Pediatric Acute Myeloid Leukemia

Disease information

Overview
Causes
and Symptoms
Treatment

Overview

Acute Myeloid Leukemia (AML) is a type of blood cancer that develops from the uncontrolled growth of abnormal cells in the blood, bone marrow, or other tissues. It shows a wide variety of clinical symptoms, cellular appearances, and genetic profiles. In children, AML represents about 23% of all leukemia cases, with an annual estimate of 80 to 100 new cases in Korea. Although the outlook for pediatric AML has not been as favorable as that for Acute Lymphoblastic Leukemia (ALL), recent advancements in aggressive chemotherapy and Hematopoietic Stem Cell Transplantation (HSCT) are leading to improvements in treatment success.

Causes and Symptoms

Although extensive research has been conducted, the precise cause of leukemia is still not fully understood. However, scientists have identified several risk factors that may contribute to the development of the disease. Some patients with leukemia have genetic mutations or chromosomal abnormalities, but these are not present in all cases. Potential risk factors such as exposure to certain viruses, radiation, organic solvents, and other environmental elements have been suggested, yet the specific cause of leukemia in individual patients often remains undetermined.

In cases of hereditary diseases for example) Down Syndrome (three copies of chromosome 21)
In cases where the individual has received past chemotherapy or radiation treatment
In cases of long-term exposure to toxic chemicals such as benzene, pesticides, paint, preservatives, and insecticides
In cases of exposure to high levels of radiation for example) victims of atomic bombings during World War II, or victims of the Chernobyl nuclear disaster in the former Soviet Union

Acute Myeloid Leukemia (AML) is known for its swift progression, which can lead to symptoms like high fever, anemia, and bleeding early in the disease process due to the rapid increase of immature, undifferentiated cells. The rapid nature of the disease means that a patient's condition can worsen quickly, highlighting the importance of early detection and immediate treatment. Unlike many other cancers, there is no staging system for acute leukemia because, by the time of diagnosis, a significant number of cancerous cells are typically present in both the bone marrow and the bloodstream. In some cases, leukemia cells may also spread to other parts of the body, such as the central nervous system, intestines, bones, gums, and skin, indicating a more extensive disease involvement.

1.
Symptoms of bone marrow failure due to conditions like leukemia typically involve anemia, which leads to feelings of fatigue and weakness; neutropenia, which increases susceptibility to infections; and thrombocytopenia, which can result in easy bruising or bleeding. Additionally, patients often report a loss of appetite and weight loss. These symptoms are key indicators of bone marrow dysfunction and should prompt medical evaluation and treatment.
- Neutropenia Symptoms of infection and fever due to decreased immunity.
- Anemia Symptoms include dizziness, headaches, difficulty breathing during physical activity, and pallor (pale skin).
- Thrombocytopenia Hemorrhagic symptoms such as gum bleeding, epistaxis, bruising, petechiae, and retinal hemorrhage.
2.
As leukemia cells grow quickly in the bone marrow, you may experience pain in your sternum, ribs, and the longer bones in your limbs. Should your white blood cell count rise above 100,000/mm³, your blood could become thicker. This condition, known as hyperleukocytosis, can increase the risk of serious health issues, including bleeding in the brain or stroke, changes in your thinking or behavior, difficulty breathing, and other effects of leukostasis – a condition where too many white blood cells slow down blood flow. These are serious symptoms that require urgent medical care. If you notice any of these signs, it's important to speak with your doctor immediately.
3.
Leukemia cells have the potential to create tumor-like growths in organs beyond the bone marrow; these are known as myeloid sarcomas. These growths are often associated with chromosomal abnormalities and can be detected at the time of leukemia diagnosis or sometimes even earlier. The presence of leukemia cells in the gums, skin, soft tissues, or the membranes covering the brain and spinal cord (meninges) is especially characteristic of acute monoblastic and monocytic leukemia. If you notice unusual lumps, swelling in these areas, or other concerning symptoms, it's important to report them to your doctor for further evaluation.

