Coronary ischemia related to alemtuzumab therapy
Authors: A.L. Basquiera, A.R. Berretta, J.J. García, E.D. Palazzo
Journal: Annals of Oncology (2004)

Alemtuzumab is a humanized monoclonal antibody targeted to lymphocytes through the CD52 receptor. This agent has been demonstrated to reduce the amount of malignant lymphocytes in patients with chronic lymphocytic leukemia (CLL), and in turn, to achieve a 33% response in patients previously treated with alkylating agents and who have failed fludarabine therapy [1.Rai K.R. Freter C.E. Mercier R.J. et al.Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine.J Clin Oncol. 2002; 20: 3891-3897Crossref PubMed Scopus (291) Google Scholar, 2.Keating M.J. Flinn I. Jain V. et al.Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study.Blood. 2002; 99: 3554-3561Crossref PubMed Scopus (895) Google Scholar]. Common side-effects have been described related to drug infusion, such as rigors, fever, nausea, vomiting and rash. In addition, dyspnea, hypotension and hypoxia may occur [2.Keating M.J. Flinn I. Jain V. et al.Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study.Blood. 2002; 99: 3554-3561Crossref PubMed Scopus (895) Google Scholar]. The use of the subcutaneous route has been associated with less severe reactions [3.Lundin J. Kimby E. Björkholm M. et al.Phase II trial of subcutaneous ant-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL).Blood. 2002; 100: 768-773Crossref PubMed Scopus (478) Google Scholar]. Herein, we present the case of a male patient with CLL who developed an acute coronary event during alemtuzumab administration. A 58 year-old patient was diagnosed with B-CLL in 1994. He initially received six cycles of fludarabine, and due to a relapse, he was placed on melphalan and prednisone for a period of 4 years. Because of no response he received other lines of chemotherapy: chlorambucil, CVP (cyclophosphamide, vincristine and prednisone) and cladribine. During the last 3 months, there has been a progressive rise in his lymphocyte count which in May 2003 reached 180 000 cell/mm3. At that time, he presented with enlargement of cervical adenopathies and skin lesions; a biopsy revealed CLL. A bone marrow core biopsy showed diffuse infiltration of CLL. The patient had a history of coronary bypass at 37 years of age and two coronary angioplasties in 1998 and 2001. After that, he remained asymptomatic. Treatment with alemtuzumab was planned and informedconsent was obtained from the patient. The white cell count was 147 000 cell/mm3. Dyphenhydramine and acetaminophen were administrated prior to infusion. He tolerated well the first intravenous dose of 3 mg and a dose of 10 mg was given on the following day. Right after the second infusion of alemtuzumab, the patient developed severe chills and fever, followed by shortness of breath, typical chest pain, hypotension and became hypoxemic. An electrocardiogram showed a depression of the ST segment in the lateral aspect. A chest radiography showed pulmonary edema. The increase of the MB fraction of creatine kinase (CK-MB) confirmed the diagnosis of non-ST elevation myocardial infarction. Echocardiographic evaluation revealed segmental hypokinesia but with normal ejection fraction, and a moderate aortic stenosis. The patient improved and two more doses of alemtuzumab 10 mg were administered subcutaneously. The following week, 30 mg was administered by the same route and 7 h after the infusion the patient developed chest pain and dyspnea. Electrocardiographic changes were observed and the patient was admitted to the coronary unit where he recovered without complications. Subcutaneous infusion of alemtuzumab was reinitiated at a dose of 10 mg and nitroglycerine patches were placed simultaneously with each injection. With this intervention no further symptoms appeared and the patient completed six more doses. One month after the beginning of therapy, the patient presented fever and had to be admitted to hospital. His white cell count was 2100 cells/mm3, blood cultures were positive for Pseudomona aeruginosa and a thorax computed tomographic scan showed multiple pulmonary infiltrates. The patient developed progressive respiratory insufficiency and died 1 week after admission. No autopsy was obtained. Damaj et al. have reported a patient with CLL without a history of coronary heart disease who suffered an acute myocardial infarction after alemtuzumab infusion [4.Damaj G. Rubio M.T. Audard V. et al.Severe cardiac toxicity after monoclonal antibody therapy [letter].Eur J Haematol. 2002; 68: 324Crossref PubMed Scopus (13) Google Scholar]. As proposed by these authors, cardiac vasospasm elicited by cytokines could be the cause of coronary ischemia. A cytokine-release syndrome has been described for intravenous therapy with rituximab, another monoclonal antibody [5.Winkler U. Jensen M. Manzke O. et al.Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with anti-CD20 monoclonal antibody (Rituximab, IDEC-C2B8).Blood. 1999; 94: 2217-2224Crossref PubMed Google Scholar]. However, our patient had chest pain even though we used the subcutaneous route. Thus, close cardiovascular monitoring should be recommended for patients receiving alemtuzumab, regardless of the route of administration.