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Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3380-3381 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.0164
Rapid Response to High-Dose Steroids of Severe Bortezomib-Related Pulmonary Complication in Multiple MyelomaDivision of Hematology, Institute of Radiology, Foundation IRCCS Policlinico San Matteo, University of Pavia, Italy To the Editor: The recent extensive use of bortezomib (Velcade; Millennium Pharmaceuticals Inc, Cambridge, MA) in multiple myeloma patients has increased our knowledge about its efficacy, but has revealed some complications whose pathogenesis remains often undefined.1 Among extrahematologic adverse effects, neuropathy and gastrointestinal symptoms are the most commonly reported, whereas severe pulmonary complications have been described only anedoctally.2,3 This ominous condition has been reported to promptly resolve with corticosteroids. We describe a case of pulmonary complication in a 66-year-old man with multiple myeloma refractory to first-line chemotherapy and treated with bortezomib (1.3 mg/mq, days 1, 4, 8, and 11 in 21-day cycles) and dexamethasone (20 mg intravenously on days 1, 2, 4, 5, 8, 9, 11, and 12). He had a history of chronic obstructive pulmonary disease and well-controlled essential hypertension. After the second cycle of bortezomib, the patient developed severe acute respiratory failure (pO2, 39.5 mmHg; SO2, 72%; pCO2, 35.8 mmHg; pH, 7.41) without fever. High-resolution computed tomography (CT) of the chest showed bilateral pulmonary lesions in prevalence in the peripheral sites of the upper lobes with bilateral pleural effusion: consolidations in dorsal segments of lower lobes with air bronchogram, ground-glass opacities (GGO) in peribronchial and perivascular areas of upper lobes. Lower lobes were GGO free. Drug-induced lung lesions are classified as bronchiolitis obliterans organizing pneumonia, diffuse alveolar damage, bronchiolitis obliterans, or desquamative alveolitis and fibrosis. This radiological pattern mainly suggested bronchiolitis obliterans organizing pneumonia because of the presence of GGO in peripheral consolidation with air bronchogram, although the prevalent apical location was atypical (Fig 1A and 1B). Peripheral leukocyte count was 5.8 x 109/L. Blood cultures tests were negative. No invasive investigations, as bronchoalveolar lavage or transbronchial biopsy were performed because of poor general conditions and severe thrombocytopenia. We administered intravenous methilprednisolone 500 mg/24 hours for 2 days and oxygen therapy. The clinical conditions rapidly improved with progressively reduced need for oxygen therapy. Patient continued steroid administration with intravenous dexamethasone 8 mg/d, tapered after 8 days to 4 mg/d intravenously, with further improvement of respiratory conditions. We performed a CT scan after 15 days since the acute event showed considerable reduction of parenchimal consolidations and disappearance of GGO (Fig 2A and 2B). The patient was discharged without respiratory symptoms.
This is a new case of severe pulmonary complication related to bortezomib, which rapidly responded and resolved with steroid administration. Its occurrence was sudden and unforeseeable. Cytohystologic evaluation is often impracticable because of the associated thrombocytopenia and the critical conditions of patients. The pathogenesis of the damage is still undefined, but a proinflammatory role of bortezomib, by release of cytokines as tumor necrosis factor-  or interleukin-6, has been suggested.4 The rapid response to steroids favors this latter hypothesis. Some differences can be found in this case with respect to those described by Miyakoshi et al.2 Respiratory failure developed, although the patient was receiving dexamethasone in association to bortezomib; the cases previously described developed pulmonary complication in early phases of treatment (approximately 1 month since the start of bortezomib), while our patient presented dyspnea after completion of the second cycle. Finally, three of four patients described by Miyakoshi et al received higher doses of steroids (methilprednisolone 1,000 mg/24 hours for 2 to 4 days) than those adopted in our patient, who showed a rapid improvement after the first dose administration of methylprednisolone at the dose of 500 mg. In conclusion, clinicians must keep into account this severe complication in patients being treated with bortezomib. However, this ominous adverse effect may rapidly resolve after prompt administration of high-dose steroids. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003 2. Miyakoshi S, Kami M, Yuji K, et al: Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma. Blood 107:3492-3494, 2006 3. Boyer JE, Batra RB, Ascensao JL, et al: Severe pulmonary complication after bortezomib treatment for multiple myeloma. Blood 108:1113, 2006 4. Min CK, Lee S, Kim YJ, et al: Cutaneous leucoclastic vasculitis (LV) following bortezomib therapy in a myeloma patient: Association with pro-inflammatory cytokines. Eur J Haematol 76:265-268, 2006[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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