Virus-associated Hemorrhagic Cystitis Research Articles

BK virus-associated hemorrhagic cystitis in pediatric stem cell transplantation: a case report and scoping review.

BK virus-associated hemorrhagic cystitis (BK-HC) is a debilitating and poorly understood complication of hematopoietic stem cell transplantation (SCT). Hematuria, dysuria, and other symptoms associated with BK-HC are common in the immediate post-SCT period, making BK-HC difficult to distinguish from other conditions presenting with these symptoms. Despite published criteria for diagnosis, the degree to which these criteria are consistently applied to either clinical diagnosis or to studies informing BK-HC management is unclear. We present a case of BK-HC in a pediatric SCT recipient, and discuss the challenges associated with treatment in the absence of rigorous data to inform clinical management. We reviewed all cases of BK viruria at our center in patients undergoing SCT between January 2015 and December 2019. We then performed a scoping review of publications in PubMed addressing BK-HC, specifically focusing on how BK-HC was defined. Publications using the keywords "BK polyomavirus" and "hemorrhagic cystitis" were included if they involved a clinical study of SCT recipients and a full-text article was available in English. Case reports were excluded. Analysis focused on whether BK-HC was explicitly defined and whether the definition incorporated elements of diagnostic criteria published by European Conference on Infections in Leukemia (ECIL). A total of 30 studies published between January 2018 and 30 June 2021 met criteria for review, including 4 clinical trials, 7 prospective observational studies, and 19 retrospective observational studies. Fifteen of these studies included pediatric patients (7 pediatric only, 8 combined adult and pediatric). Of the 30 publications, 19 included a definition of either BK-HC or BK cystitis, with only five using ECIL criteria, all of which were observational studies. Multiple interventions are described for treatment of BK-HC, including cidofovir, leflunomide, quinolones, hyperbaric oxygen, keratinocyte growth factor, and BK-specific cytotoxic T lymphocytes. However, evidence to support efficacy for any of these interventions is lacking. Although BK-HC is a well-known complication of SCT, evidence to support available treatment options is limited. Well-controlled studies that incorporate clear diagnostic criteria are needed to better define the risk factors, natural history, and ideal interventions.

Risk factors for BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis.

BK virus-associated hemorrhagic cystitis (BKV-HC) is an intractable complication leading to higher mortality and prolonged hospitalization among allogeneic hematopoietic stem cell transplantation (allo-HCT) recipients. Therefore, identifying the potential risk factors of BKV-HC after allo-HCT is crucial to improve prognosis and for early prevention. However, the risk factors for BKV-HC remain debatable. Therefore, we conducted a systematic review and meta-analysis to identify the risk factors for BKV-HC, for early prevention of the occurrence of BKV-HC and to improve the quality of life and prognosis of allo-HCT recipients. We searched relevant studies from PubMed, EMBASE, and the Cochrane Library up to February 2023. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of all risk factors were calculated to evaluate their effects on the occurrence of BKV-HC. Overall, 11 studies involving 2556 allo-HCT recipients were included in this meta-analysis. All included studies were retrospective and published between 2013 and 2022. We found that male sex (OR=1.32; 95% CI, 1.07-1.62; p=.009, I2 =34%), haploidentical donor (OR=1.84; 95% CI, 1.18-2.87; p=.007, I2 =23%), myeloablative conditioning (OR=1.76; 95% CI, 1.36-2.28; p<.0001, I2 =45%), acute graft versus host disease (aGVHD) (OR=2.73; 95% CI, 2.02-3.69; p<.0001, I2 =46%), chronic graft versus host disease (cGVHD) (OR=1.71; 95% CI, 1.12-2.60; p=.01, I2 =0%), and cytomegalovirus (CMV) reactivation (OR=3.13; 95% CI, 1.12-8.78; p=.03, I2 =79%) were significantly associated with BKV-HC in the univariable analysis. Our meta-analysis indicated that male sex, haploidentical donor, myeloablative conditioning, aGVHD, cGVHD, and CMV reactivation were potential risk factors for BKV-HC.

Decreased lymphocyte count before conditioning is associated with BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

BK virus-associated hemorrhagic cystitis (BKV-HC) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). It can cause morbidity and may increase treatment-related mortality. Previous studies showed that the occurrence of BKV-HC was related to various factors. However, there are still many controversial factors. It is not clear whether BKV-HC will affect the long-term prognosis of patients. We aimed to identify risk factors for BKV-HC after allo-HSCT and evaluate the effect of BKV-HC on overall survival (OS) and progression- free survival (PFS) of patients. We retrospectively analyzed the clinical data of 93 patients who underwent allo-HSCT. Univariate and multivariate analysis were used to identify risk factors for BKV-HC. The Kaplan-Meier method was used to estimate OS and PFS. A difference was considered statistically significant if P<0.05. A total of 24 patients developed BKV-HC. The median occurrence time of BKV-HC was 30 (range:8-89) days after transplantation, and the median duration was 25.5 (range:6-50) days. Multivariate logistic regression analysis indicated that peripheral blood lymphocyte count<1×109/L before conditioning (OR=4.705, P=0.007) and haploidentical transplantation (OR=13.161, P=0.018) were independent risk factors for BKV-HC. The 3-year OS rate was 85.9% (95%CI:62.1%-95.2%) in the BKV-HC group and 73.1% (95%CI: 58.2%-88.0%) in the non-BKV-HC group. There was no significant difference between the two groups (P=0.516). The 3-year PFS rate was 76.3% (95%CI: 57.9%-94.7%) in the BKV-HC group and 58.1% (95%CI: 39.5%-76.7%) in the non-BKV-HC group. There was no significant difference in the two groups (P=0.459). The severity of BKV-HC was not related to the OS and PFS of the patients (P value was 0.816 and 0.501, respectively). Haploidentical transplantation and decreased peripheral blood lymphocyte count before conditioning increased the risk of BKV-HC after allo-HSCT. The occurrence of BKV-HC after allo-HSCT and the severity of which did not affect OS and PFS of the patients.

