Late-onset Hemorrhagic Cystitis Research Articles

Hyperbaric oxygen therapy in the treatment of late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation

Introduction: Hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), characterized by inflammation and bleeding of the bladder. Hyperbaric oxygen therapy (HBOT) has been shown to be effective in the treatment of radiation-induced HC. However, the optimal treatment for HC after allogeneic HSCT has not yet been established. Furthermore, limited research has been conducted on the use of HBOT in this setting. This study aimed to evaluate the effectiveness and safety of HBOT in patients with late-onset HC after allogeneic HSCT. Methods: Twenty-five-year (1998–2022) retrospective analysis performed in all consecutive patients with confirmed late-onset HC after allogeneic HSCT treated with HBOT at two centers in Portugal. Medical records were reviewed for clinical and laboratory features, primary indications for allogeneic HSCT, conditioning regimen, and treatment strategies for HC. Patients received 100% oxygen at 2.1–2.5 atmosphere absolute pressure (ATA) for 70–90-minute periods, once daily, five times per week. Complete clinical response was defined as the absence of macroscopic hematuria sustained for at least 2 weeks, and partial response was described as a downgrading in the severity of HC. Statistical significance was considered for values of p < 0.05. Results: The sample included 61 patients with a mean age of 28.0 (SD 14.2) years, 33 males. Complete response was achieved in 72.1% (n = 44) of patients and partial response in 14.8% (n = 9). Concerning patients with a complete response, the median number of HBOT sessions was 15.5 sessions (IQR 10.0-26.8). Patients treated with 10 or more sessions of HBOT had a higher rate of complete or partial response (OR 12.5, 95%CI 1.9–83.2, p-value < 0.05). There was no response in 8 (13.1%) patients, and 6 interrupted the treatments early. Only 2 patients suspended the HBOT due to a lack of clinical benefit. Conclusion: Our study supports using of HBOT as an adjunctive treatment for late-onset HC after allogeneic HSCT. Furthermore, 10 or more HBOT sessions delivered seem to impact the rate of HC resolution. Prospective, randomized, and well-controlled trials are needed to establish HBOT’s definitive efficacy and safety.

Hyperbaric oxygen therapy improves the efficacy of conventional supportive treatment for late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation

ABSTRACT Objective This study aims to investigate the efficacy and safety of hyperbaric oxygen therapy (HBOT) in the treatment of late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. Methods This retrospective analysis included 16 patients with late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation between 2016 and 2022. Among them, 8 patients received HBOT in addition to conventional treatment, while the other 8 received only conventional treatment. The clinical efficacy and safety of HBOT were evaluated by comparing the Numeric Rating Scale pain scores and clinical grades of hematuria before and after treatment, reflecting the patients’ urinary pain and hematuria status. Results The patients were divided into two groups based on whether they received HBOT. The group that received HBOT (n = 8) had a shorter duration of illness compared to the non-HBOT group (n = 8) (p < 0.05). The time for the NRS to decrease to below 2 was also shorter in the HBOT group. Furthermore, the patients who received HBOT did not experience any significant adverse reactions. Conclusion The combination of conventional treatment and hyperbaric oxygen therapy (HBOT) has been shown to improve symptoms such as urinary pain, frequency, urgency, and hematuria in patients with late-onset hemorrhagic cystitis after transplantation. This approach has been proven to be safe and effective.

Risk Factors of Late-Onset Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation

The clinical data of 300 patients who underwent allo-HSCT at the First Affiliated Hospital of Chongqing Medical University from January 2015 to December 2021 were retrospectively analyzed. The relevant clinical parameters that may affect the occurance of LOHC after allo-HSCT were selected for univariate and multivariate analysis. Then, the differences in overall survival (OS) and progression-free survival (PFS) between different groups were analyzed. The results of multivariate analysis showed that the independent risk factors for LOHC after allo-HSCT were as follows: age≤45 years old (P =0.039), intensified conditioning regimen with fludarabine/cladribine and cytarabine (P =0.002), albumin≤30 g/L on d30 after transplantation (P =0.007), CMV-DNA positive (P =0.028), fungal infection before transplantation (P =0.026), and the occurrence of grade Ⅱ - Ⅳ aGVHD (P =0.006). In the transplant patients who have already developed LOHC, the occurance of LOHC within 32 days after transplantation (P =0.008) and albumin≤30 g/L on d30 after transplantation (P =0.032) were independent risk factors for the progression to severe LOHC. The OS rate of patients with severe LOHC was significantly lower than that of patients without LOHC (P =0.041). For the patients aged≤45 years old and with intensified conditioning regimen, it is necessary to be vigilant about the occurrence of LOHC; For the patients with earlier occurrence of LOHC, it is necessary to be vigilant that it develops into severe LOHC. Early prevention and treatment of LOHC are essential. Regular monitoring of CMV-DNA and albumin levels, highly effective antiviral and antifungal therapies, and prevention of aGVHD are effective measures to prevent the occurrence and development of LOHC.

