Childhood leukemia



OVERVIEW

Definition

Childhood leukemia is a malignant blood disease that occurs in childhood, due to the excessive proliferation of a certain blood cell system in hematopoietic tissues, infiltrating into various tissues and organs, thus causing a series of clinical manifestations, and it is the most common pediatric malignant tumor in China.

It is the most common pediatric malignant tumor in China. There are different types of leukemia in children with different treatments and symptoms, this entry only briefly describes the main content, for more details about the specific disease, please refer to read the corresponding disease entry.

Classification

Classified according to the course of the disease and the degree of cell differentiation

Acute leukemia in children

The disease progresses rapidly and can be divided into acute lymphoblastic leukemia and acute myeloid leukemia (also called acute nonlymphoblastic leukemia).

Acute lymphoblastic leukemia is the most common type of leukemia in children, and can be subdivided into L1, L2 and L3 subtypes based on the morphology of bone marrow cells.

Acute myeloid leukemia is further subdivided into M0 to M7 types based on cell morphology.

M0 is the microdifferentiated type of AML.

M1 is acute myeloid leukemia immature.

M2 is partially differentiated acute myeloid leukemia.

M3 is acute promyelocytic leukemia.

M4 is acute granulomonocytic leukemia.

M5 is acute monocytic leukemia.

M6 is acute red leukemia.

M7 is acute megakaryocytic leukemia.

Chronic Leukemia in Children

Chronic leukemia is rare in childhood.

It is predominantly chronic myelomonocytic leukemia (CML), which accounts for about 5% of childhood leukemias. This is followed by juvenile myelomonocytic leukemia (JMML), while chronic myelomonocytic leukemia and chronic lymphocytic leukemia are extremely rare in children.

Other specialized types

such as infantile leukemia and childhood acute leukemia with Down syndrome.

Morbidity

Leukemia is the most common cancer among children (0-14 years old), and about 15,000 cases of leukemia occur in children in our country every year.

A national study showed that the incidence rate of childhood leukemia in China from 2018 to 2020 was 42.33 per million, and the incidence rate of leukemia in adolescents (15-19 years old) was 30.08 per million.

Childhood leukemia is most common in acute lymphoblastic leukemia, which accounts for 75% to 80% of cases, acute myeloid leukemia accounts for 15% to 20% of cases, and the incidence of other types of leukemia, such as chronic myeloid leukemia, is relatively low.

Causes

Causes

At present, the cause of this disease is not completely clear, but may be related to the following factors.

Viral infection

A variety of retroviruses such as avian leukemia virus (ALV), murine leukemia virus (MLV), feline leukemia virus (FeLV), gibbon ape leukemia virus (GaLV), and reticuloendothelial tissue proliferating virus (REV) may cause leukemia.

Environmental factors

Although there are a large number of studies on the correlation between environmental factors and the development of leukemia, the only relevant factor identified so far is ionizing radiation.

Significant exposure to ionizing radiation, such as in the event of a nuclear accident or the need for radiation therapy for other reasons, can increase the risk of leukemia in children.

Prolonged exposure to benzene, chlorinated solvents, organic solvents, pesticides, etc. before, during and after pregnancy of the child’s mother and at the father’s work may also increase the risk of disease in children.

The risk of leukemia may also be increased when children live in recently renovated environments, on major traffic routes, and so on.

Alcohol consumption during pregnancy may also increase the risk of acute myeloid leukemia in infants and children after birth.

Genetic factors

Childhood leukemia is not a genetic disease, but there are certain genetic factors involved.

People with certain genetic defects are susceptible to the disease. For example, children with Down syndrome (Trisomy 21), congenital erythema with dilated distal capillaries (Bloom syndrome), congenital aplastic anemia, and congenital heart disease all have a higher incidence of leukemia than the average child.

If one of the monozygotic twins develops leukemia within 6 years of age, the other has a 25% chance of developing leukemia.

Pathogenesis

The pathogenesis of childhood leukemia is not fully understood. The following mechanisms may play an important role in the development of leukemia.

Transformation of proto-oncogenes

There are proto-oncogenes in the chromosome genome, whose main function is to participate in the regulation of cell proliferation, differentiation, and aging and death under normal conditions.

Under the action of oncogenic factors, proto-oncogenes can undergo point mutation, chromosomal rearrangement or gene amplification, and transform into oncogenes, thus leading to the occurrence of leukemia.

