Continuing Education Activity

This activity focuses on using busulfan to manage and treat allogeneic hematopoietic progenitor cell transplantation, particularly for patients with chronic myelogenous leukemia and other relevant disorders. As an antineoplastic alkylating agent, busulfan is a crucial medication for treating these conditions, which warrants a review of its indications, mechanisms of action, and contraindications. By exploring its pharmacokinetics, dosing regimens, adverse event profile, and clinical toxicology, this program equips participants with the knowledge to optimize busulfan therapy. This activity also discusses the significance of informed prescription practices and tailored dosage strategies to enhance treatment efficacy while minimizing potential adverse effects, thereby improving patient outcomes in managing chronic myelogenous leukemia and related conditions.

Healthcare practitioners will gain an understanding of busulfan therapy, empowering them to deliver precise, secure, and individualized care to patients requiring allogeneic hematopoietic progenitor cell transplantation. By thoroughly examining FDA-approved and off-label uses, monitoring protocols, and pertinent drug interactions, participants will acquire the knowledge necessary to correctly administer busulfan, ultimately improving patient outcomes in treating chronic myelogenous leukemia and related disorders.

Objectives:

• Identify the mechanism of action of busulfan.

• Identify the adverse effects profile of busulfan.

• Determine appropriate monitoring strategies for patients receiving busulfan.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from busulfan treatment.

Indications

Busulfan is an alkylating antineoplastic agent administered to patients since the 1950s.

FDA-Approved Indications

The FDA-approved indication for busulfan is for use with cyclophosphamide as part of the regimen before allogeneic hematopoietic progenitor cell transplantation, specifically for patients with chronic myelogenous leukemia.

Off-Label Uses

Non-FDA-approved indications for busulfan include patients undergoing allogeneic hematopoietic progenitor cell transplantation. However, for other acute or chronic malignancies and nonmalignant disorders like hemoglobinopathies, congenital metabolic diseases, or inborn immune system errors.[1][2]

Mechanism of Action

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 by substituting alkyl groups for hydrogen atoms on the cancer cell DNA molecule; this results in cross-linkage within the DNA chain, inhibiting the transcription of DNA into RNA. The inhibition of transcription causes inhibition of protein synthesis and further results in cytotoxic, mutagenic, and carcinogenic effects.[3]

Busulfan specifically works by having a hydrolysis reaction occur with the 2 easily displaced methanesulfonate groups located on opposite ends of a butane chain within the drug's chemical structure. This is a nucleophilic substitution reaction with the guanine molecules to create positively charged, highly reactive carbonium ions. These ions form DNA intrastrand cross-links, which, in turn, disrupt and damage the cancer cell's DNA.

Another inhibitory effect that busulfan exerts 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, increasing oxidative stress in cancer cells.[4][5]

Pharmacokinetics

Absorption: Busulfan's oral absorption in humans is variable, influenced by disease states, age, and dosage. The intravenous formulation has been developed to address erratic oral absorption, providing more consistent systemic exposure. 

Distribution: Intravenous busulfan exhibits a narrow therapeutic index with significant inter-individual variability. Approximately 32% irreversibly binds to plasma proteins. The drug enters cerebrospinal fluid, contributing to CNS adverse effects.

Metabolism: Busulfan undergoes predominant metabolism through conjugation with glutathione, occurring spontaneously and facilitated by glutathione S-transferase catalysis. The resulting conjugate undergoes extensive oxidative metabolism in the liver. 

Elimination: Only 2% of unchanged busulfan is excreted in the urine in humans. Urinary metabolites include sulfolane, 3-hydroxy-sulfolane, and tetrahydrothiophene 1-oxide. Busulfan clearance shows a coefficient of variation of 25%. Infusion rate affects clearance, emphasizing the need for standardized administration schedules. Limited unchanged busulfan in urine and detection of specific metabolites affirm the relevance of the sulfonium ion conjugate of glutathione in the mercapturic acid pathway.[4]

Administration

Available Dosage Forms and Strengths

Patients can receive busulfan either orally or by intravenous route. The intravenous solution presents a 6 mg/mL concentration, while the oral tablet is available in a 2 mg strength. Certain intravenous formulations may incorporate polyethylene glycol. 

