Acute Myelogenous Leukemia (AML) in Children

Topic Name Introduction Pathophysiology Clinical Presentation Diagnosis Treatment Prognosis

Acute Myelogenous Leukemia in Children

Key Points:

• Acute Myelogenous Leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow
• It accounts for about 20% of childhood leukemias
• Most common in children under 2 years and teenagers
• Characterized by overproduction of immature myeloid cells
• Requires prompt diagnosis and intensive treatment

Acute Myelogenous Leukemia (AML) is a rapidly progressing malignancy of the blood and bone marrow, characterized by the overproduction of immature myeloid cells. In children, AML accounts for approximately 20% of all leukemias, making it the second most common type after Acute Lymphoblastic Leukemia (ALL). AML is most frequently diagnosed in children under 2 years of age and in teenagers, with a slight predominance in males. The disease results from genetic alterations in hematopoietic stem cells, leading to uncontrolled proliferation and impaired differentiation of myeloid progenitor cells.

Pathophysiology

AML arises from genetic mutations in hematopoietic stem cells or early myeloid progenitors. These mutations disrupt normal cellular differentiation and proliferation, leading to the accumulation of immature myeloid cells (blasts) in the bone marrow and peripheral blood. The pathophysiology of AML involves several key processes:

1. Genetic alterations: Common genetic abnormalities include chromosomal translocations (e.g., t(8;21), inv(16), t(15;17)), gene mutations (e.g., FLT3, NPM1, CEBPA), and epigenetic changes.
2. Clonal expansion: Mutated cells gain a proliferative advantage, leading to clonal expansion and displacement of normal hematopoietic cells.
3. Impaired differentiation: Leukemic blasts fail to differentiate into mature, functional blood cells, resulting in cytopenias.
4. Bone marrow failure: The accumulation of blasts in the bone marrow interferes with normal hematopoiesis, leading to anemia, thrombocytopenia, and neutropenia.
5. Extramedullary involvement: Leukemic cells may infiltrate other organs, such as the liver, spleen, lymph nodes, and central nervous system.

Understanding the pathophysiology of AML is crucial for developing targeted therapies and improving treatment outcomes in pediatric patients.

Clinical Presentation

The clinical presentation of AML in children can be variable and nonspecific. Symptoms typically develop over a short period, often weeks to months, and are related to bone marrow failure and organ infiltration. Common signs and symptoms include:

• Fatigue and weakness: Due to anemia
• Pallor: Resulting from decreased red blood cell count
• Fever: Often related to infections due to neutropenia
• Easy bruising or bleeding: Caused by thrombocytopenia
• Bone and joint pain: Due to expansion of leukemic cells in the bone marrow
• Hepatosplenomegaly: Enlargement of the liver and spleen due to leukemic infiltration
• Lymphadenopathy: Swollen lymph nodes
• Gum hypertrophy: Particularly in the monocytic subtypes of AML
• Skin manifestations: Including petechiae, ecchymoses, or chloromas (granulocytic sarcomas)
• Central nervous system symptoms: Such as headaches or cranial nerve palsies, if there is CNS involvement

It's important to note that these symptoms can mimic other childhood illnesses, making early diagnosis challenging. A high index of suspicion is necessary, especially in children presenting with persistent unexplained symptoms or abnormal blood counts.

Diagnosis

The diagnosis of AML in children involves a comprehensive approach, including clinical evaluation, laboratory tests, and specialized diagnostic procedures. The following steps are typically involved in the diagnostic process:

1. Complete Blood Count (CBC): Often reveals anemia, thrombocytopenia, and variable white blood cell counts. The presence of blasts in the peripheral blood smear is suggestive of AML.
2. Bone Marrow Aspiration and Biopsy: Essential for definitive diagnosis. The presence of ≥20% blasts in the bone marrow is diagnostic of AML.
3. Immunophenotyping: Flow cytometry is used to identify specific cell surface markers characteristic of AML blasts, helping to distinguish AML from ALL and determine AML subtypes.
4. Cytogenetic Analysis: Karyotyping and Fluorescence In Situ Hybridization (FISH) are used to detect chromosomal abnormalities, which are important for risk stratification and treatment planning.
5. Molecular Studies: Polymerase Chain Reaction (PCR) and Next-Generation Sequencing (NGS) are used to detect specific gene mutations (e.g., FLT3, NPM1, CEBPA) that influence prognosis and treatment decisions.
6. Lumbar Puncture: Performed to assess for central nervous system involvement.
7. Imaging Studies: May include chest X-ray, abdominal ultrasound, or CT/MRI scans to evaluate for extramedullary disease.

The World Health Organization (WHO) classification system is used to categorize AML into subtypes based on morphology, immunophenotype, and genetic features. This classification is crucial for determining the appropriate treatment approach and predicting outcomes.