Oncogene aberrations

When oncogenes (e.g. RB, P53, P16, WT1, etc.) undergo mutation, deletion and other variations, they lose their oncogenic activity, resulting in abnormal proliferation of cancer cells and the development of leukemia.

Inhibition of apoptosis

Apoptosis is the normal way of cell removal in the development of human tissues and organs.

When apoptosis is inhibited or blocked, cells continue to proliferate without normal apoptosis, resulting in pathogenic mutations.

Symptoms

The onset of childhood leukemia varies in urgency, and the clinical manifestations are mainly related to the inhibition of normal hematopoiesis and infiltration of leukemia cells, which are mostly non-specific and can vary greatly among individuals.

Acute leukemia in children

Acute leukemia is the main cause of childhood leukemia, which usually starts rapidly, with symptoms similar to “cold” such as fatigue, malaise and lack of appetite before the onset of the disease, and with the progression of the disease, the following symptoms may appear.

Anemia

The following symptoms may appear as the disease progresses: pale skin and mucous membranes, fatigue, shortness of breath after activity, etc., which gradually worsens as the disease progresses.

Some children may not have anemia due to the short duration of the disease.

Fever

Most children have fever at the onset of the disease, which may be persistent, high or low, and irregular.

High fever often suggests secondary infection, which may occur in multiple sites, with oral, gingival, and pharyngeal infections being the most common, and localized mucosal ulceration or necrosis may occur.

Bleeding

Bleeding can occur in all parts of the body, common skin petechiae, ecchymosis, nosebleed, gum bleeding.

Bleeding from the fundus of the eye may cause visual impairment.

In severe cases, extensive bleeding throughout the body may occur due to coagulation abnormalities.

Intracranial hemorrhage may result in headache, vomiting, inconsistent pupil size on both sides, and even coma and death.

Symptoms of leukemia cell infiltration

Enlargement of lymph nodes, liver and spleen

Superficial lymph nodes throughout the body are mildly enlarged, and most of the enlarged lymph nodes are palpable in the neck, submandibular, axilla and groin. If the mediastinal lymph nodes are enlarged, it may cause choking and dyspnea.

Hepatomegaly and splenomegaly are mostly mild to moderate, with unremarkable clinical manifestations, often detected during physical examination, and may be accompanied by symptoms such as anorexia, weight loss, abdominal distension and tenderness.

Bones and joints

Pain in the long bones of the limbs, shoulders, knees, wrists, ankles and other joints is the first symptom, and local redness and swelling are not obvious.

It is often accompanied by sternal pressure and pain.

Central nervous system

When leukemia cells invade the brain parenchyma and/or meninges, they may cause central nervous system symptoms.

Common symptoms include headache, vomiting and drowsiness.

Testicular

The main manifestations are localized enlargement and tenderness of the testicles, and the scrotal skin may be reddish-black.

Others

A few children have symptoms of skin infiltration, which manifests as papules, macules, nodules or lumps.

Kidney infiltration may cause symptoms such as hematuria and more foam in the urine.

Infiltration of the gums and oral mucosa may cause localized swelling and mouth ulcers.

Childhood chronic leukemia

Chronic leukemia in children is rare in clinical practice, with a slow onset and usually no obvious symptoms in the early stage, and is usually detected by abnormal blood counts or splenomegaly during physical examination or when seeking medical treatment for other diseases.

Children often present with fatigue, weakness, lack of appetite, low-grade fever, excessive sweating, weight loss, and epigastric discomfort.

Consultation

Department of Medicine

Pediatric Internal Medicine

Children with symptoms such as fever, pallor, fatigue, skin ecchymosis, bleeding gums or nosebleeds may seek medical attention promptly.

Hematology

Children with these symptoms may also be referred to the Department of Hematology.

Preparation

How to get to the clinic: registration, preparation of documents, FAQs

Tips for the doctor

The doctor may check your child’s body, take blood or perform imaging tests. It is best to dress your child in loose-fitting clothes that are easy to put on and take off.

Parents can keep a detailed record of the symptoms your child has experienced, such as fever, areas of pain, and areas of skin bleeding.

Preparation Checklist for Medical Attendance

Symptom list

Particular attention needs to be paid to the time of symptom onset, special manifestations, etc.