Treatment

Previously, the mainstay of treatment for pediatric acute myeloid leukemia (AML) was allogeneic hematopoietic stem cell transplantation. Now, treatment approaches are increasingly personalized, with strategies being adjusted according to prognostic categories and individual responses to therapy. This shift allows for more targeted and potentially more effective treatments for children with AML.

Induction Therapy

The standard induction therapy for acute myeloid leukemia (AML) typically includes the '7+3' regimen, which involves seven days of continuous infusion of cytarabine (Ara-C) and three days of idarubicin. Similarly to acute lymphoblastic leukemia (ALL), it is also crucial to prevent a relapse in the central nervous system by administering intrathecal chemotherapy.

The effectiveness of chemotherapy is judged by achieving complete remission. This is defined as having less than 5% blasts in the bone marrow, no detectable leukemia cells in the peripheral blood, and normal recovery of blood cell counts (a neutrophil count above 1,500/mm3 and a platelet count above 100,000/mm3). Additionally, any extramedullary disease, which refers to leukemia involvement outside of the bone marrow, should be resolved. It's important to understand that complete remission is not the same as a cure. Once complete remission is reached, post-remission therapy is initiated to maintain the remission state. If complete remission is not achieved, then re-induction therapy may be necessary.

Post-Remission Therapy

Following initial treatment that induces complete remission, a substantial number of leukemia cells, estimated to be between 100 million and 1 billion, may still remain undetectable by microscopy. To prevent a relapse and move toward a cure, post-remission treatment is carefully planned based on a thorough assessment of the patient's prognosis, their risk category, and the availability of a suitable donor for transplantation if necessary. This tailored approach is key to optimizing long-term outcomes for patients with leukemia.

①
Consolidation Chemotherapy
- For the group with a good prognosis, a total of six chemotherapy treatments, including induction therapy, are performed with drugs containing cytarabine, idarubicin, etoposide, and mitoxantrone.
②
Hematopoietic Stem Cell Transplantation
- Except for cases with a good prognosis that continue with just some chemotherapy, once remission occurs, consolidation therapy is performed while conducting HLA testing to find a donor. If an appropriate donor is found, hematopoietic stem cell transplantation is performed. This is performed in the state of first remission after a total of 3-6 rounds of chemotherapy, including consolidation therapy.

If a patient requiring hematopoietic stem cell transplantation has a sibling with a matching HLA profile, this sibling is typically the preferred donor. If a sibling match is not available, if the HLA match is not suitable, or if the sibling is unable to donate for other reasons, a search for an unrelated donor is conducted through Korea's National Organ Transplant Management Center (KONOS). Should a compatible HLA donor not be located, alternative options like cord blood transplantation, which uses stem cells from umbilical cord blood, or haploidentical transplantation, where the donor is a half-match often a family member, may be considered. The decision to proceed with hematopoietic stem cell transplantation takes into account the potential side effects and risks associated with the procedure. This decision is made after careful evaluation of the benefits and potential drawbacks in relation to the patient's particular condition and the availability of a suitable donor.

Response after Induction Therapy, post-remission therapy

Acute Promyelocytic Leukemia (M3 subtype)

Acute promyelocytic leukemia (APL) cells release substances that can trigger coagulation within the blood vessels, leading to conditions such as disseminated intravascular coagulation (DIC), which includes a reduction in fibrinogen levels. This can result in significant bleeding events, such as gastrointestinal, respiratory, or even brain hemorrhages. It's crucial to begin treatment with All-trans-retinoic acid (ATRA) orally as quickly as possible if APL is suspected, even before genetic confirmation, to promote the maturation of the leukemia cells into normal blood cells and to prevent early death from bleeding through aggressive transfusion support.

In the diagnosis of APL, a specific genetic test is done to look for a translocation between the PML gene on chromosome 15 and the RARα gene on chromosome 17, resulting in the PML/RARα fusion gene, t(15;17), which is present in the majority of APL cases. For induction therapy, ATRA is used in combination with anthracycline-based chemotherapy. This is followed by three cycles of consolidation chemotherapy and then two years of maintenance therapy with oral anticancer agents and periodic ATRA administration.