INTRODUCTION — Busulfan is an alkylating agent that was previously used for treatment of chronic myelogenous leukemia, but is now used exclusively as a component of a preparative regimen prior to hematopoietic stem cell transplantation (HCT). Busulfan was the first cytotoxic drug reportedly associated with pulmonary toxicity . The reported patterns of pulmonary toxicity include acute lung injury, chronic interstitial fibrosis, and alveolar hemorrhage. Busulfan is often used in combination with other drugs, many of which cause pulmonary toxicity, which can make it difficult to ascertain which drug is the culprit. (See "Preparative regimens for hematopoietic cell transplantation", section on 'Chemotherapy without RT'.)
The clinical characteristics of busulfan-induced pulmonary injury will be reviewed here. Pulmonary toxicity caused by other chemotherapeutic agents is discussed separately. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents" and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)
EPIDEMIOLOGY AND RISK FACTORS — Symptomatic pulmonary injury is thought to occur in fewer than 8 percent of patients who receive busulfan; the incidence of pulmonary toxicity appears to be similar in children and adults [2-16]. However, the true incidence is unknown; most of the early data in patients treated with busulfan alone for chronic myelogenous leukemia (CML) consisted of single case reports [3-7,9,10]. Such treatment is no longer considered a standard approach since the introduction of oral tyrosine kinase inhibitors. (See "Overview of the treatment of chronic myeloid leukemia".)
At present the utility of busulfan is limited to preparative regimens prior to hematopoietic cell transplantation (HCT). Modern data examining the risk of pulmonary toxicity in such patients are derived from series in which patients received busulfan in addition to other myelosuppressive chemotherapy agents and/or radiation therapy prior to HCT. The incidence has been variable, and interpretation complicated by competing causes of pulmonary toxicity [14,16-21], particularly cytomegalovirus (CMV) pneumonitis:
●In a series of 84 patients receiving etoposide, busulfan, and cyclophosphamide prior to autologous or allogenic bone marrow transplantation, seven patients had severe lung toxicity (8.3 percent), five of whom had also received irradiation to the lung fields . Five deaths were attributed to alveolar hemorrhage and one to pulmonary embolism.
●In a trial of busulfan plus cyclophosphamide (Bu/Cy) versus total body irradiation (TBI) as a preparative regimen prior to allogeneic transplantation in 167 patients with leukemia, bronchiolitis obliterans was significantly more frequent after Bu/Cy than after TBI (26 versus 5 percent, respectively) after a median of seven years followup . The number of patients with grade 5 (fatal) interstitial pneumonitis was similar (6 versus 5 percent with Bu/Cy and TBI, respectively). The higher rate of pulmonary toxicity in this study compared with others could reflect graft-versus-host disease rather than busulfan toxicity.
●In an early trial of allogeneic transplantation for acute leukemia using a busulfan-containing conditioning regimen, 15 of 51 patients developed interstitial pneumonitis at a median of 47 days post transplantation . Fourteen of the 15 had CMV detected on biopsy or at autopsy, and 14 of the 15 died (including 13 with presumed CMV pneumonitis). Thus, the contribution of busulfan is unclear.
●In an analysis of data from 1230 patients with AML undergoing allogeneic HCT derived from the Center for International Blood and Marrow Transplant Research, the cumulative incidence of interstitial pneumonitis at 100 days was 3 and 5 percent among those receiving a preparatory regimen of intravenous or oral busulfan, respectively . In contrast, the rate was 10 percent after TBI combined with cyclophosphamide.
●In a study of 1483 patients undergoing allogeneic HCT for myeloid malignancies, the cumulative incidence of interstitial pneumonitis at 100 days posttransplant was 4 percent among those treated with IV busulfan compared to 6 percent with TBI .
These reports reflect symptomatic pulmonary toxicity. Subclinical lung damage, however, may develop in a considerably higher number of those exposed to this agent. Therapeutic drug monitoring (TDM) of busulfan is now used to adjust the dose according to age and serum levels; however, a number of these studies were performed prior to the routine use of TDM with busulfan. (See "Hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes in children and adolescents", section on 'Conditioning therapy'.)
The factors that contribute to the development of lung toxicity from busulfan are not well-established . In the older literature in which long-term busulfan was administered as monotherapy for CML, most (but not all ) cases were described in patients treated for longer than eight months, and the threshold dose beyond which the risk of pulmonary toxicity increased was thought to be approximately 500 mg [23,24]. (See 'Clinical features' below.)
