Leukemia

Essential Information

Summarize

1. General

Overview: Childhood leukemia is a class of hematopoietic system malignant neoplastic disease, which is the malignant tumor with the highest incidence rate among children in China. Most of the leukemias occurring in pediatrics are acute leukemias, and although the disease develops rapidly, if a clear diagnosis is made in a timely manner and appropriate treatments are used, a satisfactory outcome can often be achieved.

Manifestations: Childhood leukemia may present with varying degrees of anemia, bleeding, fever from infections, and enlargement of the liver, spleen, lymph nodes, and bone pain.

Treatment: Childhood leukemia is a general term for a large group of diseases, and treatment options vary for different types of leukemia. Parents of children with leukemia should actively cooperate with doctors to confirm the diagnosis so that appropriate treatment can be applied.

Prognosis: The prognosis of different types of leukemia varies. For example, the five-year survival rate of childhood acute promyelocytic leukemia (also known as M3) and childhood acute lymphoblastic leukemia (ALL) can reach more than 90%; while the five-year survival rate of childhood acute myeloid leukemia is 60%-70%.

2. Definition of disease

Childhood leukemia is a class of hematopoietic system malignant neoplastic disease, is the highest incidence of malignant tumors in children in China, accounting for about 1/3 of all childhood malignant tumors. leukemia occurs due to the bone marrow of hematopoietic cells abnal division and proliferation, the formation of leukemia cells, which leads to leukemia.

Epidemiological

epidemiological

According to 2013 statistics, the incidence rate of leukemia in China is 11.81 per 100,000 children under 5 years of age, 4.61 per 100,000 children between 5 and 10 years of age, 4.50 per 100,000 between 10 and 15 years of age and 4.75 per 100,000 between 15 and 20 years of age.

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children, accounting for about 70% of childhood acute leukemias. The incidence of childhood acute lymphoblastic leukemia (under 15 years of age) in China is about 3-3.5 per 100,000; if it is extended to children 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, with a gradual decline thereafter.

The incidence of childhood acute myeloid leukemia (AML) is second only to childhood acute lymphoblastic leukemia, accounting for about 20% of childhood acute leukemias. Among them, acute promyelocytic leukemia (APL) accounts for about 10% of childhood AML.

In addition, chronic myeloid leukemia (CML) is less common in children, accounting for 3-5% of childhood leukemias.

Juvenile myelomonocytic leukemia (JMML) occurs mainly in infants and children under the age of 4 years, with a median age of diagnosis of 2 years and a higher incidence in boys than in girls. Juvenile myelomonocytic leukemia accounts for 1-2% of childhood leukemias.

Classification & Stage

basic type

(1) Classification of diseases

Leukemia is usually divided into acute leukemia and chronic leukemia according to the urgency of the onset of the disease. Acute leukemia is characterized by poor cell differentiation, with predominantly primitive and early juvenile cells stagnating at an early stage, and rapid progression of the disease. Chronic leukemia is characterized by better cell differentiation, predominantly naïve or mature cells, slow development and longer disease duration.

Leukemia can also be divided into lymphocytic leukemia and myeloid leukemia by the type of blood cells that proliferate. Lymphocytic leukemia affects lymphoid cells that form lymph or lymphoid tissue. The lymphoid tissue forms the immune system. Myeloid leukemia affects myeloid cells, including red blood cells, granulocytes, monocytes, and megakaryocytes.

Taken together, childhood leukemias include the following major categories:

● Childhood acute lymphoblastic leukemia (ALL)

The tumor originates from the abnormal proliferation and aggregation of precursor B or precursor T cells (the main type of leukocyte) in the bone marrow. Abnormal proliferation inhibits normal hematopoiesis and ultimately affects the normal production of erythrocytes, granulocytes, and platelets, leading to anemia, neutropenia, and thrombocytopenia; tumor cells may also invade extramedullary tissues as well, such as the meninges, gonads, thymus, liver, spleen, lymph nodes, or bone tissues, and cause the corresponding lesions.

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

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

● Acute B-lymphoblastic leukemia (B-ALL)

According to the different stages of leukemic cell differentiation, acute B-lymphoblastic leukemia is mainly divided into four types: early pre-B, ordinary 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 divided into four main types: early T, cortical T and medullary T. The main types of acute T-lymphoblastic leukemia are T, cortical T and medullary T.

Clinically, doctors usually perform MICM typing for acute lymphoblastic leukemia, which means that the bone marrow and blood samples of children are tested in four aspects: morphology (M), immunophenotype (I), cytogenetics (C), and molecular biology. The tests are used to accurately diagnose and characterize the child's bone marrow and blood samples, and to help determine the subsequent treatment plan.

● Childhood acute myeloid leukemia (AML)

Acute myeloid leukemia is also known as acute myeloid leukemia, acute granulocytic leukemia, or acute nonlymphocytic leukemia. The bone marrow of these patients produces large numbers of abnormal red blood cells, or white blood cells, or megakaryocytes. If left untreated, they tend to deteriorate rapidly.

Based on cell morphology, AML can be classified as M0, M1 to M7 according to FAB typing criteria.

