Combined Foscarnet-Ganciclovir Treatment for Cytomegalovirus Infections After Allogeneic Hemopoietic Stem Cell Transplantation1

Abstract

In a previous study, we showed that patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT) who had cytomegalovirus (CMV) antigenemia with more than 4 CMV antigen-positive cells/200,000 have a high transplant-related mortality (TRM) rate, despite treatment with ganciclovir or foscarnet. In an attempt to reduce TRM, 32 allogeneic HSCT recipients, between the ages of 16 and 55 years (median, 35 years), with CMV antigenemia (> or = 5 positive cells) developing at a median interval from HSCT of 49 days, were given combination treatment with foscarnet and ganciclovir for 15 days. The prescribed dose was 180 mg/kg/day of foscarnet and 10 mg/kg/day of ganciclovir: the median administered dose in the first 15 days, after adjusting for creatinine levels and peripheral blood counts, was 64% for foscarnet and 53% for ganciclovir. Maintenance was given with foscarnet and ganciclovir on alternate days for an additional 2 weeks. Thirty-one of 32 patients were on cyclosporine, 30 were on systemic antibiotics, and 9 were on intravenous amphotericin. Median laboratory values on days 1 and 15 of treatment were 1.0 and 1.1 mg/100 ml creatinine, 5.7 x 10(9)/L, and 4.1 x 10(9)/L white blood cells, and 78 x lO(9)/L and 72 x 10(9)/L platelets. All patients cleared CMV antigenemia by day +15, although CMV antigenemia recurred in 5 patients on maintenance therapy and in 14 patients off maintenance therapy: the dose of foscarnet (but not ganciclovir) received in the first 15 days was significantly lower in patients in whom antigenemia recurred within 30 days (P=0.0002). Six patients died, one with interstitial pneumonia, one with multiorgan failure, and four with infections. Twenty-six patients survived 119-1051 days after transplant. The actuarial TRM rate at 1 year is 23%. Eighteen patients who had received unmanipulated bone marrow transplants from HLA-identical siblings were compared with 15 matched controls who had been treated with a single drug (either foscarnet or ganciclovir) for CMV antigenemia (> or = 5 cells): the actuarial 1 year TRM rate was 13% for patients receiving combined treatment, compared with 47% for controls receiving a single drug (P=0.02). This study shows that combined foscarnet-ganciclovir is one therapeutic option for allogeneic HSCT recipients who develop CMV antigenemia with a high number of CMV antigen-positive cells. Treatment can be given together with cyclosporine and antibiotics with appropriate dose reductions. It produces prompt clearing of CMV infection, and may reduce TRM rates in comparison to single-agent therapy.

Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection

“…Combination ganciclovir and foscarnet therapy has been utilized in AIDS patients with retinitis 20 and in allogeneic stem cell recipients. 21 Recent work suggests that a combination of reduced-dose ganciclovir and foscarnet may be effective and less toxic for ganciclovir-resistant CMV in solid organ transplant recipients. 22 Cidofovir, the third FDA-approved drug for the treatment of CMV, 23 has been used primarily for retinitis in AIDS patients and for CMV in allogeneic stem cell recipients.…”

Foscarnet therapy for ganciclovir-resistant cytomegalovirus retinitis after stem cell transplantation: effective monitoring of CMV infection by quantitative analysis of CMV mRNA

“…[14][15][16][17] In the future, initial pre-emptive therapy with this combination might be considered in patients with prolonged immunosuppression.…”

A comparison of prophylactic vs pre-emptive ganciclovir to prevent cytomegalovirus disease after T-depleted volunteer unrelated donor bone marrow transplantation

“…However, a recent study including a preponderance of sibling BMT patients has shown that CMV infection-guided treatment gives the same outcome as prophylactic GCV. 23 Future possible strategies might include alternative methods of GVHD prophylaxis, 24 suppression of CMV infection with foscarnet 25,26 or a combination of foscarnet and GCV, 27 continuing GCV prophylaxis for longer to prevent late CMV disease, adoptive transfer of CD8 + CMV-specific CTL clones derived from the marrow donor, 28 or enhancing immune reconstitution post BMT by the use of subunit anti-CMV vaccines such as gB or pp65. 29,30 …”