Childhood acute lymphoblastic leukemia



Overview

Definition

Acute lymphoblastic leukemia (ALL) in children is a malignant disease of the hematopoietic system in which immature B or T cells overproliferate and infiltrate into various tissues and organs, leading to a series of clinical manifestations [1-2].

The onset of the disease is usually rapid, as short as a few days, and in some children, the onset of symptoms is insidious and may last for several months [1].

Staging

Morphologic typing (FAB typing)

According to the size of lymphoblastoid cells, nuclear chromatin, karyotype, nucleoli and other morphological characteristics, it can be divided into L1, L2 and L3 types [1-2,4].

L1 type is the most common, accounting for more than 80%; L3 type is the least common, accounting for less than 4%.

Immunologic typing

Immunologic typing is performed by detecting lymphocyte surface antigen markers and is generally divided into two major series, T and B [1-2,4].

T-lineage acute lymphoblastic leukemia (T-ALL)

Positive for T-lymphocyte markers such as CD1, CD3, CD5, CD8 and terminal deoxyribonucleic acid convertase (TdT).

It accounts for 10% to 15% of ALL in children.

B-lineage acute lymphoblastic leukemia (B-ALL)

Accounts for 80% to 90% of childhood ALL and can be divided into 3 subtypes.

Early pre-B-cell type: positive for HLA-DR, CD79a, CD19 and/or cytoplasmic CD22 (CyCD22), negative for SmIg, CyIg.

Pre-B-cellular type: positive for CyIg, negative for SmIg, positive for other B-lineage markers and HLA-DR.

Mature B-cell type: SmIg positive, CyIg negative, other B-lineage markers and HLA-DR positive.

ALL with myeloid markers

Morphologic features of lymphoid leukemia with predominantly lymphoid lineage-specific antigens but with secondary myeloid-specific antigenic markers such as CD13, CD33, and CD14.

Cytogenetic alterations typing

Abnormal chromosome number: e.g., hypodiploidy with ≤45 chromosomes, or hyperdiploidy with ≥47 chromosomes.

Abnormal karyotype: e.g., translocation of chromosomes 12 and 21, translocation of chromosomes 9 and 22, t(4;11)/MLL-AF4 fusion gene.

Molecular biology typing

Immunoglobulin (Ig) heavy chain gene rearrangements.

T lymphocyte receptor gene (TCR) fragment rearrangement.

ALL expression-related fusion genes, etc.

Clinical typing

According to age, peripheral blood leukocyte count, response to chemotherapy treatment, and fusion gene expression, ALL is categorized into standard-risk (SR-ALL), moderate-risk (MR-ALL), and high-risk (HR-ALL) groups [1-4].

Clinical typing affects the specific chemotherapy regimen.

Morbidity

ALL in children is an acute leukemia, which accounts for 90% to 95% of all childhood leukemias, and ALL accounts for about 2/3 of all childhood leukemias [1-2].

Etiology

Causes of the disease

The causative cause of acute lymphoblastic leukemia in children is not clear, and is generally believed to be related to viral infection, physical and chemical factors, and genetic factors.

Viral infection

Adult T-lymphoblastic leukemia can be caused by viruses, so it is hypothesized that childhood leukemia may also be associated with viral infections [1].

Physical and chemical factors

Ionizing radiation

The incidence of leukemia is 10 times higher in children treated with radiation for thymic hypertrophy than in normal children.

The incidence of neonatal leukemia in pregnant women irradiated to the abdomen is 17.4 times higher than in those who are not irradiated [2]. However, the radiation dose used for general imaging is very small and there are no cases of secondary leukemia [1].

Chemical substances

Benzene and its derivatives, chloramphenicol, prednisone, ethylenediamine, cytotoxic drugs (e.g., cyclophosphamide, azathioprine, etc.), and insecticides may be associated with the development of ALL.

Genetic factors

ALL is not a genetic disease, but the incidence of ALL in people with genetic defects, such as trisomy 21, congenital distal capillary dilated erythema, and congenital aplastic anemia with multiple malformations, is higher than that in children in general.

Pathogenesis

The pathogenesis of ALL is complex and may be related to proto-oncogene transformation, oncogene aberrations, inhibition of apoptosis and “second strike”.

