Feb 28, 2005 - Solove Research Institute,. The Ohio State University,. Columbus, OH, USA;. 2Division of Pulmonary Diseases,. Arthur James Cancer Hospital.
Bone Marrow Transplantation (2005) 35, 823–824 & 2005 Nature Publishing Group All rights reserved 0268-3369/05 $30.00
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Correspondence Diffuse alveolar hemorrhage following gemtuzumab ozogamicin Bone Marrow Transplantation (2005) 35, 823–824. doi:10.1038/sj.bmt.1704886 Published online 28 February 2005 Diffuse alveolar hemorrhage (DAH) or hemorrhagic alveolitis is a severe, often fatal, pulmonary complication of myeloablative stem cell transplantation (SCT).1 The efficacy of current therapies for DAH remains unproven, although common practice is to treat patients with highdose, pulsed methylprednisolone.2 The mortality of patients who require intubation and mechanical ventilation for DAH exceeds 80%.3–5 While primarily a complication of myeloablative SCT in patients with hematologic malignancies, DAH has been described as a rare toxicity of nontransplant therapies. DAH has been observed after use of the antiglycoprotein IIb/IIIa receptor monoclonal antibody abciximab (ReoPro),6,7 but has not been associated with the humanized anti-CD33 monoclonal antibody gemtuzumab ozogamicin (Mylotarg). We report a case of DAH in a 51-year-old white male who received two doses of gemtuzumab ozogamicin for relapsed acute myelogenous leukemia (AML) after myeloablative allogeneic SCT. This patient initially achieved complete remission with 3 þ 7 induction chemotherapy with daunorubicin and cytarabine, followed by one cycle of high-dose cytarabine. He relapsed 20 months after his initial diagnosis and received three cycles of mitoxantrone and VP-16, which failed to achieve remission. He underwent myeloablative allogeneic SCT from a matched unrelated donor. His preparative regimen consisted of busulfan 14 mg/kg, VP-16 60 mg/kg and cyclophosphamide 120 mg/kg. He received methotrexate and cyclosporine as graft-versus-host-disease (GVHD) prophylaxis. Day þ 30 bone marrow biopsy showed remission, but day þ 162 bone marrow biopsy showed relapsed AML. He received gemtuzumab ozogamicin 9 mg/m2 26 weeks after his SCT. A similar dose was given 14 days later. At 3 days after his second dose, he developed cough, dyspnea and hypoxia, eventually requiring 60% oxygen by face mask. Serial chest radiographs showed development of bilateral, diffuse alveolar infiltrates, more pronounced in the upper lobes. Multiple sputum stains and cultures showed only altered oropharyngeal microbes, and DNA hybrid capture assays for cytomegalovirus were negative. Bronchoscopy 6 days after his day 15 dose showed heavy alveolar hemorrhage that worsened with bronchoalveolar lavage (BAL), numerous lymphocytes and alveolar macrophages with degenerative changes. Bacterial, acid fast, viral and fungal cultures from the BAL were all negative. He responded rapidly to methylprednisolone 1000 mg daily, tapered 50% every 2–3 days. His symptoms improved rapidly, and he was discharged home without oxygen 12 days after initiation of high-dose steroid therapy. Bone marrow biopsy 30 days after his first dose of gemtuzumab
ozogamicin showed persistent AML. He subsequently received high-dose cytarabine followed by two doses of donor lymphocyte infusion, but failed to respond to therapy. He died of AML 4.5 months after his first dose of gemtuzumab ozogamicin. Gemtuzumab ozogamicin is one of the few treatment options available to patients with AML who relapse after allogeneic SCT. However, gemtuzumab ozogamicin has significant toxicity, most notably hepatic veno-occlusive disease (VOD).8,9 DAH has not been described as a toxicity of gemtuzumab ozogamicin, although fatal hemorrhagic and pulmonary complications have been observed. In the initial phase II studies, three patients died of hemorrhage (two cerebral, one retroperitoneal), and three additional patients died of cerebral hemorrhage more than a month after receiving gemtuzumab ozogamicin.8,9 