Analysis of Varicella Zoster Virus Reactivation among Bortezomib-Treated Patients in the APEX Study.

Abstract

Abstract BACKGROUND: Bortezomib (btz, VELCADE®), a selective and reversible proteasome inhibitor, is approved for the second-line treatment of multiple myeloma (MM). There is a tendency for reactivation of varicella zoster virus (VZV;herpes zoster) among patients (pts) receiving immunosuppressive agents for cancer. Rates of VZV reactivation during btz therapy in phase 2 studies were reported to be 11% in SUMMIT and 13% in CREST. To investigate whether btz increases the incidence of VZV reactivation, data were reviewed from the phase 3 APEX trial of btz vs high-dose dexamethasone (dex) in pts with relapsed MM following 1–3 prior therapies. METHODS: The APEX trial was described previously [Richardson et al. N Engl J Med2005;352:2487–98]. Use of prophylactic anti-virals and anti-bacterials was not mandated by this protocol. RESULTS: Baseline characteristics, including age, prior ASCT, β2-microglobulin, and disease stage, were comparable between the btz and dex arms. The incidence of VZV reactivation was significantly higher with btz vs dex (13% [42/331] vs 5% [15/332], respectively; p=0.0002). Most VZV reactivation events in both arms were grade 1/2. Notably, the incidence of grade 3/4 events was similar between the two arms (1.8% [6/331] vs 1.5% [5/332]), as was the rate for serious adverse events (1.5% [5/331] vs 0.9%, [3/332], respectively). The incidence of other opportunistic infections, including VZV, was comparable between the btz and dex arms; 23% vs 20%, respectively. There were no deaths due to VZV reactivation in either arm. Median time to onset of VZV reactivation tended to be shorter in the btz arm vs dex, though this was not statistically significant (31 vs 51 days; p=0.221). At first assessment post VZV reactivation event, median ALC was significantly lower in the btz vs dex arm (1050 vs 1750 cells/μL; p=0.028). However, immediately prior to the event, median ALC was similar between arms (1030 vs 1100 cells/μL; p=0.529). CONCLUSIONS: Btz was associated with a higher incidence of VZV reactivation events than dex. The reasons for this are unclear and require further study. Preliminary evidence from recent studies has shown that this adverse event of btz could be overcome with the use of prophylactic acyclovir [Mateos et al. Blood 2006; Epub ahead of print].