INTRODUCTION — Chlorambucil is an alkylating chemotherapy agent. It can be given orally and is mainly used in the treatment of chronic lymphocytic leukemia (CLL). Very rarely, it has been used as an immunosuppressive agent in refractory autoimmune and inflammatory conditions like rheumatoid arthritis and sarcoidosis. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia", section on 'Chlorambucil-based therapy'.)
Other than myelosuppression, less common side effects of chlorambucil involve the gastrointestinal tract, liver, skin, and the central nervous system; lung toxicity is rare but well-documented. Chlorambucil-induced pulmonary injury will be discussed here. A more general discussion of the clinical presentation, diagnosis, and treatment of pulmonary toxicity in patients receiving systemic antineoplastic therapy is presented elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment".)
INCIDENCE AND RISK FACTORS — While the pulmonary toxicity of other alkylating agents like busulfan and cyclophosphamide is well-recognized, chlorambucil-induced pulmonary injury is rare [1]. The literature is confined to isolated case reports [2-19]. The absolute magnitude of risk is undefined. Contemporary clinical trials of chlorambucil in over 600 patients with a hematologic malignancy did not identify any cases of chlorambucil-induced pneumonitis [20-22]. This could be due to the rarity of the phenomenon or to underreporting of events occurring after completion of treatment.
There are no unifying risk factors. Pulmonary toxicity may develop while the patient is taking chlorambucil, or after stopping the drug. There appears to be no direct correlation between the dose or duration of therapy and the incidence of lung toxicity [8]; pulmonary injury has been described in patients receiving cumulative chlorambucil doses ranging from 540 to 8340 mg [5,9].
CLINICAL PRESENTATION — The most common pattern of lung injury reported in chlorambucil-treated patients is chronic interstitial pneumonitis (nonspecific interstitial pneumonia, although this nomenclature postdates most reports of chlorambucil lung toxicity), but acute interstitial pneumonia, pulmonary fibrosis, and organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia [BOOP]) have also been reported [5-8,11,12,18-20]. Interstitial lung disease may develop while the patient is taking chlorambucil or after stopping it.
In patients who develop chronic interstitial pneumonitis, symptoms usually develop six months to three years or longer after initiation of therapy; the most common presentation is the insidious onset of cough and dyspnea. Other symptoms may include weight loss, fever, and hemoptysis. Physical examination reveals fine basilar crackles and fever [13].
EVALUATION — Similar to other cases of drug-induced lung disease, the diagnosis of chlorambucil-induced lung toxicity requires a high index of suspicion in the appropriate clinical setting. The evaluation is designed to determine the severity of respiratory impairment and exclude other causes of respiratory symptoms and radiographic pulmonary opacities.(See "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment".)
Laboratory — Laboratory studies are nonspecific and largely used to assess for infection, heart failure, and changes in hematologic status. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates", section on 'Microbiologic assays' and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Routine testing'.)
Peripheral eosinophilia is generally not found in reported cases of chlorambucil lung toxicity. One case of drug rash with eosinophilia and systemic symptoms (DRESS) has been reported, but the patient did not have lung involvement [23].
Radiographic imaging — Chest radiographs demonstrate reticular opacities [9]. Chest computed tomography (CT) scans frequently show diffuse micronodular opacities. Increased reticular marking and areas of consolidation may also be seen [7,9].
Pulmonary function tests — Pulmonary function studies are typically obtained to assess the severity of respiratory impairment and may reveal a restrictive defect and decreased diffusing capacity [4,5,13,15,24]. Pulse oxygen saturation (SpO2) should be assessed to determine whether the patient has hypoxemia at rest or on exertion.
Bronchoscopy — A bronchoscopy with bronchoalveolar lavage (BAL) may be helpful in evaluating for other causes of interstitial opacities, such as lung infection, pulmonary hemorrhage, and leukemic infiltrates. A T cell alveolitis has been reported in association with chlorambucil lung toxicity, but this is not specific [9]. A transbronchial biopsy may help in identifying infection or leukemic infiltration [25]. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Bronchoscopy'.)
