose-response relationships observed between childhood ALL and paternal smoking before conception or after birth.

Parental Cigarette Smoking and Childhood Leukemia Subtypes

There is some evidence that the strength of the association between parental cigarette smoking and childhood leukemia varies by the cytogenetic subtype of the tumor. For example, Metayer and colleagues reported that children with a history of paternal prenatal smoking combined with postnatal passive smoking had a 1.5-fold increased risk of ALL (95% CI: 1.01–2.23), compared to those without smoking history; but this joint effect was seen for B-cell precursor ALL with t(12;21) only (OR=2.08, 95% CI: 1.04–4.16), not for high hyperdiploid B-cell ALL. Similarly, the aforementioned pooled AML analysis conducted by the Childhood Leukemia International Consortium found that the highest smoking-related risk was seen for the myelomonocytic leukemia, a subtype common in treatment-related AML. Childhood leukemia comprises many subtypes and these findings demonstrate that each subtype may have a distinct set of characteristic risk factors corresponding to its unique etiology. As such, studies that evaluate subtype-specific chemical risk factors are the most likely to identify true relationships. Tellingly, when risk factors for each leukemia subtype are considered separately, higher odds ratios tend to be revealed.

Limitations of Existing Research on Tobacco Use and Childhood Leukemia

As was the case for pesticides above, previous studies of the relationship between parental tobacco use and childhood leukemia, including pooled analyses conducted by the Childhood Leukemia International Consortium, have utilized interviews to characterize parental smoking histories. This method of exposure assessment is useful, because it allows investigators to examine the effect of parental smoking at critical windows of a child’s development and because it enables investigators to untangle the separate effects of cigarette smoking done by the mother, father, or other family members. Moreover, in contrast to other environmental exposures that are of interest to leukemia researchers, parents are conscious of the number of cigarettes they tend to smoke each day and they can help quantify their own exposures to tobacco. However, recall and reporting biases are still concerns, as parents (especially parents of children with leukemia) may not accurately remember or may not feel comfortable discussing their past tobacco use history during the interview. The lack of an observed association between maternal smoking during pregnancy and childhood leukemia may be related to this potential for bias when using interview data to assess exposure. Alternatively, the lack of an observed association may also be the result of smoking-induced adverse birth outcomes (e.g., fetal loss, still birth) that preclude the subsequent development of childhood leukemia, thereby biasing epidemiological findings.

Summary of Existing Research on Tobacco Use and Childhood Leukemia

Pooled analyses of data from studies around the world show a relationship between paternal smoking before conception and AML risk. Likewise, these findings were supported by an independent systematic review and meta-analysis. Future studies will provide an increased focus on the role of prenatal maternal smoking on leukemia risk in Latino children and will pool data from the Childhood Leukemia International Consortium for an analysis of smoking-related ALL risk.

Chemicals Found in Paints, Petroleum Solvents, and Traffic Emissions

A collection of studies have investigated the associations between childhood leukemia and a loosely-related group of environmental exposures including paint, petroleum solvents, and vehicle traffic. These general exposure categories share characteristic chemical signatures, including the leukemogenic agent, benzene.

Investigators from the California Childhood Leukemia Study examined the association between childhood leukemia and the use of paint or petroleum solvents in the home before birth and in early childhood. The analysis included 550 ALL cases, 100 AML cases, and one or two controls per case individually matched for sex, age, Latino ethnicity, and race. Conditional logistic regression techniques were used to adjust for income. Home paint exposure was associated with ALL risk (OR=1.65; 95% CI: 1.26–2.15). The association was restricted to ALL with t(12;21) (OR=4.16, 95% CI: 1.66–10.4). Home use of petroleum solvents was associated with an increased risk for AML (OR=2.54, 95% CI: 1.19–5.42) but not ALL.

Pooled Analyses of Home Exposure to Paint and Childhood Leukemia

The Childhood Leukemia International Consortium pooled individual responses to questions about home paint exposures from eight case-control studies. Data were harmonized to account for inter-study differences in reported paint types, time periods of exposure, and leukemia subtypes and a compatible format was used in logistic regression. ALL risk was associated with home paint exposure in the 1–3 months before conception (OR=1.54, 95% CI: 1.28–1.85; N=3,002 cases and 3,836 controls), during pregnancy (OR=1.14, 95% CI: 1.04–1.25; N=4,382 cases and 5,747 controls), and after birth (OR=1.22, 95% CI: 1.07–1.39; N=1,962 cases and 2,973 controls). The risk was greater if someone other than the parents did the painting, e.g., a professional painter, which is indirect evidence of a dose-response relationship. The paint-leukemia association was stronger for ALL with t(12;21) than for other cytogenetic subtypes of leukemia.