Among patients receiving a busulfan-containing conditioning regimen prior to HCT, concurrent or subsequent administration of other potentially toxic modalities, such as other chemotherapeutic agents (eg, additional alkylating agents) or lung irradiation, such as may occur with total body irradiation, may enhance pulmonary toxicity . On the other hand, the risk of busulfan-related toxicity (including pulmonary toxicity) may be reduced by the use of pharmacokinetically-based rather than traditional weight-based dosing, which is now common practice .
PATHOGENESIS AND PATHOLOGY — The mechanisms of busulfan-induced lung injury are unknown, since adequate animal models do not exist. Direct toxicity of busulfan to epithelial lining cells is suggested, but cytologic and histologic findings are nonspecific. Lung biopsy specimens reveal pneumocyte dysplasia (degeneration of type I cells, atypical hyperplastic type II cells), atypical bronchial lining cells, mononuclear cell infiltration, and fibrosis [11,26]. Occasionally, severe desquamation of injured epithelial cells into alveolar spaces leads to diffuse alveolar damage in a pattern suggestive of alveolar proteinosis . Organizing pneumonia and diffuse alveolar damage have been described in patients who received busulfan among other agents . In a single case report, pulmonary alveolar hemorrhage developed after hematopoietic cell transplantation in a patient who received busulfan in combination with other agents as part of a conditioning regimen, although it is not known whether busulfan was causative .
CLINICAL FEATURES — Patients with busulfan-induced pulmonary injury commonly complain of cough and progressive dyspnea on exertion. Fever and weight loss may also be present. Pulmonary examination may be unrevealing or may demonstrate basilar crackles.
In patients treated with busulfan monotherapy, the interval between initiation of therapy and onset of pulmonary symptoms was usually greater than four years. However, symptoms may occur insidiously after only six weeks or as long as 10 years following onset of busulfan exposure [2,14,27,28].
The time frame for pulmonary toxicity among patients receiving high-dose busulfan (most often 4 mg/kg daily for four days) as a component of the conditioning regimen for autologous or allogeneic stem cell transplantation is less well established, given that these patients often have competing causes of interstitial pneumonitis, including graft-versus-host disease and interstitial pneumonia syndrome, and lung infection due to cytomegalovirus (CMV). However, in most cases, pulmonary toxicity is manifest between 30 days and one year posttransplant . (See "Pulmonary complications after autologous hematopoietic cell transplantation" and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)
EVALUATION — The evaluation of patients who develop dyspnea and/or cough following HCT is designed to evaluate the severity of respiratory impairment and the various potential causes of these symptoms.
The differential diagnosis includes infection (eg, cytomegalovirus and other lung infections), idiopathic pneumonia syndrome, organizing pneumonia, pulmonary alveolar hemorrhage, volume overload/heart failure, and pulmonary alveolar proteinosis. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Post hematopoietic cell engraftment'.)
Laboratory testing — Laboratory tests, such as complete blood counts, coagulation tests, liver function tests, B-type natriuretic peptide (BNP), and blood cultures are nonspecific and function to exclude other processes rather than to identify evidence of busulfan toxicity. Other studies such as serologic tests for viral or fungal infection may be indicated based on specific features of the patient presentation. (See "Overview of infections following hematopoietic cell transplantation".)
Chest imaging — Chest radiographs may be normal or may reveal bibasilar reticular opacities. High resolution computed tomography is often obtained as it is more sensitive than conventional chest radiographs and it allows better clarification of the pattern of radiographic abnormalities [28,31]. Patterns associated with busulfan toxicity include ground glass opacities, asymmetric peripheral and peribronchial consolidation, centrilobular nodules, reticulation, and dependent consolidation . However, in virtually all cases, busulfan was combined with other agents, so it is difficult to know whether any particular agent was uniquely responsible.
Pulmonary function tests — Among patients with lung toxicity following busulfan therapy, pulmonary function tests (PFTs) show a reduction in the diffusing capacity for carbon monoxide (DLCO) and eventually a restrictive ventilatory defect [32,33]. One prospective study, for example, evaluated changes in PFTs among 43 patients before and after a conditioning regimen of busulfan plus cyclophosphamide prior to HCT . DLCO was decreased by 20 and 15 percent upon follow-up examination 3 and 12 months after transplant, respectively. In addition, the ratio of the forced expiratory volume in one second (FEV1) to the forced vital capacity (FVC) increased, reflecting the development of a restrictive pattern. After five years, baseline values were restored for all variables, except in four patients who developed obliterative bronchiolitis . (See "Pulmonary complications after autologous hematopoietic cell transplantation", section on 'Bronchiolitis obliterans' and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Airflow obstruction and bronchiolitis obliterans'.)