Adult Dosage 

Chronic myelogenous leukemia (Allogeneic hematopoietic progenitor cell transplantation)

Patients can receive busulfan orally or intravenously. For pre-transplantation, patients over 12 kg in weight should receive busulfan at a rate of 0.8 mg/kg every 6 hours for 4 days. Pre-transplantation treatment also includes cyclophosphamide. Intravenous administration is preferable to oral administration because multiple studies show a sizeable therapeutic variability among patients receiving therapy with oral busulfan.[6][2] Busulfan should be injected with cyclophosphamide as a conditioning regimen before bone marrow or peripheral blood progenitor cell replacement. For patients over 12 kg, use busulfan injection at 0.8 mg/kg intravenously every 6 hours for 4 consecutive days (Days -7, -6, -5, and -4), followed by cyclophosphamide at 60 mg/kg intravenously on Days -3 and -2. Hematopoietic progenitor cells should be administered on Day 0. The patient should be premedicated with anticonvulsants to prevent seizures and administer antiemetics before and throughout the busulfan injection administration. Busulfan injection clearance is best predicted using adjusted ideal body weight. Caution should be exercised with polycarbonate-containing components. A busulfan injection for intravenous infusion should be diluted with either normal saline or 5% dextrose injection. Use an administration set with minimal residual hold-up volume (2 mL to 5 mL). Aseptic techniques should be followed, and infusion pumps should be used for a 2-hour administration. The catheter line is then flushed before and after each infusion. Unused portions should be discarded and not infused concomitantly with other intravenous solutions of unknown compatibility.

Specific Patient Populations

Hepatic impairment: No dosage adjustments for busulfan are provided in the product labeling.

Renal impairment: No dosage adjustments for busulfan are provided in the product labeling.

Pregnancy considerations: Busulfan, as demonstrated by animal studies, demonstrates teratogenic effects in rabbits, mice, and hamsters, signifying potential harm to the developing fetus. The solvent dimethylacetamide (DMA) also demonstrates fetal risks in animal studies. Pregnant women should be apprised of these potential dangers, and it is advised to ensure effective contraception for females and males of reproductive potential during and post-busulfan treatment.

Breastfeeding considerations: Breastfeeding is contraindicated when undergoing treatment with antineoplastic medications. Like many other antineoplastic medications, busulfan can impact breast milk's normal microbiome and chemical composition. One case has been documented involving a woman breastfeeding while taking busulfan 4 mg/day for 5 weeks to manage myeloid leukemia. No adverse effects were recorded involving her infant's hemoglobin and leukocyte count.[7] Even with this case, there is still not enough information to say whether it is safe to take busulfan when breastfeeding.

Pediatric patients: Adverse reactions, such as pneumonia, capillary leak syndrome, veno-occlusive disease, multi-organ failure, and mortality, have been reported in pediatric patients. Therapeutic drug monitoring, cautious monitoring, and individualized dosing are recommended for pediatric patients receiving busulfan injections. Per the busulfan dosing nomogram, for patients with an actual body weight (ABW) less than or equal to 12 kgs, the recommended dosage is 1.1 mg/kg. For those with a body weight greater than 12 kg, the suggested dosage is 0.8 mg/kg.

Older patients: Studies involving busulfan did not involve a sufficient number of older patients (aged 65 and older) to ascertain whether their response differs from that observed in younger patients.

Adverse Effects

There are adverse effects that commonly correlate with busulfan use and that are common among all alkylating agents. Common adverse drug reactions 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 an adverse effect commonly associated with busulfan. This adverse effect typically occurs 10 to 20 days after hematopoietic cell transplantation, but it can present as late as 30 to 75 days with newer therapeutic regimens. 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. Weight gain is also associated with fluid accumulation. Serum enzyme and serum aminotransferase concentrations typically become elevated, with a minimal increase in alkaline phosphatase concentrations. 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][8]

Other adverse effects of busulfan include interstitial pulmonary fibrosis. This adverse effect is commonly referred to as busulfan lung, and while it is rare, it is an important adverse 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.[8][9][10]

Busulfan-induced seizure is also another adverse effect to note. The seizures are generally tonic-colonic. Incidence is reported to be 10% and is associated with high concentrations of busulfan. Busulfan rapidly distributes into the CSF; clinicians can use plasma concentration to approximate CSF concentration when using high doses of busulfan. Physicians must treat patients with prophylactic phenytoin. Other medications that have been useful as a prophylactic treatment for busulfan-induced seizures are clonazepam, lorazepam, valproic acid, and levetiracetam. Some physicians have chosen to use benzodiazepines like the antiseizure medications previously suggested because phenytoin can increase the metabolism of busulfan by upregulating many P450 enzymes. Further research into this area is underway.[4][11][12]

Other notable adverse drug reactions of busulfan include hyperpigmentation, emesis, wasting syndrome, thrombocytopenia, and sometimes medullary aplasia.[8][9][13]

Drug-Drug Interactions

Metronidazole: Metronidazole reduces busulfan clearance, potentially elevating the risk of busulfan-induced toxicity. Vigilant monitoring and dosage adjustments for busulfan may be imperative.[14][15]

Itraconazole: Itraconazole reduces busulfan clearance by 25%, warranting meticulous monitoring and potential dosage modifications due to elevated busulfan levels.[16]

Iron chelating agents: Concurrent administration with iron chelating agents reduces busulfan clearance. The precise mechanism remains unclear. To mitigate increased busulfan exposure, preemptive discontinuation of iron chelating agents before busulfan is advised.