Proto-oncogene transformation: Under the action of various oncogenic factors, the proto-oncogene changes and transforms into oncogene, leading to the occurrence of ALL.

Oncogene aberration: the genes related to the inhibition of cancer development are mutated and lose the function of cancer inhibition, and cancer cells can proliferate abnormally in the body.

Inhibition of apoptosis: high expression of genes that inhibit apoptosis and reduced expression of genes that promote apoptosis can cause the normal cell clearance process in the body to be affected.

“Second Strike”: children in the womb, after birth, respectively, changes in genetic material occur, ultimately leading to ALL.

Symptoms

Main Symptoms

Fever

Fever is the first symptom in 50% to 60% of children with childhood acute lymphoblastic leukemia and is relatively common [1-2,4].

Temperature changes during fever are poorly characterized; fever due to ALL itself resolves within 72 hours of induction therapy, and infection-related fever resolves after infection control.

Bleeding.

Bleeding is one of the common early symptoms, which can be specified as bleeding spots or petechiae on the skin and oral mucosa, rhinorrhea, and hematuria.

Anemia

Anemia manifestations such as fatigue, pallor, shortness of breath after activity, and drowsiness may also appear in the early stage and gradually worsen.

Leukemia cell infiltration

Lymph node enlargement: most children may have enlarged lymph nodes. If the lymph nodes are close to the body surface, they can be touched or directly observed; if the lymph nodes are in the body, take mediastinal lymph nodes as an example, infiltration may occur and symptoms such as choking and coughing and respiratory difficulties may appear.

Central nervous system symptoms: there may be no obvious manifestations in the early stage, and with gradual development, headache, vomiting, drowsiness, hemiparesis, convulsions, coma and other manifestations may appear.

Testicular leukemia: manifested as localized enlargement of testis, pain on touch, scrotal skin may appear reddish black.

Infiltration of eyes and structures related to visual function: it may present with hemorrhage in the eyes, loss of vision and other manifestations.

Bone and joint infiltration: it may manifest as bone and joint pain, which is the first symptom of about 1/4 children, and may occur in the long bones of the limbs, shoulder joints, knee joints, wrist joints, ankle joints and so on.

Other parts of the infiltration manifestations: skin infiltration may appear nodules, lumps and maculopapular rash, digestive system infiltration may appear lack of appetite, abdominal pain, diarrhea and so on.

Consultation

Department of Medicine

Hematology

Children are advised to seek medical attention when they develop symptoms such as bleeding, anemia, fever and bone pain.

Pediatric Internal Medicine

Children with the above symptoms may also visit the Department of Pediatric Internal Medicine.

Preparation for medical treatment

Preparing for your visit: registering, preparing your documents, and frequently asked questions.

Tips for seeking medical treatment

Parents should record the time, duration, and worsening of fever, bleeding, anemia, etc. for the doctor’s reference.

Preparation Checklist

Symptom list

Particular attention should be paid to the time of onset of symptoms, special manifestations, etc.

What are the abnormalities in the child? Are there any bleeding, fever, anemia, and other manifestations?

When was the abnormality detected? Under what circumstances does it occur?

Did the symptoms decrease or worsen? Under what circumstances do they appear?

Medical History Checklist

Does the child have a history of high-dose radiation exposure?

Was the mother exposed to ionizing radiation during pregnancy?

Has there been any exposure to benzene and its derivatives, chloramphenicol, prednisone, ethylenediamine, cytotoxic drugs (e.g., cyclophosphamide, nitrogen mustard, etc.), and chemicals such as pesticides?

Does the child have any genetic defects such as Trisomy 21?

Checklist

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

Laboratory tests: blood tests, blood smears, coagulation tests, genetic tests, blood biochemistry tests, bone marrow aspiration tests, etc.

Imaging tests: chest X-ray, echocardiogram, CT, magnetic resonance imaging (MRI), etc.

Diagnosis

Diagnosis is based on

Medical history

Children may have a history of infections, exposure to ionizing radiation, benzene and its derivatives, chloramphenicol, prednisone, ethylenediamine, cytotoxic drugs (e.g., cyclophosphamide, azathioprine, etc.), and pesticides prior to the onset of the disease.

