Children’s bodies have a wide range of responses to medications, some of which are due to their genes. Some children inherit genes that don’t allow them to break down (metabolize) certain drugs, or that cause them to metabolize the drugs very slowly. In these children, the drug can build up in the body and cause excessive toxicity.

In addition, the cancer cells in individual children vary greatly in how they respond to different chemotherapy drugs. The cancer cells in one child’s body might be extremely sensitive to a certain chemotherapy drug, while the cancer cells in another child’s body can be very resistant to that same drug. As a result, the combined variability in children’s ability to metabolize drugs and how sensitive their cancer cells are to certain drugs causes a big range in the effectiveness of standard doses of medications. How much of this variability is due to genetics is not well understood.

However, researchers are finding ways to test children’s ability to metabolize certain drugs and are tailoring treatments based on that genetic information. This area of science is called pharmacogenetics. Here are three examples of genetic characteristics that are used by doctors to tailor treatments to a child’s unique genetic makeup.

Thiopurine-S-methyltransferase (TPMT)

Some children are not genetically coded to make an enzyme called TPMT, which is involved in breaking down (metabolizing) two chemotherapy drugs used to treat leukemia—thioguanine (6-TG) and mercaptopurine (6-MP). One way to identify how children can metabolize these drugs is a type of testing called genotyping.

Around 1 in 400 people cannot metabolize 6-TG and 6-MP at all and are called “TPMT poor metabolizers.” When children with this genetic variation are given standard doses of these drugs, the drugs quickly build up to toxic levels. In these children, the numbers of red cells, white cells, and platelets drop dramatically putting the child at risk for anemia, infections, and bleeding. Children who are poor metabolizers are given only about 10% of the standard dose of 6-MP.

Ten out of every 100 people are able to slowly metabolize 6-TG and 6-MP and are called “TPMT intermediate metabolizers.” Children with this genetic makeup need lower doses of 6-TG and 6-MP to prevent big drops in blood counts. Guidelines from the Clinical Pharmacogenetics Implementation Consortium recommend a starting dose of 30 to 70% of the standard dose.

Josh has not been on full doses of 6-MP for over a year now. It did take the doctors a long time to realize that they needed to increase Josh’s 6-MP slowly. For months they would drop the dose to 50%, and in two weeks his counts were okay. Not great, but high enough to increase the dose, so they would. Another two weeks at 75% and he would crash. Finally, they did the TPMT test and sure enough he does not metabolize the 6-MP normally. I remember them telling me that 10% of the population has this enzyme deficiency and you would never know unless you had to take 6-MP.

The remainder of the population (approximately 90%) can break down these medications at the normal rate and are started on the standard dose. Some treatment centers test all children with leukemia for their genetic ability to metabolize 6-TG and 6-MP before they give them either drug. Other institutions test children if their blood counts drop dramatically after getting the first doses of these drugs. Genotyping identifies the majority of children with a decreased ability to metabolize 6-MP or 6-TG.

Even if the TPMT genotype test comes back normal, some children have high or low levels of other enzymes that affect how 6-MP and 6-TG are metabolized. In these cases, tests of 6-MP metabolites (called 6-MMPN and 6-TGN) are sometimes done.

If liver enzymes are up, it may be due to 6-MP metabolites. 6-MP is metabolized into 6-MMPN, which is liver toxic and has no anti-leukemic properties (the bad one) and 6-TGN, which is anti-leukemic (the good one). In my son’s case, his liver enzymes went up but were still well below the protocol guidelines for when to worry about liver toxicity. But he was having problems with hypoglycemia and looked ill. So they checked his metabolites just to be safe. Well, everyone was surprised because his 6-MMPN was outrageously high—should be less than 5,700 but was almost 45,000. His 6-TGN was on the low side. When the results came back, our oncologist notified us the same day and told us to take him off chemo immediately. We ended up inpatient within a week.

CYP2D6

Another genetic variation involves the CYP2D6 gene, which affects the metabolism of codeine. About 10% of people do not get pain relief from codeine because they are genetically unable to metabolize codeine into morphine. Recently, the U.S. Food and Drug Administration released a statement that codeine should not be given to children younger than age 12. Some institutions test all children with leukemia who are older than 12 for this genetic variation so the right pain medications can be prescribed.

In contrast, some people metabolize codeine very rapidly because they have extra copies of the CYP2D6 gene. This results in symptoms of opiate overdose—sleepiness, confusion, shallow breathing. Teens with this genetic variation should be given pain medications that don’t contain codeine. For more information on this topic, visit the National Institute of Health webpage called “Codeine Therapy and CYP2D6” at www.ncbi.nlm.nih.gov/books/NBK100662.

Methlyenetetrahydrofolate reductase (MTHFR)

A genetic variation called MTHFR C677T may increase some children’s sensitivity to methotrexate, resulting in liver toxicity, very low blood cell counts, and other side effects. Some institutions test children who have these reactions while receiving methotrexate for this genetic variation.

My daughter was on standard treatment for standard risk B-cell ALL with good cytogenetics. However, she didn’t tolerate the chemo well—she developed grade 3 neuropathy from the vincristine and liver problems from the methotrexate (her liver enzymes were off the chart). She had many delays in treatment and reductions of doses. After delayed intensification, she was on a 3-month chemo hold because her counts crashed and did not come back up. One of the moms on an online support group suggested that she be tested for the MTHFR gene to see if she was unable to metabolize methotrexate. The staff oncologist I initially discussed the test with resisted, but I insisted. It turns out that she is homozygous for MTHFR, and so she got only about 15% of the normal dose of that drug for the rest of treatment. She also needed the rescue drug, leukovorin, after getting intrathecal methotrexate. I gave the leukovorin every six hours for the 24 hours after every spinal tap. She got the medicine her body needed and has been in complete remission seven years now.

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Our facility did not test for MTHFR or TPMT until after my daughter was in her second year of long-term maintenance. Her blood counts were continually bottoming out and she had elevated bilirubin. It was at my request that the tests were administered. The tests showed that she is homozygous (has two copies) of MTHFR C677T; however the tests show normal ability to process 6-MP. With that said, she has spent an enormous amount of time off chemo with elevated liver enzymes and/or counts that have bottomed out. She currently is off chemo again. This will be her fourth week with no 6-MP or methotrexate. When she is on chemo, she takes 25% of the standard amount of methotrexate and 50% of 6-MP. This just goes to show how very different each child is, and why we must continue working toward protocols that are tailored to individuals and standardizing testing which helps to identify these types of anomalies at the beginning of treatment.