Childhood acute lymphoblastic leukemia

Summarize

1. General

●Overview: Acute lymphoblastic leukemia in children is a malignant neoplastic disease of the hematopoietic system, a type of acute leukemia in children, and the most common type of leukemia in children.

● Manifestations: Acute lymphoblastic leukemia in children may present with varying degrees of anemia, bleeding, fever from infections, as well as enlargement of the liver, spleen, lymph nodes, and bone pain.

● Treatment: The main treatments for childhood acute lymphoblastic leukemia include chemotherapy and hematopoietic stem cell transplantation.

● Prognosis: Currently, the five-year overall survival rate of childhood acute lymphoblastic leukemia in China has reached more than 70%, and can reach more than 85% in the low-risk group.

2. Definition of disease

Childhood acute lymphoblastic leukemia (ALL), or childhood acute leukemia, is a malignant neoplastic disease of the hematopoietic system that originates in the bone marrow from precursor B or precursor T cells (the main type of white blood cell). Childhood acute lymphoblastic leukemia is a type of childhood acute leukemia and the most common type of leukemia in children.

Epidemiological

epidemiological

Childhood acute lymphoblastic leukemia accounts for about 70% of childhood acute leukemia. The incidence of childhood acute lymphoblastic leukemia (under 15 years of age) in China is about 3-4 per 100,000; if it is expanded to under 18 years of age, there are about 10,000 new cases each year. The peak age of onset of acute lymphoblastic leukemia in children is usually 3-5 years old, after which it gradually declines.

Etiolog & Risk factors

1. General

The cause of childhood acute lymphoblastic leukemia is usually related to chromosomal and genetic variants, and many children are born with disease-related variants. However, childhood acute lymphoblastic leukemia is not a hereditary disease, and the associated variants are basically due to abnormalities during development. Because childhood acute lymphoblastic leukemia is a polygenic, multifactorial disease, the exact cause of the disease is not known, although certain environmental and genetic factors are known to be associated with the risk of childhood acute lymphoblastic leukemia.

2. Underlying causes

Acute lymphoblastic leukemia in children originates primarily from the abnormal proliferation and aggregation of precursor B or precursor T cells (the main types of white blood cells) in the bone marrow. The abnormal proliferation of these cells crowds out normal cells and inhibits normal hematopoiesis. They can also rapidly overflow into the bloodstream and travel through the bloodstream to other parts of the body, such as lymph nodes, spleen, liver, central nervous system (brain and spinal cord), testes, or other organs, where they form infiltrates that interfere with the normal functioning of other cells and lead to the various symptoms of leukemia.

Acute lymphoblastic leukemia in children occurs as a result of mutations in the relevant chromosomes and genes during the development of the child, but usually not as a single genetic mutation, but rather as a polygenic, multifactorial change, so the exact cause is not yet clear.

3. Predisposing factors

Certain environmental and genetic factors are known to be associated with the risk of childhood acute lymphoblastic leukemia:

● Significant exposure to ionizing radiation, such as nuclear radiation (e.g., atomic bomb blasts, nuclear accidents, etc.), X-rays, etc. However, ionizing radiation increases the risk of leukemia only when the cumulative dose is large. Medical examinations involving ionizing radiation, such as X-rays and CTs, which are usually performed in hospitals, do not usually accumulate to a cancer-causing dose and are therefore safe for the general population. In addition, everyday radiation such as cell phones, microwave ovens, and WIFI are not ionizing radiation, and there is no evidence that they are associated with leukemia risk.

● Certain carcinogens in the environment, such as benzene and its derivatives and formaldehyde, have also been associated with an elevated risk of leukemia.

● Certain viruses, such as HIV, are associated with the development of lymphoblastic leukemia.

Certain genetic disorders, such as Down syndrome, Neurofibromatosis type 1, Bloom syndrome, Fanconi anemia, ataxia-telangiectasia, Li-Fraumeni syndrome, and other genetic deletions associated with chromosomal mismatch repair (e.g., MLH1, MSH2, MSH6, and PMS2), are also associated with genetic deletions that are associated with chromosomal mismatch repair (e.g., MLH1, MSH2, MSH6, and PMS2). -Li-Fraumeni syndrome, and other disorders associated with chromosomal mismatch repair gene deletions (e.g., mutations in MLH1, MSH2, MSH6, and PMS2).

● Mutations in certain genes such as MLH1, MSH2, MSH6, PMS2, ARID5B, GATA3, IKZF1, CDKN2A, CDKN2B, CEBPE, PIP4K2A, TP63, PAX5, ETV6, TP53, IKZF1. Of these, germline mutations (understood as inherited mutations) in the genes PAX5, ETV6, TP53, and IKZF1 are very rare but are known to be associated with familial childhood acute lymphoblastic leukemia.

● The vast majority of childhood acute lymphoblastic leukemia is not inherited. However, in identical twins, if one child is diagnosed with childhood acute lymphoblastic leukemia before the age of one year, the other child may also be at higher risk of developing the disease.

Classification & Stage

Type of disease

1) Disease typing

i) FAB typing

According to the French-American-British classification systems (FAB), childhood acute lymphoblastic leukemia can be classified into L1, L2, and L3 based on bone marrow cytomorphology. However, this classification is no longer used as a basis for risk-stratified treatment.

ii) Lymphocyte immunophenotyping

Based on lymphocyte immunophenotyping, childhood acute lymphoblastic leukemia is classified:

:: Acute B-lymphoblastic leukemia (BALL)

Of the acute lymphoblastic leukemias in children, 80% are acute B-lymphoblastic leukemias. According to the different stages of leukemia cell differentiation, acute B-lymphoblastic leukemia is mainly divided into four types: early pre-B, normal B, pre-B, and mature B.