Causal Agent

Once again, most of the studies that have evaluated the risk of childhood leukemia associated with paint, petroleum solvents, or traffic density are based on parent interviews. As such, it is challenging to identify the specific causal agent underlying the observed associations in these existing studies. Benzene is one potential culprit as it is a well-known leukemogen that is present in oil-based paints, petroleum solvents used in occupational and residential settings (e.g., in paint thinner), and vehicle exhaust. However, given that childhood leukemia subtype analyses have yielded disparate results depending on the specific exposure measure that was used in the meta/pooled analysis, it is also possible that this loose grouping of chemical exposures actually comprises several distinct chemical risk factors for leukemia. For example, in addition to benzene, other chemicals, such as 1,3-butadiane, styrene, xylene, and polycyclic aromatic hydrocarbons (PAHs) might also play a role in some of these observed relationships. The recent development of a mouse model for childhood leukemia will enable investigators to evaluate the role of specific chemical risk factors in the etiology of childhood leukemia.

Summary of Existing Research on Paint, Solvents, Traffic and Childhood Leukemia

Pooled analyses of data from studies around the world show a relationship between home exposure to paint and ALL risk. These findings were indirectly supported by a variety of systematic reviews and meta-analyses, which showed evidence of relationships between childhood leukemia and exposure to petroleum solvents (at home and at the mother’s work) and traffic (as measured by surrounding traffic density and modeled concentrations of traffic-related air pollutants). Several possible chemical risk factors may explain the observed association, including the well-known leukemogen, benzene.

Persistent Organic Pollutants

Epidemiological studies of childhood leukemia that use environmental or biological samples are relatively scarce. A series of analyses conducted as part of the California Childhood Leukemia Study have evaluated the relationship between childhood ALL and chemical concentrations in settled dust collected from participating homes as surrogates for chemical exposures.

Polycyclic Aromatic Hydrocarbons (PAHs) and Childhood Leukemia

The California Childhood Leukemia Study evaluated the relationship between childhood ALL and PAH concentrations in settled dust. As part of this population-based case-control study, dust samples were collected from 251 ALL cases and 306 birth-certificate controls using a high-volume small-surface sampler (N=185 cases, 212 controls) or directly from participants’ household vacuum cleaner bags (N=66 cases, 94 controls). Logistic regression was used to evaluate the relationship between ALL risk and log-transformed concentrations of 9 individual PAHs, the summed PAHs, and the summed PAHs weighted by their carcinogenic potency (the toxic equivalence) while adjusting for demographic characteristics and duration between diagnosis/reference date and dust collection. Among participants with dust samples collected by high-volume small-surface sampler, risk of ALL was not associated with increasing concentration of any PAHs. However, among participants with dust samples collected by participants’ vacuum cleaners, a positive association was observed between ALL risk and increasing concentrations of benzo[a]pyrene (OR=1.42, 95% CI: 0.95–2.12), dibenzo[a,h]anthracene (OR=1.98, 95% CI: 1.11–3.55), benzo[k]fluoranthene (OR=1.71, 95% CI: 0.91–3.22), indeno[1,2,3-cd]pyrene (OR=1.81, 95% CI: 1.04–3.16), and the toxic equivalents (OR=2.35, 95% CI: 1.18–4.69). The observed association between ALL risk and PAH concentrations among participants with dust collected by vacuum suggests that PAH exposure may increase the risk of childhood ALL; however, understanding the reasons for the different results by sample type requires further scrutiny.

PAHs are byproducts of incomplete combustion that are found at high concentrations in cigarette smoke and vehicle exhaust. PAHs, especially dibenzo[a,h]anthracene, are potent human carcinogens. As such, it is possible that one PAH or a combination of PAHs may be the causal agent(s) responsible for the observed associations between parental smoking and childhood leukemia or between traffic density and childhood leukemia.

