Busulfan is an alkylating antineoplastic agent that has been in use since the 1950s. The FDA approved indication for busulfan in use with cyclophosphamide as part of the regimen before allogeneic hematopoietic progenitor cell transplantation specifically for patients with chronic myelogenous leukemia. Non-FDA approved indications for busulfan are for patients undergoing allogeneic hematopoietic progenitor cell transplantation, but for other malignancies, whether acute or chronic and other nonmalignant disorders like hemoglobinopathies, congenital metabolic diseases or inborn errors of the immune system.[1][2]

Busulfan is an alkylating chemotherapeutic agent. Alkylating agents are a broad category of antineoplastic agents, but all have a similar mechanism of action. Alkylating agents work specifically by substituting alkyl groups for hydrogen atoms on the DNA molecule; this results in cross-linkage within the DNA chain, which inhibits the transcription of DNA into RNA. The inhibition of DNA into RNA causes inhibition of protein synthesis and further results in cytotoxic, mutagenic, and carcinogenic effects.[3]

Busulfan works by having a hydrolysis reaction occur with the two easily displaced methanesulfonate groups located on opposite ends of a butane chain within the chemical structure of the drug. This reaction creates positively charged carbonium ions that are highly reactive, which disrupts and damages the DNA. The reaction that occurs is a nucleophilic substitution reaction with the guanine molecules, which creates DNA intrastrand cross-links.

Other inhibitory effects that busulfan has on DNA is binding to the cysteine molecules of histone proteins, which leads to DNA-protein binding. Busulfan also disrupts the cellular redox equilibrium by interacting with the sulfhydryl groups of glutathione, resulting in oxidative stress.[4][5]

Patients can receive busulfan either orally or IV. For pretransplantation, patients who are over 12 kg in weight receive busulfan at a rate of 0.8 mg/kg every six hours for a total of 4 days. Pretransplantation treatment also includes cyclophosphamide. IV administration is preferred over oral administration because multiple studies show a sizeable therapeutic variability among patients taking oral busulfan.[6][2]

There are side effects that commonly correlate with busulfan use, and that are common among all alkylating agents. Common side effects that are associated with all alkylating agents include intestinal mucosal damage, alopecia, pancytopenia, anemia, amenorrhea, impaired spermatogenesis, and increased risk of malignancy.

Hepatic Veno-occlusive disease is a side effect commonly associated with busulfan. It typically occurs 10-20 days after hematopoietic cell transplantation, but with newer therapeutic regimens, it can present as late as 30 to 75 days. Frequency ranges from 20 to 50%, but the incidence has decreased due to better therapeutic regimens. Hepatic Veno-occlusive disease typically presents with abdominal pain, liver tenderness, and jaundice. There is also associated with weight gain due to fluid accumulation. Serum enzyme and serum aminotransferase levels typically become elevated, with a minimal increase in the levels of alkaline phosphatase. If severe enough, it can cause hepatic failure. With the fatality rate being as high as 50%, it is important to bear in mind how much busulfan a patient is receiving because hepatic veno-occlusive disease is dose-dependent. Doses higher than 16 mg/kg, for instance, would put the patient at more risk of hepatic veno-occlusive disease.[2][3][7][3]

Other side effects of busulfan include interstitial pulmonary fibrosis. This side effect is commonly referred to as busulfan lung, and while it is rare, it is an important side effect to note. Research has not established the exact mechanism, but it is believed to be due to chemically induced inflammation of the alveoli. This inflammation then causes granular pneumocytes to proliferate, which causes the lungs to become fibrotic.[7][8][9]

Busulfan induced seizure is also another side effect to note. The seizures are generally tonic-colonic. Incidence is reported to be 10% and is associated with high levels of busulfan. Busulfan has the capability of rapid distribution into the CSF. CSF concentration can be approximately equivalent to the concentration in plasma when using busulfan in high doses. Recommended, many physicians have used prophylactic treatment with phenytoin. Other medications have been useful as a prophylactic treatment for busulfan induced seizures like clonazepam, lorazepam, valproic acid, and levetiracetam. Some physicians have chosen to use benzodiazepines like the ones suggested because phenytoin can increase the metabolism of busulfan by upregulating many P450 enzymes. Further research into this area is underway.[4][10][11]

Other notable side effects of busulfan include hyperpigmentation, emesis, wasting syndrome, thrombocytopenia, and sometimes medullary aplasia.[7][8][12]

Busulfan or any of its components causing hypersensitivity is an absolute contraindication. Many cautions are necessary when using not only busulfan but all alkylating agents like pancytopenia, gonadal dysfunction, and pubertal development in children, carcinogenicity, mutagenicity, infertility, and many others.

The FDA has declared busulfan to be pregnancy category D. Breastfeeding is contraindicated when undergoing treatment with antineoplastic medications. Busulfan, like many other antineoplastic medications, can have an impact on the normal microbiome and chemical composition of breastmilk. There has been a case where a woman breastfeeding was taking 4 mg/day of busulfan for five weeks for myeloid leukemia that resulted in no adverse effects on her infant’s hemoglobin and leukocyte count.[13] Even with this case, there is still not enough information to say whether it is safe to take busulfan when breastfeeding.