Reduced post-transplant cyclophosphamide doses in haploidentical hematopoietic cell transplantation for elderly patients with hematological malignancies.

Although post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, it is associated with toxicities, which might be dose-dependent. We compared the outcomes with PT-Cy at 80 mg/kg to those with PT-Cy at 100 mg/kg in elderly patients undergoing haploidentical hematopoietic cell transplantation (HCT). Inclusion criteria included peripheral blood stem cells, hematological malignancy, and age>65 years (or age>60 years if cardiac event history). Thirty-eight patients received PT-Cy at 80 mg/kg and 55 100 mg/kg, divided in two doses. The cumulative incidences (CI) of acute grade II-IV, acute grade III-IV, and moderate/severe chronic GVHD were 32%, 16%, and 13% with PT-Cy at 80 mg/kg compared to 33%, 13%, and 16% with 100 mg/kg, respectively. In multivariable analysis, reducing PT-Cy dose had no significant impact on GVHD. Neutrophil and platelet engraftments were significantly improved, and CI of BK virus-associated hemorrhagic cystitis was reduced with 80 mg/kg of PT-Cy compared to 100 mg/kg. At 2 years, non-relapse mortality was 16% and 31%, progression-free survival 65% and 49%, overall survival 70% and 56%, and GVHD-free, relapse-free survival 52% and 36% with 80 mg/kg and 100 mg/kg, respectively. Reducing PT-Cy dose to 80 mg/kg is safe and associated with improved hematological recovery and lower CI of hemorrhagic cystitis in elderly patients undergoing haploidentical HCT.

Pretransplant BK Virus-Specific T-Cell-Mediated Immunity and Serotype Specific Antibodies May Have Utility in Identifying Patients at Risk of BK Virus-Associated Haemorrhagic Cystitis after Allogeneic HSCT.

BK polyomavirus (BKPyV) persists lifelong in renal and urothelial cells with asymptomatic urinary shedding in healthy individuals. In some immunocompromised persons after transplantation of hematopoietic stem cells (HSCT), the BKPyV high-rate replication is associated with haemorrhagic cystitis (HC). We tested whether the status of BKPyV immunity prior to HSCT could provide evidence for the BKPyV tendency to reactivate. We have shown that measurement of pretransplant anti-BKPyV 1 and 4 IgG levels can be used to evaluate the HC risk. Patients with anti-BKPyV IgG in the range of the 1st–2nd quartile of positive values and with positive clinical risk markers have a significantly increased HC risk, in comparison to the reference group of patients with “non-reactive” anti-BKPyV IgG levels and with low clinical risk (LCR) (p = 0.0009). The predictive value of pretransplant BKPyV-specific IgG was confirmed by determination of genotypes of the shed virus. A positive predictive value was also found for pretransplant T-cell immunity to the BKPyV antigen VP1 because the magnitude of IFN-γ T-cell response inversely correlated with posttransplant DNAuria and with HC. Our novel data suggest that specific T-cells control BKPyV latency before HSCT, and in this way may influence BKPyV reactivation after HSCT. Our study has shown that prediction using a combination of clinical and immunological pretransplant risk factors can help early identification of HSCT recipients at high risk of BKPyV disease.

Intravesical alprostadil as a promising agent in BK virus-associated hemorrhagic cystitis: A report of a refractory case.

Allogeneic stem cell transplant recipients are at risk of BK virus-associated hemorrhagic cystitis. This condition causes a significant morbidity and worsens clinical outcomes. The standard cares for BK virus-associated hemorrhagic cystitis are saline irrigation and forced diuresis. Notably, several beneficial roles are proposed for antiviral and anti-inflammatory agents against BK virus-associated hemorrhagic cystitis. However, cases who are at risk of cystectomy remain refractory. Herein, we present a 13-year-old boy with severe hematuria by passing two months from his allogeneic stem cell transplantation. The laboratory work up showed high BK viremia >1.1 × 108 copies/ml in this case's urine sample. The patient was treated with antiviral agents in combination with supportive care. Moreover, intravesical alum was administered, but no clinical benefits were achieved. Finally, intravesical alprostadil was prepared under the supervision of a pediatric clinical pharmacist. In this regard, an alprostadil solution was prepared by constitution of 250 μg alprostadil in 50 mL saline. After administrating the first dose of intravesical alprostadil, an acceptable clinical response was observed, and hematuria stopped. Of note, alprostadil induces platelet aggregation and vasoconstriction. Thus, bleeding can be controlled after the administration of intravesical alprostadil. This strategy may be associated with several side effects including bladder spasm. This study is the first report describing the special role of intravesical alprostadil in refractory cases of BK virus-associated hemorrhagic cystitis. In such refractory cases, clinicians can use intravesical alprostadil rather than invasive therapies in the treatment of BK virus-hemorrhagic cystitis.