Polychlorinated Biphenyls (PCBs) and Childhood Leukemia

The California Childhood Leukemia Study has also evaluated the relationship between childhood ALL and levels of six PCBs – industrial chemicals that are probable human carcinogens and immune system disruptors – in settled dust. The PCB analysis included 184 ALL cases 0–7 years of age and 212 birth certificate controls matched to cases by birth date, sex, race, and Latino ethnicity. Dust samples were collected from the room where the child spent the most time using the high-volume small-surface sampler. In homes where any PCB was detected in the dust, there was a 2-fold increased risk of ALL (OR=1.97, 95% CI: 1.22–3.17). When considering the sum of the six PCBs analytes, compared to those in the lowest quartile of Σ6PCBs, the highest quartile was associated with about a 3-fold risk of ALL (OR=2.78, 95% CI: 1.41–5.48). The risk of ALL was positively associated with increasing concentrations of PCB congeners 118, 138, and 153 in dust. The associations with PCBs were stronger among non-Latino whites than among Latinos despite the presence of a similar distribution of PCB levels among controls in each racial/ethnic groups.

Polybrominated Diphenyl Ethers (PBDEs) and Childhood Leukemia

Along the same lines, the California Childhood Leukemia Study evaluated the relationship between childhood ALL and levels of PBDEs – chemical flame retardants – in settled dust. PBDEs are structural analogs to PCBs that also cause immune system perturbations. The PBDE analysis included 167 ALL cases 0–7 years of age and 214 birth certificate controls matched on date of birth, sex, and race/ethnicity.

Interestingly, the significant associations with ALL risk observed in this analysis were for minor PBDE congeners that are found in dust at relatively low concentrations; whereas the most abundant PBDE congeners (e.g., BDEs 47, 99, and 209) were not associated with ALL risk. These low concentration PBDE congeners were measured with less analytical precision than their more common analogs, because the measured values were relatively close to the analytical limit of detection. In other words, the low-level PBDE congeners that were associated with ALL risk in this analysis were the ones measured with the least precision and, therefore, the ones with the greatest potential for a spurious finding. Still, there may be a plausible biological mechanism to explain the inconsistency of the risk estimates between PBDE congeners, as toxic and carcinogenic effects are expected to differ by congener., The fact that PCBs and PBDEs have a similar chemical structure lends credence to the hypothesis that these chemicals may be acting via the same mechanism of action, e.g., immune dysregulation.

Strengths of Existing Research on Persistent Organic Pollutants and Childhood Leukemia

Unlike much of the research described in this section, one strength of the existing research on persistent organic pollutants and childhood leukemia is the use of objective environmental measurements to assess chemical exposures, rather than interviews. Not only does this reduce the likelihood of recall bias, but it also allows investigators to identify specific chemicals as causal agents in the etiology of leukemia. Recognizing causal agents can be the first step in planning a successful intervention that will reduce future incidence of leukemia.

Limitations of Existing Research on Persistent Organic Pollutants and Childhood Leukemia

The relative stability of persistent organic pollutants in settled dust allows for exposure measurements that have limited temporal variability. This stability is a benefit of the sampling technique, because the resulting measurements represent long-term average levels of chemical contamination, which can be useful when trying to estimate past chemical exposures. However, this stability also obscures short-term fluctuations in chemical levels that might be important to investigators who want to identify critical windows of a child’s development when chemical exposures are especially harmful. That is, measuring chemical levels in settled dust will not enable a researcher to distinguish the leukemogenic effect of prenatal vs. postnatal chemical exposures, for example.

Moreover, children are exposed to chemicals through several other pathways in addition to the ingestion of contaminated settled dust. In particular, the ingestion of settled dust plays a relatively minor role in children’s exposure to PCBs compared to the ingestion of PCB-contaminated food. This is owing to the bioaccumulative nature of PCBs and the fact that they have been banned from production in the U.S. for several decades. Indeed, it is a testament to the persistence of these hazardous chemicals that they can still be so readily measured inside homes. In these analyses, the design of the California Childhood Leukemia Study did not account for chemical exposures received via the inhalation of contaminated air, the ingestion of contaminated food, or any other pathways. As such, the dust measurements are limited surrogates for total chemical exposure.

