Childhood acute myeloid leukemia

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OVERVIEW

  • A malignant clonal disease of myeloid hematopoietic stem or progenitor cells that occurs in childhood.
  • Symptoms include fever, malaise, enlarged lymph nodes, mouth ulcers, anemia, and bleeding.
  • The cause of the disease is not clear, but may be related to gene mutation, ionizing radiation, exposure to carcinogenic substances, etc.
  • General supportive therapy, systemic chemotherapy and hematopoietic stem cell transplantation are the mainstays of treatment.

    • Definition

    Acute myeloid leukemia (AML) in children is a heterogeneous group of disorders that occur in childhood and are clonal proliferative disorders of bone marrow-derived nonlymphocytic hematopoietic cells.

    Typing and Classification

    FAB typing

    Typing Chinese nameM0 acute myeloid leukemia microdifferentiation typeM0Acute myeloid leukemia minimally differentiated typeM1 acute myeloid leukemia undifferentiatedM1Acute granulocytic leukemia undifferentiatedM2 acute myeloid leukemia partially differentiatedM2

    Acute granulocytic leukemia partially differentiated

    M3 Acute promyelocytic leukemia

  • M3
  • Acute promyelocytic leukemia
  • M4 acute granulocytic-monocytic leukemia
  • M4
  • Acute granulocytic-monocytic leukemia
  • M5 acute monocytic leukemia

    • M5

    Acute monocytic leukemia

    M6 Acute red leukemia

  • M6
  • Acute red leukemia
  • M7 Acute megakaryocytic leukemia

    • M7

    Acute megakaryocytic leukemia

    MICM typing

    The World Health Organization (WHO) uses primitive cells ≥20% as a diagnostic criterion for acute leukemia. Incorporation of cytomorphologic-immunologic-cytogenetic-molecular biological features of AML resulted in the MICM typing.The 2016 revised WHO classification on AML is as follows:

    Acute myeloid leukemia with reproducible genetic abnormalities.

  • Acute myeloid leukemia with myelodysplasia-related lesions.
  • Treatment-related myeloid tumors.
  • Acute myeloid leukemia, nonspecific.
  • Myeloid sarcoma.
  • Myelodysplasia-associated Down syndrome.
    • The typology can be subdivided into a number of subtypes, which are more complex, and it is recommended to consult the physician for the specific typology of the child.

    Immunologic typing

    A number of immunologic markers associated with childhood AML have been identified. However, the specificity of the following immunologic markers is limited, and they can only be used as a complementary means of subtyping AML on the basis of morphologic typing.

  • Myeloid: CD33, CD13, CD14, CD15, CD16, CD11, CD45 and MPO.
  • Red lineage: CD71 and blood group glycoproteins, etc.

    • Megakaryotic lineage: CD41, CD42 and CD66, etc.

    Clinical risk typing

    Low risk

    Acute promyelocytic autogenous hemorrhagic disease (M3), M2b, M4Eo and other children who carry an inversion of chromosome 16 [2].

    Intermediate-risk type

    Those who do not have low-risk conditions but also do not have the following risk factors:

  • Children ≤ 1 year of age at diagnosis.
  • Leukocytes ≥ 100 × 109/L at diagnosis.

    • Chromosomal karyotype of -7.

  • Myelodysplastic syndrome transformed into acute myeloid leukemia.
  • Failure to remit with 1 course of standard induction regimen.

    • High-risk

    Presence of any of the above 5 risk factors.

    Incidence

    The global incidence of AML is about 2.25/100,000 and the incidence of AML in China is about 1.62/100,000 population, and the incidence increases with age [5].

    AML in children accounts for about 20% of childhood acute leukemias. Among them, AML types M2, M4 and M5 are the most common [5].

  • Etiology
  • Causes of the disease
  • The specific etiology of childhood AML is unknown and may be related to the following factors.
  • Genetic mutations

    • The disease is often associated with chromosomal and genetic abnormalities (e.g., ras, myc, and other gene mutations), and many children are born with the relevant abnormal genes.

    Infections

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

    In the Burkitt’s lymphoma/leukemia endemic areas of equatorial Africa, EBV (Epstein-Barr Virus) infection has been shown to be associated with leukemia causation.

    Radiation Factors

  • Ionizing radiation, such as X-rays and gamma rays, has a leukemogenic effect, with a higher incidence in areas exposed to higher doses of radiation.
  • The probability of secondary leukemia is significantly higher than that of the general population in children who need radiation therapy for malignant tumors and certain benign diseases.
  • Exposure to carcinogenic factors
  • Substances such as benzene and its derivatives and formaldehyde are also associated with the development of leukemia.

