Annals of Oncology Advance Access originally published online on April 27, 2005
Annals of Oncology 2005 16(8):1399; doi:10.1093/annonc/mdi232
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© 2005 European Society for Medical Oncology
Letter to the Editor |
Severe interstitial pneumonitis following rituximab and bleomycin-containing combination chemotherapy
Rituximab is effective in B-cell lymphomas as a single agent or in combination with chemotherapy [1
]. Its side-effects are generally mild but cases of severe pulmonary toxicity have recently been reported [2]. We report two patients who developed severe interstitial pneumonitis after combination of rituximab with ACVBP (adriamycin, cyclophosphamide, vindesine, bleomycin, prednisone) regimen (R-ACVBP).
Case report 1
A 52-year-old man with diffuse large B-cell lymphoma was admitted for 40.5 °C fever 12 days after the third cycle of R-ACVBP. Initial clinical examination was normal and blood count showed no neutropenia. Chest radiograph revealed slight bilateral basal pulmonary infiltrate and computed tomography (CT) scan confirmed the presence of bilateral ground-glass opacities. Oxygen saturation was 91%. After 7 days of broad-spectrum antibiotics, fever persisted and CT scan showed increased interstitial lesions. Pulmonary diffusing capacity for carbon monoxide was reduced. High-dose methylprednisone (3 mg/kg) was administered 7 days after admission. The patient immediately became afebrile with normalization of spirometric tests, and improvement of the CT scan was observed 17 days after the beginning of steroid treatment. The next cycle was administered without rituximab and bleomycin. Corticosteroid treatment was stopped after 45 days with no recurrence of pulmonary abnormalities.
Case report 2
A 59-year-old man with diffuse large B-cell lymphoma was admitted for neutropenic fever 10 days after his fourth cycle of R-ACVBP. Initial chest radiograph was normal. Neutropenia was resolved after 4 days but the patient remained febrile despite anti-infectious treatment. He then developed shortness of breath, cough, persistent fever and severe hypoxemia. A CT scan showed a left pneumothorax and diffuse bilateral confluent infiltrates. The patient was transferred to the intensive care unit and died of respiratory failure despite the introduction of methylprednisone (1 mg/kg) 21 days after the beginning of respiratory symptoms.
In both cases, investigations excluded the diagnosis of infectious interstitial pneumonitis: blood cultures and bronchoalveolar lavages (BAL) were negative for common bacteria, legionella, pneumocystis, mycobacteria, fungal pathogens and viruses. BAL cytological examination revealed alveolar macrophages, histiocytes, neutrophils, activated lymphocytes and eliminated the presence of malignant cells. Eosinophils were found in the bronchoalveolar fluid in the second patient. Lung biopsy was not performed in either case.
Bleomycin is recognized to cause interstitial pneumonitis. Even though the incidence of pulmonary toxicity with the ACVBP regimen is estimated to 1% [3], these two cases occurred among only 19 patients consecutively treated with R-ACVBP regimen in our institution. We hypothesize that the pulmonary toxicity of bleomycin could be enhanced by rituximab, perhaps through a synergic activity between cytokines released after infusion of the two compounds [4]. An alternative hypothesis is that rituximab and bleomycin act synergically to produce deleterious reactive oxygen species [5].
We believe that physicians should be aware of the possible occurrence of interstitial pneumonitis after combination of rituximab and bleomycin-containing chemotherapy. Close pulmonary surveillance should be exercised during treatment, with discontinuation of bleomycin or rituximab when pulmonary-function tests are abnormal. Early treatment with high-dose corticosteroids seems to be effective, indicating that investigations should be performed promptly in patients presenting respiratory symptoms after this combined regimen.
Centre Leon Berard, 28 rue Laennec, 69008 Lyon, France
* Email: ghesquie{at}lyon.fnclcc.fr
References
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.
2. Burton C, Kaczmarski R, Jan-Mohamed R. Interstitial pneumonitis related to rituximab therapy. N Engl J Med 2003; 348: 2690–2691. discussion 2690–2691.
3. Tilly H, Mounier N, Lederlin P et al. Randomized comparison of ACVBP and mBACOD in the treatment of patients with low-risk aggressive lymphoma: the LNH871 study. Groupe d'Etudes des Lymphomes de l'Adulte. J Clin Oncol 2000; 18: 1309–1315.
4. Bienvenu J, Chvetzoff R, Salles G et al. Tumor necrosis factor alpha release is a major biological event associated with rituximab treatment. Hematol J 2001; 2: 378–384.[CrossRef][Medline]
5. Bellosillo B, Villamor N, Lopez-Guillermo A et al. Complement-mediated cell death induced by rituximab in Bcell lymphoproliferative disorders is mediated in vitro by a caspase-independent mechanism involving the generation of reactive oxygen species. Blood 2001; 98: 2771–2777.
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