Myeloablative Conditioning With PBSC Grafts For T-Replete Haploidentical Donor Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide Results In Universal Engraftment, Low Rates Of Gvhd, NRM and Excellent Survival Outcomes: An Analysis Of Two Consecutive Phase II Studies From a Single Center

Lack of a matched sibling or suitably matched unrelated donor can be a significant barrier to allogeneic hematopoietic cell transplantation in patients who stand to benefit from this procedure. HLA-haploidentical donors are readily available for nearly all such patients. Whereas previous attempts at haploidentical donor hematopoietic stem cell transplantation (haploSCT) using standard immunosuppression or ex-vivo T-cell depletion have had relatively poor outcomes, a recent approach using a T-replete bone marrow graft with non-ablative conditioning and post-transplant cyclophosphamide (ptCy) for control of alloreactivity has proved to be remarkably well tolerated (Luznik et al BBMT 2008). However, relapse of malignancy remains a major challenge with the use of this non-myeloablative regimen. The use of myeloablative conditioning and a PBSC graft may help reduce the relapse rate following T-replete haploSCT but this has not been well studied. We enrolled a total of 41 patients on two consecutive prospective phase II trials of myeloablative haploSCT and ptCy using a T-replete G-CSF mobilized PBSC graft. The first trial (NSH 864) employed a high-dose busulfan-based preparative regimen (fludarabine 30 mg/m2/d d-6 to -2, Busulfan 110-130 mg/m2/d d-7 to -3 , Cy 14.5 mg/kg/d d-6&-5) [n=20], the second (NSH 922) utilized a TBI-based regimen (fludarabine 25 mg/m2/d x 3 d and TBI 150 cGy bid on d -4 to -1 [total dose 1200cGy]) [n=21]. Post-grafting immunosuppression consisted of Cy 50mg/kg/day on days 3 and 4, MMF through d 35, and tacrolimus through d 180 on both protocols. Eligibility was limited to patients ≤60 years of age with aggressive/advanced hematologic malignancies perceived to be at high risk of relapse following nonmyeloablative transplant. Leukemia patients in CR1 were eligible if they had either poor-risk cytogenetics/molecular studies or primary chemoresistance. Median patient age was 45 years (range 24-60). Twenty-five patients were transplanted in complete remission (CR) or in chronic phase (CP), while 16 patients were transplanted with advanced disease. No patient experienced graft failure, with a median time to neutrophil and platelet recovery of 16 and 25 days, respectively. All evaluable patients achieved sustained complete donor T cell and myeloid chimerism by Day +30. Median follow-up for survivors is 20 months (NSH 864 - 39 months; NSH 922 – 11months). The cumulative incidence of grades II-IV and III-IV acute GVHD at day +100 was 30% and 17% respectively. The cumulative incidence of chronic GVHD at one year post transplant was 41% (severe in 9%). Non-relapse mortality (NRM) at 12 and 24 months was 8% and 17% respectively. Cumulative incidence of relapse was 31% at both 12 and 24 months post-transplant. The relapse rate was lower in patients transplanted in CR/CP (18%) vs. those transplanted with advanced disease (49%, p=0.044). BK virus-associated hemorrhagic cystitis (HC) occurred in 56% of patients, and was severe (requiring hospital admission for bladder irrigation and/or pain management) in 19%. The incidence of HC and severe HC was significantly lower in patients receiving TBI-containing conditioning than those receiving Busulfan (38% vs. 75%, p=0.028 and 10% vs. 30%, p=0.13, respectively). With a median follow-up of 20 months, the estimated 2 year overall survival (OS) was 51% with a 52% estimated disease-free survival (DFS). In patients transplanted in CR/CP, 2-year DFS was 64% vs. 35% in patients transplanted with advanced disease (p=0.077). There was an encouraging trend to better 2-year DFS in patients receiving TBI-based conditioning than those receiving Busulfan, 75% vs. 40%, p=0.072. Myeloablative haploSCT with PBSC grafts and ptCy allows reliable engraftment with early donor T cell chimerism; low rates of GVHD, infectious complications, and NRM; and promising survival in patients with high-risk hematologic malignancies. Outcomes are particularly good in patients treated in CR/CP (18% relapse, 64% DFS). When compared with Busulfan-based conditioning, TBI-based conditioning is associated with less risk of HC and improved DFS. Myeloablative haploSCT is a valid option for patients with aggressive/advanced hematologic malignancies who lack timely access to a conventional donor.▪▪ Disclosures:No relevant conflicts of interest to declare.