● Acute T-lymphoblastic leukemia (T-ALL)

According to the different stages of leukemia cell differentiation, acute T-lymphoblastic leukemia is mainly divided into three types: earlier T, cortical T and myeloid T.

iii) Cytogenetic typing

Staging of the disease according to chromosomal karyotype including chromosome number or structural abnormalities can be used for risk stratification, e.g., t(12;21)(p13.2;q22.1) for low-risk, t(1;19)(q23;p13) for intermediate-risk, and t(4;11)(q21;q23) for high-risk groups. See below for detailed risk stratification.

iv) Molecular biology (fusion gene) typing

Typing of the disease based on molecular biology (fusion gene) alterations in the cells of childhood acute lymphoblastic leukemia can be used for risk stratification, e.g., Tel/AML1 for the low-risk group; E2A/PBX1 for the intermediate-risk group, and MLL/AF4 for the high-risk group. See below for detailed risk stratification.

v) MICM typing

Clinically, doctors usually perform MICM typing for acute lymphoblastic leukemia, that is, the four aspects of cell morphology (morphology, M), immunophenotyping (immunophenotyping, I), cytogenetics (cytogenetics, C), and molecular biology (molecular biology, M) are tested on the Bone marrow and blood samples are tested for precise diagnostic typing to help determine the subsequent treatment plan.

2) Disease Grouping

In clinical practice, childhood acute lymphoblastic leukemia is not classified as early or late stage, but is grouped by risk for stratified treatment. Grouping is usually determined by measuring the MICM profile of leukemia cells in a child's blood, bone marrow, and lymph node or cerebrospinal fluid (CSF) samples, as well as the level of microscopic residual disease (MRD). The criteria for grouping vary slightly from center to center internationally and will continue to be refined as testing technology continues to improve. Risk grouping plays an important role in determining the treatment plan.

The most basic current risk grouping for childhood acute lymphoblastic leukemia:

● Children who met all of the following criteria were categorized into a low-risk group:

● 1 year or older and less than 10 years old.

● White blood cell count below 50 x 109/L.

● Bone marrow cytomorphology results of M1 status (primitive lymphocytes + naïve lymphocytes <5%) on days 15-19 of induction chemotherapy, or days 33-45 of induction chemotherapy.

● Minor residual disease (MRD) <1 × 10-2 on days 15-33 of induction therapy and MRD <1 × 10-4 before consolidation therapy.

● Children who meet at least one of the following conditions are categorized into the medium-risk group:

● Age 10 years or older.

● Maximum white blood cell count higher than 50 x 109/L at initial diagnosis.

● Presence of central nervous system or testicular infiltration.

●t(1;19) (E2A-PBX1) chromosome rearrangement.

● Bone marrow cytomorphometry results on days 15-19 were M2 (5% ≤ primitive lymphocytes + naïve lymphocytes < 20%) and bone marrow cytomorphometry results on days 33-45 were M1.

● Philadelphia chromosome positive (Ph+).

● iAMP21 chromosome variants.

● The type is acute T-lymphoblastic leukemia.

● 1 × 10-3 ≤ MRD < 1 × 10-1 on days 15-19 of induction therapy; or 1 × 10-4 ≤ MRD < 1 × 10-2 after induction therapy (days 33-45); or MRD < 1 × 10-4 before consolidation therapy.

● Children who meet at least one of the following conditions are categorized into the high-risk group:

● Children younger than 1 year old.

● Bone marrow cytomorphology on days 15-19 with M3 status (primitive lymphocytes + naïve lymphocytes ≥ 20%)

● Bone marrow cytomorphologic findings on days 33-45 showing incomplete remission and M2 or M3 status (≥5% primitive lymphocytes + naïve lymphocytes).

●t(4; 11) (MLL-AF4) or other MLL gene rearrangement positivity.

● Hypodiploidy (total chromosome representation ≤ 44) or DNA index (DI) < 0.8.

● IKZF deletion positive.

● There is a MEF2D rearrangement.

● Presence of TCF3-HLF/t(17;19)(q22;p13) gene rearrangement.

● After induction therapy (days 33-45), the mediastinal tumor foci did not shrink to 1/3 of the initial tumor primary tumor volume.

● MRD ≥ 1 × 10-1 on days 15-19 of induction therapy; or MRD ≥ 1 × 10-2 after induction therapy (days 33-45); or MRD ≥ 1 × 10-4 before consolidation therapy.

Clinical manifestations

1. General

The main symptoms of childhood leukemia include unexplained fever, anemia, bleeding, and leukemia cell infiltration (mainly manifested by limb pain, enlarged liver, spleen, and lymph nodes, etc.), but there can be large inter-individual variations. The duration of symptoms can be as short as a few days or as long as four or five months, with acute manifestations usually lasting two weeks to two months.

2. Typical symptoms

Acute lymphoblastic leukemia in children is mostly acute in onset, and a few are slow. Early symptoms include pallor, dysphoria, malaise, low appetite, epistaxis or bleeding gums, etc. A few children have fever and osteoarthralgia similar to rheumatic fever as the first symptom, and a few patients with advanced disease may develop malignant condition (usually manifested as weight loss, muscle loss, loss of appetite, and even multi-organ failure).