Similar to acute lymphoblastic leukemia, clinicians perform MICM typing for acute myeloid leukemia in order to perform accurate diagnostic typing and help determine subsequent treatment options.

It is important to note that AML in children includes about 10% of acute promyelocytic leukemia. Acute promyelocytic leukemia is usually accompanied by severe coagulation abnormalities, manifested by varying degrees of bleeding, and progresses very rapidly, so there are special treatment considerations. Acute promyelocytic leukemia is classified as acute myeloid leukemia type M3 according to FAB typing, with a characteristic translocation of chromosomes 15 and 17 (denoted as t(15;17)), which can be detected as a positive PML-RARα fusion gene due to this chromosomal translocation.

● Childhood chronic myeloid leukemia (CML)

Chronic myeloid leukemia is also known as chronic granulocytic leukemia (CGL). This type of leukemia is less common in children.

● Juvenile myelomonocytic leukemia (JMML)

Juvenile granulomonocytic leukemia is a rare and specific type of myeloid leukemia that occurs in early childhood, mainly in infants and young children. Juvenile granulomonocytic leukemia is neither a chronic nor an acute leukemia, and is classified by the World Health Organization (WHO) as a myelodysplastic syndrome/myeloproliferative neoplasm. Juvenile granulomonocytic leukemia is characterized by abnormal proliferation and differentiation of granulomonocytes and organ infiltration, and has a poor prognosis.

The International Working Group on Juvenile Granulomonocytic Leukemia has established the following diagnostic criteria for juvenile granulomonocytic leukemia:

I. All of the following criteria must be met at the same time:

● BCR-ABL fusion gene negative

● Absolute peripheral blood mononuclear cell count ≥1.0×109 /L

● splenomegaly

● Bone marrow or peripheral blood naïve cell ratio <20%

● II. At least one of the following must be met:

● Presence of somatic mutations in the RAS or PTPN11 genes

● Fulfills diagnostic criteria for neurofibromatosis type 1 or presence of a mutation in the NF1 gene

● Chromosome 7 monosomy (normal people have 2 chromosome 7s)

● III. At least one of the following must be met:

● Peripheral blood leukocytes ≥10×109 /L

● Presence of myeloid naïve cells in peripheral blood

● Elevated hemoglobin F

● Presence of clonal cytogenetic inheritance other than monosomy of chromosome 7

● Granulocyte-macrophage colony-stimulating factor hypersensitivity

(2) Disease Staging

Acute lymphoblastic leukemia and acute myeloid leukemia in children are usually grouped by risk only and not staged.

Chronic myeloid leukemia in children is staged as chronic, accelerated and acute depending on the progression of the disease.

● The diagnostic criteria for the chronic phase are:

● Low-grade fever, fatigue, excessive sweating, weight loss.

● The peripheral blood leukocyte count is elevated, mainly neutrophils, late granulocytes and rod-shaped nucleated granulocytes, with <10% of primitive granulocytes + early granulocytes, increased eosinophilic and basophilic granulocytes, and a small number of nucleated erythrocytes.

● Bone marrow hyperplasia is marked to active, with a predominantly granulocytic lineage and <10% primitive cells.

● Positive for Philadelphia chromosome or BCR-ABL fusion gene.

● Cultured colonies or clusters of granulocyte-macrophage colony-forming units (CFU-GM) were significantly increased from normal.

● Accelerated period that meets any of the following:

● Primitive cells make up 10-19% of the peripheral blood or bone marrow.

● Peripheral blood basophils ≥20%.

● Persistent thrombocytopenia (PLT < 100 x 109/L) or treatment-naïve persistent thrombocytosis (PLT > 1000 x 109/L).

● Progressive splenomegaly or elevated white blood cell counts for which treatment is ineffective.

● In addition to Philadelphia chromosome positivity (Ph+), other chromosomal abnormalities were present.

● Granulocyte-macrophage colony-forming unit (CFU-CM) cultures with increased clustering and decreased colonization.

● Bone marrow biopsy showed collagen fiber proliferation.

● Acute phase, meets any of the following:

● Primitive cells ≥20% in peripheral blood or bone marrow.

● Extramedullary infiltration was present.

● Bone marrow biopsy reveals primitive cells in patches or clusters.

(3) Disease Risk Grouping

In clinical practice, childhood acute lymphoblastic leukemia and acute myeloid leukemia are grouped by risk for stratified treatment. Grouping is usually determined by examining the genetic and molecular biology of leukemia cells in the child's blood, bone marrow, and lymph node or cerebrospinal fluid (CSF) samples, as well as microscopic residual disease (MRD). The criteria for grouping vary slightly from center to center internationally and will continue to be refined as testing technology improves. Risk grouping plays an important role in determining treatment options.

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

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

● 1 year or older and under 10 years of age.

● 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 induction treatment days 15-33 , and MRD <1×10-4 before consolidation treatment.

● Children who met at least one of the following conditions were categorized into the intermediate-risk group:

● Age 10 years or older.