Risk Assessment for BK Virus-Associated Hemorrhagic Cystitis After Pediatric Hematopoietic Stem Cell Transplant: A Single-Center Retrospective Cross-Sectional Study.

BK virus-associated hemorrhagic cystitis is a common complication of allogeneic hematopoietic stem cell transplant. It is known to be associated with cyclophosphamide therapy and the intensity of the conditioning regimen as well as infection with the BK virus. Data are limited for BK virus-associated hemorrhagic cystitis in pediatric recipients of allogeneic hematopoietic stem cell transplant. Therefore, we aimed to identify the risk factors and etiology of BK virus-associated hemorrhagic cystitis and determine the factors that may improve the treatment efficacy. Data from recipients of allogeneic hematopoietic stem cell transplant were retrospectively analyzed. These data included information about age, sex, underlying disease, the details of ablative conditioning, graft-versus-host disease prophylaxis, donor type, stem cell source, history of acute graft-versus-host disease, and cytomegalovirus reactivation. A total of 50 patients developed BK virusassociated hemorrhagic cystitis among 334 patients. Symptoms associated with BK virus-associated hemorrhagic cystitis manifested an average of 45.3 days after transplant. Most of the patients had grade 2 and grade 3 hemorrhagic cystitis. Risk factor analysis revealed that haploidentical donor type, treatment with busulfan and cyclophosphamide as part of conditioning regimen, and history of total body irradiation increased the risk of BK virus-associated hemorrhagic cystitis in the pediatric recipient population. We found that, despite current conditioning regimens, BK virus-associated infection still leads to a considerable incidence rate of hemorrhagic cystitis in pediatric recipients of allogeneic hematopoietic stem cell transplant. Patients with a haploidentical donor and a history of busulfan and cyclophosphamide treatment or total body irradiation had a higher risk of BK virus-associated hemorrhagic cystitis. Thus, we suggest that patients with these factors should be followed closely after allogeneic hematopoietic stem cell transplant.

Effectiveness of hyperbaric oxygen therapy for virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Although some studies have suggested the effectiveness of hyperbaric oxygen (HBO) therapy for hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT), the role of HBO has not been established. We compared the treatment outcomes of 8 patients with viral HC (adenovirus [ADV], n = 2; BK virus [BKV], n = 6) treated with HBO (HBO[+]) and 8 patients (ADV, n = 2; BKV, n = 6) treated with conventional therapy (HBO[−]), such as urinary catheterization and intravenous cidofovir. HBO therapy was performed at 2.1 atmospheres for 90 min/day until clinical improvement was achieved. The median number of HBO treatments was 10 (range 8–12). The median duration of HBO treatment was 19.5 days (range 10–23 days). All 8 HBO(+) patients achieved complete remission (CR) at a median of 14.5 days (range 5–25 days). Of the 8 HBO(−) patients, 5 (62.5%) obtained CR and 3 remained symptomatic for 2–6 months. The cumulative incidence of transplant-related mortality at day 100 after allogeneic HSCT was significantly higher in the HBO(−) patients than in the HBO(+) patients (14.2 vs. 0%, P < 0.05). No severe HBO-related adverse effects were observed. In conclusion, HBO is a feasible option for treating viral HC after allogeneic HSCT.

Economic and Clinical Burden of Virus-Associated Hemorrhagic Cystitis in Patients Following Allogeneic Hematopoietic Stem Cell Transplantation in the United States

Hemorrhagic cystitis (HC) caused by viral infections such as BK virus, cytomegalovirus, and/or adenovirus after allogeneic hematopoietic stem cell transplantation (allo-HCT) causes morbidity and mortality, affects quality of life, and poses a substantial burden to the health care system. At present, HC management is purely supportive, as there are no approved or recommended antivirals for virus-associated HC. The objective of this retrospective observational study was to compare the economic burden, health resource utilization (HRU), and clinical outcomes among allo-HCT recipients with virus-associated HC to those without virus-associated HC using a large US claims database. Claims data obtained from the Decision Resources Group Real-World Evidence Data Repository were used to identify patients with first (index) allo-HCT procedure from January 1, 2012, through December 31, 2017. Outcomes were examined 1 year after allo-HCT and included total health care reimbursements, HRU, and clinical outcomes for allo-HCT patients with virus-associated HC versus those without. Further, a generalized linear model was used to determine adjusted reimbursements stratified by the presence or absence of any acute or chronic graft-versus-host disease (GVHD) after adjusting for age, health plan, underlying disease, stem cell source, number of comorbidities, baseline reimbursements, and follow-up time. Of 13,363 allo-HCT recipients, 759 (5.7%) patients met the prespecified criteria for virus-associated HC. Total unadjusted mean reimbursement was $632,870 for patients with virus-associated HC and $340,469 for patients without virus-associated HC. In a multivariable model, after adjusting for confounders, the adjusted reimbursements were significantly higher for virus-associated HC patients with and without GVHD compared to patients without virus-associated HC (P < .0001). Patients with virus-associated HC stayed 7.9 additional days in the hospital (P < .0001) and 6.1 additional days (P=.0009) in the intensive care unit (ICU) for the index hospitalization, as compared to patients without virus-associated HC. The hospital readmission rate was higher for allo-HCT patients with versus without virus-associated HC (P < .0001), resulting in 12.9 more days in the hospital (P < .0001) and 7.3 more days in the ICU (P < .0001) after the index hospitalization. Among patients with GVHD, those with virus-associated HC had significantly higher all-cause mortality as compared to those without virus-associated HC (23.2% versus 18.4%; P=.0035). In an adjusted analysis, patients with virus-associated HC had a significantly higher risk of mortality, regardless of the presence of GVHD. When stratified by GVHD, there were no significant differences in the baseline risk for renal impairment; virus-associated HC was associated with increased risk for renal impairment in the follow-up period in patients with or without GVHD (P < .0001 for both). After allo-HCT, patients with virus-associated HC have significantly higher health care reimbursements and HRU, with worse clinical outcomes, including renal impairment, irrespective of the presence of GVHD and significantly higher all-cause mortality in the presence of GVHD. Our results highlight the unmet clinical need for effective strategies to prevent and treat virus-associated HC in HCT recipients that may also reduce costs among these patients.

