Defining Treatment Paradigms for BK Virus-Induced Hemorrhagic Cystitis in the Post-Allogeneic Hematopoietic Stem Cell Transplant Setting

BK viuria is an important and frequent infection in the post-allogeneic hematopoietic stem cell transplant (allo-HSCT) setting that results in significant morbidity and mortality. Over the years our understanding of the disease process has improved significantly but treatment algorithms remain poorly defined and developed. A variety of anti-viral therapies have been utilized in conjunction with reduced immunosuppression with modest benefits. We therefore present our institutional data and recommend a clinical practice guideline that could potentially improve the outcomes of patients with BK-virus infections.

Our retrospective analysis included 75 consecutive patients who underwent allo-HSCT from 2001–2011. Data was collected on patients with PCR proven BK-viuria under existing IRB approved protocols. SPSS version 13.0 was used for statistical analysis. Kaplan-Meier method was used to calculate survival outcomes.

12% (9/75) of all patients developed PCR proven hemorrhagic cystitis (HC). The median age of patients at transplant was 37-years (range 28–61). 77% were male. 66% had acute myeloid or lymphoblastic leukemia and the median number of prior therapies was three. 33% had a matched unrelated donor transplant while 66% received reduced intensity conditioning regimen and 33% received anti-thymocyte globulin (ATG). The mean CD34+ cell dose infused was 4.8×10⁶/kg and the mean CD3+ cell dose was 8.6×10¹¹/kg. Median days to neutrophil engraftment were 11 and for platelet engraftment were 14. The median ECOG performance status was 1 (range 0–2). The median time of onset of HC from day 0 of transplant was 44-days (range 4–158) and lasted for an average of 53-days (range 7–157). 33% patients were neutropenic at the onset of HC and the mean absolute neutrophil count was 4300/ul. Most common symptoms were dysuria in 66%, bladder spasms in 44% and urinary retention in 22%. All patients had received GVHD prophylaxis with methotrexate and tacrolimus and 77% were on concurrent steroids and mycophenolate. 88% of patients had concurrent acute graft-vs.-host disease (GVHD) at the time of HC. 88% also had concurrent CMV viremia and 11% had EBV viremia at the time of HC. 44% developed BK-viremia while 55% had BK-virus induced nephropathy defined as an increase of serum creatinine >1.5. Management approach was tiered into prophylaxis, symptomatic relief and anti-viral therapy. All patients received ciprofloxacin and 88% received intravenous immunoglobulin (IVIg). No single therapy component including reduced immunosuppression, cidofovir and leflunomide was independently identified as a more efficacious option (p>0.05) but of the patients who received cidofovir, 75% had resolution of symptoms and were able to clear the BK-viuria with the median duration of treatment of 4.5 weeks.

Our analysis supports existing data that BK-virus induced HC is the result of multifaceted host and donor interactions and the concurrent use of immune altering therapies. To address the need of reduced morbidity and improved outcomes of this commonly encountered scenario in the post allo-HSCT setting, we have developed a multi-tiered approach that includes prophylactic intervention with ciprofloxacin for patients undergoing T-cell depleting regimens; symptomatic management with continuous bladder irrigation, pyridium and oxybutynin; and antiviral therapy with cidofovir and leflunomide in select subsets of patients. This approach will provide us a tool to uniformly manage our patients with BK-viuria and HC, and continually analyze and improve outcomes in a prospective manner.

No relevant conflicts of interest to declare.