Children usually do not get cancer. Of all cancers, pediatric cancers under the age of 14 account for only about 1 percent of all cancers. The most common cancer in children is leukemia. Leukemia takes up about 30 percent of all childhood cancers. Pediatric leukemia includes acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Among these, ALL accounts for 70 percent.
ALL causes abnormal proliferation of lymphocyte-like blast cells in the blood or bone marrow. This results in problems in the blood and lymphocyte that play a crucial role in the human body’s immunity.
Korea Biomedical Review met with Professor Chung Nack-gyun at the Pediatric Catholic University of Korea Seoul St. Mary’s Hospital to learn more about ALL, the most common type of pediatric leukemia, and ALL treatment.
Question: In ALL, B-cell or T-cell leukocytes turn into malignant cells and they proliferate rapidly in the bone marrow or blood. If there are more than 20 percent of these lymphocytes in the bone marrow, it is classified as “leukemia,” and if less than 20 percent, “lymphoma.” Are they different diseases?
Answer: Lymphoma is a little different depending on the type. But in this case, you can understand them as the same disease. ALL is also known as acute lymphoblastic leukemia/lymphoma. It refers to the cancerous mutation of blood cells originating from lymphoblasts, and the treatment is not very different.
Q: Children with ALL are known to have a better prognosis than adults. Are there any characteristics in children that are different from those in adults regarding this disease?
A: There are differences in the types of genetic mutations associated with disease prognosis. In adults, the Philadelphia chromosome-positive type, which has a poor prognosis, is the most common. In children, the ETV6-RUNX1 gene mutation type, which has a good prognosis, is the most common.
In most adults, we induce remission with chemotherapy and hematopoietic stem cell transplantation (bone marrow transplantation) after consolidation treatment (maintenance treatment after remission).
In children, we can continue chemotherapy longer than adults, so there are more cases in children where treatment is completed with chemotherapy alone. It is very difficult for adults to use L-asparaginase, an anticancer drug, but it is okay for children. Children's bone marrow is young, so the recovery rate is extremely faster than that of adults, so we can continue the next treatment. The rate of osteonecrosis that can occur when a lot of steroids are used is also lower in children than in adults.
Researchers have recently confirmed that the survival rate of adolescents was higher with pediatric treatment than with adult treatment. So, not only Korea but other countries have also adopted pediatric treatment protocols.
Q: There are many causes of childhood ALL but what do you think is the most powerful causative factor?
A: It is radiation. Radiation increases the risk of ALL the most because it affects genes. In addition, magnetic fields, environmental hormones, and job-related factors are considered minor causes. But we still don't know why ALL develops.
One family shares the same environment but only one child among the family members gets it. It’s not genetic either. Even in identical twins, only one child can have it. Analyzing the genes of patients with myelodysplastic syndrome, which later becomes cancer due to genetic mutations, it seems that the mutations eventually accumulate and the disease develops, according to study results.
Q: What is the age at which pediatric ALL occurs the most, and through what paths do children come to see you?
A: ALL occurs frequently between the ages of 2 and 5 years. According to domestic statistics, the incidence rate is about twice as high in children aged 0 to 4 compared to those aged 5 to 9. Most of them come to the hospital after seeing a local pediatrician when they have a lot of bruises, have no energy, don't want to play, or when the child is too pale. These days, people don't go to the clinic often because of the risk of infection with Covid-19, so children come after the disease has become a little more serious than before.
When this disease develops, rapid hematological changes occur within two to three months. It cannot be detected by a health checkup. It takes nearly 10 billion leukemia cells to show symptoms in the body. As many as 100 million may be asymptomatic. If the number is less than 100 million, even a bone marrow examination may not reveal the presence of the disease. Usually, the stage at which a disease is discovered is when there are 100 billion or 1 trillion leukemia cells. Death occurs when the number exceeds 10 trillion, but it is usually discovered before then.
Prognosis good in children younger than 10 with fewer than 50,000 white blood cells
Q: Microscopic residual disease (MRD) and genetic mutations have recently been added as prognostic factors for this disease. Which of the current prognostic factors do you see as having a strong influence on this disease?