    • Alcohol

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

    Genetic factors

  • Although leukemia is not a hereditary disease, there is a 25% chance that one of the monozygotic twins will develop leukemia within 6 years of age and the other will develop leukemia.
  • The incidence of leukemia in first-degree relatives of children with leukemia is three times higher than in the general population.
  • Children and family members with some congenital or genetic disorders such as Down syndrome and Fanconi anemia are susceptible to AML.
  • The incidence of acute leukemia in children with Down syndrome is 10 times higher than in the normal population, and the incidence of AML-M7 type is 500 times higher than in the normal population.
  • Other Blood Disorders

    • Certain blood disorders may eventually develop into leukemia, such as myelodysplastic syndromes (MDS), aplastic anemia, and paroxysmal sleep hemoglobinuria (PNH).

    Symptoms

    Main Symptoms

    Fever

    It is the more common clinical manifestation in children with AML. Most of the children have low-grade fever, which can be as high as 39～40℃ or above, accompanied by chills and sweating.
  • Although AML itself can be febrile, high fever often indicates secondary infection.
  • Infections can occur at various sites, with respiratory infections such as tonsillitis, pneumonia, and bronchitis being the most common.
  • The source of infection may be almost any pathogen, and co-infections are more likely to occur.
    • Anemia

    This is mainly characterized by pallor of the face, nails and conjunctiva of the eyelids, weakness, depression, shortness of breath and lethargy.

    Bleeding
  • Bleeding can occur in all parts of the body, with bleeding from the skin and mucous membranes (nose, mouth and gums) being the most common, bleeding from the fundus of the eye and the bulbar conjunctiva being more likely to occur, and hematuria being less common.
  • Severe gastrointestinal, respiratory, and intracranial hemorrhage, although uncommon, is often the cause of death.
    • Type M3 is often combined with severe hemorrhage and disseminated intravascular coagulation (DIC).
  • Bleeding from the fundus of the eye can result in visual impairment, and in severe cases, widespread bleeding throughout the body occurs because of concomitant coagulation abnormalities.
  • Intracranial hemorrhage is associated with headache, vomiting, asymmetrical pupil size, and even coma and death.
  • Infiltration symptoms
    • Generally, it is a series of manifestations of proliferative infiltration of leukemia cells.

    Enlargement of liver, spleen and lymph nodes

    Generally there are no obvious symptoms. Some children may have symptoms of enlarged liver, spleen and lymph nodes, but they are mostly found during physical examination.

    Bones and joints

    Localized pressure and pain in the lower part of the sternum is a common sign of leukemia and helps in the diagnosis.

    In children, pain in the joints and bones may be persistent and increase in intensity in paroxysms.

    Bone marrow necrosis can cause severe pain in the bones.

    Eye

    In some children, granulocytic sarcoma, or green tumor, may be present, often involving the periosteum, most commonly in the orbital region, causing protruding eyes, double vision, or blindness.

    Oral cavity and skin

    Gums are hyperplastic, swollen, ulcerated, and in severe cases may have surface breakdown and bleeding.

  • The skin may appear as a blue-gray maculopapular rash with localized skin elevation, hardening, and purplish-blue nodules.
  • Central Nervous System

    • It is the most common site of extramedullary infiltration in leukemia.

    Most chemotherapeutic drugs are difficult to pass the blood-brain barrier and cannot effectively kill leukemia cells hidden in the central nervous system, thus causing central nervous system leukemia.

    In mild cases, it manifests as headache and dizziness, while in severe cases, there is vomiting, neck stiffness, and even convulsions and coma.

  • Testicular
  • Mostly painless enlargement of one testicle without enlargement on the other side.
  • Consultation
  • Department of Medicine
    • Pediatrics
  • When symptoms such as fever, anemia, bleeding, protruding eyes, abnormal growth of gums, bone pain, enlarged lymph nodes, and malaise occur, it is recommended to consult a doctor promptly.
  • Hematology
  • Children may also consult the Department of Hematology if they experience any of the above symptoms.
  • Preparation for medical treatment
  • Preparation for medical consultation: registration, preparation of documents, frequently asked questions
  • Tips for the doctor
    • It is recommended to dress the child in clothes that are easy to put on and take off to facilitate the doctor’s physical examination.

