Intravenous Immunoglobulin Post Allogeneic Stem Cell Transplantation Is Associated with Lower Levels of CMV Reactivation

Introduction

Cytomegalovirus (CMV) reactivation is a common complication of allogeneic stem cell transplantation (ASCT), particularly within the first 100 days after stem cell infusion (D+100). It results in significant cost, morbidity and potentially mortality in the case of severe CMV disease.

Intravenous polyvalent immunoglobulin (IVIg) has been used to support immunoglobulin levels post-ASCT in an attempt to reduce opportunistic infection and graft versus host disease (GVHD). Historically we employed routine IVIg therapy (0.5g/kg weekly for the first 12 weeks) as standard post-ASCT care. In July 2012 funding was withdrawn for IVIg for this indication.

Since 2001 we have been using weekly quantitative polymerase chain reaction (PCR) analysis to monitor for CMV reactivation during the first 100 days after ASCT.

We investigated whether the omission of post-ASCT IVIg altered the rate or consequences of CMV reactivation in the immediate post-ASCT setting.

Methods

We analysed sequential ASCT recipients from 2010 to 2014 and identified 100 patients who met the predetermined eligibility criteria. These subjects were then divided into two uniformly treated populations: ASCT recipients who either received (Group A, n=50) or did not receive (Group B, n=50) IVIg as part of their post-ASCT care.

Inclusion criteria: matched adult unrelated or sibling donor source, age ≥18 years and CMV positive recipient by serology within 3 months prior to ASCT or CMV positive donor by serology.

Exclusion criteria: CMV negative donor and recipient (D-/R-), umbilical cord donor source, death before day 100 or incomplete data available for analysis.

CMV reactivation was defined as any detectable level by quantitative CMV PCR in the peripheral blood. The lower limit of detection for the assay was 20 copies/mL.

A plasma CMV viral load of ≥400 copies/mL resulted in treatment with intravenous ganciclovir (5mg/kg twice daily) which was continued for a minimum of 2 weeks and was thereafter guided by weekly CMV viral load response. Patients with a CMV viral load of <400 copies/mL were observed with no specific treatment.

CMV reactivation was recorded as minor (not requiring ganciclovir treatment) if CMV viral load remained <400 copies/mL and as major (requiring treatment) if CMV viral load reached ≥400 copies/mL within a single episode of infection. Time to first CMV reactivation and cumulative days of major CMV reactivation were also recorded.

Results

A total of 169 consecutive subjects were screened for study entry.

^*: 1 subject had active CMV infection at time of death

^#: 2 subjects had active CMV infection at time of death

Demographics were similar between Group A and Group B in terms of age (median 51.0 vs 48.5 years), sex (male: 33 vs 29) and transplant indication (acute leukaemia/MDS 28 vs 28; lymphoma 11 vs 11) and D+/R- transplants (9 vs 11).

Comparing Group A and Group B, the number of subjects who had a CMV reactivation was 37 vs 39 and for minor reactivations the number was 28 vs 25. The median time to CMV infection was likewise similar: D+38 vs D+35.

The number of patients with a major reactivation, however, was significantly different between Group A and Group B (13 vs 25 – RR 0.52, 95% CI [0.30-0.90], p 0.018), as was the cumulative number of days of major reactivation (181 vs 604 – RR 0.30, 95% CI [0.25-0.35], p <0.0001). The median number of days of major reactivation per patient was 13 vs 21 respectively.

Conclusion

Routine IVIg use in the immediate post-ASCT period did not reduce the rate or latency of CMV reactivation but was associated with a lower magnitude of CMV reactivation and a reduced requirement for anti-CMV therapy. These findings suggest that the use of IVIg post-ASCT may assist in reducing CMV viral burden.