Bleeding: Usually caused by a markedly low platelet count, bleeding from the skin and mucous membranes occurs most commonly as purpura, petechiae (e.g., bruising of the skin), nosebleeds, bleeding from the gums, gastrointestinal bleeding, and hematuria. In rare cases, intracranial hemorrhage occurs, which may be life-threatening.

● Anemia: This is mainly caused by the proliferation of leukemia in the bone marrow crowding out the normal hematopoietic function, resulting in decreased red blood cell proliferation and hemorrhagic loss. Anemia is one of the early symptoms and worsens as the disease progresses. It usually occurs gradually and manifests itself as pallor, weakness, shortness of breath after activity, drowsiness, etc. Nails and eyelid conjunctiva may also appear pale to varying degrees.

● Fever: Fever is the first symptom in about 50-60% of patients and varies from person to person. Fever is mainly caused by the acute lymphoblastic leukemia itself, and it is usually a low to moderate fever of about 38°C. It does not respond to antibiotic treatment and resolves within 72 hours of induction therapy. However, children with acute lymphoblastic leukemia may also have concomitant infections due to their immunocompromised status resulting from a reduced number of leukocytes and abnormalities in their functioning, especially neutrophil counts. The most common infections are respiratory infections, such as tonsillitis, bronchitis and pneumonia, and gastrointestinal infections, such as gastroenteritis. A small number of children develop more serious infections, such as septicemia. The source of infection may be almost any pathogen, such as bacteria (Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Escherichia coli, Pseudomonas aeruginosa, etc.), fungi (Candida, Aspergillus, Pneumocystis carinii, etc.), and viruses (herpes simplex virus, chickenpox virus, cytomegalovirus, etc.), and mixed infections are likely to occur.

● Infiltration of leukemia cells: usually presenting with enlarged lymph nodes in different areas and/or hepatosplenomegaly. If leukemia cells proliferate rapidly in the bone marrow for a short period of time or infiltrate the epiphyses of the bones, the child may develop bone and joint pain. In some children, arthralgia may be the first symptom, and blood counts may be completely normal, with temporary relief with hormonal therapy. Leukemia cells may also invade the testes and brain, resulting in testicular leukemia and central nervous system leukemia (also known as meningeal leukemia).

3. Accompanying symptoms

When a child is weak due to anemia, it may show up as needing to be held by an adult (especially in younger children). Joint pain may manifest as a reluctance to walk. If the mediastinal lymph nodes are severely enlarged, they may compress the organs and cause the child to have difficulty breathing.

Clinical Department

1. General

The diagnosis and typing of childhood leukemia is made with reference to clinical symptoms, signs, myelocytological findings, immunophenotyping, genetic features and molecular biology tests. This information is important for the diagnosis, risk grouping and prognosis of the disease. Other ancillary tests, such as ultrasound, chest X-ray, blood biochemistry, etc., will also be performed to assess the physical condition of the child and the specific disease.

2. Consultation room

Hematology, Pediatrics, Hematology-Oncology.

Examination & Diagnosis

1. Diagnostic basis

In general, physicians usually suspect childhood acute lymphoblastic leukemia if the child has ≥20% primitive lymphocytes + naïve lymphocytes in the bone marrow sample at the time of presentation with manifestations and signs of childhood acute lymphoblastic leukemia.

The definitive diagnosis of childhood acute lymphoblastic leukemia is based on the results of various laboratory investigations of bone marrow and cerebrospinal fluid samples, including cytomorphological examinations, immunophenotyping, cytogenetic and molecular biological analyses.

2. Relevant inspections

1) Routine physical examination and history taking

Routine physical examination including physical condition, manifestations of disease, other abnormal signs like painless lumps. The doctor will also ask about the history of previous illnesses, family history and treatment.

2) Bone marrow biopsy

The doctor will perform a bone marrow aspiration, which is a puncture using a special hollow needle in the iliac bone area to extract a small amount of bone marrow, which will then be sent to the laboratory for relevant tests in cytomorphology, immunology, cytogenetics, and molecular biology in order to confirm the diagnosis and further typing.

3) Cerebrospinal fluid examination

Cerebrospinal fluid is a bodily fluid found in the body's central nervous system. The purpose of a cerebrospinal fluid test is to check whether a child has central nervous system leukemia (also known as meningeal leukemia, in which leukemia cells have infiltrated the central nervous system). Cerebrospinal fluid is sampled through a lumbar puncture, where a special lumbar puncture needle is used to draw the child's cerebrospinal fluid for cytology and other tests.

4) Laboratory tests

● Bone marrow cytomorphometry: FAB typing based on the morphology of the cells in the sample.

● Immunophenotyping: analysis of cell types by immunological markers on the cell surface.

● Cytogenetic and molecular biology analysis: The chromosomes and disease-related fusion genes of the cells in the sample are examined to determine whether there is damage, loss, or recombination of chromosomes or extra chromosomes, as well as whether there are disease-related fusion genes.

5) Blood tests

● Routine blood tests: platelet counts, counts of all types of white blood cells, hemoglobin levels, and red blood cell ratios. In addition to automated routine blood tests, a blood smear should be done for manual classification.

● Blood biochemistry tests: routine blood biochemistry indicators are checked to determine if any are outside the normal range. Liver and kidney function, lactate dehydrogenase levels, and electrolytes are mandatory. Patients with a high white blood cell load may have increased blood uric acid and lactate dehydrogenase levels.