    Parents can keep a detailed record of the symptoms and signs that the child has experienced for the doctor’s reference in diagnosis.

  • Preparation List
  • Symptom list
  • Pay particular attention to the time of onset of symptoms, special manifestations, etc.

    • Has the child had a fever recently? What is the highest temperature?

    Does the child have nosebleeds, bleeding gums, etc.?

    Is the child pale, weak, depressed, short of breath, drowsy, etc.?

    Has there been a recent change in weight? How is the appetite?

  • List of medical history
  • Any history of viral infections?
  • Any history of radiation therapy?
  • Have you been exposed to carcinogens such as benzene and formaldehyde? Or has the child’s permanent home been recently renovated?

    • Did the mother drink alcohol during pregnancy?

    Is there a family history of leukemia?

    Are there any diseases such as Down syndrome, Fanconi anemia, aplastic anemia, etc.? Are there any drug or food allergies?

    Checklist
  • Test results from the last 6 months, which can be brought to the doctor’s office
  • Laboratory tests: blood test, blood biochemistry, coagulation function, etc.

    • Imaging tests: ultrasound, CT, magnetic resonance imaging (MRI)

    Specialized tests: bone marrow test, chromosome karyotype test, etc.
  • Diagnosis
  • Diagnosis is based on
    • Medical history
  • Children may have a history of the following medical conditions:
  • History of hematologic disorders such as myelodysplastic syndromes, aplastic anemia, etc.
    • A history or family history of congenital disorders such as Down syndrome, Fanconi anemia, etc.
  • Having undergone tumor radiotherapy and chemotherapy, etc.
  • Long-term exposure to radiation, benzene, formaldehyde, etc.

    • Clinical manifestations

    Symptoms

    Common symptoms are fever, anemia, bleeding, bone pain, hepatomegaly, splenomegaly, enlarged lymph nodes, and malaise.

    Physical signs

    Pallor of the skin and mucous membranes can be seen.

  • In children with infiltration, lymph node and liver and spleen enlargement may be seen.
  • Laboratory Tests
  • Blood tests
  • To help clarify the presence of infection, anemia, thrombocytopenia, etc.

    • Decreased hemoglobin and thrombocytopenia may be seen, and the white blood cell count may be elevated in infection.

  • Blood biochemistry
  • Check the biochemical indicators in the blood to clarify the presence of abnormalities, such as liver and kidney function, electrolytes, uric acid and lactate dehydrogenase.

    • Blood uric acid concentration may increase during chemotherapy.

    Coagulation

  • Leukocytosis in children with acute promyelocytic leukemia (acute myeloid leukemia M3) type can be complicated by DIC (disseminated intravascular coagulation) and coagulation abnormalities.
  • Acute myeloid leukemia M4 and M5 are also prone to bleeding complications.

    • Bone marrow examination

    The degree of bone marrow hyperplasia is mostly active and markedly active, with increased numbers of primitive and early juvenile granulocytes (increased numbers of primitive and naïve monocytes), as characterized morphologically by the FAB typing criteria.

  • Histochemical staining of cells
  • Different subtypes of acute myeloid leukemia have different chemical staining characteristics, so chemical staining is very important for the diagnosis of this disease.
  • Karyotyping

    • Chromosomal karyotyping is of great value in determining the diagnosis and prognosis of acute myeloid leukemia.

  • Chromosomal abnormalities are present in 79% to 85% of children with AML, and the detection rate of karyotype abnormalities is as high as 90% using high-resolution techniques.
  • Chromosomal abnormalities in acute myeloid leukemia are predominantly structural aberrations, with about half of the children presenting with only isolated karyotypic abnormalities and the remainder with additional karyotypic abnormalities.
  • T(8;21) (q22;q22), t(15; 17) (q22; q11-12), inv(16) (p13;q22), and t(16;16) (p13;qll) are associated with a favorable prognosis.

    • Immunophenotyping

  • Immunophenotyping can indicate the differentiation series and stage of differentiation of leukemia cells, with a discrimination rate of up to 98%.
  • Therefore, immunophenotyping is very important for certain acute myeloid leukemias that are difficult to be typed by morphology alone, such as MO, Ml, M7, etc. However, immunophenotyping is not useful for acute myeloid leukemias. However, immunophenotyping has little prognostic value in AML.

    • Imaging examination

    X-ray radiography, CT and MRI are performed in those with extramedullary infiltration, and abnormal images can be found.

