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Acute respiratory failure associated with cladribine pneumonitis

We report the first described case of cladribineassociated pulmonary toxicity with the development of a diffuse interstitial pneumonitis and hypoxaemic respiratory failure after the first course of cladribine. A 75-year-old woman was referred with an IgA kappa paraprotein 12 months previously. A bone marrow aspirate showed an infiltrate with small mature lymphoid cells (CD20 + , CD5 + , CD10 – , CD19 + , CD23 + , CD79b – , weak kappa). There was no peripheral blood involvement. This is consistent with a lymphocytic nonHodgkin’s lymphoma. Her background history included mild chronic obstructive pulmonary disease (ex-smoker with a 75 pack year history, forced expiratory volume in 1 s 73% predicted), gastro-oesophageal reflux disease and spinal stenosis. Her medications included allopurinol, temazepam and paracetamol/codeine. She was treated in January 2003 for lethargy, bone pain and weight loss. Cladribine and Mabthera (anti-CD20 monoclonal antibody; Roche Products, Sydney, Australia) were used in combination. The cladribine was given in an i.v. dose of 6.4 mg daily for 3 days. One dose of mabthera was administered. Mabthera was to be given for four doses over a period of 4 weeks. Seven to 10 days after completing the course of cladribine, the patient developed a non-productive cough, progressive dyspnoea and night sweats. Examination revealed a temperature of 38.2 ° C and widespread crackles on auscultation. Arterial blood gas on room air showed a pH 7.46, pCO 2 39 mmHg, pO 2 45 mmHg and saturations of 83%. The white cell count was 5.5 × 10 9 /L with 71% neutrophils. The haemoglobin was 120 g/L and the platelet count 337 × 10 9 /L. The chest radiograph showed a new diffuse bilateral reticulonodular infiltrate and a high-resolution computed tomography image of the chest confirmed a diffuse ground glass opacification on the background of mild upper lobe centrilobular emphysema (Fig. 1). A gallium scan showed intense diffuse lung uptake. The patient was commenced on i.v. trimethoprim–sulfamethoxazole and an open lung biopsy was performed the same day. The biopsies showed an organizing interstitial pneumonitis with bronchiolitis obliterans organizing pneumonia-like changes and a desquamative interstitial pneumonia-like reaction. All special stains, cultures and nucleic acid amplification for organisms including fungi, respiratory viruses, mycobacteria and Pneumocystis jiroveci were negative. After the preliminary stains excluded an infectious agent, the i.v. trimethoprim–sulfamethoxazole was ceased and high-dose i.v. methylprednisolone (500 mg) was given daily for 3 days. Oral prednisolone (1 mg/kg) was given daily after the initial pulse of methylprednisolone. Subsequent chest radiography showed clearing of the infiltrates and gas exchange returned to normal. The patient was discharged from hospital on a tapering dose of prednisolone. This is the first case report to describe the association of cladribine and interstitial pneumonitis. Cladribine (2-Chorodeoxyadenosine, 2-CdA) is a relatively new deoxyadenosine analogue and exhibits activity against a variety of lymphoid tumours, including chronic lymphocytic leukaemia, hairy cell leukaemia and lowgrade non-Hodgkin’s lymphoma. Cladribine is chemically related to the agent fludarabine, which is also used in these diseases. The onset of symptoms after cladribine suggests that cladribine caused the pulmonary injury. This would be consistent with several case reports of fludarabine being implicated with drug-induced pulmonary disease. 1–4 Although this patient had received another agent, we believe it is less likely to be involved. Mabthera is more commonly associated with acute respiratory presentations related to the infusion. The reactions described are dyspnoea, bronchospasm, hypoxia and respiratory failure, which are unrelated to interstitial lung disease. However, a letter to the New England Journal of Medicine in 2003 has reported two