Clinical study of late-onset hemorrhagic cystitis after allo-HSCT without in vitro T-cell depletion

This study is to investigate the hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) without in vitro T-cell depletion. Patients receiving allo-HSCT in 2019 were enrolled. The occurrence and clinical characteristics of HC after HLA-identical HSCT and haploidentical HSCT were retrospectively analyzed. BK, JC, cytomegalovirus, and other viruses were monitored when HC occurred. Conventional HC treatment was performed. Additionally, 5 cases of severe refractory HC were treated with adipose-derived mesenchymal stem cell (ADSC) besides conventional HC treatment. Totally, 54 patients with allo-HSCT were enrolled, including 12 cases with HLA-identical HSCT and 42 cases with haploidentical HSCT. Among them, 17 developed late-onset HC (LOHC). There was no early-onset HC. The median onset time was 33.5 (9-189) days, with a median duration of 19 (5-143) days. There were 8 cases of grade III HC and 2 cases of grade IV HC. The cumulative incidence of LOHC in 54 patients was 29.6%, and the cumulative incidence of LOHC in 42 patients with haploidentical HSCT was 40.5%. The 1-year expected progression-free survival (PFS) of 26 patients without HC was 86.6%, and the 1-year expected PFS of 16 HC patients was 74.5%. However, there was no statistically significant difference (P = .326). The urine BK virus of 14 patients was positive, with the lowest of 1.98 × 105 copies/mL, and the highest of 8.96 × 105 copies/mL. For the 5 patients with severe refractory HC, the lowest infusion dose of ADSC was 0.9 × 106/kg and the highest was 1.4 × 106/kg. All 5 patients were cured. The incidence of LOHC is higher after haploidentical HSCT. LOHC is positively correlated with urine BK virus. LOHC has no obvious effect on the overall PFS of patients. ADSC infusion has a good therapeutic effect on severe and prolonged LOHC.

Efficacy of Mesenchymal Stromal Cells for Refractory Late-Onset Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation

INTRODUCTION Nowadays, the treatment of refractory late-onset hemorrhagic cystitis (LOHC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) still faces many difficulties and challenges. Mesenchymal stromal cells (MSCs) possess the capacity to modulate immune or inflammation response, support hematopoiesis and repair tissue. We explore the efficacy of mesenchymal stromal cells for refractory LOHC treatment after allo-HSCT. METHORDS Twenty-four patients with refractory LOHC from July 2008 to June 2021 received conventional therapy combined with MSCs obtained from bone marrow (BM) of third-party donors. MSCs were given intravenously at a dose of 1×106 cells/kg once weekly until the symptoms improving or LOHC not improving after continuous infusion of four times. The number of BK viruria (BKV)-DNA, JC viruria (JCV)-DNA, cytomegalovirus (CMV)-DNA copies in the urine were detected by real-time quantitative PCR before and at 8 weeks after the MSCs infusion. RESULTS The median number of MSC infusions for each patient was 3 (range, 2-8). Twenty patients achieved complete response, one partial response after treatment. The overall response rate was 87.5%. With a median follow-up of 397.5 days (range 39-937 days) post-transplantations, 17 patients survived and 7 died. The causes of death included aGVHD (n=1), infections (n=5) and TMA (n=1), respectively. Compared with that before MSCs infusion, the number of BKV-DNA and CMV-DNA copies were significantly lower at 8 weeks after MSCs treatment (12.105×108/mL vs 0.004×108/ml, P=0.041; 3.131×104/mL vs 0.000×104/ml，P=0.008). CONCLUSIONS The results indicate that MSCs derived from BM of a third-party donor are effective to treat refractory LOHC after allo-HSCT. MSCs might improve LOHC by regulating immune and anti-viral activity.