Lung biopsy — There is no consensus about when to obtain tissue in this setting; lung biopsy may be required to exclude alternative causes when the presentation is atypical or in patients who do not improve after cessation of the drug. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Biopsy'.)
Pathology — For patients who undergo transbronchial or surgical lung biopsy, the histopathology of chlorambucil-induced pulmonary toxicity is similar to that seen in toxicity from other drugs and reveals type II pneumocyte dysplasia, mononuclear cell infiltration, and interstitial fibrosis [12,13,16]. Organizing pneumonitis may also be seen either as isolated foci or as the predominant finding [6,7,13,24]. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Histopathology'.)
DIAGNOSIS — The diagnosis of chlorambucil-associated lung toxicity is based on the combination of the presence of a compatible clinical pattern (eg, dyspnea, cough, and radiographic opacities) in a patient who has received chlorambucil and the exclusion of infection, drug-induced pneumonitis due to other agents, radiation-induced lung injury, heart failure, leukemic infiltrates, and pulmonary hemorrhage [25,26].
Lung biopsy may not be needed. Even if performed, there are no pathognomonic findings to confirm the diagnosis of chlorambucil-induced lung injury; findings in drug-induced pneumonitis are nonspecific. The main role for lung biopsy is to exclude other processes in patients who do not improve after drug cessation. (See 'Lung biopsy' above.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of chlorambucil-induced lung toxicity includes the following:
●Infection – (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Overview of the complications of chronic lymphocytic leukemia", section on 'Infection'.)
●Leukemic infiltrates – Leukemic infiltrates were diagnosed in 6 percent of 277 patients with chronic lymphocytic leukemia (CLL) who were hospitalized with thoracic complaints [26]. The diagnosis may be suspected based on a failure to respond to drug cessation or empiric antibiotic therapy. Transbronchial or surgical lung biopsy is needed to confirm the diagnosis [25].
●Alveolar hemorrhage – Alveolar hemorrhage is a potential complication of thrombocytopenia in CLL. The diagnosis is usually made by sequential bronchoalveolar lavage (BAL). (See "The diffuse alveolar hemorrhage syndromes", section on 'Diagnostic evaluation'.)
●Heart failure – The diagnosis may be suspected on the basis of the medical history and physical examination. Brain natriuretic peptide testing and echocardiography are helpful diagnostically. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Cardiac evaluation'.)
●Pulmonary toxicity from other drugs – Many other chemotherapeutic agents are associated with pulmonary toxicity (eg, idelalisib, ibrutinib, rituximab). (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Differential diagnosis' and "Overview of the complications of chronic lymphocytic leukemia", section on 'Pneumonitis' and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Idelalisib, copanlisib, duvelisib, and alpelisib' and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Rituximab'.)
THERAPY — When chlorambucil lung toxicity is suspected, the drug should be stopped immediately. Depending on the acuity of symptoms, empiric antibiotic therapy is often indicated while waiting for the results of diagnostic studies.
The role of glucocorticoids is unclear, as many patients improve without therapy and mortality seems to be similar in patients regardless of glucocorticoid use [4,15]. In addition, chlorambucil lung toxicity has been reported in patients who were receiving combination therapy that included glucocorticoids [8]. The following represents our approach, which is based upon the severity of the respiratory impairment:
●Mild-to-moderate respiratory impairment – Given the limited data, we typically observe stable patients off of chlorambucil for a few days before considering glucocorticoid therapy.
●Persistent respiratory impairment or severe disease at presentation – For patients who do not improve within a few days after stopping chlorambucil or have severe respiratory impairment at presentation, we suggest a trial of systemic glucocorticoids since fatalities are reported, and some anecdotal reports describe success in patients with acute or subacute interstitial lung disease. (See 'Prognosis' below.)
Glucocorticoid dosing is empiric. Prednisone-equivalent doses ranging from 0.5 to 2 mg/kg per day have been used [8,20].
