Reactivation of JC Virus in 171 Allografted Patients: Incidence and Clinical Significance
Authors: Avivi Irit , Wittman Talia , Benyamini Noam , Kra-Oz Zipora , Szwrcwort Moran , Oren Ilana , Rowe Jacob M , Henig Israel , Zuckerman Tsila , Horowitz Netanel 
Published: October 2019

Abstract
Abstract 4148

Background:
Recent studies demonstrated an increased incidence of JC virus (JCV)-related progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. Expanding application of allogeneic stem cell transplantation (alloSCT) nowadays, reflecting growing availability of matched unrelated donors, is expected to increase the frequency of this complication. Therapeutic options in PML are extremely limited and patients eventually die. However, immune restoration, whenever possible, is claimed to be potentially effective.

Aims:
The current study was aimed to determine the incidence, clinical course and risk factors for JCV reactivation in patients undergoing alloSCT, and explore the possibility for preemptive detection of JCV reactivation prior to PML development.

Methods:
This retrospective study was approved by the Rambam IRB (approval # RMB 0097-12). All consecutive patients, treated with an alloSCT for various hematological malignancies at Rambam between January 2009 and December 2011 were included in the analysis. Frozen DNA samples, originally assessed for CMV-PCR, drawn monthly, starting at transplantation date up to the cessation of immunosuppression (as part of a pre-emptive CMV detection), were thawed and evaluated for JCV reactivation using a quantitative JCV-PCR analysis. In case of sample positivity, additional weekly drawn DNA samples were thawed and analyzed. JCV was detected by quantitative RT0-PCR of whole blood. The institutional electronic database was searched, focusing on hematological diagnosis, disease course prior to transplantation, transplant conditioning regimen, post-transplant complications, particularity graft- versus-host disease (GvHD), immunosuppressive therapy and neurological symptoms. Incidence and clinical significance of JCV reactivation were evaluated.

Results:
631 DNA samples, obtained from 171 consecutive allografted patients, were analyzed. Eighteen patients had a single positive blood test, 6 had repeated positive results (accounting for 100 positive samples), and 147 had consecutive negative tests. Patient characteristics are presented in Table 1. The maximal JCV load in patients anecdotally exhibiting JCV reactivation, was always lower than 500 copies/ml (130–485), whereas in all subjects demonstrating persistent reactivation (initially detected between day 0– 172 post-SCT), levels approached thousands to millions JCV- copies, though tended to correlate directly to steroid dosages applied. Five of the persistently reactivating subjects: 4 with lymphoproliferative disorders and 1 with AML, were heavily pre-treated, failing ≥ 4 prior therapies (3-had rituximab and 4- failed high dose therapy), and all were subjected to continuing immunosuppression due to GvHD. None of the “non-reactivating” and the “anecdotally reactivating” patients developed PML. Two of the 6 “persistently reactivating” subjects showed a gradual increase in JCV levels, preceding the development of clinically proven PML (confirmed by clinical features, typical MRI and JCV in CSF) within 62 and 84 days, respectively. Despite cessation of immunsuppresion, one of these 2 patients died of PML, whereas the other experienced complete durable resolution of neurological symptoms. The remaining 5 patients died within 0.75–3 months since JCV reactivation, due to other causes, in the presence of continuing positive tests for JCV.

Conclusions:
The findings of the current study suggest that JCV reactivation is relatively uncommon, occurring in 15% of SC allografted patients. Moreover, in most patients reactivation is anecdotal and not clinically significant. However, in some very heavily pretreated patients, persistent reactivation may evolve, eventually resulting in PML development. Cessation of immunosuppression, especially if performed at earlier stages of JCV reactivation/disease may reverse the PML fatal course.

Disclosures:
No relevant conflicts of interest to declare.