Busulfan

Severe and prolonged bone marrow suppression commonly occurs; reduce dose or discontinue oral busulfan for unusual suppression; may require bone marrow biopsy. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications from prolonged myelosuppression due to IV busulfan. May result in severe neutropenia, thrombocytopenia, anemia, bone marrow failure, and/or severe pancytopenia; pancytopenia may be prolonged (1 month up to 2 years) and may be reversible. When used for transplantation, monitor CBC with differential daily during treatment and until engraftment. The onset of neutropenia is a median of 4 days post-transplant; recovery is within a median of 13 days following allogeneic transplant (with prophylactic G-CSF use in most patients). Thrombocytopenia occurred at a median of 5 to 6 days. Use with caution in patients with compromised bone marrow reserve (due to prior treatment or radiation therapy). Monitor closely for signs of infection (due to neutropenia) or bleeding (due to thrombocytopenia). May require antibiotic therapy and platelet and red blood cell support.

Cardiac tamponade has been reported in children with thalassemia treated with high dose oral busulfan in combination with cyclophosphamide. Abdominal pain and vomiting preceded tamponade in most children. Monitor for signs/symptoms and evaluate/treat promptly if cardiac tamponade is suspected.

Busulfan is associated with a moderate emetic potential (depending on dose and/or administration route); antiemetics may be recommended to prevent nausea and vomiting (Dupuis 2011).

High busulfan area under the concentration versus time curve (AUC) values (>1500 micromolar•minute) are associated with increased risk of hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]) due to conditioning for allogenic HSCT. Patients with a history of radiation therapy, prior chemotherapy (≥3 cycles), or prior stem cell transplantation are also at increased risk of hepatic SOS at recommended doses regimens. Oral busulfan doses above 16 mg/kg (based on IBW) and concurrent use with alkylating agents may also increase the risk for hepatic SOS. Monitor liver function tests (serum transaminases, alkaline phosphatase, and bilirubin) daily until 28 days post-transplant to detect hepatotoxicity (which may preclude hepatic SOS).

Bronchopulmonary dysplasia with pulmonary fibrosis (“busulfan lung”) is associated with chronic busulfan use; onset is delayed with symptoms occurring at an average of 4 years (range: 4 months to 10 years) after treatment; may be fatal. Symptoms generally include a slow onset of cough, dyspnea and fever (low-grade), although acute symptomatic onset may also occur. Diminished diffusion capacity and decreased pulmonary compliance have been noted with pulmonary function testing. Differential diagnosis should rule out opportunistic pulmonary infection or leukemic pulmonary infiltrates; may require lung biopsy. Discontinue busulfan if toxicity develops. Pulmonary toxicity may be additive if administered with other cytotoxic agents also associated with pulmonary toxicity.

Tumors and acute leukemias have been reported following use. Chromosomal alterations may also occur.

Seizures have been reported with IV busulfan and with high-dose oral busulfan. When using as a conditioning regimen for transplant, initiate prophylactic anticonvulsant therapy (eg, phenytoin, levetiracetam, benzodiazepines, or valproic acid) prior to treatment. Use with caution in patients predisposed to seizures, with a history of seizures, head trauma, or with other medications associated with inducing seizures.

Cellular dysplasia in many organs has been observed (in addition to lung dysplasia); giant hyperchromatic nuclei have been noted in adrenal glands, liver, lymph nodes, pancreas, thyroid, and bone marrow. May obscure routine diagnostic cytologic exams (eg, cervical smear). Concurrent drug therapy issues:

Phenytoin increases busulfan clearance by ≥15%; busulfan kinetics and dosing recommendations for high-dose HSCT conditioning were studied with concomitant phenytoin. If alternate anticonvulsants are used, busulfan clearance may be decreased and dosing should be monitored accordingly.

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

The solvent in IV busulfan, dimethylacetamide (DMA) may be associated with hepatotoxicity, hallucinations, somnolence, lethargy, and confusion. N,N-dimethylacetamide is incompatible with many closed-system transfer devices (CSTDs) used for preparing injectable antineoplastics (ISMP [Smetzer 2015]). Other warnings/precautions:

According to the manufacturer, oral busulfan should not be used until CML diagnosis has been established. The responsible health care provider should be experienced in assessing response to chemotherapy.