Does the child have any weakness, loss of energy, low appetite?

Does the child have bleeding symptoms such as skin petechiae, bleeding gums or nosebleeds?

Does the child have bone or joint pain?

Does the child have fever?

Does the child have a feeling of abdominal fullness?

Medical History Checklist

Does the child have any congenital or genetic disorders? For example, Down syndrome, congenital erythema with dilated distal capillaries?

Has the child had any recent significant exposure to ionizing radiation or radiation therapy?

Does the child’s mother have a history of prolonged exposure to benzene, chlorinated solvents, organic solvents, pesticides, etc. during pregnancy and the father?

Does the child have any family members with leukemia?

Checklist

Test results for the last six months, which can be brought to the doctor’s office

Laboratory tests: blood tests, bone marrow tests, cytochemistry, cytogenetics and molecular biology tests

Imaging tests: ultrasonography, CT examination

Diagnosis

Diagnostic basis

Medical history

Congenital or hereditary disease, Down syndrome, congenital distal capillary dilated erythema, congenital aplastic anemia, congenital heart disease, etc.

Recent history of significant exposure to ionizing radiation or radiation therapy.

History of prolonged exposure to benzene, chlorinated solvents, organic solvents, and pesticides during the mother’s pregnancy and the father’s.

Family history of leukemia.

Clinical manifestations

Children tend to present with fever, pallor, depression, weakness, bleeding gums or nosebleeds.

Doctors will also conduct physical examination of children, and petechiae and purpura can be seen on the skin of some children. Abdominal tenderness may be present on palpation.

Laboratory Tests

Routine blood tests

The white blood cell count can assist in the diagnosis and provide a basis for clinical staging, and is mostly elevated, but can also be normal or decreased.

Hemoglobin and red blood cells are used to assess anemia and are usually decreased.

Platelets may be decreased to varying degrees.

Bone marrow examination

Bone marrow tests are important for establishing the diagnosis and evaluating the efficacy of treatment.

In most acute leukemia, the bone marrow is characterized by significant proliferation of nucleated cells, mainly primitive cells; in a few cases, the bone marrow is characterized by hypoplasia.

Chronic leukemia may be characterized by extremely active bone marrow proliferation, with predominantly granulocytes. Megakaryocytes are normal or increased and decreased in advanced stages.

This test requires bone marrow aspiration, parents should do a good job of children’s psychological comfort, do not be too nervous, relax and cooperate with the doctor can be.

Cytochemistry

It is mainly used to help identify various types of leukemia, and commonly used specimens are peripheral blood or bone marrow.

The main items include myeloperoxidase (MPO), glycogen staining (PAS), non-specific esterase (NSE) and so on.

Cytogenetic and molecular biology tests

Leukemia is often associated with specific cytogenetic (chromosomal karyotype) and molecular biological alterations (e.g., fusion genes, gene mutations).

The specimens commonly used for this test are peripheral blood or bone marrow, and it is mainly used for typing and assessing prognosis.

Blood biochemistry tests

Liver function, renal function, lactate dehydrogenase, and electrolytes are mandatory tests, mainly used to evaluate the status of the organism.

Elevated blood uric acid and lactate dehydrogenase may be seen in children with a high leukocyte load.

Imaging

Ultrasound

Abdominal ultrasound helps to visualize the abdominal organs.

Liver and spleen enlargement are seen on examination.

CT examination

CT/enhanced CT of the chest helps to evaluate the presence of enlarged mediastinal lymph nodes.

CT of the head is used to evaluate for CNS leukemia and to rule out intracranial hemorrhage. Magnetic resonance (MRI) may be performed if necessary.

Differential diagnosis

If the symptoms are atypical in the early stages of the disease, especially if the white blood cell count is normal or decreased, it must be differentiated from diseases such as aplastic anemia, infectious mononucleosis, and leukemia-like reactions.

Aplastic anemia

Similarities: Both may present with anemia, thrombocytopenia, and bleeding from the skin and mucous membranes.

Differences: aplastic anemia blood picture shows a decrease in whole blood cells, liver, spleen, lymph nodes are not enlarged, bone marrow nucleated cell hyperplasia, no naïve leukocyte hyperplasia, which can be used as a basis for differentiation.