To date, the California Childhood Leukemia Study has only utilized dust samples to identify risk factors for ALL, the most common leukemia subtype. There is an insufficient number participants with dust samples available to analyze the risk of AML or to stratify by cytogenetic subtype.

Also of some concern is the fact that the subset of California Childhood Leukemia Study participants who were eligible for and consented to dust sampling had higher socioeconomic status than the full California Childhood Leukemia Study population and its underlying source population, the State of California. As such, the findings from these studies may not be representative of the general population. Fortunately, data from the California Childhood Leukemia Study indicates that both the case families and the control families participating in dust sampling had elevated socioeconomic status, which limits the risk of differential selection bias.

Perhaps the most important limitation of these studies is that they have not been substantiated by independent investigators. Whereas many members of Childhood Leukemia International Consortium and other studies have collected interview data about pesticides, smoking, and paint; very few have measured chemicals in environmental samples. As such, there are no meta-or pooled analyses published showing the risk of ALL associated with exposure to persistent organic pollutants, as there have been previously for the other, more well-studied, ALL risk factors that were discussed above.

Summary of Existing Research on Persistent Organic Pollutants and Childhood Leukemia

Three novel findings from the California Childhood Leukemia Study suggest that home exposures to persistent organic pollutants, such as PAHs, PCBs, and PBDEs, are associated with an increased risk of ALL. Future studies should attempt to interrogate these associations to replicate or refute their veracity.

Radiation

In utero exposure to low-dose radiation delivered from medical x-rays is one of the few widely-recognized risk factors for childhood leukemia. While the prevalence of fetal exposure to x-rays in utero has decreased markedly following radiation protection standards, the use of medical imaging procedures, including computerized tomography (CT) scans, has increased drastically during the past 30 years. In fact, CT scans are now the largest medical sources of radiation in economically developed countries. In addition, CT scans deliver an effective dose of radiation that is up to several hundred times stronger than conventional x-rays (depending on the target organ), which has led to major increases in the per capita radiation dose from medical sources (up 600% in the US since 1980). The carcinogenic effects of CT scans have not been established, but exposures to children are especially concerning because they are more sensitive to radiation-induced cell damage.

Findings on children’s postnatal exposure to low-dose medical radiation and the risk of childhood leukemia are inconsistent, with modest positive associations reported in some studies, but not all., Risk prediction models have anticipated increased risks of childhood leukemia following CT scans, but these models were criticized for extrapolating from the effects of much higher levels of radiation that were observed in the Life Span Study of atomic-bomb survivors.– Only one case-control study to date has published results on self-reported history of CT scans showing no increased risk of childhood ALL, based on small numbers of exposed children. Recent cohort studies with access to medical data in Europe ,–, Australia, and the US, have reported small to moderate increases in the risk of leukemia in children exposed to CT scans; findings, however, were based on small number of excess cases ranging from 6 to 74. Pearce et al.  conducted a retrospective cohort study of 178,604 UK children and young adults with CT scans from 1985 to 2002. Patients were followed through 2008 and linked with 74 leukemia diagnoses and 135 brain cancer diagnoses. A cumulative dose of 50 milligray was estimated to triple the risk of childhood leukemia within 10 years of the first CT scan; likewise, a cumulative dose of 60 milligray tripled the risk of brain cancer. The main criticism of the study was the lack of an unexposed control group. Other cohort studies are underway including a pooled European study (EPI-CT) of about one million subjects (age 0–21 years). Although the number of excess childhood leukemia cases is still likely to be low (estimated to be approximately 60 to 100), this study will obtain more precise exposure information than previously possible, including individual doses of radiation for each organ.

Confounding by indication (reverse causation) is also a concern in studies of the relationship between medical radiation and childhood leukemia. In a French cohort study, the analyses accounting for child’s cancer-predisposing factors (mostly rare genetic conditions in less than 2% of children) showed a modest impact on the risk of childhood leukemia associated with CT scans. This was consistent with a case-control study of prenatal x-rays showing an overall 13% reduction in relative risk of childhood cancers, after adjusting for maternal illnesses during pregnancy. Others have argued that cancer-predisposing conditions may instead act as effect modifiers.– Overall, despite methodological challenges, epidemiologic studies so far mostly support an association between post-natal exposure to CT scans and childhood leukemia, while results for lower dose x-rays are less consistent.

