What We Learned From Plasma BK-Virus Monitoring in Allogeneic Hematopoietic Transplant Recipients (2016)

BK virus (BKV)-related hemorrhagic cystitis (HC) (BKHC) causes significant morbidity after allogeneic hematopoietic stem cell transplant (HSCT). The immunosuppressive state allows for BKV reactivation and active viral replication which destroys infected uroepithelial cells.1 The prevalence of this problem as reported in the literature is based mostly on retrospective analyses of patients presenting with HC as well as monitoring using urine samples for BKV, which we have previously found to have poor correlation with clinically significant HC in post-HSCT recipients.2,3 We initiated a BKV monitoring protocol that assumed that early detection or rising plasma BKV levels predicts for BKHC. A positive outcome would be the starting point for development of strategies aimed at halting progression to overt HC. The primary objective was to determine the predictive values of positive and/or incremental plasma BKV levels for clinically significant (grade ≥ 2) HC postallogeneic HSCT. Secondary objectives were to define BKHC prevalence and identify high-risk patients. Plasma BKV monitoring started before HSCT then continued weekly from days 14 to 56 using quantitative PCR targeting the VP1 protein gene paired with urine microscopy samples.4 Transplant conditioning intensity was as follows: myeloablative (busulfan-cyclophosphamide; cyclophosphamide-total body irradiation [TBI], 12 Gy; fludarabine-cyclophosphamide-TBI, 12 Gy), nonmyeloablative (fludarabine-TBI, 2 Gy; cyclophosphamide-antithymocyte globulin [ATG]; fludarabine-cyclophosphamide-TBI, 2 Gy), and reduced intensity (all others). The ATG and posttransplantation cyclophosphamide were used as in vivo T cell depletion (TCD) in all unrelated donor and haploidentical HSCTs, respectively. Our prospective monitoring included 224 consecutive allogeneic HSCT patients with a median follow-up in surviving patients of 16 months. The HSCT indication and characteristics are given in Table 1. The BKV viremia was detected in 77 patients (34.4%) at a median of 21 days from HSCT infusion. The HC occurred in 40 patients (17.9%). In 15 of these, HC was due to conditioning chemotherapy and thrombocytopenia and occurred at a median of 10 days after HSCT infusion. Blood and urine BKV PCR tests were negative in these patients. The BKHC occurred in 25 patients (11.2%) at a median of 32 days after HSCT. Of these, 17 had positive plasma BKV at a median of 16 days before the onset of HC but only 2 patients had rising levels coinciding with HC development. Four patients had positive BKV before HSCT but only 1 developed BKHC. Fifty-two patients had positive BKV without HC. Among BKV-positive patients, there was no difference in the median peaks in plasma BKV level between patients who developed HC and those who did not at 1481 copies/mL (range, 433-42 260) and 1193 copies/mL (range, 405-135 213), respectively. Therefore, no threshold of plasma BKV predicted HC development. The positive predictive value and positive likelihood ratio of plasma BKV for HC were 0.34 and 2.21, respectively. Univariate analysis for BKHC risk considered the following: conditioning intensity (myeloablative vs reduced-intensity conditioning vs nonmyeloablative), HLA-mismatch, unrelated donor HSCT, mycophenolate use, cytomegalovirus viremia (monitored weekly), cord HSCT, haploidentical HSCT, ATG, in vivo TCD, and acute graft-versus-host disease. The BKHC occurred more frequently in cord HSCT (P = 0.014) and in vivo TCD (P = 0.046) recipients. On multivariate analysis, only cord HSCT was independently associated with BKHC (hazards ratio, 12.95, 95% confidence interval, 3.34-50.18; P < .001). The positive predictive value in cord HSCT patients however was only 0.44. There was no significant difference between the absolute lymphocyte counts of cord patients who did and did not develop BKHC. This is a unique data set that informs of BKHC risk factors and the low predictive value of routine plasma BKV monitoring after HSCT. Cord HSCT was an independent risk factor for BKHC. This finding is consistent with the delayed functional immune reconstitution after cord HSCT that is due to several factors, including thymopoietic failure, and late memory T cell skewing.5 However, haploidentical HSCTs which has also been associated with an increased risk of BKV cystitis were not well represented in our cohort, and no conclusions can be drawn from our data for these patients. Our findings do not support routine BKV monitoring, whether for all HSCTs or select groups. The strategy should remain as ad hoc BKV testing if HC develops postallogeneic HSCT.TABLE 1: Characteristics of transplant patients included in the analyses