Eight patients developed acute pulmonary complications (five adult respiratory distress syndrome, three pulmonary edema) within 24 h of receiving gemtuzumab ozogamicin, and five patients died. Six of the eight patients had a leukocyte count greater than 60 000/ml, although the complications appeared to be due to a drug reaction rather than pulmonary leukostasis.8 In contrast, our patient’s respiratory symptoms developed 17 days after his first dose of gemtuzumab ozogamicin, progressively worsened over several days, and occurred in the setting of a leukocyte count less than 1000/ml. Thus, our patient developed pulmonary toxicity quite different from that reported in the phase II licensing studies. While primarily a complication of myeloablative SCT, DAH has been described as a rare toxicity of nontransplant therapies. In particular, DAH was observed after treatment with the monoclonal antibody abciximab.6,7 Abciximab is a chimeric Fab fragment specific for platelet glycoprotein IIb/ IIIa receptors used to prevent occlusion of coronary stents. The largest published study documented seven cases of severe DAH in 2553 patients (0.27%) who received abciximab after coronary stent placement.7 Three patients died. In contrast, DAH was not observed in 5412 patients who underwent similar coronary procedures without abciximab during the same time period. Thus, monoclonal antibody therapy has been associated, albeit rarely, with DAH. In conclusion, gemtuzumab ozogamicin induced DAH in our patient 6 months after myeloablative allogeneic SCT. He responded to high-dose steroid therapy and discontinuation of the offending agent. DAH in association with gemtuzumab ozogamicin may be similar to that seen with abciximab, a much more widely used monoclonal antibody. However, the etiology of DAH remains unclear, and the mechanism by which gemtuzumab ozogamicin or other drugs induce alveolar injury is unknown.
Acknowledgements We thank Drs Thomas Yunger, Rundsarah Tahboub and Jon Walker for their assistance in the care of this patient. This work
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was supported in part by The National Institutes of Health (1 K23 CA102276-01A1 to TSL), The Sidney Kimmel Cancer Research Foundation, The Leukemia and Lymphoma Society of America and The D Warren Brown Foundation. 1
TS Lin SL Penza1 BR Avalos1 MR Lucarelli2 SS Farag1 JC Byrd1 EA Copelan1
1
Division of Hematology and Oncology, Arthur James Cancer Hospital and Richard Solove Research Institute, The Ohio State University, Columbus, OH, USA; 2 Division of Pulmonary Diseases, Arthur James Cancer Hospital and Richard Solove Research Institute, The Ohio State University, Columbus, OH, USA
References 1 Robbins RA, Linder J, Stahl MG et al. Diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Am J Med 1989; 87: 511–518. 2 Metcalf JP, Rennard SI, Reed EC et al. Corticosteroids as adjunctive therapy for diffuse alveolar hemorrhage associated
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with bone marrow transplantation: University of Nebraska Medical Center Bone Marrow Transplant Group. Am J Med 1994; 96: 327–334. 3 Huaringa AJ, Leyva FJ, Giralt SA et al. Outcome of bone marrow transplantation patients requiring mechanical ventilation. Crit Care Med 2000; 28: 1014–1017. 4 Afessa B, Tefferi A, Litzow MR et al. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002; 166: 641–645. 5 Afessa B, Tefferi A, Litzow MR, Peters SG. Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002; 166: 1364–1368. 6 Khanlou H, Eiger G, Yazdanfar S. Abciximab and alveolar hemorrhage. N Engl J Med 1998; 339: 1861–1863. 7 Kalra S, Bell MR, Rihal CS. Alveolar hemorrhage as a complication of treatment with abciximab. Chest 2001; 120: 126–131. 8 Bross PF, Beitz J, Chen G et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 2001; 7: 1490–1496. 9 Sievers EL, Larson RA, Stadtmauer EA et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33positive acute myeloid leukemia in first relapse. J Clin Oncol 2001; 19: 3244–3254.
