Cidofovir (CDF) for the treatment of EBV-infection in allogeneic stem cell transplantation.

Reactivation of EBV is frequent after allogeneic stem cell transplantation and in many instances symptoms are difficult to be differentiated from those of chronic GvHD. We studied the treatment of EBV infections in 32 patients (pts) with CDF. The indication for antiviral therapy is based on the assessment of the severity of symptoms. 36 CDF treatment courses were evaluated retrospectively. Prior to transplantation 25 of 25 pts and 18 of 18 donors tested were seropositive for EBV (IgG-VCA). 25 of 30 evaluable pts developed acute GvHD and 23 of 30 chronic GvHD. The monitoring of EBV was done every 2 weeks for 120 days after BMT and additionally in cases of suspected infection. Biopsies of stomach, esophagus, lung and bone marrow were tested with in situ technique. Qualitative PCR for EBV DNA, antigenemia (DNAemia) or genome eqivalents / ml or per 20.000 cells were used for investigations of EBV in serum, blood, pleural liquid and pharyngeal swabs. Concommittant reactivation of CMV occurred in 5 pts., of HHV6 in 6 pts. and of VZV in one pt. One of these pts. had received previously antiviral therapy with Ganciclovir and Foscarnet, 2 pts received CDF combined with CDF and Foscarnet and Ganciclovir and 29 pts. received CDF alone as first line therapy. The dosage of CDF was 1-5 mg/Kg/week adjusted to the kidney function. The schedule was weekly for 2 - 3 weeks followed by maintenance every other week, pts. were treated at least once and up to 7 doses. All patients received probenecid and prehydratation. 11 pts received immunosuppressive treatment with cyclosporine A, 1 pt with tacrolimus and 8 with mycophenolic acid. 22 pts received potentially nephrotoxic drugs in addition to CDF. 4 pts suffered from presumed side effects of CDF (vomiting and nausea). CDF treatment had to be stopped in two cases because of creatinine elevation, 8 pts had moderate creatinine elevations. In 4 pts CDF treatment was repeated due to recurrent EBV-related symptoms.of CDF. Indications for the treatment with CDF were demonstration of EBV-reactivation and clinical symptoms suggestive of EBV disease. Among the pts diagnosed with symptoms of suspected viral infection were 11 pts. with a malaise syndrome comprising nausea and vomiting, loss of weight and fatigue, 7 with dyspnea and cough without fever, 4 pts with interstitial pneumonia, 5 with thrombo- or pancytopenia related to EBV in the bone marrow, 2 pts with esophagitis, 1 pt with EBV-positive skin lesions, 6 pts with diarrhea with/without fever, 4 pts with pleuritis and 1 pt with polyserositis. 13 of 32 pts were treated for a high virus load in blood and bone marrow without further clinical symptoms. 20 pts. responded to CDF treatment with clinical remissions of symptoms in combination with conversion of a positive viral test (antigenemia or PCR) to negative in the blood or biopsy. 5 pts achieved a clinical remission of symptoms without conversion of EBV positivity. In 3 pts. with primary clinical and microbiological remission EBV viremia recurred within 7 months after CDF-therapy and 3 pts had only a temporary improvement of symptoms. 4 pts did not respond to CDF neither clinically nor microbiologically. One pt. died with EBV-viremia. In 5 pts who did not respond to CDF treatment Ganciclovir and Foscarnet was given alternatively. (2 complete responses, 1 partial response, 2 pts did not respond). CDF therapy was given in 30/32 pts within 6 month after stem cell transplantation. In two cases CDF was indicatetd two and 4 years after trasnsplantations respectively. In conclusion, our results suggest a high coincidence of EBV-infection and pancytopenia, pleuritis, gastrointestinal symptoms and pneumonia in pts after stem cell transplantation. 15 % of the EBV-positiv cases tested positive for HHV6 also. CDF treatment is effective in about 65 % of cases with clinical EBV-infection and viremia. CDF-treatment therefore can be suggested for these conditions. Future results of quantitative virus load assessments should be helpful for indication for preemtive therapy.