● The highest white blood cell count was higher than 50 x 109/L at the time of 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 met at least one of the following conditions were categorized into the high-risk group:

● The age of the child was less than 1 year.

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

● Bone marrow cytomorphometry on days 33-45 showed 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.

● MEF2D rearrangements exist.

● 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.

● Risk grouping for childhood acute myeloid leukemia (excluding acute promyelocytic leukemia)

● low-risk group

Children with childhood acute promyelocytic leukemia (FAB typed as M3), and children with FAB typed as M2b, M4Eo, or other children carrying an inversion of chromosome 16.

● medium risk group

Not in the low-risk group and not having any of the following risk factors:

● The child was no more than one year old at the time of diagnosis of acute myeloid leukemia.

● White blood cell count greater than or equal to 100 X 109/L at diagnosis.

● Chromosome 7 is missing.

● myelodysplastic syndrome (medicine)

● One course of the standard regimen does not provide relief.

● high risk group

Presence of any of the five risk factors listed above.

● Risk grouping for acute promyelocytic leukemia

● Low-risk group: white blood cell count <10×109/L.

● High-risk group: white blood cell count ≥ 10 × 109/L, or presence of FLT3-ITD mutation, or molecular biology remission not achieved before maintenance therapy in the low-risk group.

Clinical manifestations

1. General

The main symptoms of childhood leukemia are unexplained fever, anemia, bleeding, and infiltration of leukemia cells (mainly in the form of enlargement of the liver, spleen, and lymph nodes), although there can be considerable inter-individual variation. Symptoms may last from a few days to four or five months, with acute manifestations lasting from two weeks to two months.

2. Typical symptoms

● Fever: The fever is mainly due to the leukemia itself, which is usually low to moderate around 38°C, is not treated with antibiotics and resolves within 72 hours of induction therapy. However, it can also be accompanied by infections due to the immunocompromised nature of children with leukemia due to the decrease in the number of white blood cells and the abnormalities in their functioning, in particular the decrease in the number of neutrophils. The most common infections are respiratory infections such as tonsillitis, bronchitis and pneumonia, but also oral mucosal infections or gastrointestinal infections (e.g. gastroenteritis). A small number of children develop more serious infections, such as septicemia. The source of infection may be almost any pathogen, and co-infections are likely to occur.

● Anemia: is one of the earlier symptoms and worsens with the progression of the disease. It usually occurs gradually and is characterized by pallor, weakness, shortness of breath after activity, drowsiness, etc. The nails and the conjunctiva of the eyelids may also appear to varying degrees of pallor.

● Bleeding: Most of the time, bleeding or ecchymosis of the skin and mucous membranes (e.g., bruising of the skin) is present, as well as unexplained nosebleeds or bleeding from the gums. Some children may have gastrointestinal bleeding or hematuria, but this is rare. Children with acute promyelocytic leukemia are at risk of fatal pulmonary or intracranial bleeding.

● Infiltration of leukemia cells: usually presenting with enlarged lymph nodes in different areas and/or hepatosplenomegaly. If the 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, particularly in acute lymphoblastic leukemia, resulting in testicular leukemia and central nervous system leukemia (also called meningeal leukemia). In addition, in acute myeloid leukemia, leukemia cells may also infiltrate the eyes, gums, or skin. In juvenile granulomonocytic leukemia, breathing difficulties may also occur because leukemia cells often infiltrate the lungs.

● Skin lesions: common in juvenile granulomonocytic leukemia and are an important feature of this disease, manifesting as maculopapular rash, discoloration of folds of the skin (e.g., groin and armpits), yellow tumors, green tumors, and milky café au lait spots.

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.

Etiolog & Risk factors

1. General

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

2. Underlying causes

When blood-forming cells in the bone marrow do not go through the normal maturation process and multiply rapidly, these abnormal cells become more and more numerous in the bone marrow and form leukemia cells. In most cases, leukemia occurs on white blood cells, but some leukemia occurs on other types of blood cells.

Leukemia cells can crowd out normal cells and can quickly 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 infiltrations that interfere with the normal functioning of the other cells and lead to the various symptoms of leukemia.

Childhood leukemia occurs when the chromosomes and genes involved are mutated during the development of the child, but usually it is not a single genetic mutation, but rather a multigene, multifactorial change; therefore, the exact cause of acute leukemia is not clear.

It is now known that chronic myelogenous leukemia is usually caused by a chromosomal variant called the "Philadelphia chromosome (Ph)". The Philadelphia chromosome refers to a translocation between chromosomes 9 and 22 (labeled t(9;22)), which results in the fusion of the BCR and ABL genes to form a BCR-ABL fusion gene.

3. Risk factors

Certain environmental and genetic factors are known to be associated with the risk of childhood 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 high. 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 linked to an elevated risk of leukemia.

● Certain viruses, such as HIV, have been linked to the development of lymphoblastic leukemia.

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

(1) Risk factors for acute lymphoblastic leukemia in children

In addition to the environmental and genetic factors mentioned above, there are factors associated with the risk of childhood acute 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). -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.

