Busulfan

General adverse effects and adverse reactions

Leukemic patients receiving marrow from HLA-identical sibling donors were randomized to either oral busulfan 16 mg/kg (n = 88) or total body irradiation (n = 79), plus cyclophosphamide 120 mg/kg [ ]. Over 5–9 years the following adverse effects occurred in the two groups:

• obstructive bronchiolitis (26% versus 5%);

• cataracts (6% versus 2%);

• veno-occlusive disease of the liver (12% versus 1%);

• complete or partial alopecia (28% versus 6%);

• hemorrhagic cystitis (32% versus 10%);

• acute graft-versus-host disease (cumulative incidence at 7 years, 59% versus 47%); death from graft-versus-host disease was more common with busulfan (22% versus 3%).

Cardiovascular

Pericardial fibrosis has been reported after busulfan treatment in a man with chronic myeloid leukemia [ ]. Endocardial fibrosis has also been reported [ ].

Respiratory

Busulfan can cause interstitial fibrosing lung disease (“busulfan lung”) with an estimated incidence of 6% [ ]. It begins gradually, causes dyspnea and cough, and is often accompanied by skin pigmentation. It usually occurs after prolonged treatment (on average 41 months, cumulative dose 2900 mg). The respiratory function pattern is characterized by reduced lung volumes with hypoxemia and hypocapnic respiratory failure. Radiology shows interstitial and predominantly basal shadows.

Various authors have discussed the differences in busulfan-induced idiopathic pneumonia syndrome, as a result of either chronic low-dose or short-course high-dose therapy. One group found that chronic low-dose therapy (even at cumulative doses of busulfan of up to 3 g) caused different lung damage from the clinical characteristics, radiological, and pathological features of the idiopathic pneumonia syndrome [ ].

Three patients with busulfan-induced interstitial pneumonitis each had circulating immune complexes and alveolitis, and histology demonstrated consistent abnormalities of type I pneumocytes and depletion of type II pneumocytes [ ].

Nervous system

Busulfan can cause generalized seizures [ ].

High concentrations of busulfan in the cerebrospinal fluid have been correlated with development of myoclonic epilepsy and/or other electroencephalographic changes after high-dose busulfan conditioning regimens for acute leukemia [ ].

• A 21-year-old woman with acute lymphoblastic leukemia underwent bone marrow transplantation after a conditioning regimen consisting of busulfan and cyclophosphamide [ ]. The day after starting busulfan, she had a generalized tonic–clonic seizure and electroencephalography showed diffuse polyspikes and spike-and-wave discharges, with persistent abnormalities (slowing of background activity intermixed with diffuse slow waves and isolated delta and theta bursts) for about 20 days and complete normalization 1 month after the seizure.

Phenytoin and benzodiazepines have been successfully used to prevent seizures during busulfan therapy; benzodiazepines may be preferable, because phenytoin can induce the metabolism of busulfan, reducing its efficacy. In 29 children undergoing hemopoietic stem cell transplantation who received high-dose busulfan, intravenous or oral lorazepam (median dose 0.022 mg/kg) before each dose of busulfan and for 24 hours after the last dose was used as seizure prophylaxis; drowsiness was the only significant adverse effect and there were no seizures [ ]. There were no tonic–clonic or myoclonic seizures in a prospective study in 16 patients with leukemia receiving busulfan before autologous bone marrow transplantation who were given phenobarbital and clonazepam, despite electroencephalographic changes in two patients after busulfan [ ].

Sensory systems

Cataract due to busulfan has been reported after long-term administration [ ].

• A 42-year-old Japanese woman received busulfan 212 mg/day for only 4 days and developed reduced visual acuity and blurred vision in both eyes; she had a posterior polar subcapsular opacity in the lenses in both eyes [ ].

• A 49-year-old man with chronic myelogenous leukemia developed dense posterior subcapsular cataracts and punctate cortical opacities after taking busulfan for 5 years [ ]. Ultrastructural examination showed cortical liquefaction, with Morgagnian droplets involving primarily the region from the equator to the posterior subcapsular space, crystalloid rays, and abundant degenerate lens fiber membranes.