Bronchoscopy — Bronchoscopy and bronchoalveolar lavage (BAL) are performed in most patients with suspicion of drug-induced pulmonary toxicity, largely to exclude other processes such as infection (eg, cytomegalovirus), lymphangitic spread of tumor, and diffuse alveolar hemorrhage. Both lymphocytosis and neutrophilia have been reported in BAL from patients with busulfan-induced pulmonary toxicity, in addition to atypia in type I pneumocytes [26,35]. Diffuse alveolar hemorrhage has been associated with busulfan in a case report, but is uncommon . However, it is not uncommon for the BAL findings to be normal. The technique of BAL and the evaluation of diffuse alveolar hemorrhage are discussed separately. (See "Basic principles and technique of bronchoalveolar lavage" and "The diffuse alveolar hemorrhage syndromes", section on 'Bronchoalveolar lavage'.)
Cellular atypia may be seen on BAL in patients who have been treated with busulfan (or other alkylating agents). While the presence of cellular atypia establishes that the patient has had significant exposure to busulfan, it does not confirm that the patient's symptoms and radiographic abnormalities are due to the drug. (See 'Pathogenesis and pathology' above.)
Among patients with chronic myelogenous leukemia who were treated with busulfan for several years, several case reports described a clinical presentation of pulmonary alveolar proteinosis (PAP) with periodic acid-Schiff (PAS)-positive lipoproteinaceous granular material and foamy macrophages on BAL or transbronchial biopsy [36,37]. However, PAP has also developed in patients with CML who were not treated with busulfan and may actually be a feature of the underlying disease related to macrophage dysfunction [38,39]. Furthermore, this complication has not been seen in patients receiving busulfan as a component of the conditioning regimen for HCT. (See "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults", section on 'Definitions and classification'.)
DIAGNOSIS — The diagnosis of busulfan-induced pulmonary toxicity is usually established clinically based upon a history of drug exposure and a compatible clinical picture, but it is a diagnosis of exclusion. The differential diagnosis includes infection, radiation-induced lung injury, pulmonary edema, lung involvement by an underlying malignancy, pulmonary alveolar proteinosis, pulmonary thromboembolism, graft-versus-host disease (in patients who have undergone hematopoietic stem cell transplantation), and pulmonary hemorrhage.
Laboratory testing (eg, complete cell counts, coagulation tests, B-type natriuretic peptide [BNP], blood cultures, sputum cultures, viral culture, and viral serology) is used to determine whether other disease processes are contributing to the patient's respiratory compromise. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Diagnosis' and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Pulmonary infections' and "Overview of infections following hematopoietic cell transplantation".)
Bronchoalveolar lavage is used to exclude infection, pulmonary alveolar proteinosis, and pulmonary hemorrhage, while lung biopsy may be used to exclude lung involvement by malignancy and infection not identified by less invasive tests. As observed with other cytotoxic drug-induced lung disease, cytologic and histomorphologic findings due to busulfan-induced pulmonary toxicity are nonspecific . (See 'Pathogenesis and pathology' above and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Bronchoscopy'.)
TREATMENT — The optimal treatment of busulfan associated lung toxicity is not known. Given that most patients with busulfan-induced pulmonary toxicity received the drug weeks to months before the diagnosis of lung toxicity, therapy is mainly supportive and includes supplemental oxygen as needed, vaccinations against influenza, COVID-19 and pneumococcal infection, and pulmonary rehabilitation. Some spontaneous improvement may occur. As an example, in a series of 43 patients who received conditioning with busulfan and cyclophosphamide prior to allogeneic hematopoietic stem cell transplantation (HCT), a 10 percent decrease in lung volumes and a 20 percent decrease in diffusing capacity were found at three months after HCT, but subsequently normal lung volumes and a partial improvement in diffusing capacity for carbon monoxide (DLCO) were noted at one year . In a followup study, lung volumes and gas transfer were decreased in 43 patients at one year after busulfan, but normalized by five years .
