Novel Insights into Predictors, Optimized Treatments, and Prognosis Factors for Virus-Induced Hemorrhagic Cystitis Post-Hematopoietic Stem Cell Transplantation: A Single-Institution Study of 427 Japanese Patients

Introduction and Objectives

Virus-induced hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and affects patients' quality of life (QOL) by causing painful urination and gross hematuria. Therefore, control of HC is crucial for maintaining QOL. However, valid predictors for the severity of HC, effective treatments for HC, and prognostic factors related to overall survival (OS) remain unclear as real-world data on HC after allo-HSCT are limited. In addition, there have been few studies of HC led by urologists. Herein, we investigated valid predictors for the severity of HC, effective treatments for HC, and prognostic factors related to OS from the perspective of urologists, in collaboration with hematologists.

Materials and Methods

Between January 2014 and December 2023, 1506 patients underwent allo-HSCT, with 427 definitively diagnosed with virus-induced HC via positive urine PCR tests. We retrospectively reviewed pre-transplant data, peri-transplant data, HC severity, hematuria resolution duration, and OS. HC severity was graded on a five-point scale referring to the previously reported HC grading system: grade 0 (pain with urination only), grade 1 (microscopic hematuria), grade 2 (gross hematuria), grade 3 (gross hematuria with small clots), and grade 4 (gross hematuria with clots causing urinary obstruction). Statistical analysis was performed to identify valid predictors, effective treatments, and prognostic factors.

Results

Among the 427 cases, 270 and 157 cases were male and female. The median patient age was 54 years (interquartile range: 42-63). A total of 294, 131, and 2 cases had myeloid, lymphoid, and other diseases such as aplastic anemia, respectively. Regarding the total number and type of allo-HSCT, 337, 83, and 7 cases underwent their first, second, and more than two allo-HSCTs. Furthermore, 381, 65, and 31 cases underwent umbilical cord blood transplantation (CBT), peripheral blood stem cell transplantation (PBSCT), and bone marrow transplantation, respectively. There were 630 events of HC in 427 cases, with grade 4 hematuria occurring in 56 cases. Among these 56 cases, 7 cases required transurethral coagulation (TUC) to resolve urinary obstruction and to stop bleeding.

Logistic regression analysis for grade 4 hematuria revealed that pre-transplant factors such as, lymphoid disease (p < 0.01), CBT (p < 0.01), PBSCT (p = 0.03) were significantly associated with the severity of HC. Additionally, peri-transplant factors, including low platelet count (p < 0.01), high white blood cell count (p < 0.01), high BK virus copies in blood (p < 0.01), and sinusoidal obstruction syndrome (SOS) (p = 0.02), were significantly related to the severity of HC.

The median OS of the 427 cases was 16 months. We divided the 427 cases into three groups based on their maximum HC grade and used survival analysis to evaluate the relationship between the severity of HC and OS. The log-rank test revealed that the severity of HC was associated with OS (p < 0.01), and Cox regression analysis showed that age (p < 0.01), performance status (p<0.01), the total number of allo-HSCTs (p=0.02), the severity of HC (p < 0.01), and SOS (p = 0.02) were significantly associated with OS.

Finally, we evaluated the relationship between treatments and the duration of hematuria resolution. Cox regression analysis revealed that cidofovir (p < 0.01), high-dose intravenous immunoglobulin therapy (p < 0.01), insertion of a urethral catheter (p = 0.03), and irrigation (p < 0.01) were associated with a shorter duration of hematuria resolution, while antibiotics and TUC were not associated.

Conclusion

This study identified pretransplant predictors and predictors at HC events for the severity of HC. Additionally, the prognostic factors related to OS such as the severity of HC was demonstrated, as well as effective treatments for HC. The predictors and effective treatments identified in this study could help avoid severe hematuria and consequently prolong OS. Furthermore, the effective treatments could help improve QOL of patients by shortening the duration of hematuria resolution. We believe that these results will assist urologists and hematologists in managing virus-induced HC.

Kaji:SymBio Pharmaceuticals: Honoraria; Sanofi K.K.: Honoraria; Pfizer Japan Inc.: Honoraria; Ono Pharmaceutical Co.: Honoraria; Meiji Seika Pharma Co.: Honoraria; Janssen Pharmaceutical KK.: Honoraria; Genmab: Honoraria; Eisai Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Bristol Myers Squibb K.K.: Honoraria; AstraZeneca: Honoraria; Asahi Kasei Pharma Co.: Honoraria; AbbVie GK.: Honoraria; Takeda Pharmaceutical Co.: Honoraria. Takagi:Takeda Pharmaceutical Co.: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; Novartis Pharma Co.: Honoraria; Nippon Shinyaku Co.: Honoraria; MSD KK (Merck & Co. Inc.): Honoraria; Kyowa Kirin Co.: Honoraria; Janssen Pharmaceutical KK.: Honoraria; GlaxoSmithKline KK.: Honoraria; Daiichi Sankyo Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Astellas Pharma Inc.: Honoraria; Asahi Kasei Pharma Co.: Honoraria; Amgen KK.: Honoraria; AbbVie GK.: Honoraria; The Japanese Society of Hematology: Research Funding; Okinaka Memorial Institute for Medical Research: Research Funding; Pfizer Japan Inc.: Honoraria; Sumitomo Pharma Co.: Honoraria. Yamamoto:Astellas Pharma Inc.: Honoraria; MSD KK (Merck & Co.) Inc.: Honoraria; JCR Pharmaceuticals Co.,Ltd.: Honoraria; Janssen Pharmaceutical KK: Honoraria; Novartis Pharma Co.: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; CSL Behring K.K: Honoraria; AstraZeneca: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Takeda Pharmaceutical Co.: Honoraria; Asahi Kasei Pharma Co.: Honoraria; Sumitomo Pharma CO.,Ltd.: Honoraria. Yamamoto:Ono Pharmaceutical Co.: Honoraria; Genmab: Honoraria; Eisai Co.: Honoraria; AstraZeneca: Honoraria; Mundi Pharma Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Bristol Myers Squibb K.K.: Honoraria; Nihonkayaku Co.: Honoraria; Daiichi Sankyo Co.: Honoraria; Meiji Seika Pharma Co.: Honoraria; Novartis Pharma Co.: Honoraria; Pfizer Japan Inc.: Honoraria; Janssen Pharmaceutical KK.: Honoraria; Sanofi K.K.: Honoraria; Takeda Pharmaceutical Co.: Honoraria. Uchida:Chugai Pharmaceutical Co.: Research Funding; Fuji Pharma Co.: Research Funding; Sumitomo Pharma Co.: Research Funding; Nippon Boehringer Ingelheim Co.: Research Funding; JCR Pharmaceuticals Co.: Research Funding; CSL Behring: Honoraria; MSD (Merck & Co. Inc.): Honoraria; Asahi Kasei Pharma Co.: Honoraria; Astellas Pharma Inc.: Honoraria; AstraZeneca: Honoraria; AbbVie GK: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; Kyowa Kirin Co.: Honoraria; SymBio Pharmaceuticals: Honoraria; Daiichi Sankyo Co.: Honoraria; Takeda Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Nippon Shinyaku Co.: Honoraria; Takeda Pharmaceutical Co.: Consultancy; Astellas Pharma Inc.: Consultancy; Novartis Pharma Co.: Honoraria.