  • Chest X-ray, abdominal ultrasound: can help to understand the cardiac function and the presence or absence of involvement of abdominal organs.
  • CT and MRI: to evaluate the head or chest and abdomen for localization, bleeding or inflammation.

    • Differential Diagnosis

  • Infectious mononucleosis
  • Infectious mononucleosis is an acute proliferative disease of the monocyte-macrophage system caused by EBV infection, and the course of the disease is often self-limiting.

    • It is characterized by irregular fever, pharyngitis, enlargement of liver, spleen, lymph nodes, etc. The total number of leukocytes in the peripheral blood increases to different degrees, with an increase in heterophilic lymphocytes as the main cause.

  • Serum heterophilic agglutination test and EBV antibody and EBV DNA viral quantification may be positive. The above clinical manifestations and laboratory tests can be differentiated from acute myeloid leukemia.
  • Leukemia-like reaction

    • Leukemia-like reaction is commonly caused by infection, poisoning, bone marrow metastasis of malignant tumors, acute blood loss, hemolysis and other reasons to stimulate the hematopoietic tissues of the body, resulting in a kind of hematological changes similar to leukemia.

    For example, the total number of peripheral blood leukocytes is increased, naïve cells can be seen in the classification, and some children may be accompanied by anemia and thrombocytopenia, but it is not a true leukemia.

    Disease differentiation is facilitated by history and laboratory tests.

  • Treatment
  • Aim of treatment: to relieve children’s symptoms, improve children’s quality of life and prolong survival time.

    • Treatment principle: Prognostic risk stratification based on children’s MICM typing results and clinical characteristics, select and design the most complete and systematic treatment program according to the wishes and financial ability of the affected party.

    Supportive treatment

    Nutritional support

    Leukemia is a serious consumptive disease, especially when chemotherapeutic drugs cause mucosal damage and dysfunction in the digestive tract of children.

    Attention should be paid to nutritional supplementation, maintaining water and electrolyte balance, giving high-protein, high-calorie, easy-to-digest food, and supplementing nutrition via vein when necessary.

  • Prevention of infection
  • Children with leukemia are often accompanied by granulocytopenia or lack of granulocytes, and are prone to infections.

    • Adhere to oral, perineal and skin cleaning care, and carry out strict bedside isolation.

    Component blood transfusion support

    Severe anemia may cause severe hypoxia, weakness and dizziness, chest tightness and shortness of breath after activity, and even fainting.

    Oxygen intake and transfusion of concentrated red blood cells can be administered.

    Blood product transfusion treatment

    Children with abnormal coagulation function, especially children with acute promyelocytic leukemia, can be transfused with blood products such as platelets, fibrinogen, plasminogen complex, plasma and other blood products to supplement the required coagulation factors and improve the bleeding symptoms.

    Prevention of hyperuricemia nephropathy

    Children with leukemia should drink more water during chemotherapy and alkalinize the urine appropriately.

    When children develop oliguria, anuria and renal insufficiency, they should be treated as acute renal failure.

  • Correction of blood clotting disorder
  • Coagulation disorder can be caused by thrombocytopenia or combined infection, and diffuse intravascular coagulation (DIC) can be complicated in serious cases, especially in acute promyelocytic leukemia, coagulation time should be closely monitored, and coagulation factors should be supplemented appropriately.
  • Chemotherapy
  • Chemotherapy is the main treatment for childhood acute myeloid leukemia, which is mainly divided into the following stages.

    • Induction of remission therapy

    For intermediate-risk and low-risk myeloid leukemia except childhood promyelocytic leukemia, the DAE regimen (Zoerythromycin + cytarabine + etoposide), or the HAD regimen (hypertriglyceride + cytarabine + etoposide) are currently preferred.

  • The IA regimen (nortriptyline + cytarabine + cytarabine) or the DAE regimen is preferred for children with high-risk myeloid leukemia.
  • Consolidation therapy

    • Children who achieve complete remission with induction chemotherapy are treated with another course of the original regimen.

    Post-radical remission treatment

    After completion of consolidation chemotherapy, chemotherapy or allogeneic hematopoietic stem cell transplantation may be an option.

    Myelosuppressive maintenance therapy

    Restricted to those who cannot undergo the above post-radical remission therapy due to economic conditions. 3 regimens of DA regimen, HA regimen, EA regimen, CE regimen in alternation.

    Prophylactic treatment for CNS leukemia

    Acute myeloid leukemia subtypes other than acute promyelocytic leukemia require intrathecal injection for prophylaxis or treatment of CNS leukemia.