Pooled analyses reported that exposure to high levels of extremely low-frequency-electromagnetic fields over 0.3 or 0.4 μT is associated with an increased risk of childhood leukemia,, which was the basis to classify extremely low-frequency-electromagnetic fields as possibly carcinogenic to humans (Group 2B). Methodological issues including possible confounding, selection bias, and measurement errors have been put forward as an alternate explanation for the observed association, and animal studies are ongoing to identify possible biological mechanisms., If the association between extremely low-frequency-electromagnetic fields and childhood leukemia is causal, the overall population attributable risk has been estimated to be 1.9% (1% to 4% depending on the countries).,

Future Steps in Identifying Environmental Causes of Childhood Leukemia

A multitude of studies on the environmental causes of childhood leukemia, including those conducted by our research team and others that are described above, have led to progress in identifying the etiological roles of environmental exposures in childhood leukemia. However, much work remains to be done. As discussed, several of the observed associations between chemical exposures and childhood leukemia are derived from interview data, an approach which can limit an investigator’s ability to identify specific chemical risk factors for childhood leukemia. As such one goal of future research will be to understand which specific causal agents underlie previously observed associations. For example, in collaboration with the National Cancer Institute, the California Childhood Leukemia Study is conducting a study to measure glyophosate in participating homes. This study will follow-up on a previously observed association between reported residential herbicide use and childhood ALL. The California Childhood Leukemia Study has observed associations between childhood leukemia risk and levels of certain PCBs, PBDEs, PAHs, and herbicides in settled dust. These unique findings need to be confirmed in independent studies, preferably in ones that use a distinct method for assessing children’s exposure to chemicals.

As an alternative approach for identifying the causal agents in childhood leukemia, the Center for Integrative Research on Childhood Leukemia and the Environment will employ a mouse model of ALL with t(12;21) to test the carcinogenic potential of a variety of chemicals, including, for example, compounds that comprise the broadly-defined groups of pesticides, solvents, or traffic pollutants. The mouse model will also be helpful in identifying mechanisms of action for the chemical risk factors of childhood leukemia. In fact, this is a central goal of the Center, as immunological factors and epigenetics will both be interrogated as possible cancer mechanisms. Moreover, state-of-the-science untargeted analytical approaches will allow investigators to identify novel chemical risk factors for childhood leukemia, by examining relationships between exposure and disease that have not been considered, to date.

DIETARY RISK FACTORS FOR CHILDHOOD LEUKEMIA

Introduction

Diet has been linked to several cancers in adults and children. These observations may be explained by various biological mechanisms such as exposure to dietary mutagens, mutagenesis due to nutrient deficiencies, and intake of micronutrients and other dietary components that may protect against the development of cancer by supporting cellular integrity, reducing inflammation and improving immune response.– A growing body of research also suggests that the influence of particular nutrients on epigenetic processes may contribute to carcinogenesis.

The role of the intrauterine environment is crucial in determining risk of disease later in life, and the “developmental origins of health and disease” hypothesis posits that nutritional and environmental exposures in utero permanently alter gene expression and the physical development of the fetus through a process called “programming”. , This hypothesis is likely central to the development of childhood leukemia, as well. Indeed, maternal nutrition during pregnancy may be related to both the occurrence of primary and secondary oncogenic events that lead to leukemia in the offspring. Subsequently, a child’s diet during the early years of life is likely to also play an important role in leukemogenesis. Breastfeeding has been consistently found to reduce leukemia risk in children, via intake of essential nutrients not readily available in newborns and due to the resulting beneficial effects of immune system priming. In contrast, the impact of diet – both the mother’s and the child’s – on childhood leukemia has been less studied.

Here we provide an overview of the current knowledge about the associations between diet and childhood leukemia.

Maternal Diet

Epidemiologic studies examining the relationship between maternal diet during pregnancy and the risk of childhood leukemia, have been mostly conducted in developed countries. Exposures of interest varied to include food groups (e.g. fruits, vegetables, proteins), micronutrients from dietary and supplement sources (e.g., folate and vitamins), food sources of topoisomerase II inhibitors (known risk factors for treatment-related leukemia), consumption of coffee, tea, and alcohol, and holistic measures of a healthy diet.