● Coagulation tests: including prothrombin time (PT), activated partial thromboplastin time (APTT), prothrombin time (TT), fibrinogen (FIB), D-dimer (DD), fibrin degradation products (FDP). The onset of leukemia can cause a decrease in prothrombin and fibrinogen, which can lead to prolonged prothrombin time and bleeding.

6) Imaging

Chest X-rays, abdominal ultrasound, and, depending on the condition, ultrasound (in order to understand cardiac function and abdominal organs), CT (to assess for head or chest and abdominal occupations, bleeding, or inflammation), or Magnetic Resonance Imaging (MRI, to assess for occupations and bleeding and vascularity).

3. Differential diagnosis

1) Central nervous system leukemia

CNS leukemia often lacks clinical symptoms at the time of onset or during the course of treatment, and abnormalities are only detected during routine testing of cerebrospinal fluid, but need to be differentiated from bacterial infections and drug-induced chemical meningitis.

2) Diagnosis of testicular leukemia

Children with acute lymphoblastic leukemia present with unilateral or bilateral testicular enlargement, hardening or nodular lack of elasticity, negative transillumination tests, and ultrasonographic findings of nonhomogeneous foci of infiltration of the testis, which may not be biopsied in children at first diagnosis. In children with bone marrow remission from systemic chemotherapy who develop testicular enlargement, biopsy should be performed to determine whether there is a relapse of testicular leukemia.

3) Leukemia-like reactions

There may be hepatosplenomegaly, thrombocytopenia, and occasional mid to late juvenile and nucleated erythrocytes in the terminal blood picture, but the leukemia-like reaction often has an infectious trigger, and the blood picture recovers when the primary disease is controlled.

4) Infectious mononucleosis

EBV infection with enlarged liver, spleen and lymph nodes, fever, positive serum heterophilic agglutination reaction, positive EBV antibody, elevated leukocytes with anisotropic lymphocytes, but normal hemoglobin and platelet counts, and no leukemic changes on bone marrow examination.

5) Aplastic anemia

Bleeding, anemia, fever, and diathesis or pancytopenia have similarities to the hypoproliferative manifestations of leukemia, but the disease is not accompanied by enlargement of the liver, spleen, or lymph nodes, and myelocyte

Hypoproliferative, no naïve cell proliferation.

6) Rheumatism and rheumatoid arthritis

Some children with leukemia have joint pain as the first symptom, and the hematological examination may be completely normal, so it is easy to be misdiagnosed as rheumatoid or rheumatoid arthritis, and bone marrow examination should be conducted as early as possible to confirm the diagnosis in atypical cases.

Clinical Management

1. General

Common treatments for childhood acute lymphoblastic leukemia include chemotherapy and hematopoietic stem cell transplantation.

Due to the rapid progression of acute lymphoblastic leukemia in children, induction chemotherapy should be carried out as soon as the diagnosis is confirmed in order to reduce the tumor load and alleviate the various clinical symptoms caused by the tumor within a short period of time. After successful induction chemotherapy, the treatment will be given in the appropriate intensity and dose according to the grading of the risk level. The treatment is usually divided into four phases: induction, consolidation, intensification and maintenance. Hematopoietic stem cell transplantation needs to be considered for some children with medium to high risk of relapse.

2. Chemotherapy

1) Chemotherapy regimen

Doctors will treat the child with a combination of chemotherapy drugs based on the child's risk grouping. Currently, for children's acute lymphoblastic leukemia, the most commonly used is chemotherapy regimens in China are regimens such as CCLG-ALL-2008 and CCCG-ALL-2015. The standard treatment process of chemotherapy for acute lymphoblastic leukemia includes 4 phases: induction therapy period, consolidation therapy period, intensive therapy period and maintenance therapy period.

To prevent and treat CNS leukemia, acute lymphoblastic leukemia requires not only intravenous chemotherapy, but also intrathecal chemotherapy, in which chemotherapeutic drugs are injected into the cerebrospinal fluid in order to kill leukemia cells in the CNS.

2) Adverse Reactions

i) Acute tumor lysis syndrome

Acute lymphoblastic leukemia is sensitive to chemotherapy, and during initial treatment, a large number of tumor cells will be lysed and necrotic, causing symptoms such as hyperuricemia, hyperphosphatemia, hypocalcemia, hypomagnesemia, and uric acid crystals blocking the renal tubules, which may lead to acute renal failure in severe cases. Therefore, if the tumor is highly loaded, tumor lysis syndrome is more likely to occur and needs to be actively prevented.

Often, doctors use medications or methods such as allopurinol, hydration, and uric acid oxidase to prevent acute tumor lysis syndrome. If acute tumor lysis syndrome occurs, it is treated aggressively for the appropriate symptoms.

ii) Cardiotoxicity

Anthracycline-based chemotherapeutic agents can cause cardiotoxicity.

Anthracyclines may cause acute myocardial injury and chronic cardiac impairment. The former is transient and reversible localized myocardial ischemia, which may be manifested by panic, shortness of breath, chest tightness and precordial discomfort. The latter is irreversible congestive heart failure and is related to the cumulative dose of the drug. If cardiac function tests suggest abnormal cardiac function and are not due to infection, anthracyclines need to be suspended until cardiac function recovers. If myocardial damage occurs, treatment with drugs such as dexrazoxane (Dexrazoxane, Zinecard, trade name: Onosine) may be indicated.

iii) Hepatotoxicity

Some chemotherapeutic agents are toxic to the liver, as evidenced by elevated aminotransferases or bilirubin. Therefore, liver function tests are usually required before each course of treatment to determine whether chemotherapy can be given on time, and every 4-8 weeks during maintenance treatment, or every 12 weeks if there are no special circumstances.