Incidence of hemorrhagic cystitis following unmanipulated peripheral blood stem cell transplantation in acute Leukemia: A retrospective single-center risk factor analysis

Hemorrhagic cystitis (HC) is an important adverse event experienced after hematopoietic stem cell transplantation (HSCT). Severe HC could lead to significant morbidity, prolonged hospitalization with increased health-care costs, and may cause considerable mortality. In order to investigate the influence of different contributing factors other than BK viruria on HC occurrence in a homogenous population, we retrospectively analyzed the potential risk factors. We conducted a retrospective study among 200 patients (median age 12.4 years, IQR: 7.9-16.1) with acute leukemia who received peripheral blood allogenic HSCT after radiation-free myeloablative conditioning regimen, in pediatric cell therapy department of Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Tehran, Iran, between December 2014 and December 2021. Associations between risk factors and outcomes were examined by univariable and multivariable logistic regression models. A total of 46 patients (23%) had developed HC during the study period. The median onset of HC was 29 (IQR: 24-37) days post-transplant, and it persisted for a median of 33 (7-270) days. The incidence of HC in our patients was estimated to be 3 in 1000 cases (95% CI: 2-4). The results of multivariable logistic model shows that the chance of HC in T-cell acute lymphoblastic leukemia (ALL) compared to B-cell All is nearly five times more (OR=4.88; 95%CI: (1.51-15.78), P=0.008). The incidence of HC in patients who underwent HSCT from haploidentical donors was significantly higher than full matched donors (P<0.001). Undergoing transplant from a matched unrelated and haploidentical donor both augment the chance of HC in about six times more than matched related donors (OR=6.36; 95%CI: (1.58-25.49), P=0.009 and OR=5.7; 95%CI: (1.83-17.75), P=0.003, respectively). In patients who developed HC compared to non-HC group, overall survival was much worse (P<0.001). Most studies have failed to demonstrate any relationship between late-onset HC and the dose of cyclophosphamide. In our study, although the dose of cyclophosphamide was similar in HSCT from MRD and MUD, the hazard of HC incidence was significantly higher in the latter group. This could be accredited to ATG, as in patients in the MRD group who had not received any ATG, the incidence of HC was much lower than the patients who had underwent HSCT from MUD or haploidentical donor group. Patients with T-cell ALL and those who under haploidentical HSCT had the highest incidence of HC.

Incidence of late-onset hemorrhagic cystitis and its effect on PFS in acute leukemia patients after haplo-PBSCT: The 5-year single-center data.

We conducted a single-center 5-year retrospective study on the occurrence of hemorrhagic cystitis (HC) and its effect on survival after haploid high-dose peripheral blood stem cell transplantation (haplo-PBSCT) in patients with acute leukemia. We retrospectively analyzed 153 patients with acute leukemia who were treated with non-in vitro T-cell depleted haplo-PBSCT and myeloablative conditioning regimen. All patients were followed up for more than 180 days after transplantation. HC occurrence and its effect on long-term progression free survival (PFS) were retrospectively analyzed. Totally, 64 out of 153 patients had late onset HC (LOHC). No early onset HC occurred. The median onset time was 38.5 (17-163) days after transplantation. The cumulative incidence of LOHC was 41.8%. The cumulative incidence of LOHC in patients under 27 years old (50.0%) and in ALL patients (54.1%) was significantly higher than that in patients over 27 years old (34.5%) and in AML patients (36.9%), respectively. The cumulative incidence of mild LOHC was 44.2% and that of severe LOHC was 28.6%. However, urine copies of BK virus were not related to LOHC duration. There was no significant difference in 3-year expected PFS between AML and ALL patients with and without LOHC, or between LOHC duration more than and less than 38.5 days (P>0.05). Conclusively, LOHC incidence is higher in patients under 27 years old and in ALL patients. LOHC occurrence is related to urine BK virus copy, but not blood BK virus load. LOHC duration and severity has no significant effect on PFS.

Clinical study of mesenchymal stem cells from third-party donors in the treatment of refractory late onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplanation

Objective: To examine the efficacy and safety of third-party bone marrow-derived mesenchymal stem cells (MSCs) in the treatment of refractory delayed hemorrhagic cystitis (LOHC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: Twenty patients with refractory LOHC received conventional therapy combined with MSCs obtained from third-party donors' bone marrow (BM) . MSCs were given intravenously at a dose of 1 × 10(6) cells/kg once weekly until either the symptoms improved or no changes in LOHC were seen after continuous infusion four times. BK viruria (BKV) -DNA, JC viruria (JCV) -DNA, and CMV-DNA were detected by real-time quantitative PCR before and 8 weeks after the MSCs infusion. Results: ① Of the 20 patients with refractory LOHC, 15 were males, and 5 were females, and the median age was 35 (15-56) years. There were 5 cases of acute lymphoblastic leukemia (ALL) , 9 cases of acute myeloid leukemia (AML) , 5 cases of myelodysplastic syndrome (MDS) , and 1 case of maternal plasma cell like dendritic cell tumor (BPDCN) . There were 4 cases of HLA identical transplantation and 16 cases of HLA incomplete transplantation. ②The median number of MSC infusions for each patient was 3 (range: 2-8) . Seventeen patients achieved complete response, and one had a partial response after treatment. The overall response rate was 90%. Over a median follow-up period of 397.5 days (range 39-937 days) post-transplantations, 13 patients survived, and 7 died. The causes of death included aGVHD (1 case) , infections (5 cases) , and TMA (1 case) . ③The copy numbers of BKV-DNA and CMV-DNA in urine in the 8th week after MSCs infusion were significantly lower than those observed before treatment (11342.1×10(8) copies/L vs 5.2×10(8) copies/L, P=0.016; 3170.0×10(4) copies/L vs 0.2×10(4) copies/L, P=0.006, respectively) , while JCV-DNA did not significantly differ when compared to before treatment (P=0.106) . ④ No adverse reactions related to MSC infusion occurred in any of the 20 patients. Conclusion: Third-party bone marrow-derived MSC has significant efficacy and good safety in the treatment of refractory LOHC after allogeneic HSCT.

Risk factors for late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: analysis of 227 cases

Risk factors for late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: analysis of 227 cases

Effect of late-onset hemorrhagic cystitis on PFS after haplo-PBSCT.

IntroductionThis study is to investigate the effect of late-onset hemorrhagic cystitis (LOHC) on progression-free survival (PFS) of patients after haploidentical peripheral blood hematopoietic stem cell transplantation (haplo-PBSCT).MethodsThis retrospective study enrolled 74 patients with hematological malignancies treated with a myeloablative conditioning regimen and haplo-PBSCT. The effect of LOHC on PFS was studied in terms of HC occurrence, grade, disease type, duration, onset time, gender, and age.ResultsThere were 28 patients with LOHC, and no case was with early-onset HC. The cumulative incidence of LOHC was 37.8% (95% CI: 26.9–48.7%). The 2-year expected PFS of 74 patients and 34 AML patients was not significantly different between LOHC patients and patients without HC (P > 0.05). Among 27 ALL patients, the 2-year expected PFS of LOHC patients was 75%, significantly higher than patients without HC (54.2%) (P < 0.05). The 2-year expected PFSs of patients with mild LOHC and severe LOHC were 69.8 and 77.8%, respectively (P > 0.05). Similarly, the onset time, duration, age, and gender of LOHC patients did not show significant effects on PFS (P > 0.05).ConclusionsAfter haplo-PBSCT, LOHC has a significant effect on the PFS of ALL patients. The HC grade, duration, onset time, gender, and age have no significant effect on PFS.

Incidence and risk factors of late-onset hemorrhagic cystitis after single umbilical cord blood transplantation with myeloablative conditioning regimen.

To explore the incidence and risk factors of late-onset hemorrhagic cystitis (LOHC) in patients undergoing single umbilical cord blood transplantation for hematological malignancies. Clinical data from 234 patients who consecutively underwent single UCBT using a myeloablative conditioning regimen without antithymocyte globulin in our center were retrospectively analyzed. In total, 64 (27.4%) patients developed LOHC with a median onset time of 40.5 (range 8-154) days, and 15 (6.4%) patients gradually developed grade III-IV LOHC. The incidence of LOHC was marginally higher in adults (31.0%) than in children (23.7%) (p = 0.248). HLA matching ≤ 6/8 (HR = 2.624, 95% CI 1.112-6.191, p = 0.028) was an independent risk factor for LOHC. The overall survival of LOHC patients (59.8%, 95% CI 61.7-85.5%) was significantly lower than that of patients without LOHC (86.8%, 95% CI 79.6-91.6%) at 130days post transplantation (p = 0.036). Patients with less well-matched grafts have a higher incidence of LOHC. Inherent deficiencies in immunity in the context of HLA disparity and more intense pharmacologic immunosuppression after severe acute graft-versus-host disease may contribute to viral activation. Prevention and treatment of LOHC have the potential to prolong long-term survival.

