11 Pharmacogenomics in Oncology

Pharmacogenomics in Oncology

Objectives and Aims

• Understand pharmacogenomics in cancer via acute lymphoblastic leukaemia (ALL).

• Explore thiopurine methyltransferase (TPMT) and its effect on 6-mercaptopurine.

General Overview

• Anticancer drugs are toxic with a low therapeutic index.

• Pharmacogenomics enhances cancer chemotherapy:

  • Increases efficacy

  • Reduces toxicity.

• Optimizes treatment for ALL through individualized approaches.

Acute Lymphoblastic Leukaemia (ALL)

• ALL is a heterogeneous disease affecting lymphoid progenitor cells in bone marrow and blood:

  • Subdivided by immunologic properties (T-cell vs B-cell).

  • Mainly affects children (peak age 2-5 years).

• Advancements in treatment over decades:

  • Survival rates improved from ~10% in the 1960s to ~80% in the 1990s due to better chemotherapy and identification of high-risk patients.

Treatment Protocols for ALL

1. Remission-Induction Therapy

   • Aims to eliminate >99% leukemia cells; restore normal blood cell formation.

2. Consolidation Therapy

   • Strengthens remission; specific agents vary by risk factors and CNS status.

3. Continuation Treatment

   • Focuses on eradicating residual leukemia and CNS treatment.

Role of TPMT in ALL Treatment

• 6-Mercaptopurine (6-MP)

  • Widely used for ALL, requires metabolism to achieve cytotoxicity.

  • Inactivation pathways involve TPMT and xanthine oxidase.

• TPMT Polymorphisms

  • Variants impact enzyme activity levels, influencing drug response and toxicity:

    • Wild-type (high activity) vs. Variants (intermediate/low activity).

    • Dose adjustments needed to prevent toxicity (e.g., significant reductions for homozygous variants).

Implications of TPMT Variations

• High TPMT activity may lead to higher leukemic relapse rates; may require higher drug dosages.

• TPMT deficiency increases risk of toxicities from drug accumulation.

• Patients with adjusted dosages based on TPMT genotype show better overall treatment quality and efficacy.

Other Considerations

• Non-genetic factors also affect drug responses:

  • Drug-drug interactions

  • Environmental factors

  • Age, sex, and organ function.

• Overall pharmacogenomics assists in optimizing individual patient therapy in ALL.