Correspondence

Interstitial Pneumonitis Related to Rituximab Therapy

N Engl J Med 2003; 348:2690-2691June 26, 2003

Article

To the Editor:

Rituximab targets CD20+ B cells. It is used increasingly for the treatment of B-cell non-Hodgkin's lymphoma, alone or in combination with cytotoxic agents.1,2 We report two patients with non-Hodgkin's lymphoma in whom interstitial pneumonitis developed after rituximab therapy.

Patient 1 was an 82-year-old woman who presented with bruising. Her blood count showed a hemoglobin concentration of 8.6 g per deciliter, a white-cell count of 57,100 per cubic millimeter, a lymphocyte count of 44,900 per cubic millimeter, and a platelet count of 32,000 per cubic millimeter. A bone marrow biopsy showed diffuse infiltration with small BCL1+ and CD20+ lymphoid cells, findings that were consistent with mantle-cell lymphoma. She was treated with weekly rituximab, at a dose of 375 mg per square meter of body-surface area. Worsening dyspnea developed with each course of treatment. The history and physical examination were unremarkable. Pulse oximetry and analysis of arterial blood gases confirmed the presence of hypoxemia. Helical computed tomographic scanning showed ground-glass shadowing. Pulmonary-function tests demonstrated a restrictive pattern and a diffusion deficit that was consistent with interstitial pneumonitis (Table 1Table 1Results of Pulmonary-Function Tests at the Diagnosis of Interstitial Pneumonitis and after Corticosteroid Treatment.).

The patient was treated with prednisolone (20 mg daily). She had a dramatic recovery that was confirmed by repeated pulmonary-function tests (Table 1). Further rituximab therapy has been withheld. We continue to follow the patient.

Patient 2 was a 69-year-old man who presented with high-grade testicular non-Hodgkin's lymphoma with para-aortic lymphadenopathy. He was treated with monthly rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisolone chemotherapy (R-CHOP).

After four courses of treatment, he reported pyrexia and shortness of breath. Examination revealed fine bibasal inspiratory crepitations. The findings on investigation were similar to those in Patient 1 and were consistent with interstitial pneumonitis (Table 1). The patient was treated with 40 mg of prednisolone daily. Pulmonary-function tests performed after two weeks of corticosteroid treatment showed improvement (Table 1).

In these two cases of interstitial pneumonitis in patients receiving rituximab, the temporal relation implicates rituximab as the cause. We acknowledge that it is difficult to completely rule out other causes of interstitial pneumonitis in immunosuppressed patients. In both cases, investigations seeking alternative causes, including blood and sputum cultures and tests for autoantibodies, antineutrophil cytoplasmic and rheumatoid factor antibodies, and avian precipitins were negative. Other cases of interstitial pneumonitis have been reported to the drug's manufacturer, with a calculated incidence of less than 0.01 percent.3

Treatment with rituximab results in the activation of complement, B-lymphocyte cytolysis, and release of tumor necrosis factor α.4 We postulate that cytokine release is the mechanism by which interstitial pneumonitis develops. Since rituximab is being prescribed with increasing frequency for hematologic and nonhematologic disorders, we believe that physicians should be aware of this rare but serious complication.

Catherine Burton, M.R.C.P.
Richard Kaczmarski, M.D., M.R.C.Path.
Riaz Jan-Mohamed, M.R.C.P., M.R.C.Path.
Hillingdon Hospital, Uxbridge UB8 3NN, United Kingdom
r.kaczmarski@ic.ac.uk

4 References

1. 1

   Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-242
   Full Text | Web of Science | Medline

2. 2

   Hainsworth JD, Burris HA III, Morrissey LH, et al. Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin's lymphoma. Blood 2000;95:3052-3056
   Web of Science | Medline

3. 3

   Roche Global Drug Safety database. UK Drug Surveillance Centre, 2002.
   

4. 4

   Bienvenu J, Chvetzoff R, Salles G, et al. Tumour necrosis factor alpha release is a major biological event associated with rituximab treatment. Hematol J 2001;2:378-384
   CrossRef | Medline

Author/Editor Response

Regarding the two cases of reversible interstitial pneumonitis reported by Burton and colleagues, the manufacturer concurs that exposure to rituximab cannot be ruled out as a possible causal or contributory factor. The current labeling of rituximab lists “pneumonitis” in the applicable safety section.

Clinically significant lung disease develops in 10 percent of patients receiving chemotherapy.1 Patients in whom drug-induced interstitial pneumonitis develops may present weeks to months after exposure to a drug, with nonspecific respiratory symptoms (e.g., fever, dyspnea, and nonproductive cough) that can mimic many pulmonary syndromes.2,3

Since the first authorization to market rituximab was given in November 1997, we have received rare reports of interstitial pneumonitis in patients with non-Hodgkin's lymphoma who have been exposed to rituximab alone or in combination with chemotherapy. The calculated reporting rate of all cases of possible drug-induced lung injury is currently less than 0.03 percent, with more than 300,000 patients worldwide exposed to rituximab.

Mark C. Benyunes, M.D.
Genentech, South San Francisco, CA 94080

Pratik S. Multani, M.D.
IDEC Pharmaceuticals, San Diego, CA 92121

Andrew Saunders, M.D.
F. Hoffmann–La Roche, CH-4070 Basel, Switzerland

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   Erasmus JJ, McAdams HP, Rossi SE. Drug-induced lung injury. Semin Roentgenol 2002;37:72-81
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   Cleverley JR, Screaton NJ, Hiorns MP, Flint JD, Muller NL. Drug-induced lung disease: high-resolution CT and histological findings. Clin Radiol 2002;57:292-299
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   Fassas A, Gojo I, Rapoport A, et al. Pulmonary toxicity syndrome following CDEP (cyclophosphamide, dexamethasone, etoposide, cisplatin) chemotherapy. Bone Marrow Transplant 2001;28:399-403
   CrossRef | Web of Science | Medline

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