(2) Risk factors for acute myeloid leukemia in children

In addition to the environmental and genetic factors previously described, there are a number of congenital factors that have been associated with the risk of AML in children, such as Down syndrome, familial monosomy of chromosome 7, Fanconi anemia, congenital dyskeratosis, Bloom's syndrome, neurofibromatosis type 1, congenital pygmy dementia syndrome (also known as Noonan syndrome), severe congenital neutropenia ( Kostmann syndrome), Shwachman-Diamond syndrome, congenital erythrocyte-only aplastic anemia (Diamond-Blackfan anemia), congenital absence of megakaryocyte thrombocytopenia, CBL syndrome, Leigh-Fraumeni syndrome (Li-Fraumeni syndrome), with a Familial platelet disorders with inherited mutations in the RUNX1 gene, myelodysplastic syndromes (MDS) with inherited mutations in the GATA2 or CEBPA genes, and specific mutations in the TERC and TERT genes.

In addition, certain acquired diseases may increase the risk of developing AML, such as severe aplastic anemia, paroxysmal sleep hemoglobinuria, and thrombocytopenia.

(3) Risk factors for juvenile granulomonocytic leukemia

In addition to the environmental and genetic factors described earlier, 80% of cases of juvenile granulomonocytic leukemia involve mutations in genes in the RAS signaling pathway, such as PTPN11, RAS, NF1, etc. The CBL, SPRED, and transcriptional intermediate factor γ1 genes are also associated with the development of juvenile granulomonocytic leukemia. Children with genetic disorders that also have mutations in these genes (e.g., neurofibromatosis type 1) have an increased risk of juvenile granulomonocytic leukemia. However, the mutations associated with juvenile granulomonocytic leukemia are usually systemic mutations, i.e., non-genetic mutations that occur later in life.

Examination & Diagnosis

1. Relevant examinations

(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 chromosome damage, loss, or recombination, or whether there are extra chromosomes, and whether there are disease-related fusion genes.

(5) Blood tests

● Routine blood tests: platelet count, counts of all types of white blood cells, hemoglobin levels, 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 biochemicals 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 leukocyte 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).

2. 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 inhomogeneous infiltrating foci of the testis, which may be excluded from biopsy 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 the testicular leukemia has relapsed.

(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 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 hypoproliferative bone marrow cells without 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.

(7) Differential diagnosis of juvenile granulomonocytic leukemia

Juvenile granulomonocytic leukemia is easily confused with other types of myelodysplastic syndromes/myeloproliferative neoplasms. However, juvenile granulomonocytic leukemia usually occurs in children younger than 5 years of age. Therefore, if juvenile granulomonocytic leukemia is suspected in a child 6 years of age or older, consideration should be given to the possibility of other types of myelodysplastic syndromes/myeloproliferative neoplasms.

At the same time, juvenile granulomonocytic leukemia is easily misdiagnosed as idiopathic or immune thrombocytopenic purpura because thrombocytopenia is often the first feature of juvenile granulomonocytic leukemia. However, juvenile granulomonocytic leukemia presents with an elevated monocyte ratio and absolute count, which can be differentiated accordingly.

In addition, cytomegalovirus and EBV infections may have hematologic similarities to juvenile granulomonocytic leukemia, which can be identified by viral serology.

Juvenile granulomonocytic leukemia can be differentiated from other hematopoietic malignancies by bone marrow aspiration smears.

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. Section

Hematology, Pediatrics, Hematology-Oncology.

Clinical Management

1. General

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

Due to the rapid progression of acute 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 intensity and dosage of the treatment will be graded according to the level of risk. The treatment of childhood acute leukemia is usually divided into three to four phases: induction, consolidation, intensification, and maintenance (some AML regimens do not have a maintenance phase and end after the intensification phase). Hematopoietic stem cell transplantation is considered for some children at intermediate to high risk of relapse.

Despite the availability of molecularly targeted drugs represented by imatinib in chronic myeloid leukemia, allogeneic hematopoietic stem cell transplantation is still the treatment of choice for its children to achieve long-term disease-free survival due to the chances of drug resistance, cumulative drug toxicities, and economic burden.

2. Treatment of acute lymphoblastic leukemia in children

Doctors will use a combination of chemotherapeutic agents to treat the child according to 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 central system 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 central nervous system.

Children with Philadelphia chromosome-positive acute lymphoblastic leukemia require a combination of the targeted agents imatinib or dasatinib during chemotherapy. If resistance occurs, hematopoietic stem cell transplantation can be performed after consolidation therapy.

Most children with acute lymphoblastic leukemia do not require radiotherapy. If CNS leukemia is present, cranial radiotherapy is required after completion of delayed intensive therapy and prior to maintenance therapy (except for those with comorbid CNS leukemia at the time of the initial diagnosis and who have responded well to treatment.) Radiotherapy is not recommended for children under 2 years of age, and the radiation dose for children over 2 years of age should be 12-18 Gy. If there is a comorbidity with testicular leukemia at the initial diagnosis, at the end of consolidation therapy with systemic chemotherapy, a If lesions remain on testicular ultrasound, biopsy is required and testicular radiotherapy is indicated if residual leukemic cells are identified. Radiotherapy is also indicated in children in bone marrow remission on systemic chemotherapy who experience a relapse of testicular leukemia. Radiotherapy is usually given to both testes at a dose of 20 to 26 Gy, or 12 to 15 Gy in younger children.The newer CAR-T cellular immunotherapy may be an effective alternative to radiotherapy for testicular leukemia.