Children may have genetic defects such as trisomy 21-trisomy.

The child’s mother may have been exposed to ionizing radiation during pregnancy.

Clinical manifestations

Symptoms.

Children may have fever, bleeding, anemia, and signs of leukemic cell infiltration.

Signs

Children may have fever, pallor/pallor, hemorrhagic spots or purpura on the skin and mucous membranes, hepatomegaly, splenomegaly, enlarged lymph nodes, and localized testicular tenderness.

Laboratory Tests

Blood count

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

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

Platelets are decreased to varying degrees.

Blood smear

Primitive and naïve lymphocytes are usually found and are diagnostically suggestive.

Coagulation Function Tests

Indicators related to coagulation function include prothrombin time (PT), activated partial thromboplastin time (APTT), prothrombin time (TT), fibrinogen (FIB), and D-dimer.

Prothrombin time may be prolonged, fibrinogen may decrease, D-dimer may increase, etc.

Genetic Testing

Genetic testing reveals relevant genetic and chromosomal abnormalities, which can provide cytogenetic and molecular biology basis for definitive diagnosis and staging.

Blood biochemistry test

Liver function, renal function, cardiac enzyme profile, lactate dehydrogenase, electrolytes, ferritin, etc. are necessary tests.

Patients with a high leukocyte load may have elevated blood uric acid and lactate dehydrogenase, and attention should be paid to the occurrence of tumor lysis syndrome.

Regular blood routine and blood biochemistry tests after the start of chemotherapy can be performed to understand the changes in white blood cell counts and liver and renal function.

Bone marrow aspiration examination

Bone marrow aspiration can be followed by biopsy, cytology and morphology examination, which are helpful in clarifying the diagnosis and evaluating the recurrence situation.

Immunologic examination

Immunologic tests can help to clarify immunologic typing.

Infectious disease screening

Including hepatitis virus, human immunodeficiency virus (HIV), syphilis antibody, EBV, etc.

It is mainly a pre-chemotherapy evaluation test.

Imaging

Chest X-ray or lung CT

Chest X-ray or lung CT is a routine examination after diagnosis.

It can find out whether there is lung infection and whether there is mediastinal lymph node enlargement.

Echocardiography

Echocardiography can help to understand the condition of the heart as chemotherapy drugs are cardiotoxic.

CT, Magnetic Resonance Imaging (MRI)

CT and MRI are mainly used to evaluate conditions such as occupancy, bleeding, inflammation and blood vessels.

The main site of examination is the head, which is used in the evaluation of children with CNS leukemia, as well as to rule out intracranial hemorrhage.

Diagnostic Criteria

All suspected diagnostic cases require morphologic-immunologic-cytogenetic-molecular biology (MICM) diagnosis and typing with one of the following criteria [1,3-4].

Bone marrow morphologic criteria: ≥20% primitive and naïve lymphocytes in the bone marrow.

If the percentage of naïve cells is less than 20%, there must be a molecular diagnosis specifying the presence of the acute lymphoblastic leukemia gene.

Differential diagnosis

Leukemia-like reaction

Similarities: Hepatomegaly, splenomegaly, thrombocytopenia may be present.

Differences: Leukemia-like reactions are usually secondary to certain infections. Bone marrow cell classifications are basically normal, platelets and hemoglobin are mostly normal, and white blood cell counts may return to normal after controlling the primary disease.

Infectious mononucleosis

Similarities: hepatomegaly, splenomegaly, enlarged lymph nodes, fever, and elevated white blood cells.

Differences: Infectious mononucleosis is caused by EBV infection, EBV antibody test is positive, EBV DNA replication is positive, hemoglobin and platelet counts are normal, and there is no leukemic changes in bone marrow examination, which can be used as the basis for differentiation.

Aplastic anemia

Similarities: Bleeding, anemia, fever, and pancytopenia may occur.

Differences: aplastic anemia without hepatomegaly, splenomegaly, lymph node enlargement, bone marrow hypoplasia, no naïve cell hyperplasia, can be used as a basis for differentiation.

Rheumatism and rheumatoid arthritis

Similarity: fever, joint pain, joint pain is wandering, multiple.

Differences: rheumatism and rheumatoid arthritis can be differentiated by the absence of leukemic changes in bone marrow examination.

