Cumulative Incidence Of Hemorrhagic Cystitis Research Articles

Phase I/II Study of Reduced Dosing of Post-Transplantation Cyclophosphamide (PTCy) after HLA-Identical Peripheral Blood Hematopoietic Stem Cell Transplantation

Introduction Post-transplant cyclophosphamide (PTCy)-based prophylaxis for acute graft versus host disease (aGvHD) has become a standard protocol in HLA haploidentical bone marrow transplantation. Preliminary evidence indicates that compared to the standard dosage (50 mg/kg on days +3 and +4 post-transplantation), a regimen of half the typical cyclophosphamide dosage is both feasible and effective. However, the optimal dosage and timing of PTCy for aGvHD prophylaxis in a HLA identical setting, using peripheral stem cells as the graft, remain unknown. This study aims to investigate the efficacy and safety of a reduced PTCy dosage regimen in patients undergoing peripheral blood stem cell transplants (PBSCT) with HLA indentical donors. Methods This prospective, single-center phase I/II study enrolled patients scheduled for PBSCT with HLA identical donors. The aGVHD prophylaxis regimen comprised PTCy on days +3 and +4, followed by cyclosporine initiation from day 5 post-transplant. In the phase I stage, an initial cohort of five patients received PTCy at a dosage of 50 mg/kg/day on days +3 and +4 (designated as dose level 1, DL1). This was followed by a 3+3 dose de-escalation design with subsequent dose levels as follows: DL2, 50 mg/kg on day +3 and 25 mg/kg on day +4; and DL3, 25 mg/kg on both day +3 and +4. The dose-limiting toxicity for this de-escalation was defined as the occurrence of grade III-IV aGVHD within the first 100 days post-transplantation. The phase II stage comprised an expansion cohort, which was based on the optimal dose identified during phase I. aGvHD classification was established using the Mount Sinai Acute GVHD International Consortium (MAGIC) criteria, while chronic GvHD (cGvHD) was assessed per the latest National Institutes of Health Consensus on cGvHD. Patients were closely followed-up at +1, +2, +3, +4, +6, +9, +12, +18, and +24 months post-transplant. Results In the first stage, a total of 11 patients (5 in DL1, 3 in DL2, and 3 in DL3) were included, and no patient developed grade III-IV aGVHD. Based on this, DL3 was selected as the PTCy dose for phase II, which comprised 18 patients. Overall, 29 patients (17 females, 12 males) with a median age of 39 years (range 17-65) were included, and the median follow-up duration was 12.7 months (range 2.2-22.1). Patient and disease characteristics are summarized in Table 1. By day +30 post-ASCT, all patients achieved complete remission (CR) and minimal residual disease (MRD) clearance. No patient developed grade III-IV aGVHD within 100 days post-transplantation. There was no significant difference in the neutrophil and platelet engraftment interval among the three groups (Figure 1A, B). Among the 21 patients who received the DL3 dose of PTCy, the estimated cumulative incidence of grade II to IV aGVHD at day +100 was recorded at 28.6%, and the incidence of aGVHD at day +100 presented no difference among the three DL groups (Figure 1C). In addition, 1 patient in DL3 developed grade IV intestinal aGVHD on day +141 and died one month later. The estimated 1-year cumulative incidence of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) reactivation was 19.3% and 19%, respectively (Figure 1D). Five patients (all in DL3) experienced relapse, with a median interval of 6.7 months and an estimated 1-year cumulative incidence of 10.6%. A total of 5 fatalities occurred during our study (1 in DL1, and 4 in DL3), 1 due to relapse, 2 from COVID-19-associated pulmonary aspergillosis, 1 from severe septicemia and 1 due to grade IV aGVHD as mentioned above. The estimated 6-month cumulative incidence of NRM was 9.5%, presenting no difference among the three DL groups (Figure 1E). Among the 20 evaluable patients, the estimated 1-year cumulative incidence of chronic GVHD (cGVHD) and moderate cGVHD was 37.3% and 16% (Figure 1F), respectively, with no severe cGVHD observed. No cases of patient relapse were reported. The estimated 1-year progression-free survival (PFS) and overall survival (OS) were 61.2% and 80.4%, respectively (Figure 1G). Conclusion The findings of this study substantiate that a two-day regimen of PTCy at 25 mg/kg/day serves as an effective and safe prophylactic measure against aGVHD, comparable to the standard dosing protocol. However, to definitively establish whether the de-escalated PTCy dosage provides superior outcomes to the standard regimen, longer-term follow-up and comparative studies are warranted.