Prior to high-dose methotrexate (MTX), a delay in dosing is required if transaminases are elevated 5-fold or more. In other courses, if the simple aminotransferase index (ALT/AST) is not elevated more than 10 times the high normal standard, then no adjustment of chemotherapy can be made; if ALT/AST reaches 10 times or more of the high normal limit, chemotherapy can be delayed, and if it is still abnormal after one week, chemotherapy can be given under close observation.

If direct bilirubin is elevated during chemotherapy and it is determined that it is due to leukemic cell infiltration, chemotherapy is given as usual; if it is not leukemic infiltration, the dose of chemotherapy is adjusted according to the condition. Prior to the start of the chemotherapy course, chemotherapy can be delayed for 1 week if the direct bilirubin is too high; if the bilirubin is still high after 1 week, the dose is adjusted and chemotherapy is started. When the direct bilirubin is too high, attention should be paid to adjusting the dose of Zoerythromycin, Vincristine, Mentholase, and high-dose methotrexate.

At present, there are some "liver-protecting drugs" on the market, but their role is not clear, the international major clinical programs do not routinely use "liver-protecting drugs", and there is no "liver-protecting drugs" to increase the safety of chemotherapy. There are no reports that "liver-protecting drugs" increase the safety of chemotherapy. In addition, hepatoprotective drugs may interact with chemotherapeutic drugs and increase the complexity of chemotherapeutic drug metabolism, therefore, the use of adjuvant or prophylactic hepatoprotective drugs is not recommended.

iv) Neurotoxicity

The chemotherapeutic drugs cytarabine and vincristine are neurotoxic.

The dose of cytarabine in the treatment regimen needs to be adjusted when symptoms of cytarabine-associated neurotoxicity are so pronounced that they interfere with the normal life of the child.

Vincristine should not be used in a single maximum dose of more than 2 mg. Common mild neurotoxic side effects of Vincristine can be manifested as jaw pain, constipation, diminished deep reflexes, and sometimes vocal disturbances. If obvious signs of toxicity such as persistent abdominal colic, unsteady gait, severe pain, and abnormal secretion of the antidiuretic hormone urokinetic hormone (SIADH) are present, the dosage needs to be reduced or switched to the less neurotoxic vincristine. Antifungal drugs (azoles) can increase the neurotoxicity of neoplasms, and caution is needed if they are used concomitantly.

v) Acute Respiratory Distress Syndrome (ARDS)

Cytarabine is toxic to the lungs and may cause acute respiratory distress syndrome, which manifests itself as, for example, dyspnea, hypoxemia (SpO2 < 92%), and chest X-rays suggestive of infiltrates in both lungs. Children with such symptoms need to first rule out the possibility of pulmonary infection and cardiotoxicity of other chemotherapeutic agents by chest CT and cardiac ultrasound. If acute respiratory distress syndrome due to cytarabine is identified, it can be treated with glucocorticoids, with methylprednisolone recommended. A pediatric pulmonologist may be invited to consult if necessary.

vi) Nephrotoxicity

Nephrotoxic drugs (e.g., acyclovir) can cause subclinical renal abnormalities. Therefore, if a child is given these drugs at the same time as high-dose methotrexate, the administration of nephrotoxic drugs should be delayed until 20 hours after the high-dose methotrexate, if appropriate, or until the methotrexate has been adequately excreted.

vii) Mentholase-related side effects

Mentholase may trigger allergies, pancreatitis and clotting disorders.

Mentholase allergy may be manifested by a positive skin test, rash, allergic asthma, anaphylaxis, laryngeal edema, or redness, swelling, heat, or pain at the site of muscle injection. Severe anaphylactic (grade 3-4) reactions usually occur within 2-3 hours after administration of the drug, so it is necessary to stay in the hospital for observation for at least 3 hours after administration of the drug. If an allergic reaction occurs, the medication needs to be stopped immediately and the symptoms of the allergic reaction are treated with antihistamines and epinephrine.

If a child presents with abdominal pain suspected to be pancreatitis, blood and urine powdered enzyme fixation, abdominal ultrasound, CT, or magnetic resonance imaging (MRI) must be done to determine if pancreatitis is present. If pancreatitis is confirmed, the medication regimen will need to be adjusted and the patient will be treated symptomatically for pancreatitis.

Mentholase has an effect on coagulation. If the child has obvious signs of bleeding or thrombosis and confirmed significant coagulation abnormalities, the appropriate blood product may be transfused.

viii) Hematological toxicity

Chemotherapeutic agents remove leukemia cells while also affecting normal hematopoiesis. Before chemotherapy with anthracyclines, the blood picture should meet the following criteria: white blood cell count (WBC) ≥ 2.0 × 109 /L, absolute neutrophil count (ANC) ≥ 0.8 × 109 /L, platelet (PLT) ≥ 80 × 109 /L.

Granulocyte colony-stimulating factor (GCSF) may be used if the child's neutropenia persists for 2-4 weeks and does not recover, or if it is anticipated that the child may have a prolonged neutropenia. Platelets should be transfused if the platelet count is less than 20 x 109/L. The indications for transfusion may be relaxed if the child has significant bleeding or infection.