    Hematopoietic stem cell transplantation therapy

    Hematopoietic stem cell transplantation, or stem cell transplantation for short, refers to the injection of hematopoietic cells from a normal donor or autologous source into a child to re-establish normal hematopoietic and immune functions after the child has been pre-treated with systemic irradiation, chemotherapy and immunosuppression.

    According to whether the hematopoietic cells are taken from a healthy donor or from the child itself, it can be categorized into allogeneic hematopoietic stem cell transplantation and autologous hematopoietic stem cell transplantation.

  • Hematopoietic stem cell transplantation is required for children with high-risk or relapsed refractory AML (unless acute promyelocytic leukemia).
  • For children with low-risk and intermediate-risk forms, chemotherapy is generally the preferred treatment, and allogeneic HSCT is not superior to chemotherapy in terms of long-term outcome.
  • Cutting-edge treatments
  • Nucleoside analogs

    • Cladribine and fludarabine, two of the first arabinosyl derivatives to be developed, differ from cytarabine in that the latter reduces the pool of deoxyribonucleotides by inhibiting DNA polymerase and nucleotide reductase, which in turn inhibits cell proliferation.

    In children with relapsed acute myeloid leukemia, cladribine has been shown to be more effective in combination with desmethylzoxazolidine.

    FLT3 inhibitors

    FLT3 inhibitors are developed to target mutations in the FLT3 gene present in leukemia cells. Although the novel FLT3 inhibitor AC220 has achieved better efficacy in single-agent trials, some scholars have suggested that it can exert its anti-leukemia effect to a greater extent when combined with conventional chemotherapeutic agents.

    Immunomodulation therapy

  • CD33 antigen is expressed on the surface of 90% of acute myeloid leukemia cells, and the successful drug developed to target this is Gituzumab (GO), which is a drug that couples an antitumor antibiotic (khakimycin) with a recombinant humanized IgG4 antibody targeting the CD33 antigen, which causes DNA double-stranded breaks and cell death to achieve therapeutic effects.
  • Prognosis
  • Cure.

    • In recent years the ongoing exploration of the cytogenetic and molecular aspects of the disease has provided more individualized treatment options for children with AML, with event-free survival (EFS) rates of more than 50% and overall survival (OS) rates of more than 60% in children with AML.

  • Prognostic Factors
  • Prognostic factors are factors that have an impact on a child’s overall survival and quality of life.
  • Poor prognostic factors
  • Certain karyotypic abnormalities such as -5, -7 or the presence of complex karyotypes, as well as the presence of aberrant gene mutations such as FLT3-ITD.MLL-PTD and EVI-1 [2].

    • Bone marrow leukemia cells ≥ 0.15 at the end of induction therapy [2].

  • Bone marrow leukemia cells > 0.05 on day 15 of induction therapy [2].
  • The prognosis is worse for age of onset <1 year or >10 years [2].
  • Factors with a better prognosis

    • Presence of chromosomal heterozygosity for a given birth karyotype, e.g., presence of t(8;21) in M2b, presence of t(15;17) in M3, children carrying an inversion of chromosome 16, etc. [2].

  • Daily
  • Daily management

    • Dietary management

  • Reasonable arrangement of diet, so as to achieve balanced nutrition and rich variety.
  • Intake of vitamin-rich fresh fruits, vegetables, meat, eggs and milk can be increased to replenish vitamins and proteins needed by the body and promote recovery.

    • Eat less high-fat and high-cholesterol food such as fatty meat, fried chicken and cakes.

    Life management

  • The living room should be kept with fresh air and sufficient sunshine, and the temperature and humidity should be suitable; children should be given more or less clothes in time according to the change of temperature, and should not go to crowded places as much as possible.
  • Children can engage in activities that they like, are within their ability, and are suitable for their condition, and avoid activities that are dangerous and easy to bump into.
  • Children with severe anemia and thrombocytopenia are advised to stay in bed to avoid bumping, bleeding and infection.
  • Encourage children to drink plenty of water and keep their mouths clean.
  • Psychological support
  • Relieve mental stress and provide more care, guidance, understanding and encouragement to children with activity intolerance.
  • Parents should give children adequate companionship, create a warm family atmosphere and encourage children to socialize within their abilities.
  • Parents need to guide their children to face the disease with a positive and optimistic mindset, accept their physical changes, and maintain contact and play with classmates and friends appropriately on the premise of ensuring safety during the treatment process.