Busulfan
CH3 CH2CH2CH2CH2O CH3 S O S
O
O
O
O
Trade Names
Myleran, Busulfex
Classification
Alkylating agent
Category
Chemotherapy drug
Drug Manufacturer
GlaxoSmithKline
Mechanism of Action
Methanesulfonate-type bifunctional alkylating agent.
Interacts with cellular thiol groups and nucleic acids to form DNADNA
and DNA-protein cross-links. Cross-linking of DNA results in
inhibition of DNA synthesis and function.
Cell cycle–nonspecific, active in all phases of the cell cycle.
Mechanism of Resistance
Decreased cellular uptake of drug.
Increased intracellular thiol content due to glutathione or glutathione related
enzymes.
Enhanced activity of DNA repair enzymes.
Absorption
Excellent oral bioavailability with peak levels in serum occurring within
2–4 hours after administration. About 30% of drug is bound to plasma
proteins.
Distribution
Distributes rapidly in plasma with broad tissue distribution. Crosses the
blood-brain barrier and also crosses the placental barrier.
Metabolism
Metabolized primarily in the liver by the cytochrome P450 system.
Metabolites, including sulfoxane, 3-hydroxysulfoxane, and methanesulfonic
acid, are excreted in urine, with 50%–60% excreted within 48 hours.
Metabolism may be influenced by circadian rhythm with higher clearance
rates observed in the evening, especially in younger patients. The terminal
half-life is 2.5 hours.
Indications
Chronic myelogenous leukemia (CML) (standard dose).
Bone marrow/stem cell transplantation for refractory leukemia,
lymphoma (high dose). Use in combination with cyclophosphamide
as conditioning regimen prior to allogeneic stem cell transplantation
for CML.
Dosage Range
CML: Usual dose for remission induction is 4–8 mg/day PO. Dosing
on a weight basis is 1.8 mg/m 2 /day. Maintenance dose is usually
1–3 mg/day PO.
Transplant setting: 4 mg/kg/day IV for four days to a total dose of
16 mg/kg.
Drug Interaction 1
Acetaminophen—Acetaminophen may decrease busulfan metabolism
in the liver when given 72 hours before busulfan, resulting in enhanced
toxicity.
Drug Interaction 2
Itraconazole—Itraconazole reduces busulfan metabolism by up to 20%.
Drug Interaction 3
Phenytoin—Phenytoin increases busulfan metabolism in the liver by
inducing the activity of the liver microsomal system.
Special Considerations
Monitor CBC while on therapy. When the total WBC count has
declined to approximately 15,000/mm 3 , busulfan should be withheld
until the nadir is reached and the counts begin to rise above this
level. A decrease in the WBC count may not be seen during the first
10–15 days of therapy, and it may continue to fall for more than one
month even after the drug has been stopped.
Monitor patients for pulmonary symptoms as busulfan can cause
interstitial pneumonitis.
Ingestion of busulfan on an empty stomach may decrease the risk of
nausea and vomiting.
Pregnancy category D. Breast-feeding should be avoided.
Toxicity 1
Myelosuppression with pancytopenia is dose-limiting toxicity.
Toxicity 2
Nausea/vomiting and diarrhea are common (_80% of patients) but generally
mild with standard doses. Anorexia is also frequently observed.
Toxicity 3
Mucositis is dose-related and may require interruption of therapy in some
instances.
Toxicity 4
Hyperpigmentation of skin, especially in hand creases and nail beds. Skin
rash and pruritus also observed.
Toxicity 5
Impotence, male sterility, amenorrhea, ovarian suppression, menopause,
and infertility.
Toxicity 6
Pulmonary symptoms, including cough, dyspnea, and fever, can be seen
after long-term therapy. Interstitial pulmonary fibrosis, referred to as “busulfan
lung,” is a rare but severe side effect of therapy. May occur 1–10 years
after discontinuation of therapy.
Toxicity 7
Adrenal insufficiency occurs rarely.
Toxicity 8
Hepatotoxicity with elevations in LFTs. Hepato-veno-occlusive disease
is observed with high doses of busulfan (_16 mg/day) used in transplant
setting.
Toxicity 9
Insomnia, anxiety, dizziness, and depression are the most common
neurologic side effects. Seizures can occur, usually with high-dose therapy.
Toxicity 10
Increased risk of secondary malignancies, especially acute myelogenous
leukemia, with long-term chronic use.