Chlorambucil

A patient developed an interstitial pneumonitis while receiving chlorambucil for a chronic lymphocytic leukemia (cumulative dose, 8,340 mg). Withdrawal of drug treatment was followed by rapid improvement in the clinical condition. Bronchoalveolar lavage showed a T-lymphocytic alveolitis, whereas blood lymphocytes were predominantly of the B phenotype. The T-lymphocytic alveolitis persisted 6 weeks after drug therapy cessation with a predominant CD8 + phenotype, as observed in some hypersensitivity pneumonitis induced by drugs.

Chlorambucil (CLB) is an alkylating agent widely used in the treatment of lymphoproliferative diseases. Although the pulmonary toxicity of other alkylating agents such as busulfan and cyclophosphamide is not rare, only 13 cases of CLB-induced pulmonary disease have been reported in the literature.[1-7]

We report the first case, to our knowledge, of CLB pneumonitis with documented bronchoalveolar lavage (BAL) cell data. The results suggest a cell-mediated immunologic mechanism in the pathogenesis of this iatrogenic pneumonitis.

CASE REPORT

A 48-year-old male nonsmoker was admitted to the hospital because of a 2-week history of nonproductive cough and exertional dyspnea. He had been treated with CLB from 1985 to 1988 and again since July 1991 for 8 months for chronic lymphocytic leukemia. The cumulative dose of CLB ingested was 8,340 mg. He did not receive any other treatment. Anamnesis did not detect any exposition to inhaled antigens.

At the time of hospital admission, the patient was in good general condition; his temperature was 38 [degrees] C. Physical examination revealed bibasilar crackles. A chest radiograph, which was normal 3 years earlier, disclosed a diffuse reticulonodular pattern. High-resolution computed tomography of the chest disclosed an important profusion of micronodules diffusely and homogenously disseminated in both lungs (Fig 1). No mediastinal lymphadenopathy was found. Arterial blood gas analysis detected severe hypoxemia (50 mm Hg) with hypocapnia (30 mm Hg) while breathing room air. The blood white cell count was 17.4 x [10.sup.9]/L with 12.2 x [10.sup.9]/L lymphocytes. Lactate dehydrogenase level was normal, and no other biologic abnormality was present. Serologic testing for Mycoplasma, Chlamydia, Legionella, and HIV-1 was negative. Results of fiberoptic endobronchial examination were normal.

The BAL cell analysis disclosed a high cell count with marked lymphocytosis (1,000 x [10.sup.3] cells per milliter with 68 percent lymphocytes). Specific stains and cultures for pathogens were negative. Hemosiderin-laden macrophage stains were negative. Diagnosis of CLB-associated lung disease was suspected and the drug treatment was withdrawn. Within 24 h, apyrexia was observed and clinical condition rapidly improved without any treatment. Six days after withdrawal of the drug therapy, the blood gas values and the chest radiograph had returned to normal. The lung volumes, as measured by spirometry, were within the normal range, whereas the diffusing capacity of carbon monoxide was slightly reduced (68 percent of predicted value).

Six weeks later, while the clinical condition and the chest radiograph were normal, a second BAL was performed. The BAL cell results are shown in Table 1. A marked alveolar T lymphocytosis, predominantly of the CD8 + phenotype, was found, contrasting with the peripheral blood B lymphocytosis. Resumption of drug therapy was not attempted because this procedure was judged to be potentially harmful.

DISCUSSION

Pleuropulmonary damage associated with CLB has been reported in 13 cases since the original report of Rubio et al[1] in 1972, despite its wide use as an antineoplastic agent, particularly in the treatment of chronic lymphocytic leukemia.[1-7] The clinical and radiographic features are nonspecific and usually include cough, dyspnea of subacute onset, fever, and anorexia. Bibasilar crackles are common. Chest radiographs reveal a diffuse bibasilar reticulonodular pattern. A restrictive ventilatory defect and a marked reduction in the Dco have been reported.[4,5] In the previously reported cases, diagnosis was made on the basis of the pulmonary histopathologic results. Findings are similar to those associated with other alkylating agents, involving hyperplasia of alveolar lining cells with marked nuclear atypia along with a mononuclear cell interstitial infiltrate and focal interstitial fibrosis.[4,5] In a few cases, pulmonary disease developed while the patients received a combination of CLB and cortiocosteroids.[2,3,6,7] There was no correlation between the cumulative oral dose of the medication and the development of lung toxicity since total doses ranged between 2,000 [mg.sup.7] and 7,500 [mg.sup.5] and treatment duration ranged from 6 months to 3.5 years.

