Oral Valganciclovir As Preemptive Therapy for Cytomegalovirus Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Abstract

Introduction: Cytomegalovirus (CMV) infection remains one of the most important complications after allogeneic hematopoietic stem cell transplantation (AlloHSCT). Preemptive therapy with oral VGC or intravenous ganciclovir has replaced universal prophylaxis. We investigated the effect of oral VGC as preemptive therapy on CMV reactivation or infection in AlloHSCT. Patient & Methods: We retrospectively studied 30 consecutive adult recipients of HLA-identical sibling allogeneic peripheral blood stem cell transplant from June 2011 through June 2014 to analyze the safety and efficacy of preemptive therapy for the treatment of CMV infection. Among 30 patients we studied the results of 13 patients with CMV DNA positivity. All 13 recipients and their donors were seropositive for CMV Ig G status. Their diagnosis of pretransplantation were as 8 acute myeloid leukemia (61 %) and 5 acute lymphocytic leukemia (39 %). Median age was 39 years (range 21-54). There were 9 men and 4 women (Table-1). The patients received no prophylaxis against CMV. Blood/serum samples from all patients were routinely monitored for CMV-DNA using PCR twice weekly. We iniciated pre-emptive therapy for CMV as the viral load was above and equal to 500 copies/ml in two consecutive samples. VGC was given twice daily 900 mg for 2 weeks, and maintened at a dose daily 900 mg until viral load is undetectable. Results: The PCR test was persistently negative in 17 patients (57 %) and positive at least once in 13 (43%)patients. All patients with CMV reactivations were on immunsupressive treatment. CMV infection was cleared in most patients within 2 weeks, but for those with stable or increasing CMV levels, the induction period was continued. Twelve patients were treated with oral VGC on an outpatient basis and they all became CMV negative after the first week of treatment. Only one patient received intravenous ganciclovir and he was also CMV negative after the first week of treatment. While no positivity was identified in any of the patients who received VGC on day 21, clinically unimportant low titer CMV positivity was noted in three of these patients. VGC was continued at same dose and no positivity was detected after 2-3 weeks. We were obligated interrupt VGC in only four patients for serious side effects namely neutropenia and thrombocytopenia. We did not observe CMV-related mortality. Conclusions: We concluded that VGC therapy could be safely used at outpatient clinics, with frequent monitorization to prevent severe myelotoxicity. In conclusion, based on our findings, oral VGC is effective and safe in the pre-emptive treatment of CMV disease following allo-HSCT. Therefore, preemptive strategy by oral VGC appears preferable to the prevention of CMV disease in alloHSCT with its advantage of effectiveness and usage in outpatient clinic condition. Table- 1: Management and outcome of the patient characteristics with CMV-reactivation Patients with CMV reactivation/Total number of patient 13/30 Median age, years (range) 39 (21-54) Gender Male Female 9 4 Diagnosis AML ALL 8 5 CMV serologic status Donor+/Recipient + 13 Preperative regimen Bu-Cy CY-TBI Flu/Amsc(FLAMSA) 8 4 1 GVHD propylaxis CSA+MTX CSA+MTX+MM 12 1 GVHD prior to CMV reactivation Acute chronic without GVHD 7 1 5 Prednisolone treatment at the time of starting VCG Yes No 8 5 IST at the time of starting VGC Yes No 13 0 Median duration of CMV reactivation (day) 44 (8-330) Viral load before antivial treament (copies/ml) 1153 (78-12800) Treatment VGC (900 mg, twice daily for induction) GC (5 mg/kg, twice daily for induction) VGC+GC 9 (70 %) 1 (7 %) 3 (23 %) Total treatment duration (day) 24 (10-51) CMV DNA at the end of the treatment Conversion to negative Persistently positive (low titer < 50 copies/ml) 10 (77 %) 3 (23 %) Serious side effects Interruption of therapy due to neutropenia Interruption of therapy due to thrombocytopenia Reactivation 3 (23 %) 1 (7 %) 2 (15 %) Abbreviations: AML: acute myeloid leukemia, ALL: acute lymphoblastic leukemia, CMV: cytomegalovirus,GVHD: graft-versus host disease, CSA: cylosporine, MTX: methotrexate, MMF: mycophenolate mofetil, PDN:prednizolone, IST: Immunosupressive treatment, VGC: valganciclovir, GC: ganciclovir, Bu: Busulfan, Cy: cylophosphamide, TBI: total body irradiation Disclosures No relevant conflicts of interest to declare.

Evidence supporting the use of therapeutic drug monitoring of ganciclovir in transplantation

“…The systemic exposure achieved between the intravenous and oral formulation are comparable, therefore they are often used interchangeably unless gastrointestinal absorption is impaired [23,24]. Both antivirals have similar safety profile and efficacy in the clearance of CMV viremia [25][26][27][28][29][30].…”