Phase I-II Trial of Foscarnet for Prevention of Cytomegalovirus Infection in Autologous and Allogeneic Marrow Transplant Recipients

Abstract

The safety and efficacy of foscarnet for prevention of cytomegalovirus (CMV) infection was evaluated in 19 CMV-seropositive bone marrow transplant (BMT) recipients. All patients received intermittent intravenous (iv) foscarnet: 40 mg/kg every 8 h from 7 days before to day 30 after BMT, then 60 mg/kg once a day until day 75. The main toxicity was transient renal dysfunction, with a >50 pmol/L increase in serum creatinine above baseline in 5 of the 7 autograft recipients and in 6 of the 12 allograft recipients. Only 4 allograft recipients developed CMV infection during foscarnet prophylaxis, and no patient showed evidence ofCMV disease. Because 3 allograft recipients receiving concomitant iv amphotericin B showed rapid impairment of renal function, foscarnet prophylaxis should not be given to allograft recipients requiring amphotericin B; otherwise, foscarnet prophylaxis at this dose appears safe after BMT.Infection due to cytomegalovirus (CMV) causes significant morbidity and mortality among bone marrow transplant (BMT) recipients [1]. In two published series, the probability ofCMV infection within the first 100 days after BMT among patients who were CMV-seropositive before transplant was up to 80%and 60%for allograft and autograft recipients, respectively [2,3]. Mortality was primarily related to CMV pneumonia, which developed in 37% of allograft and in 22% of autograft recipients who had evidence of active CMV infection [2,3]. Thus, the prevention of CMV infection and disease after BMT is of foremost importance.Antiviral chemotherapy aimed at preventing reactivation of latent virus may be the most promising approach to CMV prophylaxis both among CMV-seropositive autograft and allograft recipients and among seronegative allograft recipients who have a seropositive marrow donor. CMV drug prophylaxis should cover the early period after BMT in which a deficiency in CMV-specific immunity can contribute to the risk of severe CMV disease [4].The antiviral agent acyclovir given intravenously at high doses was shown to be partially effective in preventing CMV infection and disease among seropositive BMT recipients [5].

Randomized clinical trial of ganciclovir vs acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation

“…32 Other antiviral drugs, including foscarnet, cidofovir and valganciclovir are also being studied for prevention of CMV disease. [33][34][35][36] As prophylactic and early treatment strategies aimed at further reduction of CMV antigenemia and disease are developed and tested, consideration should be given to comparison with high-dose acyclovir or valacyclovir in study designs.…”

Foscarnet prophylaxis of cytomegalovirus infections in patients undergoing allogeneic bone marrow transplantation (BMT): a dose-finding study

“…There was no influence on white blood cells engraftment: in the first group the median of the day of engraftment was 16 (11)(12)(13)(14)(15)(16)(17)(18), in the second group 22 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), in the third 16 (14)(15)(16)(17)(18)(19)(20)(21), in the fourth 15 (13)(14)(15)(16)(17)(18).…”

“…18,19 Prophylactic ganciclovir has been shown to be effective in preventing CMV disease in two randomized studies. 16,17 However, it did not improve the outcome of the transplant, and survival was comparable in patients receiving placebo. This is due to the myelotoxicity and neutropenia in ganciclovir-treated patients.…”

“…[2][3][4] There are two approaches for the prevention of CMV disease: the first is pre-emptive treatment of CMV infection, on the basis of CMVAg-emia [5][6][7][8] positive blood CMV-PCR [9][10][11][12] or positive broncho-alveolar lavage. [13][14][15] The second option is CMV prophylaxis with agents such as gancyclovir 16,17 or foscarnet. [18][19][20] Prophylaxis is probably necessary in patients at high risk of developing CMV infections: namely those receiving T cell-depleted grafts, and transplants from unrelated or mismatched donors.…”

Foscarnet against human herpesvirus (HHV)-6 reactivation after allo-SCT: breakthrough HHV-6 encephalitis following antiviral prophylaxis

“…22 While PFA may be more appropriate than GCV as a prophylactic agent, renal toxicity remains problematic for prophylactic use. 21 The effects of PFA in preventing CMV infection have been studied previously, 23,24 but this agent is not currently in common used for prophylaxis due to its toxicity.…”