Hyperbaric Oxygen Therapy for Late-Onset Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation and Effective Factors Prediction

Background: Late-onset hemorrhagic cystitis (LO-HC) is one of the common complications and major causes of morbidity in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The classic treatment for HC includes hydration, alkalization, bladder irrigation, immunosuppressant reduction, and platelet transfusion. When the HC was considered to be associated with aGVHD, more immunosuppressive agents such as glucocorticoids will be added in. However, too intensive immunosuppressive measures leave the patients susceptible to infection and, in turn, increases the accidence of non-relapse mortality (NRM). It is important to explore novel, less-toxic, more effective, and cost-effective strategies for LO-HC. Hyperbaric oxygen therapy (HBOT) can stimulate fibroblast proliferation, angiogenesis, and wound healing. We deduce that HBOT might benefit patients with LO-HC after allo-HSCT. Methods: In this study, we retrospectively analyzed 238 patient underwent allo-HSCT in our center. From 2018, patients with LO-HC have been given HBOT in addition to conventional treatment in our center. The data in HBOT and the control group were collected and compared. Patients' characteristics were compared using the x2 test in case of discrete variables or the Mann-Whitney test in case of continuous variables. Logistic regression examined factors might be used as effective predictors for HBOT. Sensitivity and specificity were estimated based on four parameters cut-off point for additional glucocorticoid necessity. Results: A total of 238 patients who underwent allo-HSCT from 2014 to 2020 were enrolled in this study. Among them, 55 (23.11%) developed LO-HC (36 received regular treatment, and 19 received HBOT in addition to the regular therapy). The clinical &amp; transplantation parameters of the patients with LO-HC were listed in table 1. There is no significant difference in the age, gender, primary disease distribution, conditioning regimen, donor, HLA compatibility, stem cell sources, the occurrence of aGVHD between two groups. There is also no significant difference in the initial day of LO-HC post-HSCT and duration, peak red cells count in the urine, and whether additional glucocorticoid for HC control had been added between the two groups. It is worth noting that compared with the HBOT group, we found higher HC grade distribution, higher CMV-DNA copies, and decreased levels of SOD2 within the 1st week of the initial therapy for LO-HC in the control group. The comparison of the demographic and medical characteristics of subjects with LO-HC were listed in table 2. According to the results of logistic regression analysis, patients who developed LO-HC with higher HC grade (p = 0.001) and decreased SOD2 level (p = 0.002) might benefit more from HBOT, indicating that they might be used as effective predictors for HBOT (Figure 1A). Only higher HC grade (p = 0.011) could predict whether or not additional glucocorticoid would be necessary for LO-HC control (Figure 1B). The predictive power of additional glucocorticoid during the LO-HC treatment process for 4 different titers (HC grade and duration, CMV, and SOD2 level) was evaluated by ROC analysis. According to the area under the curve (AUC), the best diagnostic capabilities of four parameters were shown in Figure 2A, 2B, 2C, and 2D. None of our patients experienced severe adverse events of HBOT, such as gas emboli, pulmonary edema, and seizures. Only one patient with AML discontinued after 1 session due to the reversible ear barotrauma which was suspected with HOBT. Conclusions: In summary, HBOT was effective and well-tolerated in patients with LO-HC post-allo-HSCT. Patients who received HBOT exhibited with short disease duration and mild LO-HC grade. Higher HC grade and decreased SOD2 levels might be used as effective predictors for HBOT. Higher HC grade might be used as a predictor to determine whether or not additional glucocorticoid would be necessary for HC control. In the future, HBOT might be not only used as an adjunctive care application for LO-HC, but also might be as the first-line treatment therapy for this population, regardless of the causes of LO-HC. Based on our preliminary result, we plan to enroll more eligible patients to establish the definitive efficacy and safety of HBOT in patients with LO-HC after allo-HSCT (NCT04502628). Disclosures No relevant conflicts of interest to declare.

Effects and long-term follow-up of using umbilical cord blood-derived mesenchymal stromal cells in pediatric patients with severe BK virus-associated late-onset hemorrhagic cystitis after unrelated cord blood transplantation.