19 - Economic and Clinical Burden of Virus-Associated Hemorrhagic Cystitis in Pediatric and Adult Patients Following Allogeneic Hematopoietic Stem Cell Transplantation

19 - Economic and Clinical Burden of Virus-Associated Hemorrhagic Cystitis in Pediatric and Adult Patients Following Allogeneic Hematopoietic Stem Cell Transplantation

95 - Allogeneic, Off-the-Shelf Multi-Virus Specific T-Lymphocytes for the Treatment of Virus-Associated Hemorrhagic Cystitis in the Post-HSCT Setting

95 - Allogeneic, Off-the-Shelf Multi-Virus Specific T-Lymphocytes for the Treatment of Virus-Associated Hemorrhagic Cystitis in the Post-HSCT Setting

Possible nosocomial transmission of virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Adenovirus (ADV)- or BK virus (BKV)-associated hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several risk factors have been previously reported; however, it is unclear whether virus-associated HC can be transmitted. To clarify this point, we performed a retrospective cohort study on 207 consecutive patients who underwent allo-HSCT at Kyoto University Hospital between 2012 and 2018. We evaluated the incidence and risk factors of virus-associated HC and performed a phylogenetic analysis of the ADV partial sequence. The median age at transplantation was 50 (range, 17-68) years. Fifty-eight patients (28%) developed HC. ADVs were detected in 18 cases, BKVs were detected in 51, both were detected in 12, and only John Cunningham virus (JCV) was detected in 1 case. No factor was significantly associated with HC. However, both ADV- and BKV-HC occurred intensively between April 2016 and September 2017, which suggested possible nosocomial transmission of ADV and BKV. Genome sequencing of the hexon, E3, and penton regions of detected ADVs identified 7 cases of ADV type 11, 2 cases of type 35, and 3 cases of a type 79-related strain. A sequence analysis revealed that these strains in each type were almost identical, except for one case of a type 79-related strain. In conclusion, ADV-HCs with possible nosocomial transmission were described based on genotyping of the virus and partial sequencing of the viral genome. Although viral HC after allo-HSCT is thought to mainly be due to reactivation of a latent virus, nosocomial transmission of ADV or BKV should also be considered.

BK Virus Epidemiology, Risk Factors, and Clinical Outcomes: An Analysis of Hematopoietic Stem Cell Transplant Patients at Texas Children's Hospital.

BK virus-associated hemorrhagic cystitis (BKV-HC) is a serious complication after hematopoietic stem cell transplantation (HSCT). A retrospective review was performed to determine the frequency of BKV-HC and identify risk factors and renal morbidity associated with BKV-HC in pediatric HSCT recipients at our institution. A total of 314 pediatric recipients underwent allogeneic HSCT for either malignant (173, 55.1%) or nonmalignant disorders (141, 44.9%) from January 1, 2011, to December 31, 2015, with a minimum follow-up of 5 years post-HSCT. Severe BKV-HC (grades 3 and 4) was prevalent in 46 out of 67 (68.7%) recipients. Timing to presentation of severe BKV-HC (grades 3 and 4) occurred at a median of 37 days (26, 74; IQ1, IQ3) post-HSCT, with the duration of macroscopic hematuria lasting a median of 37.5 days (18, 71; IQ1, IQ3). In the first 60 days post-HSCT, peak acute kidney injury (AKI) stages 2 and 3 were seen more frequently in HSCT recipients who developed BKV-HC than those without (P = .004). Similarly, during post-HSCT days 61 to 100, peak AKI stage 3 was also more frequently seen in HSCT recipients who already developed BKV-HC prior to or during this time period than those without BKV-HC (P = .0002). Recipients who developed BKV-HC within 1 year of HSCT had more frequent mild to moderate chronic kidney disease (CKD stages 2-3) than those without BKV-HC (P = .002 and .007, respectively). On multivariate analysis, BKV-HC was associated with all-cause mortality (hazard ratio [HR]: 2.22; 95% confidence interval [CI]: 1.35-3.65). The following clinical variables were associated with time to development of HC on multivariate analysis: age (subdistribution HR [sHR] 1.11; 95% CI: 1.06-1.16) and myeloabalative conditioning regimen (sHR 4.2; 95% CI: 2.12-8.34). Pediatric HSCT patients with BKV-HC experience significant morbidity and mortality. Renal morbidity, including AKI and CKD, is associated with BKV-HC.

