Overview.
It is a special subtype of acute myeloid leukemia with abnormal proliferation of granulocytes in the bone marrow.
Common symptoms include bleeding, fever, pallor, and malaise.
The cause of the disease is not fully understood, and may be related to physical and chemical factors, genetic factors, viral infections, etc.
Induction of differentiation by arsenic trioxide (AS2O3) is the mainstay of treatment, supplemented by chemotherapy and supportive therapy.
Definition
Acute promyelocytic leukemia (APL) in children is a disease that occurs in children and is characterized by a marked increase in the number of abnormal promyelocytes, which belongs to acute myeloid leukemia (AML), a hematological malignancy [1-2].
It often starts with severe bleeding tendency and becomes life-threatening at an early stage [3].
Types
Acute promyelocytic leukemia in children is a morphologic phenotype of acute myeloid leukemia, generally expressed as M3 or APL; it may still be typed morphologically or based on genetic features.
Morphologic typing
Based on the morphology of the granules in the cytoplasm of the abnormal promyelocytes, it can be divided into coarse-granular (M3a) and fine-granular (M3b) types [2].
Genetic typing
After typical
Genetic tests, such as gene testing, reveal t(15;17)(q22;q21) or PML-RARα positivity [1-3].
This type is the most common type of acute promyelocytic leukemia and is specifically referred to by international practice [3].
Variant
Acute promyelocytic leukemia in which genetic testing reveals other abnormalities, collectively referred to as variant type, may have the following findings.
t(11;17)(11q23;q12)/PLZF-RARα.
t(5;17)(5q35;q12)/NPM-RARα.
t(11;17)(11q13;q21)/NuMA-RARα.
Morbidity
Acute promyelocytic leukemia in children belongs to a specific subtype of acute myeloid leukemia.
AML accounts for about 20% of acute leukemias in children; there is no gender difference in incidence; it can occur at any age, with the first peak occurring within 1 year of age, followed by a gradual decline, and is more stable after 4 years of age.
The incidence rate is about (5-7)/1 million and increases again in adolescence [2].
Etiology
Causes
The etiology of acute promyelocytic leukemia in children is still unclear, and is generally considered to be the result of the interaction between environment and heredity, and is related to physical and chemical factors, genetic factors, and viral infections.
Physical and chemical factors
Ionizing radiation
The prevalence of APL is increased in children who receive radiation therapy for thymic hypertrophy.
After X-ray irradiation of the abdomen in pregnant women, the incidence of leukemia in their newborns was 17.4 times higher than in those who did not receive irradiation [2]. However, the radiation doses used for general imaging are small and there are no cases of secondary leukemia [1].
Chemical substances
Benzene and its derivatives, chloramphenicol, povidone, ethylenediamine, cytotoxic drugs (e.g., cyclophosphamide, azathioprine, etc.), and pesticides may be associated with the development of APL.
Genetic factors
The incidence of APL is higher in people with genetic defects, such as children with trisomy 21, congenital distal capillary dilated erythema, and congenital aplastic anemia with multiple malformations, than in children in general.
Viral infections
T-lymphoblastic leukemia in adults can be caused by viruses, so it is hypothesized that APL in children may also be associated with viral infections [1].
Pathogenesis
Proteins produced by genetic abnormalities in classical acute promyelocytic leukemia, which can lead to blocked cell differentiation and insufficient apoptosis, are the main molecular mechanisms of pathogenesis.
Symptoms
Main Symptoms
Bleeding
Severe bleeding tendency is a common first symptom of acute promyelocytic leukemia in children [3], which may be manifested as skin purpura and petechiae, nosebleeds, gum bleeds, black stools, bloody stools, and hematuria [1-2].
Intracranial hemorrhage is one of the most serious conditions, which can be manifested by headache, vomiting, asymmetrical pupil size, and in severe cases, coma and even life-threatening.
Anemia
Due to prolonged and massive bleeding, anemia manifestations can occur, including pallor, weakness, and shortness of breath after activity [2].
Fever
Fever is a common symptom in children, and the temperature of fever is variable, and the fever caused by infection is mostly high [2].
