Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation

Abstract

The present study compared foscarnet with ganciclovir for preemptive therapy of cytomegalovirus (CMV) infection after allogeneic blood or marrow stem cell transplantation (SCT). Patients with CMV infection, as detected by weekly antigenemia or polymerase chain reaction (PCR) in blood leukocytes, were randomized to intravenous therapy for 2 weeks with either foscarnet at 60 mg/kg or ganciclovir at 5 mg/kg administered every 12 hours; if CMV infection remained detectable, patients received an additional 2 weeks of intravenous foscarnet at 90 mg/kg or ganciclovir at 6 mg/kg given once daily for 5 days per week, after which therapy was stopped. Primary efficacy endpoint was the occurrence of CMV disease or death from any cause within 180 days after SCT. A total of 213 patients were treated with either foscarnet (n ‫؍‬ 110) or ganciclovir (n ‫؍‬ 103). Kaplan-Meier estimates of event-free survival within 180 days after SCT were similar in the 2 treatment groups (P ‫؍‬ .6). During study treatment, severe neutropenia (< 0.5 ؋ 10 9 /L) occurred in 11 (11%) patients on ganciclovir versus 4 (4%) patients on foscarnet (P ‫؍‬ .04), and impaired renal function was observed in 5 (5%) patients on foscarnet versus 2 (2%) patients on ganciclovir (P ‫؍‬ .4). Neutropenia or thrombocytopenia required discontinuation of ganciclovir in 6 (6%) patients but in no foscarnet-treated patient (P ‫؍‬ .03). After allogeneic SCT, preemptive therapy of CMV infection with foscarnet shows similar efficacy as with ganciclovir, but is associated with a lower proportion of patients who develop severe neutropenia and who require discontinuation of antiviral therapy due to hematotoxicity. IntroductionCytomegalovirus (CMV) remains a leading cause of infectious complications after allogeneic bone marrow or peripheral blood stem cell transplantation (SCT). In the absence of preventive measures, the incidence of CMV infection is 60% to 70% in the first 3 months after allogeneic SCT when graft donor or patient are pretransplantation CMV seropositive, and one third of patients with evidence of CMV infection develop CMV pneumonia. 1-3 CMV pneumonia is a serious condition, which, with the best presently available therapy, is associated with a high mortality. 4 Therefore, major emphasis must be placed on the prevention of CMV disease in allograft recipients.For CMV-seropositive patients or seronegative patients with a seropositive graft donor, 2 main strategies are currently used to prevent CMV disease in the posttransplantation course. Prophylactic drug treatment is aimed at suppressing CMV reactivation, and is given to all patients irrespective of the results of virologic monitoring. [5][6][7][8] Alternatively, preemptive therapy consists of initiating antiviral treatment only when active CMV infection is documented in order to prevent the development of CMV disease. [9][10][11][12] Thus, with the preemptive therapy approach, the use of potentially toxic drugs against CMV, such as ganciclovir and foscarnet, is restricted to patients at highest risk for CMV ...

Valganciclovir is safe and effective as pre-emptive therapy for CMV infection in allogeneic hematopoietic stem cell transplantation

“…The incidence of CMV disease in that trial was 5%. 28 Only one case of CMV enteritis was diagnosed in our study in a patient with presumably GCV-resistant CMV that recovered with foscarnet therapy.…”

“…The rates of CMV infection and disease seen in our retrospective analysis were comparable to other reports in the literature. 13,28 Even among the few patients with subsequent positive assays after completion of a 3 week treatment course with oral VGC, recurrent viremia did not appear to occur at a higher frequency or have a worse outcome than in those patients with recurrent positive assays after IV GCV based on our single-institution historical data. It should be noted that we took a rather aggressive approach to pre-emptive therapy by using a very sensitive assay and intervening on the first positive result, rather than requiring two consecutive positive assays, which may be the practice at some centers.…”

Risk factors for fatal infectious complications developing late after allogeneic stem cell transplantation

“…23 The strategy of preemptive therapy with either ganciclovir or foscarnet for patients with CMV detected in the blood has been used since 1990. 24,25 Cytomegalovirus viremia, infection, disease, reactivation and acute infection were defined according to Ljungman et al 26 Patients were treated for CMV infection as previously published. 27,28 Obliterative bronchiolitis Definitive diagnosis of obliterative bronchiolitis is based on histological examination of lung biopsies, and this was not routinely carried out.…”

CMV infections after hematopoietic stem cell transplantation

“…Ganciclovir is the most used drug. Although foscarnet is as effective as ganciclovir, 12 it is more commonly today used as a secondline drug. Valganciclovir has been studied in uncontrolled studies and in two small randomized pharmacokinetic studies.…”

“…11 Preemptive therapy based on early detection of CMV has become the most commonly used strategy for the prevention of CMV disease after allo-SCT. 12 As early identification of patients with CMV infection reduces virus-related morbidity and mortality, monitoring with antigenemia or quantitative PCR is indicated in allo-SCT patients. Ganciclovir is the most used drug.…”