Infectious mononucleosis

Similarity: both may present with hepatomegaly, splenomegaly, and increased leukocyte count.

Differences: the course of the disease is generally good, and the blood picture mostly returns to normal in about 1 month; the serum isophilic agglutination reaction is positive, and the bone marrow does not have leukemic changes.

Leukemia-like reaction

Similarities: both may present with a significant increase in white blood cell count.

Differences: leukemia-like reaction is often complicated by severe infections, malignant tumors and other underlying diseases, and has the clinical manifestations of the corresponding underlying diseases; platelets and hemoglobin are mostly normal. After control of the underlying disease, the white blood cells return to normal.

Treatment

Aim of treatment: The treatment goal of acute leukemia is to completely eliminate leukemia cells in the body and restore normal hematopoietic function, and chemotherapy is the most important means.

Treatment principle: Doctors will stratify the prognostic risk according to the results of specific typing of the disease and clinical characteristics, and select and design the best, complete and systematic treatment plan. Chronic leukemia can be relieved by medication, radiation therapy and splenectomy in the chronic stage, and chemotherapy is needed to control the disease in the acute stage.

Supportive therapies

Anti-infection treatment

During the chemotherapy stage, protective environmental isolation has a good effect on reducing nosocomial cross-infection. In case of concurrent bacterial infection, strong antibacterial drugs should be preferred to control the disease, and antibacterial drugs should be adjusted according to the results of drug sensitivity test.

Commonly used broad-spectrum antibacterial drugs include levofloxacin and amoxicillin.

The use of antibacterial drugs should be under the guidance of a doctor, do not self-medicate.

Component blood transfusion

For bleeding caused by thrombocytopenia, platelet concentrate can be transfused; red blood cells can be transfused for obvious anemia; immunoglobulin can be transfused intravenously when appropriate.

If there is any discomfort during the process of blood component transfusion, or if children have red, swollen, itchy skin, etc., notify the healthcare personnel promptly for treatment.

Chemotherapy

The main goal of chemotherapy is to kill leukemia cells and relieve the symptoms caused by leukemia cell infiltration, so as to alleviate the condition and consolidate the therapeutic effect, reduce drug resistance and cure.

Chemotherapy may include induction therapy, early intensive therapy, consolidation therapy after remission, delayed intensive therapy, maintenance therapy, and prevention and treatment of extramedullary leukemia. Depending on the child’s condition, intermediate therapy (continuation of therapy) may be added after delayed intensive therapy.

Induction phase treatment is the key to long-term disease-free survival in children, and commonly used chemotherapeutic agents include cyclophosphamide (CTX), vincristine (VCR) or vinblastine (VDS), doxycycline (DNR), and levodopa monocytogenes (L-asp). Glucocorticoids such as prednisone (Pred) and dexamethasone (Dex) are also part of the treatment regimen in this phase.

Children are susceptible to adverse effects of myelosuppression after chemotherapy, so report any adverse effects such as nausea, vomiting, fever, or diarrhea to your doctor.

Other drugs

Colony Stimulating Factor

Colony-stimulating factors such as granulocyte colony-stimulating factor (G-CSF) may be given to help raise white blood cell counts during chemotherapy breaks if bone marrow suppression is evident.

Adverse effects such as fever, itchy skin, maculopapular rash and muscle pain may occur.

Molecularly Targeted Therapy

Molecular targeted therapy is a therapeutic method that targets specific (or relatively specific) molecules of tumor tissues or cells, and uses molecular targeted drugs to specifically block the biological function of the target, selectively inhibit the growth of tumor cells at the molecular level, or even eliminate the tumor.

Commonly used drugs are Imatinib.

Interferon-alpha

Interferon-alpha (IFN-α) was the drug of choice before the advent of molecularly targeted drugs.

It is mainly used in children who are not candidates for TKI and hematopoietic stem cell transplantation.

Radiation Therapy　

The doctor will decide whether radiation therapy needs to be scheduled based on the treatment plan.

Irradiation of the splenic region may be used in children with chemotherapy-resistant chronic granulocytic leukemia with extremely enlarged spleens, and local radiotherapy may also be used if there are bone and soft tissue infiltrates.

Radiation therapy can be considered for those with significant lymph node enlargement, nerve invasion, vital organ or bone infiltration with localized symptoms, which can reduce the number of lymphocytes to a certain extent but does not prolong survival.

