Sulfolane (a metabolite of busulfan) Levels Could Predict Occurrence Of Hemorrhagic Cystitis In Children Receiving Busulfan Based Myeloablative Conditioning Before Hematopoietic Stem Cell Transplantation

Late-Onset Hemorrhagic Cystitis in Children after Hematopoietic Stem Cell Transplantation for Thalassemia and Sickle Cell Anemia: A Prospective Evaluation of Polyoma (BK) Virus Infection and Treatment with Cidofovir

Hemorrhagic cystitis (HC) is the main complication after hematopoietic stem cell transplantation (SCT). Adenovirus (AdV) is the leading cause of late-onset HC after SCT in Japan. The incidence and outcome of HC were studied in 77 adults who underwent unrelated cord blood transplantation (CBT). Thirty-two patients developed HC in a median of 19 days (range, 11-170 days) after CBT. The cumulative incidence of HC was 41.8% at 1 year. Ten patients developed gross hematuria. The cumulative incidence of moderate-to-severe HC was 13.2% at 1 year. Only 1 patient developed severe HC; AdV was detected in a urine sample from that patient. AdV was also detected in a urine sample from another patient with moderate HC after CBT. AdV in both patients was identified as AdV type 11. The cumulative incidence of AdV-induced HC was 2.8% at 1 year. The incidence of AdV-induced severe HC after CBT may be relatively low among Japanese adults. The role of other viruses, including BK virus, in the pathogenesis of HC after CBT needs to be examined.

Hemorrhagic Cystitis and BK Virus Infection in Children after Hematopoietic Stem Cell Transplantation.

Hemorrhagic cystitis (HC) is one of the complications of busulfan-cyclophosphamide (BU-CY) conditioning regimen during allogeneic hematopoietic stem cell transplantation (HSCT) in children. Identifying children at high risk of developing HC in a HSCT setting could facilitate the evaluation and implementation of effective prophylactic measures. In this retrospective analysis genotyping of selected candidate gene variants was performed in 72 children and plasma Sulfolane (Su, water soluble metabolite of BU) levels were measured in 39 children following treatment with BU-CY regimen. The cytotoxic effects of Su and acrolein (Ac, water soluble metabolite of CY) were tested on human urothelial cells (HUCs). The effect of Su was also tested on cytochrome P 450 (CYP) function in HepaRG hepatic cells. Cumulative incidences of HC before day 30 post HSCT were estimated using Kaplan–Meier curves and log-rank test was used to compare the difference between groups in a univariate analysis. Multivariate Cox regression was used to estimate hazard ratios with 95% confidence intervals (CIs). Multivariate analysis included co-variables that were significantly associated with HC in a univariate analysis. Cumulative incidence of HC was 15.3%. In the univariate analysis, HC incidence was significantly (p < 0.05) higher in children older than 10 years (28.6 vs. 6.8%) or in children with higher Su levels (>40 vs. <11%) or in carriers of both functional GSTM1 and CYP2C9 (33.3 vs. 6.3%) compared to the other group. In a multivariate analysis, combined GSTM1 and CYP2C9 genotype status was associated with HC occurrence with a hazards ratio of 4.8 (95% CI: 1.3–18.4; p = 0.02). Ac was found to be toxic to HUC cells at lower concentrations (33 μM), Su was not toxic to HUC cells at concentrations below 1 mM and did not affect CYP function in HepaRG cells. Our observations suggest that pre-emptive genotyping of CYP2C9 and GSTM1 may aid in selection of more effective prophylaxis to reduce HC development in pediatric patients undergoing allogeneic HSCT.Article summary:(1) Children carrying functional alleles in GSTM1 and CYP2C9 are at high risk for developing hemorrhagic cystitis following treatment with busulfan and cyclophosphamide based conditioning regimen.(2) Identification of children at high risk for developing hemorrhagic cystitis in an allogeneic HSCT setting will enable us to evaluate and implement optimal strategies for its prevention.Trial registration: This study is a part of the trail “clinicaltrials.gov identifier: NCT01257854.”

The purpose of this multicenter study was to assess the incidence and the treatment of hemorrhagic cystitis (HC) in 1218 pediatric patients, with a mean age of 10.8 years, who underwent hematopoietic stem cell transplantation (HSCT). In all, 44 patients (3.6%) developed HC a median 23 days after HSCT. The incidence of HC was higher in allogeneic than in autologous HSCT recipients (P=0.0001). Of the 44 patients, 37 (84%) recovered from HC in a median 30 days (range 3-100); the other seven children died while still suffering from HC. Hyperbaric oxygen therapy (HOT) achieved significantly better results than prostaglandin therapy (P=0.02) in the treatment of grade II-III HC. By multivariate analysis, age <96 months and allogeneic HSCT were significantly associated with the occurrence of HC: P=0.008 and 0.013, respectively. After a median follow-up of 5.75 years, the 5-year survival of patients who did or did not develop HC was: 43 vs 52%, P=0.03, respectively. This study indicates that age and type of HSCT are factors predisposing to HC in children given HSCT and demonstrates the promising role of HOT in a conservative approach to HC treatment.

