BK Virus Reactivation and Disease after Allogeneic Hematopoietic-Cell Transplantation: A Natural History Study

Background: BK virus reactivation (BKVR) occurs frequently after allogeneic hematopoietic-cell transplant (allo-HCT). BKVR resolves spontaneously in many patients, but others develop BK virus-associated disease (BKVD), which is associated with a wide spectrum of symptoms ranging from mild dysuria to severe hemorrhagic cystitis. Despite the common occurrence of BKVR and BKVD in the post-transplant setting, the natural history of viral activation, progression to disease manifestations and clinical outcomes are not well defined. Methods: We prospectively enrolled 99 adult patients prior to allo-HCT. Participants at higher risk of DNA virus reactivation were preferentially recruited, including those with donor mismatch, haploidentical donors, umbilical cord blood grafts and T-cell depleted grafts. Clinical data, paired blood and urine samples, quality of life and genitourinary pain surveys were collected before the onset of HCT conditioning, at engraftment, and at 1, 2, 3, and 6 months after transplant. BK virus loads were measured in blood and urine samples and BK virus-specific antibodies were measured in plasma. Select patients with genitourinary symptoms underwent bladder and renal ultrasound exams. BKVD was defined as the presence of BK virus in blood and/or viral load exceeding 4 log10 gEq/mL in urine and the presence of new genitourinary symptoms without an alternative explanation for the symptoms. Results: The study cohort included; 49 patients with matched unrelated donors, 24 with haploidentical related donors, 20 with mismatched unrelated donors, and 6 with matched related donors. The median age was 63 years (range, 19 to 78). Mobilized peripheral blood stem cells were used in 76% of patients. Caucasians comprised 90% of the study population. Twenty-eight patients developed BKVR, 16 developed BKVD, and 55 served as controls. Five patients without evidence of BKVR who developed genitourinary symptoms were included in the control group. Most cases of BKVR were detected within 30 days after transplant, while the median time to identify cases of BKVD was 55 days (range, 26-180). Significant differences among the three groups included older median donor age (p=0.05), a higher prevalence of male recipients with female donors (p=0.04), and more frequent use of PTCy for GVHD prophylaxis in the BKVD group (p=0.001). No difference in acute or chronic GVHD incidence or neutrophil/platelet engraftment time was found between groups. Viral loads were significantly higher in urine than blood (p=0.0005) and BK virus could not be detected in blood in 9 of 35 (25.7%) patients despite being present in urine, demonstrating a significantly higher detection rate in urine compared to blood (p=0.0005). Low lymphocyte counts before transplant conditioning predicted both BKVR and BKVD, showing a linear relationship with BK severity in multivariable analysis, with BKVR being less severe than BKVD. In patients with BKVD, only 38% reported hematuria, while increased urinary frequency (88%), pain or burning during urination (63%), and sensation of not emptying their bladder (56%) were more commonly reported symptoms. The median follow-up time was 24.3 months among participating patients. The incidence of CMV reactivation was similar in BKVR, BKVD and control patients. Notably BKVD, but not BKVR, was correlated with an increased non-relapse mortality (NRM) risk, with 4 out of 5 NRM cases in the BKVD cohort occurring within the first year post-allo-HCT (hazard ratio 5.19, 95% CI: 1,49, 18.1, p=0.01 from multivariable analysis). BK virus IgG antibody titers, kidney ultrasound findings, and urine cytology did not differ significantly among the 3 groups; these factors were incapable of predicting the occurrence of BKVD or distinguishing BKVR cases that progress to BKVD. Conclusions: Our prospective study identifies urine as the preferred specimen for BK virus monitoring and shows that genitourinary tract symptoms are more prevalent than hematuria in patients with BKVD. Low lymphocyte counts before conditioning are a significant risk factor for BKVR and BKVD. This study also emphasizes the clinical impact of BKVD, demonstrating a significant association with increased risk of NRM after allo-HCT. These findings highlight the need to develop anti-BK virus therapeutics, including cellular therapies, to improve patient outcomes.

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