3. Radiotherapy

1) Radiotherapy program

Most children with acute lymphoblastic leukemia do not require radiotherapy. In the case of CNS leukemia, if there is a recurrence of the disease after targeted chemotherapy, cranial radiotherapy is required after completion of delayed intensive therapy and before maintenance therapy (except in cases of CNS leukemia at the time of the initial diagnosis and with a good response to treatment.) Radiotherapy is not recommended for children under 2 years of age, and the dose of radiation for children over 2 years of age ranges from 12 to 18 Gy.

If the initial diagnosis of combined testicular leukemia is made, at the end of consolidation therapy with systemic chemotherapy, a biopsy will be performed if lesions remain on testicular ultrasound, and testicular radiotherapy will be required if residual leukemic cells are identified.

Radiotherapy is also required in children in bone marrow remission on systemic chemotherapy who experience a relapse of testicular leukemia. Radiotherapy is usually bilateral testicular radiotherapy at a dose of 20 to 26 Gy, with 12 to 15 Gy used in younger children.

2) Adverse Reactions

Acute side effects of radiotherapy include fatigue, gastrointestinal effects (e.g., nausea and vomiting), and darkening of the skin in the irradiated area.

4. Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation is considered if a child with acute lymphoblastic leukemia meets any of the following indications:

● Failure of treatment to induce remission (bone marrow morphology did not reach complete remission on day 33).

● Bone marrow assessment of microscopic residual disease (MRD) ≥ 1 × 10-2 on day 45.

● Children with t(9;22)/BCR-ABL1, MLL rearrangement, acute precursor T-lymphoblastic leukemia (EPT-ALL), or iAMP21 chromosomal abnormality with MRD ≥ 1 × 10-4 at week 12.

Children with Philadelphia chromosome-positive acute lymphoblastic leukemia who develop resistance to targeted agents may undergo hematopoietic stem cell transplantation after consolidation therapy.

5. Cutting-edge treatment

1) Targeted therapy

Targeted therapy is a treatment that selectively stops the growth of tumor cells by targeting specific molecules on the tumor cells, minimizing the effect on normal cells. Side effects still exist with targeted therapy and are usually less severe than with chemotherapy due to its specificity. However, chemotherapy is still the primary treatment for childhood acute lymphoblastic leukemia since a high survival rate is usually achieved with chemotherapy. Current targeted therapies are:

i) Tyrosine kinase inhibitors

In tumor cells, a protein called tyrosine kinase is often over-activated, which induces excessive cell proliferation cancer. Tyrosine kinase inhibitors inhibit the activity of tyrosine kinase, thereby suppressing tumor growth.

In Philadelphia chromosome mutation-positive childhood acute lymphoblastic leukemia, tyrosine kinase inhibitors are part of standard therapy, and chemotherapy is given in combination with the targeted agents imatinib or dasatinib.

Several other tyrosine kinase inhibitors, such as nilotinib and dasatinib, are being studied for clinical applications.

ii) Monoclonal Antibody Drugs

These drugs recognize antigens specific to the tumor, which identify and kill the tumor cells or inhibit their growth. Antibodies can work alone or by carrying cytotoxic or radioactive substances into the tumor cells. Bispecific antibodies (Blinatumomab) and etolizumab (Inotuzumab) are antibody drugs used to treat relapsed childhood acute lymphoblastic leukemia.

iii) Proteasome inhibitors

The proteasome is an organ in the cell that is used to degrade useless proteins; when the proteasome is inhibited, the proteins accumulate in the cell causing cell death. These drugs kill tumor cells by inhibiting the proteasome in the tumor cells. One of these drugs, bortezomib (Bortezomib), is used to treat relapsed childhood acute lymphoblastic leukemia.

2) CAR-T cell immunotherapy

The full name of CAR-T is "Chimeric Antigen Receptor T Cell". It uses gene editing to alter the T cells of a child's autologous or allogeneic donor so that they can recognize antigens on the surface of the tumor, and then expand them and infuse them back into the patient's body to attack the tumor cells. These edited and modified T cells are called CAR-T cells.

Currently CAR-T therapy is mainly used for patients with refractory relapsed acute B lymphoblastic leukemia. If acute B-lymphoblastic leukemia cannot achieve complete remission with 1-2 courses of chemotherapy (primary drug resistance), or relapses during chemotherapy, or relapses after stopping chemotherapy and again chemotherapy is ineffective (drug-resistant relapses), a remission rate of 80% can be obtained by treating with CAR-T therapy.Although CAR-T therapy can obtain a very high rate of complete remission, most of the refractory relapsed children who obtain a complete remission with CAR-T therapy, but most children with refractory relapses will still relapse after CAR-T therapy. Allogeneic HSCT may be considered after a complete remission with CAR-T therapy.

Currently, the U.S. Food and Drug Administration (FDA) has formally approved Novartis' Kymriah for refractory relapsed acute B lymphoblastic leukemia in children and young adults. Current CAR-T therapies in China are all in the clinical research stage.

Prognosis

1. General

According to statistics from the National Cancer Institute (NCI) of the United States of America, the five-year survival rate for children with acute lymphoblastic leukemia under the age of 15 is about 90%, and the five-year survival rate for children between the ages of 15 and 19 is 75%. The overall survival rate in China is slightly lower than that in developed countries, but the five-year overall survival rate for childhood acute lymphoblastic leukemia has now reached 70%, and can reach more than 85% in the low-risk group.

