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How I treat ALL in Down's syndrome: pathobiology and management

Shai Izraeli1, Ajay Vora, C Michel Zwaan

  • 1Department of Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Tel-Hashomer, Ramat Gan, and Tel Aviv University Medical School, Tel Aviv, Israel;

Blood
|November 16, 2013
PubMed

Insights

Children with Down syndrome have a high risk of leukemia (DS-ALL), often leading to poor outcomes. Improving survival requires understanding unique biology, new therapies, and better infection control.

Area of Science:

  • Pediatric Oncology
  • Genetics
  • Immunology

Background:

  • Children with Down syndrome (DS) face a significantly higher risk of B-cell precursor acute lymphoblastic leukemia (DS-ALL).
  • DS-ALL presents unique biological characteristics, differing from typical childhood ALL, including specific genetic aberrations like CRLF2-IL7R-JAK-STAT pathway activation.
  • Outcomes for DS-ALL are often poor, primarily due to high relapse rates and treatment-related mortality (TRM) from infections.

Observation:

  • While relapse is a major concern, a subset of DS-ALL patients (10-15%) with specific genetic profiles (ETV6-RUNX1 or high hyperdiploidy) experience TRM as the main challenge.
  • Infection-related TRM is a persistent risk throughout all treatment phases, including maintenance therapy, necessitating vigilant monitoring and support.
  • Current treatment strategies may need adjustment, potentially allowing for chemotherapy de-escalation in specific low-risk DS-ALL subgroups to mitigate TRM.

Findings:

  • DS-ALL biology is distinct, characterized by underrepresentation of common cytogenetic subgroups and overrepresentation of specific activating genetic aberrations.
  • Treatment failure and TRM in DS-ALL are multifactorial, influenced by the leukemia's unique biological properties and susceptibility to infections.
  • There is a critical need for enhanced supportive care, particularly infection management, throughout the treatment course for DS-ALL patients.

Implications:

  • Future improvements in DS-ALL outcomes depend on a deeper understanding of treatment failure and TRM causes.
  • Targeting the unique biological features of DS-ALL with novel therapies is essential for advancing treatment.
  • Establishing a prospective DS-ALL registry and developing tailored supportive care guidelines are crucial next steps to improve outcomes for this vulnerable population.

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