This is a retrospective study to evaluate the efficacy and safety of umbilical cord blood-derived mesenchymal stromal cells (MSCs) for the treatment of pediatric patients with severe BK virus-associated late-onset hemorrhagic cystitis (BKV-HC) after unrelated cord blood transplantation (UCBT). Thirteen pediatric patients with severe BKV-HC from December 2013 to December 2015 were treated with MSCs. The number of MSCs transfused in each session was 1×106 /kg once a week until the symptoms improved. The median follow-up time was 1432 (89-2080) days. The median frequency of MSC infusion was 2 (1-3), with eight cured cases and five effective cases; the total efficacy rate was 100%. The copy number of urine BKV DNA was 4.43 (0.36-56.9) ×108 /mL before MSC infusion and 2.67 (0-56.3) ×108 /mL after MSC infusion; the difference was not significant (P=.219). There were no significant differences in the overall survival, disease-free survival, and the incidence of relapse and acute and chronic graft-versus-host disease between the MSC infusion group and non-MSC infusion group. There was also no significant difference in the cytomegalovirus, Epstein-Barr virus (EBV), and fungal and bacterial infection rates between the two groups. Although umbilical cord blood-derived MSCs do not reduce the number of BKV DNA copies in the urine, the cells have a high efficacy rate and minimal side effects in treating severe BKV-HC after UCBT among pediatric patients. MSCs do not affect the rates of relapse, long-term infection, or survival of patients with leukemia.

Successful Treatment of Chemotherapy Induced Hemorrhagic Cystitis with Intravesical Application of A Specific Product in n Ambulatory Setting

Background and Aim: Hemorrhagic cystitis (HC) is an inflammation of the urinary bladder defined by signs of urinary bladder irritation and hematuria. It is thought that damage to the Glycosaminoglycan- (GAG) layer, which coats the uroepithelium and provides the initial barrier for physiological protection, may be the first step in its development. The disease can be triggered by chemotherapeutic drugs exposure and radiation therapy. The incidence rate of HC is predicted to rise substantially in the future as more aggressive treatments of cancer are implemented. Case Presentation: A 53-year old female patient presented with persistent dysuria, frequent voiding and nocturia. At the time the patient received adjuvant chemotherapy for her breast cancer. The patient presented with late-onset hemorrhagic cystitis after completing four cycles of chemotherapy. We treated her with intravesical instillations of hyaluronic acid and chondroitin sulphate in order to substitute the GAG layer. The report’s primary aim is to present the significant effect of an intravesical application of a GAG layersubstitution product. In our case report, we outline the indications as well as procedural steps of our approach and compare the results with those of other therapies and troubleshooting recommendations. The treatment was held in an ambulatory setting, making it both cost-effective and lifestyle-friendly for our patient. To the best of our knowledge, the treatment as described has not yet been used in chemotherapy-induced HC. Conclusions: This is the first report showing complete regression of haemorrhagic cystitis after inravesical application of a specific product. Prospective studies should evaluate if the treatment effect is reproducible and if this approach could be a useful profilactic measure as well as a sucessful treatment for chemotherapy-induced haemorrhagic cystitis.

BK polyomavirus-pathogen, paradigm and puzzle.

BK virus is a polyomavirus with seroprevalence rates of 80% in adults. Infection is usually acquired during childhood, and the virus is benign or pathologic depending on immune status. The virus reactivates in immunodeficiency states, mostly among transplant (either kidney or bone marrow) recipients. There are approximately 15 000 renal transplants every year in the USA, of which 5-10% develop BK polyomavirus nephropathy; 50-80% of patients who develop nephropathy go on to develop graft failure. BK virus is associated with BK polyomavirus nephropathy, ureteral stenosis, late-onset hemorrhagic cystitis, bladder cancer and other nonlytic large T-expressing carcinomas. The renal spectrum begins with viruria and can end with graft failure. The clinical spectrum and outcomes vary among transplant patients. New noninvasive diagnostic methods, such as urinary polyomavirus Haufen detected by electron microscopy, are currently under study. Treatment is primarily directed at decreasing immunosuppression but may be associated with graft rejection. Repeat transplantation is encouraged as long as viral clearance in plasma prior to transplant is accomplished. There remain no definitive data regarding the utility of transplant nephrectomy.

Risk Factors and Different Therapeutic Patterns of Late-Onset Hemorrhagic Cystitis after Haploidentical Allogeneic Stem Cell Transplantation

