0041-1337/98/6610-1330$03.00/0 TRANSPLANTATION Vol. 66, 1330 –1334, No. 10, November 27, 1998 Copyright © 1998 by Lippincott Williams & Wilkins Printed in U.S.A. RESULTS OF DIFFERENT STRATEGIES FOR REDUCING CYTOMEGALOVIRUS-ASSOCIATED MORTALITY IN ALLOGENEIC STEM CELL TRANSPLANT RECIPIENTS 1 PER LJUNGMAN, 2,3 JOHAN ASCHAN, 2 ILONA LEWENSOHN-FUCHS, 4 STEFAN CARLENS, 5 KAJSA LARSSON, 2 BERIT L ¨ ONNQVIST, 2 JONAS MATTSSON, 5 ELDA SPARRELID, 6 JACEK WINIARSKI, 7 AND OLLE RINGD ´ EN 5,8 Departments of Hematology, Clinical Virology, Clinical Immunology, Infectious Diseases, Pediatrics, and Transplantation Surgery, Huddinge University Hospital, Karolinska Institutet, Huddinge, Sweden Background. Several preventive strategies against cytomegalovirus (CMV) disease have been developed during the last decade. These have frequently been used in combination, and it has been difficult to iden- tify each strategy’s contribution. Methods. Risk factors for CMV disease, death in CMV disease and transplant-related mortality were ana- lyzed in 584 patients, who underwent a total of 594 allogeneic bone marrow transplants. Results. The overall probability of CMV disease was 8.9%. No seronegative patient who had a seronegative marrow donor developed CMV disease. The corre- sponding probabilities for seronegative patients with seropositive donors, seropositive patients with sero- negative donors, and seropositive patients with sero- positive donors were 5.4%, 13.7%, and 11.7%, respec- tively. In multivariate Cox models, the use of preemptive antiviral therapy and being CMV-seroneg- ative reduced the risk for CMV disease, CMV-associ- ated death, and transplant-related mortality (TRM). Patients who received unrelated or mismatched fam- ily donor transplants had increased risks for CMV dis- ease, CMV-associated death, and TRM. Older age was a significant risk factor for CMV disease and TRM. A total of 258 patients who were monitored by polymer- ase chain reaction for CMV DNA were analyzed sepa- rately to assess whether addition of another CMV pre- ventive strategy could give benefit. Patients who received mismatched or unrelated donor transplants had increased risk for CMV disease, death in CMV disease, and TRM. High-dose acyclovir prophylaxis or addition of intravenous immune globulin had no influ- ence. Conclusions. Preemptive therapy based on polymer- ase chain reaction for CMV DNA was associated with reduced risks for CMV disease, CMV-associated death, and TRM, whereas other prophylactic modalities did not give additional benefit. Cytomegalovirus (CMV*) infection has been one of the most important complications to allogeneic bone marrow transplantation (BMT). For many years, effective manage- ment of CMV infection was hampered by slow diagnostic techniques and no effective prophylaxis. During the last de- cade, several new developments have allowed the use of different strategies for management of CMV infections after BMT. Intravenous immune globulin has been used exten- sively, although its efficacy has been controversial. Antiviral chemoprophylaxis with acyclovir or ganciclovir was studied in large randomized trials (1–3). Preemptive therapy with ganciclovir or foscarnet based on antigenemia or polymerase chain reaction (PCR) has during the last few years evolved as a widely used preventive strategy (4–7). However, these de- velopments have happened more or less simultaneously; moreover, these strategies have often been used concur- rently. Therefore, it has been difficult to assess each devel- opment’s impact on risk for and outcome of CMV disease in allogeneic BMT recipients. The aims of the present study were to investigate the impacts of factors known at the time of transplant on subsequent CMV disease, CMV-associated mortality, and transplant-related mortality (TRM) and to identify patients with increased risk for development of CMV-associated complications with modern preventive strat- egies. PATIENTS AND METHODS A total of 584 consecutive allogeneic BMT patients who received transplants between 1975 and June 30, 1997 were included in the study. Ten patients received repeat transplants after receiving a second preparative regimen due to rejection or relapse. Thus, 594 transplants were analyzed in the study. Patients who received syn- geneic transplants were excluded from the study. Patient character- istics are shown in Table 1. Preparative regimens. The BMT procedures have been published previously (8 –10). Patients with malignancies were in almost all cases treated with either cyclophosphamide (60 mg/kg for 2 consec- utive days) followed by total body irradiation (TBI; 10 Gy) with the lungs shielded to receive a dose of 9 Gy or busulfan (4 mg/kg for 4 consecutive days) followed by cyclophosphamide (60 mg/kg for 2 consecutive days). In a small series of patients receiving T-cell- depleted grafts, the dose of TBI was reduced to 7.5 Gy with a lung dose of 7 Gy in combination with 6 Gy of total lymphoid irradiation. In patients receiving unrelated donor transplants for hematological malignancies, antithymocyte globulin (ATG) or OKT-3 was added 1 Supported by the Swedish Cancer Society. 2 Department of Hematology. 3 Address correspondence to: Per Ljungman, Department of He- matology, Huddinge University Hospital, SE-14186 Huddinge, Swe- den. E-mail: per.ljungman@medhs.ki.se. 4 Department of Clinical Virology. 5 Department of Transplantation Surgery. 6 Department of Infectious Diseases. 7 Department of Pediatrics. 8 Department of Clinical Immunology. * Abbreviations: ATG, antithymocyte globulin; BMT, bone marrow transplantation; CMV, cytomegalovirus; GVHD, graft-versus-host disease; PCR, polymerase chain reaction; TBI, total body irradiation; TRM, transplant-related mortality. 1330