Polyoma (BK) Viruria Prior to Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) from Donors Other Than Matched Siblings: A Prospective Evaluation of Hemorrhagic Cystitis (HC) Incidence

Risk Factors and Prognosis of Hemorrhagic Cystitis after Allogeneic Stem Cell Transplantation: Retrospective Analysis in a Single Institution

To explore the risk factors for hemorrhagic cystitis (HC) in children with β-thalassemia major (TM) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). A retrospective analysis was conducted on clinical data of 247 children with TM who underwent allo-HSCT at Shenzhen Children's Hospital from January 2021 to November 2022. The children were divided into an HC group (91 cases) and a non-HC group (156 cases) based on whether HC occurred after operation. Multivariable logistic regression analysis was used to explore the risk factors for HC, and the receiver operating characteristic curve was used to analyze the predictive efficacy of related factors for HC. Among the 247 TM patients who underwent allo-HSCT, the incidence of HC was 36.8% (91/247). Univariate analysis showed age, incompatible blood types between donors and recipients, occurrence of acute graft-versus-host disease (aGVHD), positive urine BK virus deoxyribonucleic acid (BKV-DNA), and ≥2 viral infections were associated with the development of HC after allo-HSCT (P<0.05). Multivariable analysis revealed that incompatible blood types between donors and recipients (OR=3.171, 95%CI: 1.538-6.539), occurrence of aGVHD (OR=2.581, 95%CI: 1.125-5.918), and positive urine BKV-DNA (OR=21.878, 95%CI: 9.633-49.687) were independent risk factors for HC in children with TM who underwent allo-HSCT. The receiver operating characteristic curve analysis showed that positive urine BKV-DNA alone or in combination with two other risk factors (occurrence of aGVHD, incompatible blood types between donors and recipients) had a certain accuracy in predicting the development of HC after allo-HSCT (area under the curve >0.8, P<0.05). Incompatible blood types between donors and recipients, occurrence of aGVHD, and positive urine BKV-DNA are risk factors for HC after allo-HSCT in children with TM. Regular monitoring of urine BKV-DNA has a positive significance for early diagnosis and treatment of HC.

To investigate the risk factors for hemorrhagic cystitis (HC) in children with severe beta-thalassemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical data of 152 children under the age of 15 who underwent allo-HSCT between January 2011 and December 2021 were retrospectively analyzed. The incidence of HC and related variables were evaluated using univariate analysis. Variables with statistical significance (P < 0.05) were included in a multivariable logistic regression model to identify independent risk factors for HC. Among the 152 children, 42 developed HC, with an incidence rate of 27.63%. The median onset time of HC was 25 days (IQR: 10-38.75 days). Univariate analysis indicated that older transplantation age, elevated pre-transplant serum ferritin levels, cytomegalovirus (CMV) infection, and prolonged neutrophil engraftment time were associated with HC occurrence (P < 0.05). Multivariable logistic regression further confirmed that older transplantation age (OR 1.236, 95% CI: 1.031-1.531, P = 0.033), elevated pre-transplant ferritin levels (OR 1.053, 95% CI: 1.028-1.086, P < 0.01), CMV infection (OR 11.522, 95% CI: 2.912-76.345, P = 0.002), and prolonged neutrophil engraftment time (OR 1.385, 95% CI: 1.109-1.793, P < 0.01) were independent risk factors for HC. Older transplantation age (>5.95 age years old), elevated pre-transplant serum ferritin levels, CMV infection, and delayed neutrophil engraftment are independent risk factors for HC in children with severe beta-thalassemia after allo-HSCT. Early identification and intervention for these risk factors are crucial in reducing the incidence of HC.

Development of BK Virus-Associated Hemorrhagic Cystitis (HC) Is Associated with Decreased Survival Post-Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

A retrospective cohort of 163 children with 171 hematopoietic stem cell transplantation (HSCT) performed during Mar. 1992-Dec. 2005 were analyzed to evaluate the incidence, risk factors, management, and outcome of hemorrhagic cystitis (HC). Fourteen patients (8.2%) developed HC (6 boys, median age 6.6 years) at 0-166 days after HSCT (median 25 days), and lasted for 3-96 days (median 26 days). Older age at transplant (median 11.0 vs. 6.4 years, P = 0.013), allogeneic transplant (OR = 4.4, P = 0.02), cyclophosphamide-containing conditioning (OR = 4.87, P = 0.008), moderate-to-severe acute graft-versus-host disease (GVHD) (OR = 3.56, P = 0.025) and hepatic GVHD (OR = 3.62, P = 0.017) were associated with higher risks of HC in univariate but not multivariate analyses. While estrogen was ineffective in most patients, intravesical formalin, which was used in five patients, was found to be a very effective yet safe treatment for intractable HC. Patients with HC had longer hospital stay (median 175 vs. 88 days, P = 0.004). HC resolved after treatments in all cases but eight of the 14 patients subsequently died of other complications of HSCT. In conclusion, HC is a serious complication of allogeneic HSCT. Treatment with intravesical formalin appears effective and safe and can be considered early in severe HC to reduce the risk of morbidity and mortality.