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

● Failure of induction of remission therapy (bone marrow morphology did not reach 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.

3. Treatment of childhood acute myeloid leukemia (excluding acute promyelocytic leukemia)

● induction therapy period

Intermediate-risk, and low-risk myeloid leukemias other than childhood promyelocytic leukemia: the DAE regimen (Zoerythromycin (DNR) + Cytarabine (also known as Ara-C) + Etoposide (VP16)) or the HAD regimen (Hauteric Triglyceride (HRT) + Cytarabine + Etoposide) are currently the preferred choices.

Children with high-risk myeloid leukemia are preferred to be treated with IA regimen [desmethoxylated erythromycin (IDA) + cytarabine] or DAE regimen. Alternatively, chemotherapy with novel antitumor agents may be chosen based on the physician's recommendation. If the child's white blood cell count is greater than 100 X 109/L before induction therapy, small doses of cytotoxic drugs can be used to reduce the leukemic cell load and prevent tumor lysis syndrome, and combination chemotherapy can be given after the white blood cell count is less than 50 X 109/L.

Children with hypoproliferative AML or co-infections should be treated with moderate chemotherapy in conjunction with infection control, and then enter induction chemotherapy as described above when their general condition improves.

● consolidation period

Those in complete remission with induction chemotherapy were given another course of the original regimen.

● intensive treatment period

Intensive treatment is mainly chemotherapy with medium- and high-dose cytarabine in combination with other chemotherapeutic agents to prevent recurrence and improve long-term disease-free survival.

● Maintenance therapy or hematopoietic stem cell transplantation

Currently, maintenance therapy is not advocated for children with AML in the low-risk group after induction of remission and consolidation and intensification. Children with childhood acute myeloid leukemia in the intermediate- and high-risk groups are prone to relapse with chemotherapy alone; therefore, hematopoietic stem cell transplantation is actively performed after induction of remission with a suitable donor. The choice of transplant donor should follow the advice of the transplant surgeon.

● intrathecal chemotherapy

Acute myeloid leukemia subtypes other than the M3 subtype require intrathecal injection for prophylaxis or treatment of CNS leukemia.

4. Treatment of acute promyelocytic leukemia in children

Acute promyelocytic leukemia is a malignant blood disease with significant coagulation abnormalities, and all-trans retinoic acid therapy should be started as soon as acute promyelocytic leukemia is suspected, even if all laboratory tests have not been completed. The cure rate can be more than 90% if the risk of bleeding from vital organs caused by early onset coagulation abnormalities is overcome by treatment. The efficacy of all-trans retinoic acid as well as arsenic in acute promyelocytic leukemia is precise, and the combination has a synergistic effect, which has a positive significance on the clearance of leukemic stem cells (for specific regimens, see the "Diagnostic and Treatment Guidelines for Childhood Acute Promyelocytic Leukemia (2018 Edition)", and the treatment regimens for PML-RARa fusion gene-negative acute promyelocytic leukemia can be found in the "Clinical pathway for childhood acute promyelocytic Leukemia Clinical Path (2017 edition)).

The low-risk group regimen is: oral all-trans retinoic acid (ATRA) + arsenic (either intravenous arsenic trioxide (ATO) or oral compounded yellow dock tablets (RIF)). All-trans retinoic acid needs to be administered immediately upon morphological confirmation of acute promyelocytic leukemia in the bone marrow. Arsenic needs to be administered at the time of molecular biology confirmation of a positive PML-RARa fusion gene, which is recommended within one week.

The regimen for the high-risk group was: oral all-trans retinoic acid + arsenic (IV arsenic trioxide or oral cotrimoxazole tablets) + IV anthracycline (desmethoxyzoxazolam (IDA) or zorubicin (DNR)). The timing of administration of all-trans retinoic acid and arsenic was consistent with the low-risk group.

If the initial or post-induction white blood cell count is greater than 10 x 109/L, choose one of the following drugs: hydroxyurea, cytarabine, or hypertriglycerides. Anthracyclines are added to this in the high-risk group.

Allogeneic hematopoietic stem cell transplantation is also recommended if a negative-to-positive PML-RARa fusion gene condition occurs after discontinuation of the drug and persists for more than 2 times.

Because acute promyelocytic leukemia in children can cause diffuse intravascular coagulation (DIC), which is very dangerous, it is imperative that intrathecal chemotherapeutic injections be given during the induction therapy period after the control of diffuse intravascular coagulation, in order to prevent or treat CNS leukemia.