Treatment

The treatment of AML in children is complex and intensive, typically involving a multidisciplinary approach. The main goals of treatment are to achieve remission and prevent relapse. The standard treatment approach includes:

1. Induction Therapy:
   • Aim: To achieve complete remission (CR) by eliminating leukemic cells
   • Typically consists of intensive chemotherapy regimens
   • Common drugs: cytarabine and an anthracycline (e.g., daunorubicin)
   • Duration: Usually 7-10 days
2. Consolidation Therapy:
   • Aim: To eliminate residual leukemic cells and prevent relapse
   • May involve multiple cycles of high-dose chemotherapy
   • Allogeneic hematopoietic stem cell transplantation (HSCT) is considered for high-risk patients
3. Central Nervous System (CNS) Prophylaxis:
   • Intrathecal chemotherapy to prevent CNS relapse
   • May include cranial radiation in some high-risk cases
4. Targeted Therapies:
   • FLT3 inhibitors (e.g., midostaurin) for FLT3-mutated AML
   • Gemtuzumab ozogamicin for CD33-positive AML
5. Supportive Care:
   • Management of treatment-related complications
   • Blood product transfusions
   • Antibiotic prophylaxis and treatment of infections
   • Nutritional support

Treatment protocols are often risk-adapted, with more intensive therapy for high-risk patients. Clinical trials investigating novel therapies, including immunotherapies and molecularly targeted agents, are ongoing and may offer additional options for some patients.

Prognosis

The prognosis for children with AML has improved significantly over the past few decades, but it remains challenging compared to other pediatric cancers. Several factors influence the prognosis:

• Cytogenetic and Molecular Features:
  • Favorable: t(8;21), inv(16), t(15;17), NPM1 mutation (without FLT3-ITD), biallelic CEBPA mutation
  • Unfavorable: Complex karyotype, monosomy 7, FLT3-ITD mutation, TP53 mutation
• Response to Initial Therapy: Early response to induction chemotherapy is a strong predictor of outcome
• Age: Infants and adolescents tend to have poorer outcomes compared to children aged 1-10 years
• Initial White Blood Cell Count: Higher counts at diagnosis are associated with poorer prognosis
• Presence of Extramedullary Disease: May affect treatment approach and outcome

Overall survival rates for pediatric AML have improved to approximately 60-70% in recent years. However, outcomes can vary significantly based on individual risk factors. Long-term follow-up is essential due to the risk of late effects from intensive chemotherapy and potential radiation therapy.

Future Directions:

Ongoing research focuses on improving outcomes while minimizing toxicity. Areas of active investigation include:

• Development of novel targeted therapies
• Optimization of risk stratification
• Immunotherapy approaches, including CAR T-cell therapy
• Strategies to reduce treatment-related morbidity and improve quality of life for survivors

Acute Myelogenous Leukemia in Children

1. What percentage of childhood leukemias are Acute Myelogenous Leukemia (AML)?
   Approximately 15-20%
2. Which AML subtype is most common in children with Down syndrome?
   Acute megakaryoblastic leukemia (AMKL or M7)
3. What is the characteristic genetic abnormality in acute promyelocytic leukemia (APL)?
   t(15;17) PML-RARA fusion
4. Which presenting symptom is more common in AML compared to ALL?
   Bleeding or bruising
5. What is the name of the chromosome abnormality associated with a favorable prognosis in AML?
   t(8;21)
6. Which drug is used for induction therapy in acute promyelocytic leukemia?
   All-trans retinoic acid (ATRA)
7. What is the typical number of cycles of intensive chemotherapy used in AML treatment?
   4-5 cycles
8. Which AML subtype is associated with Auer rods on peripheral blood smear?
   Acute promyelocytic leukemia (APL)
9. What is the overall cure rate for childhood AML?
   Approximately 60-70%
10. Which gene is commonly mutated in core-binding factor AML?
    KIT gene
11. What is the name of the life-threatening complication associated with APL treatment?
    Differentiation syndrome
12. Which chemotherapy drug is the backbone of AML induction therapy?
    Cytarabine
13. What is the most common site of extramedullary involvement in AML?
    Skin (leukemia cutis)
14. Which molecular marker is associated with poor prognosis in AML?
    FLT3-ITD mutation
15. What is the name of the AML subtype associated with inv(16) or t(16;16)?
    Acute myelomonocytic leukemia with eosinophilia
16. Which test is used to detect minimal residual disease in AML?
    Multiparameter flow cytometry or PCR
17. What is the role of hematopoietic stem cell transplantation in childhood AML?
    Indicated for high-risk patients in first remission or any patient in second remission
18. Which syndrome is associated with an increased risk of developing AML?
    Fanconi anemia
19. What is the name of the AML subtype characterized by monocytic differentiation?
    Acute monocytic leukemia (M5)
20. Which chromosome abnormality is associated with therapy-related AML?
    11q23 (MLL) rearrangements
21. What is the typical duration of maintenance therapy in childhood AML?
    Maintenance therapy is not routinely used in AML
22. Which organ is most commonly affected by granulocytic sarcoma in AML?
    Orbit (eye)
23. What is the name of the gene commonly mutated in AML with normal cytogenetics?
    NPM1
24. Which laboratory finding is characteristic of acute promyelocytic leukemia?
    Disseminated intravascular coagulation (DIC)
25. What is the name of the AML subtype associated with bilineage or biphenotypic features?
    Mixed phenotype acute leukemia (MPAL)
26. Which targeted therapy is used in FLT3-mutated AML?
    Midostaurin
27. What is the most common late effect of anthracycline therapy in AML survivors?
    Cardiomyopathy
28. Which imaging modality is used to detect CNS involvement in AML?
    MRI of the brain and spine
29. What is the name of the phenomenon where AML cells infiltrate the gums?
    Gingival hypertrophy
30. Which epigenetic modifier is commonly mutated in childhood AML?
    DNMT3A

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