Management of BK virus-associated haemorrhagic cystitis in allogeneic stem cell transplant recipients.

BK virus (BKV)-related haemorrhagic cystitis (HC) is an important cause of morbidity following allogeneic haematopoietic stem cell transplantation (HSCT). The various risk factors include high-level BKV viruria and/or viremia, myeloablative conditioning, acute graft versus host disease (GVHD), cytomegalovirus viremia, and unrelated or HLA-mismatched donor. The presence of high plasma BK viral load and cytopenias have been implicated as important predictors for protracted disease course. These patients frequently require hospitalisation which may extend for several weeks. Supportive measures in the form of analgesics, intravenous hydration, bladder irrigation, and transfusion support remain the mainstay of management. Various drugs have been used with limited success in this setting. These include antiviral drugs, fluoroquinolones, leflunomide, growth factors, clotting factors, estrogens, and prostaglandins. The role of adoptive cellular immunotherapy has also been explored but lacks clinical validation. The strategies aimed at expediting urothelial repair like hyperbaric oxygen therapy (HBOT), intravesical fibrin glue and platelet-rich plasma (PRP) are emerging. Some patients with severe disease do require surgical intervention to relieve urinary obstruction. The frequent co-occurrence of acute GVHD and CMV disease further complicates the management in such patients. There is an unmet need for effective and evidence-based options for the prevention and management of this disease. Due to lack of robust data supported by randomised trials, the acceptability of the available guidelines to simplify the treatment is expected to be low. Despite the availability of various treatment options, the management of BKV-related HC in day-to-day practice continues to be a challenge. The aim of this article is to put forward an up-to-date review of the preventive and therapeutic strategies for BKV-related HC.

Economic and Clinical Burden of Virus-Associated Hemorrhagic Cystitis in Patients Following Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Hemorrhagic cystitis (HC) due to viral infections, such as BK virus, cytomegalovirus and/or adenovirus, after Allogeneic Hematopoietic Cell Transplantation (allo-HCT) causes morbidity and mortality, impacts quality of life, and poses a substantial burden to the health care system. Virus-associated HC (V-HC) occurs in up to 25% and 54% of pediatric and adult allo-HCT recipients respectively. V-HC is associated with incapacitating pain, life-disturbing urinary symptoms, and in severe forms, severe hematuria requiring transfusion support, bladder obstruction, renal impairment and increased mortality. At present, management is purely supportive as there are no approved or recommended anti-virals for V-HC. The impact of V-HC on health resource utilization (HRU) and HCT outcomes has not been studied at a national level. The objective of this study was to compare the economic burden, HRU and clinical outcomes among allo-HCT recipients with V-HC to those without V-HC using a large US claims database. Methods: A US claims database obtained from the Decision Resources Group Real World Evidence Data Repository was used to identify patients with first (index) allo-HCT procedure from 1/1/2012-12/31/2017. The 1-year period prior to the index allo-HCT was considered as the baseline period. Although, there are diagnosis codes in the International Classification of Diseases (ICD-9 or ICD-10) coding system for HC, there are no specific diagnosis codes to identify V-HC. Hence, an algorithm was developed through clinical guidance to identify these patients among those with HC diagnosis codes (Figure 1). Outcomes were examined in the 1-year post allo-HCT and included total healthcare reimbursements, HRU and clinical outcomes for allo-HCT patients with vs. without V-HC. Total reimbursements were estimated from submitted charges using a reimbursement-to-charge ratio of 0.425 and were reported in 2019 US dollars, adjusted using the medical care component of the US Consumer Price Index. Further, a generalized linear model was used to determine adjusted reimbursements stratified by the presence or absence of any acute or chronic graft-versus-host diseases (GVHD) after adjusting for age, health plan, underlying disease, stem cell source, number of comorbidities, baseline costs, and follow-up time. Results: Of 13,363 allo-HCT recipients, 759 (5.7%) patients met the criteria for V-HC. Total unadjusted mean reimbursement was $632,870 (SD=$640,815) for patients with V-HC and $340,469 (SD=$377,591) for patients without V-HC (Table 1). In multivariable model after adjusting for confounders, the adjusted reimbursements were significantly higher for V-HC patients with and without GVHD compared to patients without V-HC (p&amp;lt;.0001) (Figure 2). V-HC was associated with increased hospital length of stay (LOS) and readmission rates. Patients with V-HC had 7.9 additional days in the hospital (35.5 vs 27.6 days; p&amp;lt;.0001) and 6.1 additional days (34.3 vs. 28.2 days; p=0.0009) in the intensive care unit (ICU) for the index hospitalization, as compared to patients without V-HC (Table 1). The hospital readmission rate was higher for allo-HCT patients with V-HC compared to those without V-HC (3.5 vs. 1.9 per person yr; p&amp;lt;.0001), resulting in 12.9 more days in the hospital (50.0 days vs. 37.1 days; p&amp;lt;.0001) and 7.3 more days in the ICU (25.8 days vs. 18.5 days; p&amp;lt;.0001) after the index hospitalization (Table 1). V-HC was associated with increased mortality in patients with GVHD and increased risk of renal impairment in all allo-HCT patients. Among patients with GVHD, those with V-HC had significantly higher all-cause mortality as compared to those without V-HC (23.2% vs. 18.4%; p=0.0035) (Table 2). When stratified by GVHD, there were no significant differences in the baseline risk for renal impairment; while V-HC was associated with increased risk for renal impairment in the follow-up period in patients with or without GVHD (p&amp;lt;.0001 for both) (Table 2). Conclusions: Allo-HCT patients with V-HC have significantly higher healthcare reimbursements, health resource utilization, and worse clinical outcomes including renal impairment, irrespective of the presence of GVHD; with significantly higher all-cause mortality in the presence of GVHD. Our results highlight the unmet clinical need for effective strategies to prevent and treat V-HC in HCT recipients that may also reduce costs among these patients. Disclosures McGuirk: Pluristem Ltd: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; Bellicum Pharmaceutical: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding. Moon:AlloVir, Inc.: Current Employment, Current equity holder in publicly-traded company. Chandak:AlloVir, Inc.: Other: Independent contractor. Zhang:AlloVir, Inc.: Other: Independent contractor. Papanicolaou:Chimerix: Other: Consulting and other fees, Research Funding; Astellas Pharma: Other: Consulting and other fees, Research Funding; Merck &amp; Co.: Other: Consulting and other fees, Research Funding; Octapharma: Other: Consulting and other fees; Partner Therapeutics: Other: Consulting and other fees; ADMA Biologics: Other: Consulting and other fees; Shionogi: Other: Consulting and other fees; Cidara: Other: Consulting and other fees; Amplyx: Other: Consulting and other fees; Siemens: Other; Takeda: Research Funding.

