Preemptive Detection Of JC Virus In Peripheral Blood Of Patients Undergoing Allogeneic Stem Cell Transplantation: A Potential Tool To Prevent Progressive Multifocal Leukoencephalopathy In High-Risk Patients?
Authors: Avivi Irit , Wittmann Talya , Benyamini Noam , Kra-Oz Zipora , Szwarcwort Moran , Oren Ilana , Rowe Jacob M. , Zuckerman Tsila , Horowitz Netanel 
Published: October 2019

Introduction
Elevated frequency of JC virus (JCV) associated progressive multifocal leukoencephalopathy (PML) was recently reported in immunocompromised patients. Current extended use of allogeneic stem cell transplantation (alloSCT) may further increase the incidence of this disorder. While the paucity of therapeutic options makes PML a lethal disease, immune restoration is deemed to be potentially effective in the management of this condition. The aim of the present study was to assess the frequency, risk factors and course of JCV reactivation in allografted patients, focusing on the potential impact of its preemptive identification on patients' outcome.

Methods
This study, approved by the Rambam IRB (# RMB 0097-12), included all consecutive patients (aged ≥ 17 years) with hematological malignancies who underwent alloSCT at Rambam between January 2008 and December 2011. Required clinical data were obtained from computerized patient charts. Quantitative JCV-PCR analysis was employed to assess JCV reactivation in whole blood DNA samples monthly drawn for CMV detection, beginning with transplant date up to the end of immunosuppressive therapy. In JCV positive patients, additional DNA samples were weekly drawn and analyzed. The incidence, clinical significance and risk factors of JCV reactivation were evaluated.

Results
The study included 164 patients (mean age 43.4 years; range 17.5-71.8) diagnosed with acute leukemia (n=108), myelosdysplasia (n=10), lymphoproliferative disorder (LPD) (n=37), multiple myeloma (n=5) and myeloproliferative disorders (n=4) and treated with alloSCT during the study period. Median time from diagnosis to alloSCT was 7.1 months (range 0-181.1).Thirty patients previously received rituximab and 36 failed to respond to high-dose therapy. Ninety four patients had a matched related, 61 a matched unrelated and 9 had a cord blood (CB) transplant, receiving either a conventional conditioning regimen (CC) (n=90), or reduced intensity conditioning regimen (RIC) (n=74). Anti-thymocyte globulin was used in 66 patients. Fifty five patients had prolonged GvHD requiring therapy beyond one year after transplant. Forty patients developed JCV reactivation: 20 anecdotal (appearing only once) and 20 persistent (reported at least in 2 tests). In124 patients, consecutive tests were negative. The maximal JCV load in patients with anecdotal JCV reactivation was<500 copies/ml (130-485), while in all subjects with persistent reactivation, initially detected between days 0-172 post-SCT, JCV levels approached at least several thousand copies. None of the “non-reactivating” or “anecdotally reactivating” patients developed PML. Two of the “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 presence in CSF) within 96 and 138 days after initial reactivation (822 and 199 days post allograft). Despite cessation of immunosuppressive therapy, one of the two patients died of PML, whereas the other experienced complete durable resolution of neurological symptoms. The remaining 5 “persistent reactors” died within 0.75-3 months from initial JCV reactivation due to other infections, exhibiting continuously positive JCV tests. LPD (HR = 2.165, 95% CI: 1.140-4.112, p=0.018), RIC regimen (HR = 1.92, 95% CI: 0.99-3.72, p=0.053) and older age at transplantation (age 41-60 years: HR = 6.265, 95% CI: 1.441-27.232, p=0.014; age >60: HR= 8.933, 95% CI: 1.694-47.101, p=0.01 in reference to age<31) were found to be related to a significantly increased risk of JCV reactivation.
Multivariate analysis confirmed age to be the most significant predictive factor for JCV reactivation. Additionally, prolonged GvHD predicted an increased risk of developing persistent versus anecdotal JCV reactivation (p=0.04).

Conclusions
The findings of the current study suggest that JCV reactivation is relatively uncommon. JCV reactivation is associated with older age and tends to be persistent in patients with prolonged GvHD, in whom it is more likely to eventually progress to PML. Preemptive detection of JCV reactivation in high risk patients, entailing early discontinuation of immunosuppressive therapy, may prevent the development of lethal PML.

Disclosures:
No relevant conflicts of interest to declare.