TLR4 Asp299Gly Variant Confers Strong Protection against BK Virus-Associated Hemorrhagic Cystitis After Hematopoietic Stem Cell Transplantation in Children.

Hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic stem cell transplantation (HSCT). The incidence is about 7% to 68%, and some patients have to suffer a long period of frequent, urgent, and painful urination, which brings great pain. This study aimed to analyze risk factors of HC and its effect on patient survival. We collected the medical records of 859 patients who underwent HSCT at our hospital between August 2016 and August 2020. Patients with and without HC were matched using propensity score matching at a 1:1 ratio based on sex, age, and diagnosis, and logistic regression analyses were used to identify factors associated with HC. We used Kaplan–Meier curves to analyze the survival rates of patients in the HC and non-HC groups. We also analyzed the relationship between BK viral load and the occurrence of HC using receiver operating characteristic curve (ROC) analysis. After propensity score matching, there were 131 patients each in the HC and non-HC groups. In the HC group, 89 patients (67.9%) had mild HC (stage II°) and 43 (32.1%) had severe HC (stage III–IV). The median interval between stem cell transplantation and HC development was 31 (3–244) days. Univariate analysis indicated that donor age, hematopoietic stem cell source, HLA, acute graft-versus-host disease, busulfan, anti-thymocyte globulin (ATG), total body irradiation, cytomegalovirus (CMV) (urine), and BK polyomavirus (BKV) (urine) were significantly associated with HC. ATG, CMV (urine), and BKV (urine) were independent risk factors for HC based on the multivariate analysis. The Kaplan–Meier survival analysis showed no significant difference between the HC and non-HC groups (P = .14). The 1- and 2-year survival rates in the HC group were 78.4% and 69.6%, respectively, and the corresponding rates in the non-HC group were 84.4% and 80.7%, respectively. ROC analysis indicated that a urine BKV load of 1 × 107 copies/mL was able to stratify the risk of HC. In conclusion, when the BKV load is >1 × 107, we need to be aware of the potential for the development of HC.

Continuous Intravenous Injection Of Mesna Can Reduce Acute Hemorrhagic Cystitis Occurrence Rate In Hematopoietic Stem Cell Transplantation: 359 Allo-HSCT Cases Report

BackgroundThe risk factors for hemorrhagic cystitis (HC) in children undergoing hematopoietic stem cell transplantation (HSCT) are unclear. Therefore, we conducted this systematic review and meta-analysis to investigate the risk factors for HC in children undergoing HSCT.MethodsWe performed this meta-analysis by retrieving studies from PubMed, EMBASE, and the Cochrane Library up to October 10, 2023, and analyzing those that met the inclusion criteria. I2 statistics were used to evaluate heterogeneity.ResultsTwelve studies, including 2,764 patients, were analyzed. Male sex (odds ratio [OR] = 1.52; 95% confidence interval [CI], 1.16–2.00; p = 0.003, I2 = 0%), allogeneic donor (OR = 5.28; 95% CI, 2.60–10.74; p < 0.00001, I2 = 0%), human leukocyte antigen (HLA) mismatched donor (OR = 1.86; 95% CI, 1.00–3.44; p = 0.05, I2 = 31%), unrelated donor (OR = 1.58; 95% CI, 1.10–2.28; p = 0.01, I2 = 1%), myeloablative conditioning (MAC) (OR = 3.17; 95% CI, 1.26–7.97; p = 0.01, I2 = 0%), busulfan (OR = 2.18; 95% CI, 1.33–3.58; p = 0.002, I2 = 0%) or anti-thymoglobulin (OR = 1.65; 95% CI, 1.07–2.54; p = 0.02, I2 = 16%) use, and cytomegalovirus (CMV) reactivation (OR = 2.64; 95% CI, 1.44–4.82; p = 0.002, I2 = 0%) were risk factors for HC in children undergoing HSCT.ConclusionsMale sex, allogeneic donor, HLA-mismatched, unrelated donor, MAC, use of busulfan or anti-thymoglobulin, and CMV reactivation are risk factors for HC in children undergoing HSCT.