Food Groups

Fruits and vegetables contain a variety of vitamins and minerals that have anti-cancer, anti-proliferative, and anti-inflammatory effects, and the consumption of fruits and vegetables has been associated with a reduced risk of various types of cancer. Some food groups, in particular fruits and vegetables, have been associated with childhood leukemia risk in several studies. Research has found statistically significant negative associations between maternal consumption of fruits and vegetables and risk of childhood ALL,– and one study found significant or near-significant inverse linear trends between the risk of infant leukemia and maternal consumption of fresh fruits and vegetables, especially for specific ALL subtypes. Negative associations have also been observed for childhood leukemia and maternal consumption of other food groups, specifically protein sources such as fish and seafood as well as beans and beef., One study demonstrated an increased risk of ALL with increased maternal consumption of meat or meat products and sugars or syrups.

Folate and Other One-carbon Metabolism Nutrients

The one-carbon metabolism cycle is critical for the synthesis of DNA and RNA, the conversion of homocysteine to methionine, and the formation of s-adenosylmethionine (SAM), the primary methyl donor for DNA, RNA, proteins, and lipids. Folate and other B vitamins are important cofactors in the one-carbon metabolism cycle, and maternal folic acid supplementation during pregnancy has been demonstrated to influence DNA methylation in children. Maternal folic acid supplementation also protects against some childhood diseases, such as neural tube defects. High folate intake has been associated with reduced risk of breast and colorectal cancer and increased risk of prostate cancer among adults, whereas meta-analyses have indicated no effect of folic acid supplementation on adult cancer incidence.– Maternal intake of folate and other nutrients involved in one-carbon metabolism may influence childhood leukemia risk due to the importance of these nutrients for DNA synthesis and repair, chromosomal integrity, and epigenetic processes that determine gene expression and influence cancer risk, including histone modification, levels of non-coding RNAs, and DNA methylation.,

Practices of prenatal folic acid supplementation have varied substantially across countries and over time, and individual epidemiologic studies that have evaluated the relationship between maternal folate intake through supplements and the risk of childhood ALL have yielded mixed findings. However, a recent Childhood Leukemia International Consortium analysis, the largest to date, pooled original interview data from 12 studies (representing 6,963 ALL, 585 AML, and 11,635 healthy controls) to observe that folic acid supplementation was protective against childhood leukemia. Folic acid taken before conception or during pregnancy– with or without intake of other vitamins –was associated with a reduced risk of childhood ALL (OR=0.80, 95% CI: 0.71–0.89) and AML (OR=0.68, 95% CI: 0.48–0.96), after adjustment for study center. Interestingly, the reduced risks were seen only among women with low and medium education levels – a surrogate marker for low socio-demographic status and possibly for a low-quality (low-folate) diets — suggesting that women who enter the peri-conception period with inadequate folate/vitamin levels would benefit the most from prenatal folate and vitamin supplementation.

Only a small number of studies, however, have examined the role of folate intake from food or the role of any other nutrients involved in the one-carbon metabolism cycle in the development of childhood leukemia. In addition, there has been only limited consideration of the role of maternal diet on risk of AML. A case-control study in Australia found some evidence that higher dietary intakes of folate and B12 from food in the last six months of pregnancy were associated with a decreased risk of ALL, whereas higher dietary intakes of vitamin B6 were unexpectedly associated with an increased risk of ALL. Previous analyses from a subset of the California Childhood Leukemia Study population examined the total intake of folate, vitamin B6 or vitamin B12 from both diet and supplements, and found no associations with ALL.,, However, in a recent and expanded California Childhood Leukemia Study analysis (681 ALL cases, 103 AML cases, and 1,076 controls) that employed principal components analysis to account for the high correlations between nutrients, higher maternal intake of one-carbon metabolism nutrients from food and supplements was associated with a reduced risk of ALL (OR=0.91, 95% CI: 0.84–0.99) and possibly AML (OR=0.83, 95% CI: 0.66–1.04). The association of ALL with nutrient intake exclusively from food (excluding supplements) was similar to the association of total nutrient intake from food and supplements, both in the study population overall and within racial/ethnic groups. However, high intake of B vitamins from supplements (versus none) was associated with a statistically significant reduced risk of ALL in children of Latinas (OR=0.36 95% CI: 0.17–0.74), but not in children of non-Latina white women (OR=0.76, 95% CI: 0.50–1.16) or Asian women (OR=1.51, 95% CI: 0.47–4.89). Racial/ethnic differences in nutrient intake and in genetic polymorphisms in the one-carbon (folate) pathway may partly explain the observed difference in leukemia risk.