Introduction Late-onset hemorrhagic cystitis (LOHC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with an incidence ranging from 6.5% to 70% and leads to prolonged hospitalization and even death (Silva Lde P et al, Haematologica, 2010; LAM et al, Transpl Infect Dis, 2017). The pathogenesis of LOHC remains obscure, but in our previous study, viral infections and acute graft-versus-host disease (aGVHD) have frequently been shown to be associated with its development (Han et al., Am. J. Hematol, 2014). Therapeutic strategies for LOHC are still not standardized due to the complicated clinical background and given the paradoxical phenomenon that immunosuppressive agents, such as steroids, are necessary for aGVHD but cause an immunosuppressive state. We aimed to investigate the incidence, risk factors and outcomes of LOHC after allogeneic stem cell transplantation. Additionally, for the first time, we propose four therapeutic patterns and their impact on prognosis of LOHC to aid in clinical decision making. Methods This retrospective, nested, case-control study reviewed data from 2158 patients who received allo-HSCT from January 2014 to December 2018. In total, 364 (16.87%) patients were diagnosed with LOHC. Individual matching was performed by randomly selecting 3 controls from the same cohort for each identified LOHC patient according to the time of allo-HSCT. Standard basic measures included hyperhydration, forced diuresis, insertion of a vesical catheter for intermittent or continuous bladder irrigation and evacuation of clots. Patients with grade III-IV LOHC were divided into four groups according to immunosuppressant use (steroid, MMF and Basiliximab) 1 week before and after the onset of LOHC: an intensified-intensified (I-I) group, intensified-not intensified (I-N) group, not intensified-intensified (N-I) group and not intensified-not intensified (N-N) group. "Intensified" was defined as an increase in any immunosuppressant, and "not intensified" was defined as maintenance or tapering of all immunosuppressants. Data concerning the baseline characteristics, incidence, treatment patterns and outcomes were recorded. Results In total, 364 patients developed LOHC at a median of 29 days (range, 23-37.75 days), with a cumulative incidence of 16.87%. AML (HR =0.493 95% CI, 0.244-0.997; p=0.049), AA (HR =0.444, 95% CI,0.18-1.096; p=0.078), HLA match(HR =0.149, 95% CI, 0.036-0.616; p=0.009), days to platelet engraftment(HR =1.023, 95% CI, 0.998-1.049;p=0.069)and CMV viremia (HR =2.365, 95% CI, 1.179,4.733;p=0.015)were associated with LOHC. Only HLA match (HR =0.111, 95% CI, 0.014-0.878; p=0.037)remained significant in the multivariate analysis. 6.5%, 12.9%, 48.39% and 32.26% patients with III-IV LOHC were divided into I-I, I-N, N-I and N-N groups, respectively. There were no significant differences in overall survival (p=0.05) and the incidence of CMV viremia (p=0.187) among the four groups. The incidence of relapse (p=0.007) and the incidence of aGVHD (p=0.01) was highest in the I-I group, followed by the N-I, I-N and N-N groups. 50% of the patients in N-I group showed the improvement of LOHC, which is significantly highest among the four groups(p=0.000). However, no statistical significance was found regarding the CMV viremia turning shade or the improvement of aGVHD. Non-relapse mortality (NRM) was observed in 25% of patients without resolution of LOHC. NRM was 0% among patients without intensified immunosuppression but was 25%, 0% and 50% among those with intensified immunosuppression before LOHC, after LOHC and before and after LOHC, respectively. Conclusion The independent risk factors for LOHC after allo-HSCT were HLA mismatch. Avoiding intensified immunosuppression that damages endothelium or reactivates the related virus may improve transplant outcome. The N-N pattern could reduce the incidence of CMV viremia or aGVHD in the LOHC patients, and the N-I pattern might be more promising as a therapeutic strategy for LOHC. Disclosures No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.

Etiological Study of Late Onset Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation in Children

To prospectively study the correlation BKV with the occurrence and development of late onset hemorrhagic cystitis (LOHC) after allogeneic hematopoietic stem cell transplantation(allo-HSCT). The clinical data of a total of 276 patients with allo-HSCT in our department between January 1998 and March 2016 were analyzed ratrospectvely. Quantitative Real-time PCR assay was used to prospectively monitor the BKV DNA load of the urine and plasma for 23 patients accepting allo-HSCT from August 2015 to March 2016. LOHC(24.28%) occurred in 67 of 276 cases with allo-HSCT. Univariate analysis showed that age older than 6 years, different diseases, unrelated donor, pretreatment with BU, Ⅲ-Ⅳ aGVHD significantly correlated with LOHC. Multivariate analysis demonstrated that age older than 6 years (P<0.01), pretreatment with BU(P<0.05), and aGVHD of grade Ⅲ-Ⅳ （P= 0.011） were the independent risk factors for LOHC. Among 23 patients after allo-HSTC, 10 of which were positive of urine BKV, and LOHC occurred in 6 cases. The positive rate of urine BKV (85.7%)in group LOHC+ was significantly higher than that in the group LOHC-(25.0%）(χ2=5.043, P<0.01). The incidence of LOHC positively correlated with the positive rate of BKV (r=0.564, P<0.01), and the severity of LOHC positively correlated with urinary BKV load (r = 0.502, P<0.01). And 5 of 6 petriatic patients with LOHC had aGVHD. All of them were subject to the strengthened antiviral treatment, and 4 of them accepted intensive immunosuppression therapy. Age ≥6 years old, precenditioning regieme with BU and aGVHD of grade Ⅲ-Ⅳ are independent risk factors for LOHC after allo-HSCT, the positive rate of urine BKV load positively correlates with the severity of LOHC after allo-HSCT.