Anecdotal reports, almost all of which involve patients who were receiving long-term busulfan for chronic myelogenous leukemia (CML), describe responses to systemic glucocorticoids, but no controlled studies are available and some patients had only a transient response [1,27,28,40,41]. For patients who are believed to have busulfan toxicity following HCT, the decision to initiate glucocorticoid therapy usually depends on the severity and rapidity of worsening of pulmonary impairment and on the pulmonary histopathology, if known. As an example, if the patient has a known histopathology that is usually responsive to glucocorticoids (eg, organizing pneumonia, nonspecific interstitial pneumonitis), it is reasonable to use glucocorticoid therapy as would be done for that disease in other clinical settings. In addition, for patients with rapid deterioration in lung function and no evidence of infection, we initiate a trial of oral glucocorticoids with the equivalent of prednisone at a dose of 1 mg/kg per day. If no response is seen within four to six weeks, the glucocorticoids are tapered and stopped. The approach to glucocorticoid therapy for pulmonary toxicity associated with antineoplastic therapy is discussed separately. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Glucocorticoids'.)
Subsequent tapering of glucocorticoid therapy is based on the clinical response, as assessed by symptoms, pulse oxygen saturation, pulmonary function tests, and radiographic imaging. The potential adverse effects of glucocorticoid therapy are reviewed separately. (See "Major adverse effects of systemic glucocorticoids".)
The issue of rechallenge with busulfan in patients with prior lung toxicity has not been directly assessed, but it is generally not clinically relevant as administration of busulfan is a one-time event in patients undergoing HCT. (See 'Epidemiology and risk factors' above.)
SUMMARY AND RECOMMENDATIONS
●Symptomatic pulmonary injury is thought to occur in fewer than 8 percent of patients who receive busulfan, especially since routine pharmacokinetic monitoring of busulfan blood levels has been established in many transplant centers; however, the true incidence is unknown. Modern data examining the risk of pulmonary toxicity are derived from patients receiving busulfan in addition to other myelosuppressive chemotherapy agents and/or radiation therapy prior to hematopoietic cell transplantation, where the incidence has been variable and interpretation complicated by competing causes of pulmonary toxicity, particularly cytomegalovirus (CMV) pneumonitis. Nonetheless, the risk of pulmonary injury may be lower in busulfan-containing preparative regimens, compared with those that include total body irradiation. (See 'Epidemiology and risk factors' above.)
●The cytologic and histologic findings in busulfan-induced pulmonary toxicity are nonspecific. Lung biopsy specimens reveal pneumocyte dysplasia (degeneration of type I cells, atypical hyperplastic type II cells), atypical bronchial lining cells, mononuclear cell infiltration, and fibrosis. (See 'Pathogenesis and pathology' above.)
●Symptoms of busulfan-induced pulmonary injury typically include cough and progressive dyspnea on exertion. Fever and weight loss may be present. (See 'Clinical features' above.)
●On high resolution computed tomography (HRCT), radiographic patterns associated with busulfan lung toxicity include ground glass opacities, asymmetric peripheral and peribronchial consolidation, centrilobular nodules, and increased reticular markings. (See 'Chest imaging' above.)
●The diagnosis of busulfan-induced pulmonary toxicity is usually established clinically and is a diagnosis of exclusion. The differential diagnosis includes infection (particularly with CMV), radiation-induced lung injury, pulmonary edema, lung involvement by an underlying malignancy, pulmonary alveolar proteinosis, and pulmonary hemorrhage. (See 'Diagnosis' above.)
●For patients with suspected lung toxicity due to busulfan, the main purpose of bronchoalveolar lavage (BAL) is to exclude other processes such as infection, pulmonary alveolar proteinosis, diffuse alveolar hemorrhage, and metastatic spread of the underlying cancer. A lung biopsy is indicated when the patient has progressive or severe disease and the cause of the pneumonitis is uncertain. (See 'Diagnosis' above and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Diagnosis'.)
●For patients with busulfan-induced pulmonary toxicity, the main therapeutic intervention is supportive care. (See 'Treatment' above.)
●For patients with moderate to severe busulfan-induced pulmonary toxicity (eg, dyspnea at rest, a decrease in oxygen saturation below 90 percent or more than 4 percent decrease from baseline, or worsening clinical status) and no evidence of infection, we suggest administering systemic glucocorticoid therapy, rather than observation and supportive care alone (Grade 2C). The initial dose is the equivalent of oral prednisone 1 mg/kg daily; intravenous glucocorticoids may be used initially. (See 'Treatment' above and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Glucocorticoids'.)
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