2. Sequelae

Children with acute lymphoblastic leukemia who have received radiotherapy are at risk for long-term side effects and secondary tumors, which may occur even many years later. Therefore, attention needs to be paid to review and follow-up, as well as tumor screening after a certain age.

3. Complications

1) Neutrophil deficiency with fever

Children with acute lymphoblastic leukemia have low neutrophils and may develop granulocyte deficiency in combination with infections, which are usually aggressive and rapidly progressive, and therefore require prompt initial empirical treatment, followed by targeted therapy once the pathogen has been identified.

In the event of granulocyte deficiency with fever, or significant mucosal inflammation, chemotherapeutic agents other than neosteroids and glucocorticoids need to be temporarily discontinued until the temperature is normalized, mucositis is restored, and the infection is controlled. If menthylase is used, the physician will consider its use in the context of the patient's condition. If the course of treatment has reached 20 days or more at the time of discontinuation, or if 80% of the current course of chemotherapy has been completed, no additional chemotherapy is needed, or else the course of treatment needs to be made up.

2) Anemia

Children with acute lymphoblastic leukemia are prone to anemia. It can usually be relieved by transfusion of red blood cells, and blood transfusion is necessary if the hematocrit reaches less than 60 g/L.

3) Pneumocystis carinii infection

Because children with acute lymphoblastic leukemia are immunocompromised and at risk for infection with Pneumocystis carinii, long-term administration of cotrimoxazole (SMZco) tablets is usually recommended for the prevention of Pneumocystis carinii infection until 3 months after the end of chemotherapy. Cotrimoxazole needs to be discontinued 24 hours prior to the administration of high-dose methotrexate and restarted until methotrexate concentrations are less than 0.4 μmol/L at least 72 hours after methotrexate administration.

4. Recurrence

15-20% of children with childhood acute lymphoblastic leukemia experience relapses. Relapses usually occur within 3 years of the end of treatment and can occur within or outside the bone marrow, or even both. Usually, extramedullary relapses have a better prognosis than intramedullary relapses.

Follow-up & Review

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The current review and follow-up program adopted by most hospitals in the country is:

● For 1 year after stopping the drug: review every 3 months or so.

● Years 2 to 5 after stopping the drug: review every 6 months or so.

● After 5 years of discontinuation: annual review.

Usually, the review after the end of treatment includes a thorough general physical examination, laboratory tests, sometimes imaging and/or bone marrow aspiration, and possibly liver and kidney function tests. The exact tests to be performed will depend on the child's specific condition and will be based on the doctor's recommendation.

Routine

1. General

Complete the treatment as prescribed by the doctor, maintain good living habits and a clean living environment, and take care to prevent infection. Regular follow-ups should be conducted after the completion of treatment in order to monitor recurrence and long-term adverse effects. Meanwhile, in daily life, children should be provided with nutritionally balanced diets, encouraged to have moderate activities, and attention should be paid to the psychological health of the children.

2. Home care

Since children under treatment often have reduced immunity, care should be taken to prevent infection. Pay attention to washing hands frequently, keeping food and drinking water clean and hygienic, and good living hygiene habits. Keep the living environment neat and clean, open windows regularly to maintain air circulation. Do not put fresh flowers and potted flowers indoors for the time being. Garbage cans should be covered and garbage should not be stored for more than 2 hours. At the same time, the contact between the child and the infected patient should be reduced, and the infection of the accompanying staff should also be noted. If someone in the family has a cold, contact with the child should be avoided as much as possible; if contact with the child is necessary, hand washing (with soap or hand sanitizer), wearing a mask and other protective measures must be done. At the same time, parents should pay attention to daily observation of the child's condition and seek medical attention as soon as possible if there are signs of infection or fever.

3. Management of daily life

1) Diet

Both during and after treatment, it is recommended to provide children with a nutritious and balanced diet, guaranteeing the intake of high-quality proteins (e.g., meat, eggs, milk, poultry, fish and shrimp, soybeans and soybean products, etc.), as well as more grains and cereals, vegetables and fruits, and moderate consumption of dairy products and nuts to ensure the intake of other nutrients. At the same time should eat less refined rice and white flour, deep-processed snacks and processed meats, control oil and salt.

In addition, during the treatment period, the child's immunity will be reduced and expired, spoiled, unclean and potentially food-safe foods should be avoided. Specific dietary advice can be obtained from the dietitian at your hospital.

2) Movement

If the physical condition of the child allows, you can encourage and assist the child to do some activities. Moderate exercise is helpful in preventing muscle atrophy, increasing physical strength and endurance, and promoting appetite.

Appropriate regular exercise is recommended after the child has finished treatment. If available, consider 30-60 minutes of moderate-intensity exercise per day (e.g., brisk walking, bicycling, yoga, table tennis, etc.) or a moderate amount of high-intensity exercise per week (e.g., running, swimming, jumping rope, aerobics, basketball, etc.).

3) Lifestyle

The patient needs to be guaranteed a sleep schedule. Regular and quality sleep is helpful for recovery and immunity. A suitable sleep environment (usually dimly lit, quiet, and at the right temperature) may be helpful in improving the patient's quality of sleep.

Studies have shown that children with leukemia have a higher risk of cardiovascular disease, metabolic disease, and secondary cancer in the long term than the general population. A healthy lifestyle, such as a balanced diet and moderate exercise, is the most important and effective means of preventing these diseases. Children are also advised to pay attention to weight control, as being overweight may increase the risk of developing cancer (e.g., breast, pancreatic, rectal, endometrial, etc.) later in life.

