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What is the optimal dosage of valganciclovir as preemptive therapy for CMV infection in allogeneic hematopoietic SCT?

Bone Marrow Transplantation volume 42, pages 207–208 (2008)Cite this article

CMV infection is a common complication after allogeneic hematopoietic SCT (HSCT). Valganciclovir hydrochloride (VGC) is an orally available prodrug of ganciclovir (GCV; L-Valyl ester), that was first approved for the prevention of CMV disease in high-risk (donor positive, recipient negative) solid organ transplants (1800 mg/day as a standard dose) and for the treatment of CMV retinitis in HIV positive patients.1 We read with interest the paper by Ayala et al.2 about the safety and efficacy of VGC preemptive therapy for CMV infection in allogeneic HSCT. However, the optimal dosage of the drug in this setting has not been established yet. Previous studies in HIV-infected patients and liver transplant recipients have shown that a VCG dose of 900 mg/day results in an area under the plasma concentration-time curve (AUC) for GCV similar to that of i.v. GCV 5 mg/Kg/day.3, 4 A recent study by Einsele et al.5 showed that exposure to GCV after the administration of 1800 mg/day of VGC as a preemptive therapy in HSCT is significantly higher compared with i.v. GCV 10 mg/Kg/day. Similarly, Winston et al.6 reported that GCV exposure after 900 mg of VGC orally was non-inferior to that of i.v. GCV (5 mg/Kg) in HSCT recipients with gastrointestinal GVHD.

Here, we report our experience using two different dosages of VGC as preemptive CMV therapy in HSCT. During a 12-month period, VGC was administered on an outpatient basis to 30 consecutive HSCT recipients with a CMV-positive antigenemia, detected after a median time of 86 days (range: 59–480) from transplant. Patients were 17 male subjects and 13 female subjects with various hematological malignancies (leukemia 13, lymphoma 8, myeloma 6, myelofibrosis 3). The median age was 51 years (range: 21–63); 18/30 patients underwent HSCT from unrelated and 12/30 from related donors. Seventeen patients (57%) received a reduced-intensity conditioning regimen. Antiviral prophylaxis consisted of acyclovir in all cases. At the detection of CMV infection, 21 patients (70%) had an acute or chronic GVHD for which they were receiving immunosuppressive therapy with prednisone or other agents. According to the standard practice at our center, pp65 antigenemia assay was performed on peripheral blood leukocytes and pp65-positive cells were counted and referred to 2 × 105 examined peripheral blood leukocyte. A positive antigenemia test result was defined as one or more cells with characteristic immunofluorescence/2 × 105 peripheral blood leukocytes. A value of 1–10 positive cells was defined as mild positivity, 11–50 as intermediate positivity and >50 CMV-positive cells as strong positivity. The pp65 antigenemia assay was positive in all cases with a mean number of positive cells of 22.5±43. All patients gave written informed consent to VGC therapy. The first 15 cases received VGC 1800 mg/day (Group A), while the following 15 patients were treated with VGC 900 mg/day (Group B). The treatment with VGC was continued in all cases until the CMV antigenemia, tested two times a week, became negative in two consecutive samples, or until the treatment failure (increase of antigenemia in two consecutive samples). The two groups resulted well balanced, without significant differences in age, sex, underlying diseases, transplant type, mean number of positive nuclei or CMV serology status at HSCT. Overall, 27/30 (90%) cases obtained a complete clearance of antigenemia (14/15 in the Group A and 13/15 in the Group B), with a mean time to the first CMV antigenemia negativity of 9±3.3 and 10±2.7 days, respectively. The median duration of VGC therapy was 18 (range: 8–64) and 22 (range: 8–61) days, respectively (P=NS). No cases of CMV disease were reported. A total of 15 (50%) patients experienced one or more recurrence of CMV infection after discontinuation of VGC therapy, without significant differences in the two groups (8/15 vs 7/15). Seven cases required i.v. therapy with foscavir, but no patient developed CMV disease. Only three patient (two in the Group A and one in the Group B) developed a mild deterioration of renal function that required dose halving (VGC 900 mg/day in two from the Group A, 450 mg/day in the Group B case). None of the patients developed gastrointestinal toxicity WHO grade ⩾ II. Overall, 14/30 patients (47%) experienced hematologic toxicity. Reversible WHO grade I-II neutropenia was reported in 12 cases (40%), reversible grade I-II anemia in 9 (30%) and reversible grade I-II thrombocytopenia in 12 patients (40%), without significant differences between the two groups, even if there was a trend toward higher incidence of hematological side effects in the 1800 mg/day dose group.

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Authors and Affiliations

  1. Division of Hematology and Bone Marrow Transplantation, Department of Medical and Morphologic Research, University of Udine, Italy

    A Candoni, E Simeone, M Tiribelli & R Fanin

  2. Institute of Hygiene and Epidemiology, DPMSC, University of Udine, Italy

    C Pipan

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Correspondence to A Candoni.

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Candoni, A., Simeone, E., Tiribelli, M. et al. What is the optimal dosage of valganciclovir as preemptive therapy for CMV infection in allogeneic hematopoietic SCT?. Bone Marrow Transplant 42, 207–208 (2008). https://doi.org/10.1038/bmt.2008.98

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