Failure to Prevent Severe Graft-Versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in Chronic Granulomatous Disease.

Haploidentical related donor (HRD) transplantation was performed in 7 recipients with chronic granulomatous disease (CGD) who had no matched-related or unrelated donor. Peripheral blood cell (PBC) products were used with a conditioning regimen consisting of low-dose cyclophosphamide, fludarabine, total body irradiation, and busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of high-dose post-transplant cyclophosphamide and sirolimus. Recipients were ages 14-26years, and 3 had severe infections active at transplant. All 7 recipients achieved full engraftment with complete donor chimerism early in the post-transplant period. Acute GVHD occurred in all cases and was grade 3 or steroid refractory in 3. Two patients with steroid-refractory GVHD died. Three patients with severe infectious complications active at transplant, 1 Nocardia pneumonia and 2 extensive invasive fungal infections), survived and were cured of their infection at last follow-up. Bacterial disease occurred post-transplant in all recipients, and viral infections/reactivation were common, including 4 cases of BK virus-associated hemorrhagic cystitis. Seven patients with CGD achieved rapid and full-donor engraftment from HRDs utilizing PBCs and a conditioning regimen with PTCy and sirolimus GVHD prophylaxis. However, the incidence of grade 3 and steroid-refractory GVHD was high and led to 2 deaths. Patients with active infections at transplant had successful transplant courses and were cured of their disease. Although there was an initial success with this regimen, the cumulative experience does not support its use in CGD due to an unacceptable rate of severe GVHD.

BK Virus-Associated Hemorrhagic Cystitis in Allogeneic Hematopoietic Cell Transplantation (HCT) Recipients with Primary Immunodeficiency