5. Treatment of chronic myeloid leukemia in children

There are two main effective approaches to the treatment of childhood chronic myeloid leukemia: the first-generation tyrosine kinase inhibitor (TKI) imatinib and allogeneic hematopoietic stem cell transplantation. Which one to choose as the first-line treatment is still somewhat controversial. At present, there is no unified treatment plan for childhood chronic myeloid leukemia at home and abroad. Due to the effect of TKI drugs on children's growth and development, it is currently believed that imatinib combined with allogeneic hematopoietic stem cell transplantation may be the best treatment.

The American Society of Hematology's 2012 guidelines for the treatment of pediatric chronic myeloid leukemia recommend the following therapies:

● In children in the chronic phase, it is recommended to start treatment with hydroxyurea, and once BCR-ABL fusion gene positivity is confirmed, treatment with imatinib is initiated and continued while disease status is monitored every 3 months. If the child does not achieve remission, the BCR-ABL fusion gene is tested and the child is switched to dasatinib, a second-generation tyrosine kinase inhibitor. If the child's disease still progresses or relapses, allogeneic hematopoietic stem cell transplantation is performed.

● Children in the accelerated phase are recommended to start treatment with dasatinib and once remission is achieved, allogeneic bone marrow transplantation is initiated.

● If it has entered the acute phase, it is necessary to start anti-leukemic chemotherapy, as well as allogeneic bone marrow transplantation once remission is achieved with the application of dasatinib.

As far as the current status in China is concerned, imatinib is preferred as the first-line treatment for only some patients in the chronic phase of childhood chronic myeloid leukemia. Once poor efficacy or drug resistance occurs in children, allogeneic hematopoietic stem cell transplantation is required if there is no financial ability to increase the drug dose or choose dasatinib. For children in the accelerated and acute stages, allogeneic HSCT plays an important role in the treatment.

6. Treatment of juvenile granulomonocytic leukemia

Conventional chemotherapy is not effective in juvenile-type granulomonocytic leukemia, and allogeneic hematopoietic stem cell transplantation is currently the only curative tool. Some children may receive antimetabolic chemotherapeutic agents (e.g., 6-mercaptopurine) or chemotherapy with demethylating agents to reduce the number of leukemic cells before undergoing hematopoietic stem cell transplantation.

7. Frontline therapy

(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 chemotherapy due to its specificity. However, chemotherapy is still the primary treatment for childhood leukemia since a high survival rate is usually achieved with chemotherapy. Current targeted therapies are:

● Tyrosine kinase inhibitor

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.

For pediatric chronic myeloid leukemia, tyrosine kinase inhibitors are first-line agents. Tyrosine kinase inhibitors are also part of the standard therapy in Philadelphia chromosome mutation-positive childhood acute lymphoblastic leukemia.

And several other tyrosine kinase inhibitors, such as nilotinib and dasatinib, are under clinical investigation.

● monoclonal antibody drug

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.

● proteasome inhibitor

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.

● Targeted drugs against the RAS signaling pathway

Since mutations in the RAS signaling pathway are present in 80% of juvenile granulomonocytic leukemias, targeted drugs against the RAS signaling pathway, such as the MEK1/2 inhibitor trametinib, may be expected to improve the prognosis of juvenile granulomonocytic leukemia. Currently, there are clinical trials in the United States that are investigating the use of trametinib in the treatment of refractory and relapsed juvenile granulomonocytic leukemia.

(2) CAR T-cell immunotherapy

The full name of CAR T is "Chimeric Antigen Receptor T Cell". CAR T cells are genetically engineered to recognize antigens on the surface of a tumor, and then expanded and infused back into the patient to attack the tumor cells. These edited and altered 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 discontinuing chemotherapy and then chemotherapy again is ineffective (drug-resistant relapse), a re-remission rate of 80% can be obtained by treatment with CAR T therapy.Although CAR T therapy can obtain a very high rate of complete remission, most of the refractory relapsed children who have obtained a complete remission by CAR T therapy still have relapses. CAR T therapy can achieve a high rate of complete remission, but most children with refractory relapses who achieve complete remission with CAR T therapy still relapse. After complete remission with CAR T therapy, allogeneic hematopoietic stem cell transplantation may be considered.

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

The prognosis for different types of leukemia varies. According to international studies, acute promyelocytic leukemia in children can reach more than 90 per cent, the five-year survival rate for childhood acute lymphoblastic leukemia is currently more than 80 per cent, and the overall five-year survival rate for childhood acute myeloid leukemia is more than 60 per cent.

(1) Prognosis of acute lymphoblastic leukemia in children

According to statistics from the National Cancer Institute (NCI) of the United States, 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 85% in the low-risk group.

(2) Prognosis of acute myeloid leukemia in children

According to the National Cancer Institute (NCI), the five-year survival rate for children under 15 years of age with acute myeloid leukemia is approximately 68%, and 57% for children 15-19 years of age. Certain treatment centers in the country have outcomes similar to international ones. The prognosis of children depends on their molecular biology subtype. Survival rates for childhood acute promyelocytic leukemia are better, with the vast majority of studies showing a five-year survival rate of more than 90%.