Treatment

Treatment principle: chemotherapy is the main means of treatment for children with acute lymphoblastic leukemia, and according to the situation of children, chemotherapy, molecular targeted drug therapy, cellular immunotherapy, hematopoietic stem cell transplantation, radiotherapy, etc., supplemented by supportive therapy. The specific plan should be determined by the doctor according to the clinical typing of the child.

Treatment objective: to completely remove leukemia cells from the body and restore normal hematopoietic function.

Chemotherapy

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

Chemotherapy may include induction therapy, early intensive therapy, consolidation therapy after remission, delayed intensive therapy, maintenance therapy, and prevention and treatment of extramedullary leukemia [1,2,3,4]. Depending on the child’s condition, intermediate therapy (continuation of therapy) may be added after delayed intensive therapy [4].

The specific chemotherapy regimen needs to be determined by the physician based on the risk of the child’s condition, as well as the response to treatment.

Induction therapy

is the key to long-term disease-free survival in children.

Commonly used chemotherapeutic agents are cyclophosphamide (CTX), vincristine (VCR) or vinblastine (VDS), doxycycline hyclate (DNR), levodopa monocytogenes (L-asp).

Glucocorticoids such as prednisone (Pred) and dexamethasone (Dex) are also part of the treatment regimen in this phase.

Early intensive therapy

Commonly used chemotherapeutic agents include cyclophosphamide, cytarabine (Ara-C), 6-mercaptopurine (6-MP), and pegylated enzyme (PEG-ASP), with the exact course of treatment determined by the risk of the child’s condition.

Consolidation therapy after remission

Commonly used chemotherapeutic agents are high-dose methotrexate (HD-MTX) and tetrahydrofolate (CF).

Dexamethasone, oxaliplatin (CF), cytarabine, vitamin B6, isocyclophosphamide (IFO), pembrolizumab, Zoerythromycin, and etoposide (VP-16) may also be used in high-risk children.

Delayed intensive therapy

VDLD or VDLA regimen may be composed of vincristine or vinblastine, dexamethasone, levomentase, flexerodine or adriamycin.

Or choose cyclophosphamide, cytarabine, pembrolase, 6-mercaptopurine, etc. to form CAM or CAML regimen.

Intermediate treatment

Commonly used chemotherapeutic agents include 6-mercaptopurine, methotrexate, vincristine, dexamethasone, pembrolase and so on.

Maintenance phase treatment

There are 6-mercaptopurine combined with methotrexate, as well as the regimen of vincristine and dexamethasone on top of it.

Drug therapy

Molecularly targeted drug therapy

Molecularly targeted drugs include imatinib mesylate, rituximab, alemtuzumab, and eptalizumab, as well as FLT3 inhibitors, farnesyltransferase inhibitors, and γ-secretase inhibitors, which are mostly in the stage of clinical trials [1-4].

Symptomatic treatment drugs

ALL children are prone to infections and need to choose appropriate anti-infective drugs, such as antifungal drugs like amphotericin B, antiviral drugs like acyclovir, and antimicrobial drugs like cephalosporins.

Colony-stimulating factors (e.g., G-CSF) may be used if significant bone marrow suppression occurs during chemotherapy breaks.

Allopurinol or labrylase may be used to prevent and treat hyperuricemia.

Cellular immunotherapy

Chimeric antigen receptor T (CAR-T) cell therapy has specific killing efficacy and relatively manageable adverse effects [1,3-4].

CAR-T19, CAR-T20, and CAR-T22 target tumor cells expressing CD19, CD20, and CD22, respectively.

CAR-T therapy is a dynamic treatment and the potential long-term adverse effect is chronic B-cell deficiency.

Surgical treatment

Primarily hematopoietic stem cell transplantation (HSCT), HSCT combined with chemotherapy is the treatment of choice for the eradication of most ALL [1-2].

Certain indications need to be met, such as failure of induction remission therapy and high-risk type 1 complete remission (CR1) [2,4].

Radiotherapy.

Cranial radiation therapy can be used for the treatment of specific children with CNS leukemia, but its users are currently decreasing due to long-term side effects [1-2,4].