The optimal duration of glucocorticoids for chlorambucil lung toxicity is not known. If the patient improves with glucocorticoid therapy, tapering of the oral dose can be carried out over one to two months, as tolerated. Ongoing monitoring is needed as systemic glucocorticoid therapy is associated with a number of adverse effects, including opportunistic infection and hyperglycemia. For patients who do not improve after two to four weeks of glucocorticoid therapy, we taper more quickly to reduce adverse effects.
●Pulmonary fibrosis – The role of glucocorticoids for patients with evidence of interstitial fibrosis is less clear, as fibrosis is not glucocorticoid responsive. For patients with high-resolution computed tomography findings of honeycombing and coarse linear opacities, a brief trial of glucocorticoids may be reasonable in case a component of reversible pneumonitis is present.
Supportive measures such as supplemental oxygen and vaccination to prevent infection are employed, as indicated.
PROGNOSIS — The overall prognosis of chlorambucil lung toxicity is variable, but fatalities are common. In case reports, approximately 50 percent of patients have died despite withdrawal of the drug and treatment with glucocorticoids [2,4,6,8,9]. In a systematic review of 18 literature reports of chlorambucil lung toxicity, seven patients expired, although whether the death was directly attributed to lung damage and whether glucocorticoid therapy was administered were not always reported [20]. Many of the fatal cases seem to have developed pulmonary fibrosis [2,6,12].
This emphasizes the need for a high index of suspicion and early withdrawal of chlorambucil once lung toxicity is suspected.
Recurrent episodes of acute respiratory distress with subsequent exposures to the drug have also been described [4,12,16].With the approval of new alternative and effective therapies for chronic lymphocytic leukemia, rechallenge should rarely be necessary.
SUMMARY AND RECOMMENDATIONS
●Pulmonary toxicity from chlorambucil is rare, but well-documented by many case reports. The most common pattern is chronic interstitial pneumonitis, but acute interstitial pneumonitis and organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia [BOOP]) have also been reported. (See 'Introduction' above.)
●No direct correlation has been found between the incidence of lung toxicity and the dose or duration of therapy. (See 'Incidence and risk factors' above.)
●In chronic interstitial pneumonitis, symptoms may not develop for six months to three years after therapy. Insidious onset of cough and dyspnea is typical; fever, weight loss, and hemoptysis may also occur. (See 'Clinical presentation' above.)
●A high index of suspicion is key to making the diagnosis. Laboratory testing is nonspecific: pulmonary function tests may show restriction and a decreased diffusing capacity; chest radiographs reveal increased interstitial opacities; and chest CT scan typically shows diffuse micronodular or reticular opacities. (See 'Evaluation' above.)
●Bronchoalveolar lavage (BAL) may show a lymphocytic alveolitis, but this is not specific for chlorambucil toxicity. BAL is most useful to exclude other causes of pulmonary opacities, such as infection or hemorrhage. Transbronchial biopsy may show evidence of lung injury and provide additional information about possible infection or leukemic infiltration. (See 'Bronchoscopy' above.)
●Open or video-assisted lung biopsy is usually not necessary unless the presentation is unclear or the patient fails to improve with chlorambucil cessation. (See 'Lung biopsy' above.)
●We recommend stopping chlorambucil as soon as pulmonary toxicity is suspected.(See 'Therapy' above.)
●Although data are limited, a period of observation for a few days after stopping chlorambucil before considering glucocorticoids seems reasonable, as long as the patient has mild to moderate pulmonary symptoms and signs. (See 'Therapy' above.)
●For patients whose lung disease is persistent or progressing off chlorambucil, or who have more severe initial disease, we suggest starting glucocorticoids (eg, prednisone 1 to 2 mg/kg per day) (Grade 2C). Tapering of the oral dose can usually be accomplished over one to two months, as tolerated. (See 'Therapy' above.)
●The role of glucocorticoids for patients with CT evidence of interstitial fibrosis (eg, honeycombing, coarse linear opacities) is less clear, as fibrosis is not glucocorticoid responsive. A brief trial of glucocorticoids may be reasonable in case a component of reversible pneumonitis is present. (See 'Therapy' above.)