Symptoms of leukemia cell infiltration
Bone or joint pain, abdominal distension, and testicular enlargement are common [1].
Central nervous system infiltration may present with headache, vomiting, lethargy, paraplegia, convulsions, coma and other symptoms.
Complications
Disseminated intravascular coagulation
Acute promyelocytic leukemia in children often presents with severe bleeding, with disseminated intravascular coagulation as its most serious complication.
Decreased blood pressure may occur, as well as various signs of shock, such as irritability, apathy or coma, pale skin, and decreased urine output.
Consultation
Department of Medicine
Hematology
When children develop symptoms such as bleeding, anemia, fever, and bone pain, prompt medical attention is recommended.
Pediatric Internal Medicine
Children with these symptoms may also be referred to the Department of Pediatric Internal Medicine.
Preparation for medical treatment
How to prepare for your visit: registering, preparing documents, and common problems.
Tips for seeking medical care
Parents should keep a record of the time the child develops symptoms, how long they last, and whether they get worse for the doctor’s reference.
Preparation Checklist
Symptom list
Pay special attention to the time of onset of symptoms, special manifestations, etc.
What is the child’s abnormality? Is there bleeding, fever, anemia, bone pain, etc.?
When was the abnormality detected? Under what circumstances does it occur?
Did the symptoms decrease or worsen? Under what circumstances do they occur?
List of medical history
Has there been any exposure to high doses of radiation?
Was the mother exposed to ionizing radiation during pregnancy?
Has there been any exposure to benzene and its derivatives, chloramphenicol, prednisone, ethylenediamine, cytotoxic drugs (e.g., cyclophosphamide, nitrogen mustard, etc.), and chemicals such as insecticides?
Are there any genetic defects such as Trisomy 21?
Checklist
Test results from the last six months, which can be brought to the doctor’s office
Laboratory tests: blood tests, blood smears, coagulation tests, genetic tests, etc.
Imaging Tests: Chest X-ray, Echocardiogram, Cranial CT, Cranial Magnetic Resonance Imaging (MRI)
Other tests: electrocardiogram
Diagnosis
Diagnosis is based on
Medical history
Children may have exposure to ionizing radiation, benzene and its derivatives, chloramphenicol, prednisone, ethylenediamine, cytotoxic drugs (e.g., cyclophosphamide, azathioprine, etc.), and insecticides prior to the onset of the disease.
Children may have genetic defects such as trisomy 21-trisomy.
The child’s mother may have been exposed to ionizing radiation during pregnancy.
Clinical manifestations
Symptoms.
Children may present with bleeding, anemia, fever, and signs of leukemic cell infiltration.
Signs
Children may have fever, infections, skin and mucosal hemorrhages and petechiae, bloody urine and stools, convulsions due to intracranial hemorrhage, hepatomegaly, splenomegaly, enlarged lymph nodes, and localized testicular tenderness.
Laboratory Tests
Blood test
Anemia and thrombocytopenia may be detected in routine blood tests.
Leukocyte counts are often decreased, but may be elevated or normal.
Blood smear
Abnormal early granulocytes can be found, which is suggestive of the diagnosis.
Coagulation tests
Since bleeding is more significant in children with acute promyelocytic leukemia, coagulation is a routine test to assess the child’s coagulation function and to prevent and treat severe bleeding as early as possible.
D-dimer test will also be performed if there are signs of disseminated intravascular coagulation.
Genetic Testing
Genetic testing reveals relevant genetic abnormalities and is an important basis for definitive diagnosis.
Blood biochemistry tests
Uric acid levels are used to monitor the development of tumor lysis syndrome.
Blood biochemistry tests are performed regularly after the start of chemotherapy to understand liver and kidney function.
Bone Marrow Puncture
Bone marrow aspiration examination reveals that the bone marrow is dominated by abnormal promyelocytic hyperplasia, with azurophilic granules in the cytoplasm of the cells, which can be used as the basis for definitive diagnosis.
Cerebrospinal fluid examination
It is mainly used to identify the presence or absence of central nervous system leukemia.