Efficacy and safety analysis of umbilical cord blood combined with haploid hematopoietic stem cell transplantation in the treatment of malignant hematological malignancies

Objective: To investigate the efficacy and safety of umbilical cord blood combined with haploid HSCT (haplo-cord HSCT) in the treatment of hematological malignancies. Methods: The data of 82 patients with hematologic malignancies who received haplo-cord HSCT from January 2017 to June 2021 in the Affiliated Cancer Hospital of Zhengzhou University were retrospectively analyzed. There were 52 male and 30 female patients, aged [M(Q1, Q3)] 29 (20, 41) years. All patients received myeloablative preconditioning regimen. The day of the donor stem cell infusion was recorded as day 0 (0 d), the day before the infusion was recorded as day-1 (-1 d), and the day after the infusion was recorded as day+1 (+1 d), and so on. Eighty-two patients received transfusion of peripheral blood and/or bone marrow stem cells from unrelated cord blood and haplotype donors after the myeloablative preconditioning regimen. The graft-versus-host disease (GVHD) prophylaxis regimen was 8 mg/kg ATG combined with cyclosporine, morte-macrolide, and methotrexate. Patients were evaluated for implantation and the occurrence of transplant-related complications such as GVHD, infection, hemorrhagic cystitis, and long-term patient survival. Results: The time of neutrophil engraftment [M(Q1, Q3)] was 13 (11, 15) days and 15 (13, 21) days for platelet. The 30-day cumulative incidence of neutrophil engraftment was 98.8% (81/82) and 100-day cumulative incidence of platelet engraftment was 92.7% (76/82). The cumulative incidence of acute graft-versus-host disease (aGVHD) in degree Ⅱ-Ⅳ and Ⅲ-Ⅳ was 24.4% (20/82) and 6.1% (5/82), respectively. The cumulative incidence of chronic GVHD in+18 months was 13.5% (11/82). The follow-up time [M(Q1, Q3)] was 26 (13, 41) months, and the overall survival (OS) rate, event-free survival (EFS) rate, cumulative recurrence rate (CIR) and non-recurrence mortality (NRM) rate at 3 years after transplantation were 70.5% (95%CI: 59.7%-81.3%), 66.1% (95%CI: 56.1%-76.1%), 6.3% (95%CI: 5.7%-26.9%) and 20.8% (95%CI: 12.0%-29.6%), respectively. The cumulative incidence of cytomegalovirus and EBV reactivation was 37.8% (31/82) and 14.6% (12/82), respectively. The cumulative incidence of hemorrhagic cystitis was 32.9% (27/82). Conclusion: The efficacy of haplo-cord HSCT in the treatment of hematologic malignancies is reliable, with rapid hematopoietic reconstitution, low incidence of GVHD and virus reactivation.

Comparison of 2 Different Doses of Antithymocyte Globulin in Conditioning Regimens for Haploidentical Hematopoietic Stem Cell Transplantation.

Antithymocyte globulin is extensively used for prophylaxis of graft-versus-host disease in patients undergoing haploidentical hematopoietic stem cell transplantation. However, different doses of antithymocyte globulin are administered in clinical practice. This study aimed to identify the optimal dose of antithymocyte globulin (thymoglobulin) in haploidentical hematopoietic stem cell transplantation. We retrospectively analyzed the effects of 10 mg/kg (2.5 mg/kg on days -5 to -2) versus 7.5 mg/kg thymoglobulin (2.5 mg/kg on days -4 to -2) on patients receiving haploidentical hematopoietic stem cell transplantation with myeloablative conditioning. We observed significant differences between the 2 treatment groups with regard to cumulative incidence of grade II to IV acute graft-versus-host disease (15.3% vs 14.6%; P = .93) and 3-year chronic graft-versus-host disease (12.1% vs 14.3%; P = .77). The probabilities of 3-year overall survival (68.9% vs 73.5%; P = .98) and graft-versus-host disease-free/relapse-free survival (66.7% vs 53.1%; P = .14) were comparable between the 2 groups. However, there was a trend for lower cumulative incidence of hemorrhagic cystitis in the 7.5 mg/kg treatment group compared with the 10 mg/kg treatment group (40.7% vs 24.4%; P = .07). For patients who received a reduced dose of antithymocyte globulin (7.5 vs 10 mg/kg), there was no impaired effect on prophylaxis of graft-versus-host disease, with a trend of reduced incidence of hemorrhagic cystitis. Further studies of the 7.5 mg/kg dose of antithymocyte globulin are warranted for patients receiving haploidentical hematopoietic stem cell transplantation.

