Chronic Myelogenous Leukemia in Children

Topic Name Introduction Epidemiology Pathophysiology Clinical Presentation Diagnosis Treatment Prognosis

Chronic Myelogenous Leukemia in Children

Key Points:

• Rare in children, accounting for 2-3% of pediatric leukemias
• Characterized by the presence of the Philadelphia chromosome (BCR-ABL1 fusion gene)
• Three phases: chronic, accelerated, and blast crisis
• Tyrosine kinase inhibitors (TKIs) are the primary treatment
• Allogeneic hematopoietic stem cell transplantation may be considered in some cases

Chronic Myelogenous Leukemia (CML) is a myeloproliferative neoplasm characterized by the uncontrolled production of mature and maturing granulocytes. It is rare in children, accounting for only 2-3% of all pediatric leukemias. CML is defined by the presence of the Philadelphia chromosome, resulting from a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11), which leads to the formation of the BCR-ABL1 fusion gene.

Epidemiology

CML is uncommon in children, with an annual incidence of approximately 1 case per million children. The median age at diagnosis in pediatric patients is around 11-12 years, with a slight male predominance. Unlike adult CML, which shows a steady increase in incidence with age, pediatric CML has a more uniform distribution across childhood and adolescence.

Risk factors for pediatric CML are not well-established, but exposure to high-dose ionizing radiation has been associated with an increased risk. There is no clear hereditary predisposition to CML in children.

Pathophysiology

The hallmark of CML is the presence of the BCR-ABL1 fusion gene, which results from the Philadelphia chromosome translocation. This fusion gene produces a constitutively active tyrosine kinase that leads to dysregulated cell proliferation and survival of myeloid progenitor cells.

CML progresses through three phases:

1. Chronic Phase: Characterized by an expansion of mature granulocytes and their precursors. Most patients are diagnosed in this phase.
2. Accelerated Phase: Marked by an increase in immature blast cells (10-19% of blood or bone marrow cells) and additional cytogenetic abnormalities.
3. Blast Crisis: Resembles acute leukemia, with ≥20% blasts in the blood or bone marrow. It can be myeloid or lymphoid in nature.

Clinical Presentation

The clinical presentation of CML in children can be variable. Many patients are asymptomatic at diagnosis, with the disease detected incidentally on routine blood tests. When symptoms are present, they may include:

• Fatigue
• Weight loss
• Abdominal discomfort or early satiety due to splenomegaly
• Fever
• Night sweats
• Bone pain

Physical examination may reveal:

• Splenomegaly (present in about 50% of pediatric cases)
• Hepatomegaly
• Lymphadenopathy (rare in chronic phase)

Diagnosis

The diagnosis of CML in children involves a combination of clinical, laboratory, and genetic studies:

1. Complete Blood Count (CBC): Typically shows leukocytosis with a left shift, often with basophilia and eosinophilia. Platelet count may be normal or elevated.
2. Peripheral Blood Smear: Reveals a spectrum of myeloid cells at various stages of maturation.
3. Bone Marrow Aspiration and Biopsy: Shows hypercellularity with myeloid hyperplasia.
4. Cytogenetic Analysis: Detects the Philadelphia chromosome t(9;22)(q34;q11).
5. Fluorescence In Situ Hybridization (FISH): Identifies the BCR-ABL1 fusion.
6. Reverse Transcriptase Polymerase Chain Reaction (RT-PCR): Quantifies BCR-ABL1 transcript levels, essential for monitoring treatment response.

The diagnosis is confirmed by the presence of the Philadelphia chromosome or the BCR-ABL1 fusion gene, along with compatible clinical and laboratory findings.

Treatment

The treatment of CML in children has been revolutionized by the introduction of tyrosine kinase inhibitors (TKIs). The current standard of care includes:

1. Tyrosine Kinase Inhibitors (TKIs):
   • Imatinib is the first-line treatment for most pediatric CML patients.
   • Second-generation TKIs (dasatinib, nilotinib) are used in case of resistance or intolerance to imatinib.
   • Dose adjustments are necessary for pediatric patients based on body surface area.
2. Monitoring:
   • Regular monitoring of BCR-ABL1 transcript levels by RT-PCR is crucial to assess treatment response.
   • Cytogenetic analysis is performed periodically to evaluate for clonal evolution.
3. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT):
   • Considered for patients who fail multiple TKIs or progress to advanced phases.
   • The role of HSCT in pediatric CML has diminished in the TKI era but remains an important option for some patients.
4. Supportive Care:
   • Management of TKI side effects, which can include growth retardation and bone metabolism abnormalities in children.
   • Psychosocial support for patients and families dealing with a chronic illness.