(3) Prognosis of chronic myeloid leukemia in children

According to current domestic and international studies, the three-year overall survival rate of children with chronic myelogenous leukemia using only allogeneic hematopoietic stem cell transplantation is 64.2%, and the overall survival rate of applying imatinib treatment is 78.4%. Factors affecting the prognosis are mainly the child's clinical indications and hematological indicators, including the child's age, spleen size, platelet count, primitive cell count, eosinophil count, and eosinophil count.

(4) Prognosis of juvenile granulomonocytic leukemia

Conventional chemotherapy for juvenile granulomonocytic leukemia is unsatisfactory, with a long-term survival rate of only 10%. Allogeneic hematopoietic stem cell transplantation can achieve an overall survival rate of more than 50%.

2. Complications

(1) Acute tumor lysis syndrome

Tumors that are sensitive to chemotherapy will have a large number of tumor cells lysed and necrotic during initial treatment, 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. In the treatment of acute lymphoblastic leukemia, since this type is sensitive to chemotherapy, tumor lysis syndrome is more likely to occur if the tumor is highly loaded 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.

(2) Differentiation syndrome (DS)

In children with acute promyelocytic leukemia, differentiation syndrome is a common complication that occurs after the use of all-trans retinoids or arsenicals, usually 2-3 days after administration, and may be life-threatening in severe cases.

A child may have differentiation syndrome if three or more of the following clinical signs are present at the same time: increased peripheral blood leukocytes, dyspnea, respiratory distress, fever, pulmonary edema, pulmonary infiltrates, pleural or pericardial effusion, peripheral edema, short-term weight gain (10% or more over the concomitant basal body weight), bone pain, headache, hypotension, congestive heart failure, acute renal function insufficiency, and abnormal liver function. If a child develops differentiation syndrome, it may be treated with steroid hormones and other symptom-relieving medications, and the dosage of all-trans retinoic acid and arsenic may be adjusted according to the child's condition.

(3) Cardiotoxicity

Anthracyclines and arsenic 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 injury occurs, drugs such as dexpropylenetramine (Zinecard) may be selected for treatment according to the condition.

Arsenic agents can cause cardiac arrhythmias. Therefore, ECGs also need to be checked before each course of arsenicals and reviewed every 1-2 weeks. Once the risk of arrhythmia is detected, close observation is needed to correct electrolyte disturbances, discontinue suspected medications that may be causing the associated symptoms (e.g., macrolide antibiotics, azole antifungals, and antiarrhythmics), and review the ECGs at least once a week. If symptoms are severe, the arsenic will need to be tapered or discontinued. If torsion tachycardia occurs, arsenic should be permanently disabled.

(4) 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 the direct bilirubin is elevated during chemotherapy and it is determined that it is due to leukemic cell infiltration, then chemotherapy is given as usual; if it is not due to leukemic infiltration, then the dose of chemotherapy is adjusted according to the condition. In children with acute promyelocytic leukemia, when elevated direct bilirubin occurs, the cause of differentiation syndrome should also be excluded; if it is indeed due to differentiation syndrome, treatment should be based on differentiation syndrome. Prior to the start of chemotherapy, if the direct bilirubin is too high, chemotherapy can be delayed for 1 week; if the bilirubin is still high after 1 week, the dose is adjusted and chemotherapy is started. When direct bilirubin is too high, attention should be paid to adjusting the doses 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, so the use of adjuvant hepatoprotective drugs is not recommended.

(5) 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 may 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 their concomitant use should be used with caution.

(6) Acute Respiratory Distress Syndrome (ARDS)

Cytarabine is toxic to the lungs and may cause acute respiratory distress syndrome, which manifests as, for example, dyspnea, hypoxemia (SpO2 < 92%), and a chest line 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 available.

(7) 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.

(8) 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, an abdominal ultrasound, CT, or magnetic resonance imaging (MRI) must be performed to determine if pancreatitis is present. If pancreatitis is confirmed, the medication regimen will need to be adjusted and the child 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.

(9) 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.

In tyrosine kinase inhibitor therapy in children with chronic granulocytic leukemia, the following is recommended: tyrosine kinase inhibitors may cause myelosuppression during the first 6 months of treatment. If the absolute neutrophil count is less than 0.75 x 109 /L or platelets are less than 50 x 109 /L, it is necessary to discontinue imatinib and restart treatment with the same dose of tyrosine kinase inhibitor after the absolute neutrophil count is greater than 1 x 109 /L.

Granulocyte colony-stimulating factor (commonly known as leukapheresis) may be used if the child's neutropenia persists for 2-4 weeks without recovery or if it is anticipated that the child may have a prolonged period of neutrophil deficiency. Platelets should be transfused if the platelet count is less than 20×109 /L. The indication for transfusion may be relaxed if the child has significant bleeding symptoms or manifestations of infection.

(10) Neutrophil deficiency with fever

Children with leukemia who have low neutrophils may develop granulocyte deficiency combined 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.