Hemorrhagic Cystitis after Haploidentical Transplantation with Post-Transplantation Cyclophosphamide: Protective Effect of MESNA Continuous Infusion.

Hemorrhagic cystitis (HC) is an important complication after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PT-CY). Sodium 2-mercaptoethanesulfonate (MESNA) can prevent bladder injury when given with PT-CY. However, the best way to deliver MESNA is not known. This study assessed the incidence of HC after haplo-HSCT with PT-CY with 2 different methods of MESNA administration. The cumulative incidence of HC was lower in patients who received MESNA as a continuous infusion compared with those who received it as an intermittent bolus (5.6% versus 27.8%; P=.01). MESNA administration as an infusion was associated with a lower risk of developing HC (hazard ratio [HR], .19; 95% confidence interval [CI], .04 to .86; P=.02) on univariate analysis. This effect remained significant after adjustment in multivariate analysis (HR, .21; 95% CI, .04 to .88; P=.03). MESNA delivered as a continuous infusion is a simple and potentially useful way to prevent HC after PT-CY.

Higher Incidence of Hemorrhagic Cystitis after Haploidentical Compared to Matched Sibling Donor Transplantation

Introduction: Hemorrhagic cystitis (HC) causes significant morbidity following allogeneic hematopoietic cell transplantation (HCT). Reactivation of BK polyoma virus frequently occurs following transplantation and appears to be the most commonly associated factor, although high dose cyclophosphamide, other viruses, and numerous other factors contribute. A higher incidence of BK HC was reported with the use of matched unrelated or cord blood donors compared to HLA-matched siblings (El-Zimaity M, et al. Blood. 2004), however, the intensity of GVHD prevention regimens varied according to cell source complicating interpretation of these data. The effect of HLA-mismatched donors on the incidence of BK HC has been disputed and a large study of mismatched donors detected no association of HC with mismatched compared to matched donors (Giraud G, et al. Bone Marrow Transplant, 2008; Gilis L, et al. Bone Marrow Transplantation, 2014.)We analyzed a cohort of patients biologically assigned to matched sibling (MSD) or haploidentical family donor (based on presence of a suitable MSD donor) who received identical myeloablative or nonablative conditioning regimens and identical PTCy-based GVHD prevention to directly analyze the association of donor source with HC.Methods: To evaluate the role of haploidentical vs MSD donor source, we analyzed all patients undergoing haploidentical or MSD HCT at the Levine Cancer Institute between March 2014 and June 2018. Patients received identical myeloablative (BuCy) or nonmyeloablative (Flu/Cy/TBI) conditioning regimens followed by peripheral blood stem cell grafts and identical PTCy-based regimens which included tacrolimus and mycophenolate for GVHD prevention. The cumulative incidence of HC was calculated in a competing risk setting with death from any cause as a competing event. Group comparisons of incidences were determined by a Gray's test. Cox regression was conducted to evaluate risk factors for the development of HC. It was also used to evaluate HC as a time-dependent risk factor for overall survival. Fisher's exact test was used to analyze categorical patient characteristics, and two-sample t-test was employed for continuous variables.Results: From March 2014 to June 2018, 39 patients (32%) underwent MSD transplantation and 84 patients (68%) received transplants from haploidentical donors. Baseline characteristics were similar except for younger donor age of haploidentical donors (median 40 yrs vs 54 yrs P< .001). The rates of acute GVHD, Chronic GVHD, NRM and overall survival were similar between the two groups. The cumulative incidence of HC was higher in patients who received cells from haploidentical donors when compared to matched related donors (p=0.05). In multivariate analysis of risk factors associated with HC (Table 1), haploidentical donor (HR: 1.80, 95% CI 0.95-3.44, P= .07) and, grade III-IV acute GVHD (HR: 4.93, 95% CI 1.01-23.93 P = .05), were associated with development of HC. 33/53 HC patients (62%) were tested positive for BK virus. The intensity of the conditioning regimen, disease status at transplant, donor and recipient age were not associated with development of HC. For patients who received cells from haploidentical donors, there was a trend towards severe (grade 3-4) HC, but this did not reach statistical significance (HR 2.71, 95% CI 0.59-12.24 P=.19). The incidence of HC was not associated with overall survival (HR 0.58 95% CI 0.3-1.15 P=0.12), even when severe (grade III-IV) HC events were evaluated (HR 1.79 95% CI 0.75-4.3 P=0.19).Conclusions: In adults undergoing allogenic transplantations using identical conditioning regimens and PTCy based GVHD prevention, the use of a haploidentical donor results in a higher incidence of HC than does a MSD. [Display omitted] DisclosuresGrunwald:Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medtronic: Equity Ownership; Genentech: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Jacobs:Genentech: Honoraria. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding.