Allogeneic HCT recipients may develop BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC), typically early after engraftment. Yet, BKV levels in urine and blood are not routinely monitored pre- or post-HCT. Among HCT recipients with primary immunodeficiency diseases (n=40), we prospectively monitored BKV levels by quantitative PCR in blood and urine pre-HCT, as well as weekly post-HCT through day +100 on NCT02579967. Thirty patients were considered at-risk for BKV-HC based on BKV detection in urine/blood at any timepoint. Of these, 22 (73%) developed BKV-HC. Of recipients treated on the reduced-intensity conditioning (RIC) busulfan-containing arms of the trial, 22 of 27 (81%) at-risk patients developed BKV-HC (Fig 1). By contrast, on the non-myeloablative conditioning arms, identical to RIC except for the absence of busulfan (Fig 2), 0 of 3 at-risk patients developed BKV-HC (p=0.01). No patients received antiviral or cellular therapies for BKV-HC, although 3 received cidofovir and/or brincidofovir for adenovirus infection. Three required continuous bladder irrigation; 1 required multiple cystoscopies for clot evacuation but no intravesicular therapy. Disease outside the bladder was rare: 1 patient (Fig 1 - P36, with notably atypical pattern of BKV levels in relation to symptoms) developed tissue-proven BKV nephropathy, along with radiographic and cytopathologic (SV40+ cells on bronchoalveolar lavage) evidence of BKV pneumonitis; thus, further evaluation for extravesicular disease, particularly in those without significant gross hematuria, is under way. Patient discomfort and supportive care needs were significant, especially during gross hematuria (n=19; median duration 21 days, range 2-41; see Fig 1). With neutrophil engraftment at median day +17 (range 13-42), median onset of BKV-HC symptoms was day +22 (range +5-74), with median duration of 26 days (range 6-145 days). Starting on day +21, the trajectory of urine BKV levels diverged between RIC-HCT recipients with or without BKV-HC (Fig 3), with significantly higher BKV in urine at day +28 for BKV-HC patients, median 8.98 log10 IU/mL, compared to those without, median 4.99 log10 IU/mL, Mann-Whitney p=0.02. At BKV-HC onset, median level of BKV in urine was 9.66 log10 IU/mL (range 6.01 to >9.81) and, at full resolution, 8.39 log10 IU/mL (range 2.87 to >9.81). Swimmer's plot (Fig 1) shows the peak in urine BKV to occur soon before or early into symptom onset in most and that blood BKV peak levels vary more in timing. In conclusion, in this cohort, the use of busulfan seems to be an important co-factor in BKV-HC risk, as also noted by others. The trajectory of BKV levels in urine differed between those with and without BKV-HC, although the identification of early BKV-HC predictors is limited by the short interval between divergence in case/control values and symptom onset.

Intravesicular Cidofovir in the Treatment of BK Virus-Associated Hemorrhagic Cystitis Following Hematopoietic Stem Cell Transplantation.

Background: BK virus hemorrhagic cystitis (BKV-HC) is a common complication following hematopoietic stem cell transplant (HSCT); optimal management remains uncertain. Supportive care (bladder irrigation and blood transfusions) and intravenous and intravesicular cidofovir have all been used with varying success. Objective: The purpose of this study was to determine the safety and effectiveness of intravesicular cidofovir for BKV-HC following HSCT. Methods: A retrospective analysis of all HSCT patients with BKV-HC prescribed intravesicular cidofovir from 2012 to 2017. Results: 33 patients were treated for BKV-HC. The median age was 50 years (range 23-73), and 18 (55%) were male. The median HC symptom severity was 2, with a median BK urine viral load pretreatment of 100,000,000 IU/mL. Patients received a median of 2 intravesicular treatments (range 1-7) at a dosage of 5 mg/kg per instillation. In all, 19 (59%) patients demonstrated complete clinical resolution of symptoms; 9 (28%) had a partial response; and 4 (13%) had no change in symptoms. Patients with a high pretreatment BK viral load (>100 million) and high HC grade (2-4) had a lower frequency of complete remission. The main side effect of intravesicular instillation was severe bladder spasms in 4 patients (12%). Conclusion and Relevance: This is the largest study of intravesicular cidofovir treatment of BKV HC reported to date; 88% of patients with BVK-HC achieved clinical improvement of symptoms with minimal side effects. Clinical trials of intravesicular cidofovir could provide further evidence for this treatment for BKV-HC.

1763. The Use of Haploidentical Donors Compared with HLA-Matched Unrelated Donors is Associated with Increased Risk of BK Viruria and Hemorrhagic Cystitis

BackgroundBK virus-associated hemorrhagic cystitis (BK-HC) is a common and often serious complication of hematopoietic cell transplantation (HCT). Studies have suggested a higher incidence of BK-HC in patients receiving haploidentical (haplo) HCTs compared with those receiving matched unrelated donor (MUD) transplants.MethodsWe retrospectively identified all adult patients receiving HCT from MUD or haplo donors at Washington University School of Medicine between January 1, 2011 and January 1, 2016. Via informatics queries, we obtained the results of every urine BK test performed on these patients. Patients with BK viruria were then evaluated for BK-HC and graded according to established criteria. The last day of follow-up was April 31, 2017.Results503 MUDs and 140 haplos were identified for inclusion in the study. Haplo patients were significantly more likely to be nonwhite (21% vs. 5%, P < 0.001) and were younger (median age: 51.5 vs. 55, P = 0.01). Conditioning regimens were also significantly different; haplos were less likely to receive myeloablative conditioning (44% vs. 57%, P < 0.001) and busulfan-based conditioning (13% vs. 39%, P < 0.001), but were more likely to receive total body irradiation-based conditioning (83% vs. 26%, P < 0.001). Haplos were also more likely to have undergone previous allogeneic HCT (26% vs. 6%, P < 0.001). The cumulative incidence of both BK viruria and BK-HC were significantly higher in haplos (both P < 0.001). This was observed at 100 days, 180 and 365 days (Table 1).ConclusionWe found a significantly higher incidence of both BK viruria and BK-HC in patients receiving haplo HCT compared MUD HCT. Significant demographic and clinical imbalances exist between our two cohorts and attribution of increased risk for BK-HC to donor type vs. other factors should be further explored. Disclosures All authors: No reported disclosures.