Acetaminophen: If used concomitantly or within 72 hours before busulfan, acetaminophen may reduce busulfan clearance. This is attributed to acetaminophen's documented property of diminishing glutathione levels, influencing busulfan elimination.

Phenytoin: Phenytoin increases busulfan clearance, likely through the induction of glutathione-S-transferase. Individuals not receiving phenytoin may exhibit altered busulfan clearance and increased exposure (AUC), necessitating dosage adjustments in phenytoin-treated subjects.[4]

Contraindications

Busulfan or any of its dosage form components causing hypersensitivity is an absolute contraindication.

Box Warning

Busulfan induces severe and prolonged myelosuppression, requiring hematopoietic progenitor cell transplantation to prevent potentially fatal complications.[17] Severe granulocytopenia, thrombocytopenia, anemia, or a combination may occur, necessitating close monitoring of complete blood counts, including white blood cell differentials and quantitative platelet counts. Daily monitoring is crucial during treatment until graft success is confirmed. Use antibiotic therapy and blood product support when medically indicated.

Warning and Precautions

• Cautions are necessary when using busulfan and all alkylating agents like pancytopenia, gonadal dysfunction, pubertal development in children, carcinogenicity, mutagenicity, infertility, and busulfan-induced lung injury.[18][19]
• Embroyfetal toxicity has been reported with busulfan. The FDA has declared busulfan to be a pregnancy category D medication. Breastfeeding is not recommended when undergoing treatment with busulfan.[7] 
• Cardiac tamponade has been reported with high doses of busulfan and cyclophosphamide.[20]

Monitoring

Optimal monitoring of busulfan uses the concentrations represented as the area under the concentration-time curve (AUC). AUC has significantly helped clinicians monitor the therapeutic concentrations and correct them as needed for better outcomes after allogeneic hematopoietic cell transplantation. An AUC of 100 mg*h/L reaches optimal efficacy in most patients, but the optimal target varies due to factors that include age and diagnosis. Anything less than 100 mg*h/L increases the risk of graft rejection or disease relapse. Anything greater than 100 mg*h/L or 1500 μM for AUC increases a patient’s risk of hepatic venous-occlusive disease.[1][21] Other tests to use when analyzing the effects of busulfan on a patient include complete blood count, liver function tests, and pulmonary function tests.

Toxicity

Signs and Symptoms of Toxicity

When using busulfan, toxicity concerns are primarily associated with hepatic venous-occlusive disease, acute graft-versus-host disease, and chronic graft-versus-host disease. Most research indicates that maintaining the AUC between 78 to 101 mg*h/L significantly increases event-free survival for patients.[21]

Management of Toxicity

Treatment for hepatic venous-occlusive disease (also known as a hepatic sinusoidal occlusive syndrome) includes defibrotide, an antiplatelet agent, and an antithrombotic agent. Research has shown that 25 mg/kg/d of defibrotide IV for 21 days has effectively treated hepatic venous-occlusive disease.[22] Standard first-line therapy for both acute and chronic graft-versus-host disease is corticosteroids.[23]

Enhancing Healthcare Team Outcomes

Busulfan, a chemotherapeutic agent, requires a precise clinical strategy to maximize therapeutic efficacy while managing adverse effects during cancer treatment. Considering the serious adverse effects, busulfan should only be prescribed and administered by experienced oncologists and pharmacists. Chemotherapy protocols must be reviewed by a hematologist/oncologist. Pulmonologist consultation may be necessary for busulfan-induced pulmonary fibrosis.[24] These protocols also enhance the care for the many people who survive allogeneic hematopoietic progenitor cell transplantation. Some predict that by 2030, hematopoietic cell transplantation survivors will surpass half a million in the United States. There are currently patient-centered delivery models for cancer survivors, but not for patients who have survived hematopoietic cell transplantation. This area should be a focus of research in the future with the increasing number of patients who survive hematopoietic cell transplantation, and clinicians and healthcare workers should always be working together to help patients survive after undergoing chemotherapeutic treatments.[25]

The interprofessional healthcare team of clinicians (MDs, DOs, PAs, NPs), oncologists, nurses, and pharmacists should coordinate the treatment of patients with busulfan effectively; monitoring and repeating essential laboratory tests is important. These tests include a complete blood count, liver function test, and pulmonary function test when an adverse effect is suspected. When a suspected adverse effect seems present in a patient, especially during allogeneic hematopoietic progenitor cell transplantation, nurses and other medical staff should relay this information to the doctor. Effective interprofessional communication is critical in this situation because the sooner the adverse effect is identified, the easier it will be for the clinician to treat the problem or terminate its use, improving patient outcomes while mitigating adverse events.