In a biomarker analysis conducted as part of the California Childhood Leukemia Study, folate concentration measured in neonatal blood samples were similar between children with leukemia (313 ALL cases and 44 AML cases) and 405 controls, suggesting that folate levels at the end of pregnancy did not affect leukemia risk. The study was conducted in California where most pregnant women used prenatal vitamin supplementation, therefore limiting the ability to detect an association. Moreover, late pregnancy may not be the period of a child’s development during which a beneficial effect of folic acid and multivitamins, is critical to leukemia risk. However, this explanation would not be consistent with observations from the large pooled analyses of the Childhood Leukemia International Consortium that showed reduced risks of ALL and AML associated with self-reported supplementation during each trimester of the pregnancy.

Newborn and child serum-nutrient levels are influenced by many factors, including maternal and child genetic polymorphisms. Many studies have found significant associations between single nucleotide polymorphisms (SNPs) in folate-related genes, such as MTHFR variants, and childhood leukemia; but, there are inconsistencies in the specific SNPs that have been identified across studies.,– A study examining the largest number of genes and SNPs in the folate pathway found statistically significant associations between SNPs in genes CBS, MTRR, and TYMS/ENOFS (but not MTHFR) and childhood ALL. Levels of maternal folate intake during pregnancy, and child’s Latino ethnicity were found to modify some of these associations.

Topoisomerase II Inhibitors

The use of topoisomerase II inhibitors (a nuclear enzyme involved in DNA replication) in cancer chemotherapy has long been known to be associated with common MLL gene translocations that are characteristic of therapy-related AML. Consequently, it was hypothesized that topoisomerase inhibitors may be involved in the etiology of infant leukemia, because this subtype commonly involves the same MLL gene translocation that has been identified in these therapy-related leukemias. Aside from chemotherapeutic agents, topoisomerase inhibitors are found in diverse sources, including herbal medicines, quinolone antibiotics, certain types of laxatives, and pesticides. Certain dietary sources also contain topoisomerase inhibitors including, but not limited to, tea, coffee, wine, and certain fruits and vegetables. Recent laboratory studies, however, suggest that tea, wine and cocoa do not inhibit topoisomerase activity in vitro and thus are unlikely to increase the risk of MLL translocations.

A small exploratory study examining maternal exposure to topoisomerase inhibitors during pregnancy and the risk of childhood leukemia found an increased risk of AML with increasing topoisomerase II inhibitor exposure (OR=10.2, 95% CI: 1.1–96.4; N=29 cases) for high exposure], but no increased risk for ALL (OR=1.1, 95% CI: 0.5–2.3; N=82). Subsequent studies confirmed a positive relationship between maternal dietary intake of topoisomerase II inhibitors and risk of infant AML with a MLL gene translocation, but have found no association between dietary intake of topoisomerase II inhibitors and risk of other subtypes of infant AML or any type of ALL.,

Coffee, Cola, and Tea

An early case-control study of 280 cases and 288 hospitalized controls found an increased risk of ALL among children of mothers reporting coffee consumption greater than four cups a day during pregnancy (OR=2.4, 95% CI: 1.3–4.7 for 4–8 cups, and OR=3.1, 95% CI: 1.0–9.5 for >8 cups), with similar ORs observed for acute non-lymphoblastic leukemia that did not reach statistical significance. Subsequent case-control studies have found maternal consumption of coffee during pregnancy to be associated with an increased risk of ALL, AML, and possibly infant leukemia, while others have failed to find an association, as summarized in a recent meta-analysis. There is some evidence from these studies that the increased risk of leukemia with maternal coffee consumption may be more pronounced among children born to non-smoking mothers., Similarly, cola-based drinks have been associated with increased risk of childhood ALL (summary OR=1.31, 95% CI: 1.09–2.47), while reduced risks have been reported with maternal tea consumption during pregnancy (summary OR=0.85, 95% CI: 0.75–0.97). A general limitation of those studies is the lack of information on the type of drinks (e.g., caffeinated or not, green or black tea), which contain different nutrients and other compounds with either anti-or pro carcinogenetic properties.