A: The strongest prognostic factor is MRD. Even in complete remission, it is now an unchanging principle that the fewer cancer cells there are, the more effective treatment is. If the cancer cell count falls quickly, recurrence is unlikely. If MRD remains after consolidation treatment, use the treatment once more and if the count falls to the point of being undetectable, the prognosis is very good. In Korea, a multi-center treatment protocol based on MRD is currently being prepared.
Genetic mutations are also important. The prognosis is poor in those with the Philadelphia chromosome and good in those with the ETV6-RUNX1 gene. In the past, it was believed that hematopoietic stem cell transplantation was necessary if the Philadelphia chromosome was present. Also, for those with ETV6-RUNX1, we don’t use strong treatment because the patient can be cured. That's why we use “risk adaptive therapy.”
‘CAR-T cell therapy, less beneficial in poor prognosis’
Q: Many new treatments have come out recently but doctors still use chemotherapy in ALL. How do you treat pediatric ALL?
A: We use medicines that were used in the 1980s but they work well. About 80 percent of childhood ALL is treated with these old medicines. But 20 percent of those patients experience recurrence or drugs do not work well in them. About 5-10 percent of children need a bone marrow transplant.
If the disease recurs 36 months after the first diagnosis, chemotherapy is given again because it works well. If it recurs within 36 months, the same chemotherapy does not work well. Treatment should be different, and that is bone marrow transplantation.
Recently, targeted therapy with fewer side effects has emerged but they are expensive. From the viewpoint of a doctor, I think it would be nice if these treatments could be used a little earlier. CAR-T cell treatment is also covered by insurance in Korea when recurrence occurs after bone marrow transplantation. Since CAR-T treatment is much safer than bone marrow transplantation, it would be nice to be able to use it at the front end.
Bone marrow transplantation requires whole-body radiation as a pre-treatment treatment. Because of this, almost all of them become infertile. Cataracts or various hormonal disorders may also ensue. In some cases, boys have to receive hormone injections every month because secondary sexual characteristics do not occur, and girls also continue to take medications.
Infants with ALL under one year have the worst prognosis because their overall survival rate is only about 50 percent. So, almost all of them get bone marrow transplants. These children do not have permanent teeth. Given the long survival after complete recovery, I hope doctors could use safe treatment in the first stage for a better quality of life.
Also, this disease relapses at different times in each patient. As leukemia cells acquire resistance to anticancer drugs, few leukemia cells remain alive but then gradually amplify and recur. Leukemia cells hidden during treatment could grow up gradually.
As I said earlier, if it recurs after a bone marrow transplantation, we can use CAR-T cell therapy. But if it recurs again, we do a bone marrow transplantation again. However, the more time passes, the poorer the prognosis. If a child had chemotherapy and the disease came back, or if the child is receiving maintenance treatment but the medicine does not work well, the child can receive CAR-T cell treatment.
Q: The treatment period for childhood ALL is quite long. How is the treatment carried out?
A: For six months, the patient is hospitalized for chemotherapy and discharged several times. Then, maintenance therapy follows for two years. During maintenance therapy, oral medications are given, so there is no need to be hospitalized.
Even when hospitalization and discharge are repeated, treatment schedules vary depending on the type of injection.
Q: After discharge, what situation is urgent for a pediatric ALL patient?
A: After chemotherapy, the white blood cell count drops, making it an easy environment for bacteria to invade. So if a child aged 15 or younger has a fever of 38 degrees Celsius or higher, the child should come to the emergency room as soon as possible. People over 15 years old should go to the emergency room immediately if the temperature is 37.5 degrees or higher. Even a little too late can lead to death from sepsis.
Q: Do you have any comments for pediatric ALL patients and their families?
A: This disease is not caused by someone’s fault and it can be cured. Its treatment outcome is good. If you have hope and get treatment, you can earn good results. If you trust your doctor and work together, you will come to the end of treatment one day.
This article was originally published in Korea Healthlog, a sister paper of Korea Biomedical Review.