4) Emotional psychology

The process of treating acute lymphoblastic leukemia in children is challenging and requires attention to the child's mental health. Physical changes and pain caused by the disease and treatment, isolation and lack of external peer contact during treatment, falling behind in school, and fear of not being accepted by peers can all affect the child's mental health. Parents need to guide their children to face the disease with a positive attitude, accept their physical changes, and encourage them to maintain external contacts, play with classmates and friends, and return to school and reintegrate into the society as early as possible under the premise of ensuring hygiene during the treatment process. If the child has a psychological disorder, a psychologist can be called in to intervene.

4. Daily condition monitoring

It is necessary to pay attention to the side effects caused by radiotherapy (e.g., hair loss, fatigue, vomiting, etc.), recurrence of tumor metastasis, and abnormal growth and development. Consult your doctor when fever, worsening symptoms, new symptoms, and treatment-induced side effects occur.

5. Special Considerations

1) Precautions to be taken when platelets are too low

If the child's platelets are too low (usually less than 20x109 /L), care needs to be taken to avoid bleeding, to stay away from sharp, prickly toys and objects, and to avoid all impact sports (such as bouncing, soccer, basketball, etc.). When eating, avoid bones and other foods that tend to poke the mouth, and use a soft-bristled brush when brushing teeth. At the same time, for younger children, should try to avoid violent crying to avoid intracranial hemorrhage. In addition, take care to keep the child's bowels clear, and do not self-administer anal suppositories or measure anal temperature to avoid rectal bleeding. Do not give your child medications that tend to cause bleeding, such as aspirin or ibuprofen, unless your doctor recommends it. Some over-the-counter cold medicines may have ingredients such as ibuprofen that require special attention.

2) Precautions during hormone/steroid therapy

Care needs to be taken to control your child's blood sugar during treatment with hormones/steroids. Take care to limit the intake of sugar, syrups and sugary drinks, and eat less food that tends to raise blood sugar quickly, such as refined white rice and noodles, potatoes, and highly confectionary melon products (e.g., candied fruit, raisins, etc.). Eat more healthy low-calorie and calcium-rich foods. Meanwhile, hormones/steroids can promote appetite, so care should be taken not to allow children to eat uncontrollably, and to eat more healthy low-calorie foods to control body weight. In addition, hormones/steroids can interfere with the absorption of calcium and vitamin D. Therefore, care should be taken to ensure that calcium-rich foods are consumed, and that vitamin D and/or calcium supplements are taken if necessary. Consult your doctor and dietitian for details.

3) Dietary precautions during treatment with menthol drugs

Because of the potential for pancreatitis to be induced by menadione drugs (e.g., menadionease), it is necessary to limit the child's fat intake from 3 days prior to the start of the medication to 3-5 days after discontinuation of the medication. During this period, particular attention should be paid to the restriction of animal fats and oils high in saturated fats (lard, tallow, butter and fatty fats) and to the choice of foods lower in fat or supplementation with suitable fats.

It is important to note that a low-fat diet does not mean a fat-free diet, and a completely fat-free diet can cause essential fatty acid deficiencies that can affect your child's health. Care should also be taken to ensure your child's protein intake (e.g. lean meat, fish and shrimp, chicken breast, egg white, etc.).

4) Keeping case records

Patients with childhood acute lymphoblastic leukemia have a risk of long-term side effects and secondary tumors, the onset of which may occur many years after the end of treatment for childhood acute lymphoblastic leukemia, and this risk is related to the regimen and dosage used in the treatment of leukemia. Therefore, it is important to keep a record of all the child's medical visits and treatments for future review and reference.

6. Prevention

Since the exact cause of childhood acute lymphoblastic leukemia is not known, there are no methods of prevention. However, certain environmental factors and genetic disorders are known to be associated with an increased risk of childhood acute lymphoblastic leukemia (see "Predisposing Factors"). Therefore, parents can take care to avoid relevant environmental factors. If the child has a related hereditary disease, he/she should be screened for childhood leukemia. In addition, parents can pay attention to the early symptoms of childhood acute lymphoblastic leukemia, and seek early medical attention for early detection and early treatment, in order to achieve the best therapeutic outcome.

Cutting-edge Therapeutic & Clinical Research

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References

1. Wang N, Feng YJ, Wang BH, Fang LW, Cong SH, Li YC, Yin P, Zhou MK, Wang LH. Analysis of the burden of disease of leukemia in the Chinese population in 1990 and 2013. Chinese Journal of Epidemiology. 2016. 37(6): 783-787.

2. National Health and Health Commission of the People's Republic of China. Diagnostic and therapeutic norms for acute lymphoblastic leukemia in children (2018 edition).

http://www.nhc.gov.cn/ewebeditor/uploadfile/2018/10/20181016180401747.doc

3. NCCN Clinical Practice Guidelines in Oncology: Pediatric Acute Lymphoblastic Leukemia (Version 1, 2020)

4. Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) (Health Professional Version)

5. Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) (Patient Version)

6. http://www.danafarberbostonchildrens.org/conditions/leukemia-and-lymphoma/relapsed-acute-lymphoblastic-leukemia.aspx

7. arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016. 127(20): 2391-2405.

8. Salem, CB et al. Acute lung injury and acute respiratory distress syndrome. Lancet. 2007. 370(9585): 383.

9. Lee-Chiong Jr, T, Matthay RA. Drug-induced pulmonary edema and acute respiratory distress syndrome. Clin Chest Med. 2004. 25: 95-104.