Cytomegalovirus Reactivation Prophylaxis With Low Dose Valgancyclovir After Hematopoietic Stem Cell Transplantation

Cytomegalovirus (CMV) reactivation is one of the most frequent complication after hematopoietic stem cell transplantation (HSCT). Pre-transplant CMV-positive recipient serostatus is the most significant independent variable for viral reactivation.

Oral valgancyclovir (VGCV) is a prodrug of intravenous gancyclovir (GCV) and is an effective and safety alternative for the management of CMV reactivation prophylaxis and preemptive therapy. However, VGCV at standard dose (900 mg twice a day) increases risk of myelosuppression in HSCT recipients.

The efficacy of low dose (LD, 450 mg daily) oral VGCV was retrospectively evaluated in 30 allogeneic HLA-matched related patients and 2 unrelated, with a median age of 40 years (range, 18-59) and a median follow-up of 30 months (range, 3-56). Primary diseases were acute myeloid leukemia (AML, n=19), acute lymphoblastic leukemia (n=4), non-Hodgkin’s lymphoma (n=3), multiple myeloma (n=3) and myelodysplastic syndrome (n=3). Seventeen of twenty-three acute leukemia (AL) patients were transplanted in first complete remission (CR), while the remaining (n=6) were transplanted in 2nd CR. Five patients suffered from AML secondary to long-lasting MDS (n=3) or Hodgkin disease and breast cancer (n=2).

Based upon CMV serostatus (D/R, donor/recipient), thirty (94%) of HSCT recipients were classified as high risk (D-/R+ = 3 and D+/R+ = 27) for CMV reactivation and only 6% as low risk (D-/R- = 2); none of the patients was in the intermediate risk group (D+/R-).

Fifteen and 17 patients received a myeloablative and RIC regimens, respectively. Twenty-one patients received GvHD prophylaxis with cyclosporin A (CsA, 1 mg/kg intravenously from day -1 to +21, then 8 mg/kg orally for at least 6 months) and short-course methotrexate (MTX, 10 mg/kg on days +1, +3, +6 and +11). The others (n=11) received CsA with MTX and antithymocyte globulin (ATG, as a part of the conditioning regimen at 10 mg/kg at days -3, -2 and -1). According to the Glucksberg scoring system, thirteen patients experienced grade I-II and two grade III-IV acute GvHD, while 7 patients developed limited (n=6, 18%) and extensive (n=3, 10%) chronic GvHD.

Starting from time of engraftment, LD oral VGCV was given prophylactically for at least 6 months. CMV infection was monitored weekly using polymerase chain reaction (PCR) in high risk seropositive recipients and we started preemptive therapy when the peak viral load exceeding 1000 copies/mL in two consecutive plasma samples.

Six patients (4 early and 2 late) developed a positive PCR after a mean of 59 days post-HSCT successfully treated with 900 mg of VGCV twice a day for at least when PCR negative (in a median of 12 days). Only one patient developed late fatal gastrointestinal CMV disease. Indeed, asymptomatic early and late CMV-DNA PCR reactivation occurred only in 17% (n=5) of high risk seropositive HSCT recipients, in contrast to 37% and 18% of early and late CMV reactivation observed in matched gender, disease phase, graft source and CMV serostatus cohort of 32 HSCT recipients treated prophylactically with oral acyclovir (ACV, 15 mg/kg daily) and high dose intravenous immunoglobulins (IVIG, 0.4 gr/kg weekly for at least 6 months) .

Seven patients presented hematological toxicity do not requiring drug discontinuation. The rate of non CMV-related infections was 25% and was similar in both groups with and without CMV reactivation. At the end of the follow-up, 18 of 32 (56%) patients were alive with a median follow-up of 31 months (range, 2-56). Relapsed-related mortality was 20%, transplant-related mortality was 9% and did not differ between group with and without CMV reactivation.

Our data provide evidence that LD-VGCV is safe and effective as CMV reactivation prophylaxis in allogeneic HSCT recipients. These results require further validation in randomized studies.