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In our patient, CLB-induced interstitial pneumonitis seems likely. First, the rapidly favorable outcome without specific treatment and the BAL lymphocyte phenotyping ruled out pulmonary involvement by the chronic lymphocytic leukemia. Second, neither infectious cause nor any systemic disease could be detected on the basis of clinical and biologic data. Finally, the patient received no other medication and there was no exposition to inhaled antigens.

This pneumonitis had the clinical, radiologic, and functional features of hypersensitivity pneumonitis. Withdrawal of CLB therapy was immediately followed by relief of symptoms and clearing of chest radiographs without the need for steroids. The BAL cell analysis gave results similar to those obtained in hypersensitivity pneumonitis due to inhalation of organic dusts[8] or to treatment with other drugs,[9,10] namely, lymphocytosis and a decrease in the helper/suppressor (CD4/CD8) T-cell ratio. Persistent BAL lymphocytosis 6 weeks after cessation of drug therapy is not surprising in this context.[10] In our patient, 16 percent of CD8 + BAL lymphocytes were also HLA-DR-positive, suggesting that they were activated. A substantial proportion of alveolar T lymphocytes have been shown to be activated in organic antigen-induced hypersensitivity pneumonitis.[11]

In summary, this patient presented with a CLB-associated interstitial pneumonitis with characteristics of an hypersensitivity pneumonitis. Bronchoalveolar lavage ruled out the pulmonary involvement of chronic lymphocytic leukemia and an infectious process, and suggested the diagnosis of drug-induced pneumonitis. Early diagnosis of CLB-associated interstitial pneumonitis is needed because drug treatment cessation provides resolution of symptoms and possibly inhibits development of irreversible pulmonary fibrosis.

REFERENCES

[1] Rubio FA. Possible pulmonary effects of alkylating agents. N Engl J Med 1972; 287:1150-51

[2] Rose MS. Busulfan toxicity syndrome caused by chlorambucil. BMJ 1975; 1:123

[3] Refyem O. Fatal intra-alveolar and interstitial lung fibrosis in chlorambucil-treated chronic lymphocytic leukemia. Mt Sinai J Med (NY) 1977; 44:847-51

[4] Cole SR, Myers TJ, Klatsky AU. Pulmonary disease with chlorambucil therapy. Cancer 1978; 41:455-59 chlorambucil. Chest 1979; 76:471-73

[6] Lane SD, Besa EC, Justh G, Joseph RR. Fatal interstitial lung disease following high dose chlorambucil therapy. Proc Am Soc Clin Oncol 1979; 20:313

[7] Giles FC, Smith MP, Golstone AH. Chlorambucil lung toxicity. Acta Haematol 1990; 83:156-58

[8] Hirata T, Nagai S, Ohshima S, Izumi T. Comparative study of T-cell subsets in BAL fluid patients with hypersensivity pneumonitis and sarcoidosis. Chest 1982; 82:232

[9] Israel-Biet D, Venet A, Caubarrere I, Bonan G, Danel C, Chretien J, et al. Bronchoalveolar lavage in amiodarone pneumonitis: cellular abnormalities and their relevance to pathogenesis. Chest 1987; 91:214-19

[10] Akoun GM, Cadranel JL, Milleron BJ, D'Ortho MP, Mayaud CM. Bronchoalveolar lavage cell data in 19 patients with drug-associated pneumonitis. Chest 1991; 99:98-104

[11] Semenzato G, Agostini C, Zambello R, Trentin L, Chilosi M, Pizzolo G, et al. Lung T cells in hypersensitivity pneumonitis: phenotypic and functional analyses. J Immunol 1986; 137:1164-72

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