Alcohol

Maternal alcohol intake before or during pregnancy has been hypothesized to influence childhood leukemia risk by altering immune function or by teratogenic effects on cell differentiation. Alcohol is also an antagonist to folate metabolism and methionine synthase and may modify DNA methylation status in interaction with folate levels. A systematic review and meta-analysis of 21 case-control studies found that alcohol intake during pregnancy was associated with AML (summary OR=1.56, 95% CI: 1.13–2.15 produced from 9 studies comprising 731 cases) but not with ALL (summary OR=1.10, 95% CI: 0.93–1.29 produced from 11 studies comprising 5,108 cases). Heterogeneity between studies was explained in part by some studies , that demonstrated a negative association of childhood leukemia with maternal alcohol consumption during pregnancy. Repeating the meta-analysis by subgroup of alcohol indicated an increased risk of AML associated with reported consumption of wine but not beer or spirits, providing some additional support for the topoisomerase II hypothesis. For ALL, there was an association between maternal consumption of spirits during pregnancy, but not beer or wine. One subsequent study supported the finding of an increased risk of AML with maternal alcohol consumption during pregnancy while another did not find an association; neither found a relationship between maternal alcohol consumption and ALL. In contrast, two other recent studies found that maternal consumption of alcohol during pregnancy was associated with a decreased risk of ALL and of infant leukemia.

Healthy Diet Index

In contrast to studies that have evaluated the role of a limited number of specific nutrients or food components, measures of overall diet quality may better represent nutritional status and the complex biological interaction of multiple nutrients. Diet quality indices are often positively correlated with biological markers of micronutrient intake and have been associated with reduced risk of all-cause mortality, including cancer risk., Maternal dietary patterns and quality have also been associated with birth outcomes, such as neural tube and congenital heart defects.

In a recent study overall maternal diet quality, as summarized by a diet quality index using a modified version of the 2010 Healthy Eating Index, was associated with a reduced risk of childhood ALL (OR for each five point increase on the index = 0.88, 95% CI: 0.78–0.98). A more pronounced reduction in risk was observed among younger children and children of women who did not use vitamin supplements before pregnancy. There was a similar reduced risk of AML with increasing maternal diet quality score, although this assosciation was not statistically significant (OR=0.76, 95% CI: 0.52–1.11). No single diet quality index component (i.e. food group or nutrient) appeared to account for the results, suggesting that the quality of the whole diet and the cumulative effects of many dietary components may be important in influencing childhood leukemia risk.

Paternal Diet

In contrast to maternal diet, very few studies have examined the relationship between paternal diet before conception and childhood leukemia. One study suggested that the risk of childhood leukemia increased with increasing paternal consumption of hot dogs (sources of carcinogenic compounds from N-nitroso precursors). Also, there is no strong indication that paternal intake of folate and other vitamins from diet and supplements before the child’s conception reduced the risk of leukemia in the offspring.,

Child’s Diet

As mentioned earlier, breastfeeding and duration of breastfeeding (six months of more) have been associated with the risk of childhood ALL, as summarized in recent pooled and meta-analyses conducted by the Childhood Leukemia International Consortium. Besides breastfeeding, little is known about the influence of child’s early diet. Feeding with formula as early as 14 days after birth, alone or in combination with breastmilk, was associated with an increased risk of childhood ALL and dose-response relationships were reported for the duration of formula feeding., These studies contrasted previous null findings. Infants and children fed with milk formula have been found to have higher serum levels of IGF-1 than those breastfed, and fetal growth pathway has been hypothesized to play a role in leukemogenesis. Associations between a child’s consumption of various food groups and the risk for childhood ALL or for all leukemias combined are inconsistent, especially regarding the consumption of fruits and fruit juice, as well as the consumption of meat.,,– Older age at introduction to solid food in general, and possibly older age at introduction to vegetables in particular, was associated with an increased risk of childhood ALL, while a reduced risk was reported for late introduction to eggs. Child’s consumption of cola-based drinks does not appear to be associated with leukemia, in contrast to maternal consumption during pregnancy.