(11) Pneumocystis carinii infection

Because children with leukemia are immunocompromised and at risk for infection with Pneumocystis carinii, long-term administration of cotrimoxazole (SMZco) is usually recommended to prevent 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 until at least 72 hours after methotrexate administration, when the methotrexate concentration is less than 0.4 μmol/L. Cotrimoxazole needs to be discontinued 24 hours prior to the administration of high-dose methotrexate, until at least 72 hours after methotrexate administration, when the methotrexate concentration is less than 0.4 μmol/L.

(12) Anemia

Children with leukemia are prone to anemia. This can usually be relieved by transfusion of red blood cells, which is mandatory for hematocrits below 60 g/L.

(13) Graft-versus-host disease

In children who have undergone allogeneic hematopoietic stem cell transplants, immune cells in the child's body attack the graft and develop graft-versus-host disease (GVHD) due to differences in the genes of the donor and the child. Symptoms of GVHD focus on the skin, liver, and digestive tract and include redness, rashes, blisters, painful skin on the palms of the hands and feet, dry cracked or flaky skin, darkened, flaky, thickened, or even hardened skin, rashes (with a mossy appearance), jaundice (yellowing of the skin and/or the whites of the eyes), nausea, vomiting, abdominal pain, diarrhea, and more.

Usually, children need to take anti-rejection drugs to control graft-versus-host disease. Commonly used drugs include glucocorticoids, cyclosporine, sirolimus, mertiomaxolide, azathioprine, and tacrolimus. Since mild cases of graft-versus-host disease have some anti-leukemic effect and can help prevent leukemia recurrence, graft-versus-host disease is usually kept under control with medications in the appropriate range. The exact course of treatment will be determined by the doctor based on the type of disease, the type of transplant, donor selection, and post-transplant complications.

3. 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.

Acute myeloid leukemia has a certain relapse rate. Most relapses occur within 4 years of diagnosis. The vast majority of AML relapses are bone marrow relapses and central nervous system relapses are rare (3-6%).

Juvenile granulomonocytic leukemia is more prone to relapse, with a 30% relapse rate even after hematopoietic stem cell transplantation.

Follow-up & Review

Review and Follow-up

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

● Within 1 year of 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 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.

At the same time, the process of treating childhood leukemia can be very challenging for the child and requires attention to the child's mental health. The physical changes and pain caused by the disease and treatment, the lack of external peer contact due to isolation during the treatment, falling behind in school, and the 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.

3. Management of daily life

(1) Rest and exercise

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.

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.).

(2) 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, quinoa, etc.), as well as more grains and cereals and fruits and vegetables, and dairy products and nuts in moderation, in order to ensure the intake of other nutrients. At the same time should eat less refined rice and white flour, deep-processed snacks and processed meat tumors, 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.

(3) Living habits

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. Special considerations

(1) Precautions in case of low platelets

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 before starting the drug to 3-5 days after stopping it. 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) Maintaining case records

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

6. Prevention

Since the exact cause of childhood leukemia is not known, there are no appropriate methods of prevention. However, certain environmental factors and genetic disorders are known to be associated with an increased risk of childhood leukemia (see "Risk Factors"). Parents can therefore take care to avoid relevant environmental factors. If your child has a related genetic disorder, you should be aware of screening for childhood leukemia. In addition, parents can pay attention to the early symptoms of childhood leukemia, and seek early medical treatment once detected, so as to achieve early detection and early treatment, and strive for the best therapeutic effect.

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. Hematology Group of the Chinese Medical Association Pediatrics Branch, Editorial Committee of the Chinese Journal of Pediatrics. Recommendations for the diagnosis and treatment of acute myeloid leukemia in children. Chinese Journal of Pediatrics. 2006. 44(11): 877-878.

8. Liu Lanbo, Tang Jingyan. Advances related to the treatment of childhood acute myeloid leukemia. Journal of Clinical Pediatrics. 2012. 33(5): 487-491.

9. Hematology Branch of Chinese Medical Association. Chinese guidelines for diagnosis and treatment of chronic myeloid leukemia (2016 edition). Chinese Journal of Hematology. 2016. 37(8): 622-639.

10. Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®) (Health Professional Version)

11. Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®) (Patient Version)

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

http://www.nhc.gov.cn/ewebeditor/uploadfile/2018/10/20181016180416637.doc

13. chinese medical association. Clinical pathway for acute promyelocytic leukemia in children (2017 edition).

https://www.cma.org.cn/attachment/201765/1496631243573.rar

14. andolina JR, Neudorf SM, Corey SJ. how I treat childhood CML. blood. 2012. 119(8): 1821-1830. doi:10.1182/blood-2011- 10-380774

15. Wu Y, Wu RH. Advances in the treatment of pediatric chronic granulocytic leukemia. Chinese Journal of Pediatric Hematology and Oncology. 2014. 19(3): 154-157.

16.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.

17. Wan Z, Gao J. Pathogenesis and diagnostic criteria of juvenile granulomonocytic leukemia. Chinese Clinical Journal of Practical Pediatrics. 2013. 28(3): 229-230.

18. Gao J, Liu XL. Progress in the diagnosis and treatment of juvenile granulomonocytic leukemia. Chinese Journal of Maternal and Child Clinical Medicine. 2012. 8(5): 557-559.

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

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