Supportive therapy

Children with anemia and bleeding may be given component blood transfusions, including red blood cells and platelet concentrates.

Chemotherapeutic drugs may have cardiotoxicity, hepatotoxicity, neurotoxicity, pulmonary toxicity, nephrotoxicity, etc., which need to be closely monitored, and appropriate therapeutic measures are taken once detected.

During chemotherapy, attention should be paid to replenish water, electrolytes and nutrition.

Bed rest should be given in case of fever and bleeding.

Prognosis

Cure

Acute lymphoblastic leukemia in children is no longer considered a lethal disease, and the 5-year survival rate can reach about 85% [1-2].

The 5-year survival rate refers to the percentage of patients who survive for more than 5 years after the tumor has been treated with a variety of comprehensive therapies. the probability of relapse after 5 years is very low, and it can generally be regarded as a clinical cure.

Prognostic factors

The following risk factors are associated with poor prognosis in childhood acute lymphoblastic leukemia [1-2,4].

Age <1 year at diagnosis or ≥10 years.

Peripheral blood leukocyte count ≥ 50 × 109/L at diagnosis.

Central nervous system leukemia or testicular leukemia had occurred at diagnosis.

Immunophenotype of T-ALL.

Unfavorable cytogenetic and molecular genetic features: hypodiploidy with a chromosome number <45 (or DNA index <0.8); t(9;22)(q34;q11.2)/BCR-ABL1; t(4;11)(q21;q23)/MLL-AF4 or other MLL gene rearrangement; t(1;19)(q23;p13)/E2A-PBX1 ( TCF3-PBX1), Ph-like, iAMP21, IKZF deletion, TCF3-HLF and MEF2D rearrangements.

Bone marrow not in remission (≥20% primitive and naïve lymphocytes) at the end of induced remission therapy, or bone marrow not in complete remission at the end of induced remission therapy with >5% primitive and naïve lymphocytes.

Microscopic residual disease (MRD) level: e.g., MRD ≥ 10-1 early in induction remission therapy (days 15-19), MRD ≥ 10-2 after induction remission therapy (days 33-45), or MRD ≥ 10-4 prior to the start of consolidation therapy (around week 12).

Hazards.

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

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

Daily

Daily Management

Dietary management

For children under 6 months old, the original feeding method can generally be continued.

For children over 6 months of age, it is necessary to choose light and easy-to-digest food, and eat small and frequent meals, so as to ensure nutrition and reduce the discomfort and other effects of anorexia, nausea, vomiting, etc. caused by chemotherapy.

Life management

During illness and chemotherapy, children are prone to infections. They need to pay attention to warmth and rest, reduce close contact with people, and reduce the risk of respiratory and oral infections by wearing masks, washing hands, and gargling with saline.

Children should pay attention to protection during activities to avoid trauma, and use soft-bristled toothbrushes to prevent bleeding.

Keep the living environment clean and hygienic, ventilate and disinfect appropriately, and change clothes in time.

After the condition improves, you can start with walking and other intense exercise and gradually resume normal exercise.

Psychological support

For children under 1 year old, parents need to strengthen soothing and reduce their crying.

For children over 1 year old, especially those of school age, parents need to provide guidance to reduce psychological pressure and avoid depression and other negative emotions; communicate with school teachers to help children return to school after treatment.

Follow-up review

Within two years after stopping the drug: routine blood test every 3 months or so, and comprehensive physical examination once a year, focusing on lymph nodes, liver, spleen and testicles.

After the third year of drug cessation: routine blood tests every 6 months or so, and comprehensive physical examination once a year.

Follow up anytime symptoms appear.

Prevention

There is no clear-cut method of prevention. Avoiding exposure to suspected environmental factors and adhering to a good lifestyle will help maintain good health.

Avoid exposure to ionizing radiation (e.g. X-rays, etc.) and mothers should also avoid exposure during pregnancy.

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

Avoid pediatric exposure to benzene and its derivatives, chloramphenicol, prednisone, ethylenediamine, cytotoxic drugs (e.g., cyclophosphamide, nitrogen mustard, etc.), and insecticides.

Those with a history of genetic disease should have good genetic counseling.

Exercise moderately, pay attention to balanced nutrition, improve physical fitness, and avoid low immunity due to malnutrition.