Hematopoietic stem cell transplantation combined with chemotherapy

Hematopoietic stem cell transplantation involves the intravenous infusion of normal human hematopoietic stem cells into a child who has undergone pretreatment (chemotherapy/radiation) to re-establish hematopoietic and immune functions for the treatment of certain diseases.

Hematopoietic stem cell transplants can be classified as autologous, homozygous and allogeneic according to donor genetics.

Hematopoietic stem cell transplantation can be arranged if required by the child’s treatment plan.

After HSCT, children are advised to take their medication regularly, avoid cross-infections and observe good hygiene.

Surgery

Splenectomy should be performed if there is a huge spleen with significant symptoms of chronic granulocytic leukemia or if there is hypersplenism.

The timing of splenectomy for children has certain requirements. Children younger than 9 years of age should not have their spleens removed as much as possible, and the specific timing of the surgery can be decided by the doctor after evaluating the condition and weighing the pros and cons of the surgery.

Splenectomy may be complicated by infection, embolism or bleeding, or even death from severe infection.

Prognosis

Cure

The prognosis of different types of childhood leukemia varies as follows.

Childhood acute lymphoblastic leukemia is no longer considered lethal, with a 5-year survival rate of 70% to 95%.

After chemotherapy combined with hematopoietic stem cell transplantation for acute non-lymphoblastic leukemia in children, the 5-year disease-free survival rate can reach 60% to 70%.

Chronic granulocytic leukemia, once transformed into acute leukemia, has a poorer prognosis.

The 5-year survival rate refers to the percentage of patients who have survived for more than 5 years after various comprehensive treatments for the tumor. 5 years later, the probability of recurrence is very low, and it can generally be regarded as a clinical cure.

Hazards

Although the overall 5-year survival rate for childhood acute lymphoblastic leukemia is high, it can still be life-threatening.

Children may suffer from disruption of normal schooling and life due to the disease. Psychological stress may be associated with prolonged hospitalization and treatment.

Daily

Daily Management

Daily management

Limit strenuous exercise to prevent bleeding from bruises and falls.

Provide children with a safe living environment and prohibit them from playing with unsafe toys.

This disease requires long-term treatment and parents need to comfort children and reduce their psychological pressure.

Dietary management

Children under 6 months of age can generally continue with their original feeding regimen.

For children over 6 months old, supplemental food has been added or normal diet has been taken. It is recommended to choose light and easy-to-digest food, and eat small and frequent meals to ensure balanced nutrition.

Pay attention to dietary hygiene and sterilization of tableware.

Skin management

Children are advised to choose clothes that are easy to put on and take off, pure cotton, soft and loose.

Cut children’s nails short to prevent skin scratching.

Pay attention to keep the mouth clean and rinse with warm water or mouthwash before and after eating.

Children should be diligent in changing clothes and pants, and avoid cleaning the skin with soap or shower gel containing fragrance to avoid skin irritation.

Children should maintain good bowel habits, pay attention to keep the gastrointestinal tract healthy, and clean the perianal area with warm water or light saline after defecation to prevent perianal abscesses.

Follow-up and review

After receiving treatment, children are advised to follow the doctor’s arrangement for regular review.

Blood and/or bone marrow tests are usually required.

If a child develops bleeding from the skin or mucous membranes or fever after treatment, it is advisable to consult the doctor promptly.

Prevention

There is no clear-cut prevention method for childhood leukemia. Avoiding exposure to suspected environmental factors and adhering to a good lifestyle can help maintain good health.

Avoid exposure to ionizing radiation (e.g. X-rays, etc.). Mothers should also avoid exposure during pregnancy, and take precautions if they must be exposed.

Help children to develop good hygiene habits, such as not touching the eyes, mouth, nose and ears with their hands, not sharing utensils and other household items with others, and washing their hands frequently to prevent infection.

Those with a family history of leukemia should undergo genetic counseling and regular medical checkups.

Emphasis should be placed on prenatal checkups to reduce the birth rate of children with Down’s syndrome, congenital testicular hypoplasia and other diseases.

During women’s preparation for pregnancy and during pregnancy, both men and women should avoid exposure to chemical substances such as benzene, chlorinated solvents, organic solvents and pesticides.

Create a good living environment for children and try to avoid living in freshly renovated rooms.