Efficacy and Safety of MSC Infusion in Treatment of Children with Refractory LOHC: A Clinical Study

To study the curative effect and safety of menchymal stem cell infusion in treatment of children with refractory late-onset hemorrhagic cystitis(LOHC) after allogeneic HSCT. Thirty cases of children with refractory LOHC after allo-HSCT in our department between December 2010 and July 2016 were analyzed retrospectively, out of 30 cases 7 received MSC treatment. The used MSC of all were four-to-five generation MSC from bone marrows of third party donors, and were infused into patients with (1.87±0.456)×106/kg MSCs once a week (1-4 times in total) until the hematuria and odynuria symptoms being improved. To observe whether unfavorable reactions occurred after MSC treatment, the patients accepted daily physical examination and regular assistant examination. The cytokine levels were also measured and dynamically detected in 2 cases before and after MSC treatment. In 30 children with refractory LOHC, the hematuria difficultly reached the remission after routine hydration, alkalizing and antiviral therapy, Among 25 cases who were received methylprednisolone, MTX and CTX therapy, 7 cases received MSC infusion for 1-4 times with dose of (1.87±0.456)×106/(kg·time) as a result, 7 cases of LOHC were cured. The TNF-α and IL-2R levels in 2 cases progressively decreased after MSC infusion, no occurence of fever, rash, embolism and so on were found in 7 cases received MSC infusion; the BKV detection showed that the viral load did not increase; the leukemia relapse or secondary cancer did not occure. The MSC treatment is safe and effective for refractory LOHC after allo-HSCT.

Treatment of late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: the role of corticosteroids.

We aimed to evaluate the treatments, particularly the role of corticosteroids, in patients with late-onset hemorrhagic cystitis (LOHC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). One hundred and sixty-three consecutive patients who underwent non-T-cell-depleted allo-HSCT and met the criterion of LOHC after allo-HSCT were enrolled in this study. The median time from allo-HSCT to the occurrence of LOHC was 29 (range, 4–155) days. Pathogens identified in blood and/or urine samples from 143 patients were mostly viruses. All of the patients with LOHC received intravenous fluid hydration, alkalization, and forced diuresis, of which 2 patients achieved complete remission (CR) after these treatments. The remaining 161 patients received anti-infection therapies and 71 achieved CR after the therapies. Corticosteroids were additionally applied to 83 out of 90 patients who did not achieve CR after anti-infection therapies, and 88.0% (n = 73) of them showed a grade 3 to 4 LOHC at the beginning of corticosteroid therapy. Thirty-five patients showed an immediate response (CR or downgraded at least one grade) within 1 week after the beginning of the corticosteroid therapy. Sixty-four patients (77.1%) achieved CR after corticosteroid therapy, and the median period from the beginning of corticosteroid therapy to CR was 17 days. Thus, we observed that viruses were the most common pathogens in LOHC after allo-HSCT and that anti-infection therapies were critical. For patients not showing a satisfactory response to anti-infection therapies, additional corticosteroid therapy may help to achieve CR.

Research progress of hemorrhagic cystitis after hematopoietic stem cell transplantation

Hemorrhagic cystitis (HC) is one of the common complications of hematopoietic stem cell transplantation (HSCT). And its clinical features are hematuria, accompanied by urinary frequency, urgency, urine pain and other bladder irritation symptoms. Early onset hemorrhagic cystitis (EOHC) mainly results from uroepithelial injury induced by irradiation/chemotherapy during conditioning regimen particularly high-dose cyclophosphamide. With the use of mesna, the incidence decreased significantly. Late onset hemorrhagic cystitis (LOHC) is usually associated with viral infection and immune dysfunction, but the treatment of LOHC remains a challenge. As the HSCT is extensively used, the researches on diagnosis and treatment of HC are increasing. This article reviews literatures on the etiology, pathogenesis, diagnosis and treatment of HC. Key words: Cystitis; Hematopoietic stem cell transplantation; Etiology