Immunologic examination
Immunological examination can assist in defining the typing, positive antigens commonly include CD13, CD33, etc., CD34, HLA-DR are often negative.
Infectious disease screening
Including hepatitis virus, human immunodeficiency virus (HIV), syphilis antibody, EBV, etc.
Mainly pre-chemotherapy evaluative tests.
Imaging
Chest X-ray
Chest X-ray or lung CT is a routine examination after diagnosis.
It can find out whether there is lung infection and whether there is mediastinal lymph node enlargement.
Echocardiography
Chemotherapy drugs are cardiotoxic, echocardiography can find out the condition of the heart.
Cranial CT, cranial magnetic resonance imaging (MRI)
Mainly used in the evaluation of children with CNS leukemia.
Electrocardiogram (ECG)
Since arsenic agents are cardiotoxic, regular ECGs are needed to monitor for conditions such as prolonged QT interval.
Differential Diagnosis
Other myeloid leukemias
Similarities: Both may present with bleeding, anemia, fever, etc. Immunostaining may reveal myeloid antigens such as CD13 and CD33.
Differences: Children with acute promyelocytic leukemia have t(15;17) and RARα gene fusion, while other myeloid leukemias do not have this gene abnormality, which can be used as a basis for differentiation.
Myeloid natural killer cell leukemia
Similarities: both may present with obvious bleeding, and examination may reveal cytoplasmic granular promyelocyte-like cells.
Differences: mainly through laboratory tests, myeloid natural killer cell leukemia does not have specific genetic alterations such as t(15;17), and is positive for CD33 and CD56, but negative for CD34, CD-16 and HLA-DR.
Megaloblastic anemia
Similarities: Both may present with a decrease in whole blood cells, with bleeding, anemia, and fever.
Differences: Blood routine and blood smear examination of megaloblastic anemia may reveal that the anemia is macrocytic orthochromatic anemia, which can be treated effectively by supplementation of folic acid and can be used as a basis for differentiation.
Myelodysplastic syndrome
Similarity: Childhood cells can be found in the bone marrow.
Differences: Children with acute promyelocytic leukemia usually have more than 20% of primitive and promyelocytic cells in the bone marrow and are positive for the PML-RARα fusion gene.
Leukemia-like reaction
Similarities: Naïve cells may be found in the peripheral blood and leukocytosis may be increased.
Differences: Leukemia-like reactions are usually secondary to certain infections. Bone marrow cell classifications are basically normal, platelets and hemoglobin are mostly normal, and white blood cell counts may return to normal after controlling the primary disease.
Treatment
Treatment: Chemotherapy is the mainstay of acute promyelocytic leukemia in children, and appropriate drugs are used to control symptoms according to the child’s condition. The specific chemotherapy regimen needs to be determined by the doctor after the prognosis is clear based on the child’s laboratory test results.
Treatment objective: to completely eliminate leukemia cells in the body and restore normal blood production function.
Chemotherapy
The main chemotherapeutic drugs used for acute promyelocytic leukemia in children are arsenic trioxide (ATO), compound Huangdai tablets (RIF), and all-trans retinoic acid (ATRA) [1-3].
Depending on the prognostic staging and stage of chemotherapy, anthracycline chemotherapeutic agents (e.g., Zoerythromycin), methotrexate (MTX), and 6-mercaptopurine (6-MP) may be added to the regimen.
Chemotherapy is generally divided into three phases: induction therapy, consolidation therapy, and maintenance therapy.
The goal of the induction therapy phase is to kill leukemia cells and normalize the bone marrow examination, which is generally 30-42 days, usually not more than 60 days [3].
The goal of consolidation and maintenance therapy is to remove residual, leukemia cells that cannot be detected by conventional examination methods.
Drug therapy
Drug therapy is mainly based on children’s symptoms to choose appropriate drugs for improvement.
Drugs to control hyperleukemia
The main drugs are hydroxyurea (HU) or cytarabine and zorubicin for children with a white blood cell count >10 × 109/L at initial diagnosis or during induction therapy.
