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Viral Infections Randomized Clinical Trial of Ganciclovir Vs Acyclovir for Prevention of Cytomegalovirus Antigenemia After Allogeneic Transplantation

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Viral Infections Randomized Clinical Trial of Ganciclovir Vs Acyclovir for Prevention of Cytomegalovirus Antigenemia After Allogeneic Transplantation Bone Marrow Transplantation (2002) 30, 945–951 2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Viral infections Randomized clinical trial of ganciclovir vs acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation LJ Burns, W Miller, C Kandaswamy, TE DeFor, ML MacMillan, J-A van Burik and DJ Weisdorf Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN, USA Summary: Bone Marrow Transplantation (2002) 30, 945–951. doi:10.1038/sj.bmt.1703770 Cytomegalovirus (CMV) disease remains a major cause Keywords: cytomegalovirus; ganciclovir; acyclovir; ran- of morbidity following allogeneic stem cell transplan- domized clinical trial tation (SCT). In a prospective randomized trial, we tested prophylactic therapy with ganciclovir or acyclo- vir for patients at high risk of disease. Ninety-one CMV seropositive recipients of related (n = 53) and unrelated Cytomegalovirus (CMV) disease is a frequent complication (n = 38) donor transplants were enrolled. All patients following allogeneic stem cell transplantation (SCT).1,2 received intravenous (i.v.) ganciclovir 5 mg/kg every CMV seropositive recipients are at a high risk of CMV h days ؊7to؊2, followed by acyclovir 10 mg/kg i.v. disease, as reactivation of latent endogenous virus is the 12 every 8 h from day ؊1 until neutrophil engraftment. dominant mechanism of infection in immunocompromised Patients were then randomly assigned to either ganciclo- patients.1–5 Despite recent advances in therapy, the mor- vir (n = 45) or acyclovir (n = 46) until day 100 post tality from CMV disease, and particularly CMV pneu- transplant. Any degree of antigenemia was treated with monia, remains quite high. Recent therapeutic strategies ganciclovir 5 mg/kg i.v. twice a day for 2 weeks, fol- have focused on the prevention of CMV disease. lowed by 5 mg/kg i.v. each weekday for 6 weeks. At day Acyclovir and ganciclovir have each been shown to be 100, the cumulative incidence of antigenemia was 31% effective prophylaxis for patients at high risk of CMV dis- (95% CI 17–45%) for ganciclovir and 41% (95% CI ease. Two prospective studies demonstrated a decrease in 26–56%) (P = 0.22) for acyclovir prophylaxis, respect- the occurrence of CMV disease as well as a survival benefit ively. The assigned prophylaxis cohort did not predict of high-dose acyclovir for allogeneic marrow transplant for CMV antigenemia. The cumulative incidence of recipients.5–7 Ganciclovir has been incorporated into vari- CMV disease at 12 months was 13% (95% CI 3–23%) ous prophylactic strategies.8–15 In each of three randomized and 17% (95% CI 6–28%) (P = 0.59) for the studies,8–10 ganciclovir prophylaxis decreased CMV infec- ganciclovir- and acyclovir-treated groups, respectively. tion and/or disease; however, there was no benefit in .An absolute neutrophil count (ANC) р1500 ؋ 106/l at overall survival randomization (P < 0.01) and grade II–IV acute graft- This study was designed to test whether prophylactic versus-host-disease (P = 0.01), but not the assigned ganciclovir is superior to high-dose acyclovir, when gan- prophylaxis cohort (P = 0.62), were independent risk ciclovir is used pre-emptively at first evidence of active factors for CMV disease. The incidence of fungal infec- CMV replication, in a prospective, randomized study. We tions and renal insufficiency was similar across treat- report an analysis of the incidence of CMV antigenemia ment groups; however, bacterial infections and second- measured at 100 days post transplant and CMV disease, in ary neutropenia occurred more frequently in the addition to a comparison of the frequency of complications ganciclovir group. With our study powered to detect a by prophylactic therapy. 60% reduction in antigenemia with ganciclovir prophy- laxis, we did not find a statistically significant difference between ganciclovir and acyclovir when used as part of Materials and methods an overall strategy for prevention of CMV antigenemia and disease in SCT, although fewer side-effects Patients occurred with acyclovir treatment. Ninety-one CMV seropositive recipients of related (n = 53) and unrelated (n = 38) donor SCT were enrolled, irrespec- Correspondence: Dr LJ Burns, University of Minnesota, Mayo Mail Code tive of donor CMV status. All patients were first-time trans- 286, Minneapolis, MN 55455, USA plant recipients. HLA (human leukocyte antigen matching) Received 26 April 2002; accepted 16 September 2002 was determined by A, B serology and DRB high-resolution Ganciclovir vs acyclovir for CMV prophylaxis LJ Burns et al 946 techniques. Data regarding the pre-transplantation charac- CMV surveillance teristics, post-transplantation complications, and survival were collected prospectively by the Biostatistics Support Antigenemia assays