Treatment goals include achieving complete hematologic, cytogenetic, and molecular responses. The duration of TKI therapy in children who achieve deep molecular responses is an area of ongoing research.

Prognosis

The prognosis for children with CML has improved dramatically with the introduction of TKIs. Factors influencing prognosis include:

• Phase of disease at diagnosis (chronic phase has the best prognosis)
• Response to initial TKI therapy
• Development of TKI resistance
• Presence of additional cytogenetic abnormalities

With current treatments, the 5-year overall survival rate for children with CML in chronic phase exceeds 90%. However, long-term follow-up is essential to monitor for late effects of TKI therapy and potential disease progression.

Challenges specific to pediatric CML include the impact of long-term TKI therapy on growth and development, fertility concerns, and the psychosocial impact of managing a chronic disease throughout childhood and adolescence.

Chronic Myelogenous Leukemia in Children

1. What is the full name of CML?
   Chronic Myelogenous Leukemia
2. What percentage of pediatric leukemias does CML account for?
   Approximately 2-3%
3. What is the characteristic genetic abnormality in CML?
   Philadelphia chromosome (BCR-ABL1 fusion)
4. Which chromosomes are involved in the Philadelphia chromosome translocation?
   Chromosomes 9 and 22
5. What protein is produced by the BCR-ABL1 fusion gene?
   A constitutively active tyrosine kinase
6. What are the three phases of CML?
   Chronic phase, accelerated phase, and blast crisis
7. In which phase are most pediatric CML cases diagnosed?
   Chronic phase
8. What is the most common presenting symptom of CML in children?
   Fatigue
9. What physical finding is common in pediatric CML at diagnosis?
   Splenomegaly
10. What is the typical white blood cell count at diagnosis in pediatric CML?
    Often >100,000/μL
11. What cell type is predominantly elevated in the peripheral blood in CML?
    Neutrophils and their precursors
12. What is the gold standard for CML diagnosis?
    Detection of BCR-ABL1 fusion by cytogenetics or molecular testing
13. What class of drugs revolutionized CML treatment?
    Tyrosine kinase inhibitors (TKIs)
14. Which TKI is typically used as first-line treatment in pediatric CML?
    Imatinib
15. What is the typical starting dose of imatinib for children with CML?
    340 mg/m²/day
16. What is the goal of CML treatment with TKIs?
    Achievement of deep molecular response
17. How is treatment response typically monitored in CML?
    Quantitative PCR for BCR-ABL1 transcripts
18. What is the definition of major molecular response (MMR) in CML?
    BCR-ABL1 transcripts ≤0.1% on the International Scale
19. What is the role of hematopoietic stem cell transplantation in pediatric CML?
    Reserved for TKI-resistant cases or advanced disease
20. What is a common side effect of TKI therapy in children?
    Growth impairment
21. What is the approximate 5-year overall survival rate for children with CML treated with TKIs?
    >90%
22. What is the recommended frequency of BCR-ABL1 monitoring during the first year of TKI therapy?
    Every 3 months
23. What is the definition of complete cytogenetic response in CML?
    No detectable Philadelphia chromosome-positive cells in bone marrow
24. What is the typical duration of TKI therapy in pediatric CML?
    Indefinite; lifelong therapy is often required
25. What is the role of second-generation TKIs (e.g., dasatinib, nilotinib) in pediatric CML?
    Used for imatinib resistance or intolerance
26. What is the approximate median age at diagnosis for pediatric CML?
    11-12 years old
27. What is the male to female ratio in pediatric CML incidence?
    Approximately 1.2:1 (slight male predominance)
28. What percentage of pediatric CML cases progress to blast crisis?
    About 10-15%
29. What is the definition of accelerated phase in CML?
    10-19% blasts in blood or bone marrow
30. What is the role of interferon-alpha in current pediatric CML treatment?
    Limited; mainly used in special circumstances (e.g., pregnancy)

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