Reducing the leukocyte level as soon as possible may prevent the coagulation disorder from worsening.
Drugs to improve bleeding and coagulation abnormalities
Primarily used in children with coagulopathies, platelets and coagulation factors can be replenished by aggressive transfusion of blood products.
Invasive operations such as central venous cannulation and lumbar puncture should also be avoided as much as possible to prevent increasing the risk of bleeding and thrombosis caused by disseminated intravascular coagulation [3].
Drugs against differentiation syndrome
Glucocorticoids are mainly used for the prevention and treatment of differentiation syndrome.
The commonly used drugs are dexamethasone, but also prednisone and others.
Drugs for pseudotumor cerebri
The use of all-trans retinoic acid in children carries a risk of pseudotumor cerebri, and the main therapeutic drugs are dexamethasone, mannitol, and/or acetazolamide, along with medication tapering, etc., as prescribed by the physician.
Biologic agents
Anti-CD33 monoclonal antibody GO is also used to treat acute promyelocytic leukemia.
Prognosis
Cure
The cure rate of acute promyelocytic leukemia in children can be more than 90% with timely and effective treatment [3].
Prognostic factors
The prognostic staging of acute promyelocytic leukemia in children is mainly based on the peripheral blood leukocyte count at the initial diagnosis [3].
A leukocyte count ≤10×109/L at initial diagnosis is considered non-high risk.
A leukocyte count >10×109/L at initial diagnosis is considered high-risk.
Hazard
Children with childhood acute promyelocytic leukemia have a marked tendency to bleed, which may be life-threatening if not diagnosed and treated in time.
Children may be affected by the disease in their normal study and life. Long-term hospitalization, etc. may bring psychological pressure.
Daily
Daily Management
Dietary management
Children under 6 months of age can continue to be fed in the same way as before.
For children over 6 months old, supplemental food can be added normally, and attention should be paid to choosing light and easy-to-digest food, and eating less and more frequent meals, so as to alleviate anorexia, nausea, vomiting and other discomforts caused by chemotherapy.
Life management
During illness and chemotherapy, children are prone to infections. They need to pay attention to warmth and rest, reduce close contact with people, and reduce the risk of infection by wearing masks, washing hands, and gargling with saline.
Children have a serious tendency to bleed, so they should pay attention to protection when moving around to avoid trauma; it is advisable to use soft-bristled toothbrushes for brushing teeth.
The living environment should be clean and hygienic, properly ventilated and disinfected, and clothing should be changed in a timely manner.
When the condition improves, start with walking and other intense exercise, and gradually resume normal exercise.
Psychological support
For children under 1 year old, parents need to strengthen soothing to minimize crying.
For children over 1 year old, especially those of school age, parents need to provide guidance to reduce psychological pressure and avoid depression and other negative emotions; communicate with school teachers to help children return to school after treatment.
Follow-up and review
Regular checkups are required by the doctor, and the doctor will determine the exact time according to the child’s condition.
Generally, the micro residual foci (MRD) of bone marrow specimens are monitored at the end of consolidation therapy, and then the MRD of peripheral blood or bone marrow specimens are reviewed every 3 to 6 months, which lasts for at least 24 months after the end of maintenance therapy [3].
Prevention.
There is no definitive method of prevention, and avoidance of exposure to suspected environmental factors, as well as adherence to a good lifestyle, can help maintain good health.
Avoid exposure to ionizing radiation (e.g., X-rays, etc.), and mothers should also avoid exposure during pregnancy.
Help children to develop good hygiene habits, such as not touching their eyes, mouth, nose and ears with their hands, not sharing utensils and other household items, and washing their hands frequently to prevent infection.
Avoid children’s exposure to benzene and its derivatives, chloramphenicol, prednisone, ethylenediamine, cytotoxic drugs (e.g., cyclophosphamide, nitrogen mustard, etc.), and insecticides.
For those with a history of genetic disease, genetic counseling should be done.
Moderate exercise, pay attention to balanced nutrition, improve physical fitness, avoid malnutrition leading to low immunity.