were performed weekly from day 0 to Group at the University of Minnesota using standardized day 100 post transplant. The assay was done using a com- methods. Details of CMV therapy and clinical outcomes mercial kit (CMV-Vue: Incstar, Stillwater, MN, USA) were obtained from a review of patients’ medical records. according to the manufacturer’s instructions. Standard methods were used for isolation of CMV from broncho- alveolar lavage fluid and tissue samples, as previously Protocol design described.15 As shown in Figure 1, all patients received intravenous (i.v.) ganciclovir 5 mg/kg every 12 h days Ϫ7toϪ2, fol- CMV therapy lowed by acyclovir 10 mg/kg i.v. every 8 h from day Ϫ1 With any degree of antigenemia (у1 positive cell/50 000 until neutrophil engraftment (absolute neutrophil count leukocytes), prophylaxis was discontinued and patients (ANC) у750 ϫ 106/l for 2 consecutive days). Patients were treated pre-emptively with an induction dose of gan- were then randomly assigned, with stratification for related ciclovir 5 mg/kg i.v. twice daily for 2 weeks, followed by vs unrelated donor transplant, to either acyclovir 800 mg 5 mg/kg i.v. every weekday for 6 weeks. If antigenemia (adults) or 18 mg/kg (children) orally 5 times a day (n = 46) recurred during or after the maintenance phase, induction or ganciclovir 5 mg/kg i.v. every weekday (Monday to with twice daily ganciclovir was restarted and was again Friday) (n = 45) until day 100. All patients received i.v. followed by 6 weeks of maintenance therapy. Foscarnet immunoglobulin (IVIg) 500 mg/kg on days Ϫ6, 0, 7, 21, was given to patients whose antigenemia did not resolve 35, 55, 76 and 98. All patients had CMV serology tested with ganciclovir therapy. All patients in whom CMV dis- within 4 weeks prior to transplantation. Donor CMV serol- ease was diagnosed were treated with the same schedule ogy was tested before blood stem cell or bone marrow har- and duration of ganciclovir, with the addition of IVIg vest. The Institutional Review Board of the University of 500 mg/kg on alternate days for 2 weeks, then twice a week Minnesota approved the trial, and all enrolled patients or for another 4 weeks. If disease recurred during the mainte- their legal guardians gave written informed consent. nance phase, induction was restarted. Supportive care Definitions Patients who developed an ANC of <750 ϫ 106/l but > CMV antigenemia: one or more positive cells per 50 000 500 ϫ 106/l during prophylactic therapy were treated with (or fewer) leukocytes examined. Recurrent antigenemia granulocyte colony-stimulating factor (G-CSF) at a dose of was defined as any degree of antigenemia occurring follow- 5 ␮g/kg/day and continued receiving the assigned CMV ing complete resolution of antigenemia as a result of pre- prophylaxis. If the ANC fell to <500 ϫ 106/l, prophylaxis emptive ganciclovir therapy; persistent antigenemia was was discontinued until recovery to >750 ϫ 106/l, then defined as failure to resolve CMV antigenemia with pre- restarted with continued G-CSF support. Patients received emptive ganciclovir therapy. CMV disease: signs/symptoms ongoing oral prophylaxis for bacterial infections (penicillin of disease in conjunction with culture of CMV (by conven- V potassium 250 mg twice daily), fungal infections tional or shell-vial technique) from visceral tissue or cer- (fluconazole 200 mg daily), and Pneumocystis carinii pneu- ebrospinal fluid, or pathologic changes of CMV in biopsy monia (trimethoprim-sulfamethoxazole, one double- tissue. CMV pneumonia was defined as interstitial infil- strength tablet twice daily every Monday and Tuesday). trates on chest radiograph accompanied by histologic dem- onstration of CMV in lung biopsy material or a positive CMV culture from bronchoalveolar lavage fluid. CMV gastroenteritis was defined as gastrointestinal symptoms Ganciclovir Acyclovir Ganciclovir 5 mg/kg i.v. accompanied by histologic demonstration of CMV or a 5 mg/kg i.v. 10 mg/kg i.v. MondayFriday positive CMV culture from biopsy material obtained by every 12 h every 8 h n = 45 endoscopy. Early CMV disease was defined as disease occurring prior to day 100 post transplant; late CMV dis- Acyclovir 800 mg or ease as disease occurring after day 100. CMV related death: 18 mg/kg orally 5 times a day death occurring within 6 weeks of the diagnosis of CMV n = 46 disease in which CMV disease was clinically felt to be a contributing cause. Day 7 2/1 ANC 750 ´106/l +100 Statistical analysis Figure 1 Clinical protocol schema. Patients received intravenous (i.v.) ganciclovir 5 mg/kg every 12 h days Ϫ7toϪ2, followed by acyclovir Prestudy sample size and power projections: The study 10 mg/kg i.v. every 8 h from day Ϫ1 until absolute neutrophil count was designed as a prospective randomized trial. The pri- (ANC) у750 ϫ 106/l for 2 consecutive days. Patients were then randomly assigned, with stratification for type of transplant, to either ganciclovir mary endpoint of the study was the incidence of CMV anti- 5 mg/kg i.v. Monday to Friday (n = 45) or acyclovir 800 mg (adults) or genemia at day 100.
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