What is the relationship between Chlorambucil (Leukeran) and vitamin B12 deficiency?

Relationship Between Chlorambucil and Vitamin B12 Deficiency

Long-term use of chlorambucil may be associated with vitamin B12 deficiency, requiring periodic monitoring of vitamin B12 levels, particularly in patients with anemia or peripheral neuropathy.

Mechanism and Evidence

• Chlorambucil is an alkylating agent commonly used in the treatment of chronic lymphocytic leukemia (CLL) and other lymphoid malignancies 1, 2
• Similar to metformin, long-term use of chlorambucil has been associated with vitamin B12 deficiency, which can lead to worsening of neurological symptoms 1
• The risk of vitamin B12 deficiency appears to increase with prolonged treatment duration, particularly when chlorambucil is used as indefinite therapy for conditions like CLL 3, 4

Clinical Implications

• Vitamin B12 deficiency can manifest as:

  • Megaloblastic, macrocytic anemia 1
  • Peripheral neuropathy with sensory and/or motor symptoms 1
  • Gait disturbances 1

• Untreated vitamin B12 deficiency can lead to serious neurological complications, including subacute combined degeneration of the spinal cord 1

Monitoring Recommendations

• Periodic testing of vitamin B12 levels is recommended for patients on long-term chlorambucil therapy 1
• Monitoring is particularly important for patients who present with:
  • Anemia, especially macrocytic anemia 1
  • Unexplained sensory or motor symptoms 1
  • Gait abnormalities 1

Treatment Approach for Vitamin B12 Deficiency

• For patients with neurological involvement:

  • Administer hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement is observed 1
  • Follow with maintenance treatment of 1 mg intramuscularly every 2 months 1

• For patients without neurological involvement:

  • Administer hydroxocobalamin 1 mg intramuscularly three times a week for 2 weeks 1
  • Follow with maintenance treatment of 1 mg intramuscularly every 2-3 months 1

• Important: Vitamin B12 deficiency should be treated immediately before initiating folic acid supplementation, as folic acid can mask severe vitamin B12 depletion and potentially worsen neurological complications 1

Clinical Considerations

• When using chlorambucil, especially for extended periods, clinicians should maintain vigilance for symptoms of vitamin B12 deficiency 1
• The risk-benefit profile of chlorambucil should be carefully considered, particularly given its potential for other adverse effects including increased risk of epithelial cancers 4
• In patients requiring both chlorambucil and metformin, the risk of vitamin B12 deficiency may be compounded, warranting more frequent monitoring 1