The Association of Combined GSTM1 and CYP2C9 Genotype Status with the Occurrence of Hemorrhagic Cystitis in Pediatric Patients Receiving Myeloablative Conditioning Regimen Prior to Allogeneic 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.”

Incidence and risk factors for hemorrhagic cystitis in unmanipulated haploidentical transplant recipients.

Hemorrhagic cystitis (HC) is a common complication after hematopoietic allogeneic stem cell transplantation (HSCT) associated with intensity of the conditioning regimen, cyclophosphamide (Cy) therapy, and BK polyomavirus (BKPyV) infection. We analyzed 33 consecutive haploidentical (haplo) HSCT recipients transplanted for hematologic diseases. Eleven patients had a previous transplant. Median follow-up was 11 months. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine + mycophenolate mofetil and post-HSCT Cy. Thirty-two of 33 patients achieved neutrophil recovery. Cumulative incidence (CI) of platelet recovery was 65%. CI grade II-IV acute GVHD was 44%. Twenty patients developed HC in a median time of 38 days. CI of HC at day 180 was 62%. BKPyV was positive in blood and urine of 91% of patients at HC onset. HC resolved in 18/20 patients. Factors associated with HC were previous transplant (P = 0.01) and occurrence of cytomegalovirus reactivation before HC (P = 0.05). Grade II-IV acute GVHD was not associated with HC (P = 0.62). CI of day 180 viral infections was 73%. Two-year overall survival (OS) was 50%; HC did not impact OS (P = 0.29). The incidence of HC after haplo with post-HSCT Cy is high and is associated with morbidity, especially in high-risk patients such as those with a previous transplant history and with impaired immune reconstitution.

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

Background One of the complications of myeloablative conditioning regimen with busulfan (BU) and cyclophosphamide (CY) in children undergoing hematopoietic stem cell transplantation (HSCT) is the occurrence of hemorrhagic cystitis (HC). Pathophysiology of HC involves multiple factors, such as damage to the bladder's transitional epithelium and the endothelium of blood vessels by BU, CY and their metabolites, viruses, bacterial infections, or other disease processes. It is well established fact that damage to the urothelium is the initial step during pathogenesis of HC. Though it is known about acrolein (metabolite of CY) contribution to HC development, the role of BU or its metabolites is not yet known completely. We recently developed an analytical method for sulfolane (Su) quantification, a water soluble metabolite of BU. Using this method we explored the relation of Su levels in plasma with HC before day 30 post-transplant, in 39 children (20 females, 19 males) receiving BU-CY conditioning prior to HSCT. Methods Hospital ethics committee approved the study, and all patients or their parents have signed the informed consent. Out of 39 patients 16 were diagnosed with nonmalignant disease. BU was administered in 16 dose infusions, with each infusion lasting two hours for every six hours. Bone marrow and cord blood were graft sources in 18 and 21 patients, respectively. Twenty patients had HLA–matched donor. HC was defined as the presence of hematuria (both microscopic and macroscopic) for more than a week from the initiation of the conditioning regimen up to 30 days post-transplant. All patients received MESNA as prophylaxis for HC. Plasma from patients collected before dose 7 and after dose 9 infusions of BU was used for measuring Su levels using gas-chromatography. Plasma levels of Su adjusted to cumulative BU dose up to Su level measurements (upto dose 6 for before dose 7 levels, upto dose 9 for after dose 9 levels) in mg/kg were used in the analysis. Mann-Whitney U test was used to analyze the relation of Su levels (ng/mL//mg/kg) and HC. A receiver–operator characteristic curve (ROC) for Su levels was plotted to show the trade-off in sensitivity versus 1- specificity rates for HC, as the cut-off of the test was shifted from low to high. Two sided p values were represented and probability at 0.05 was considered as statistically significant. Cumulative incidences of HC were estimated using Kaplan-Meier curves and log-rank test was used to compare the difference between groups divided based on cutoff defined in ROC curves, in univariate analysis. Univariate cox-regression was used to estimate hazard ratios with 95% confidence intervals. Results The overall cumulative incidence of HC was 20.5 %. We observed higher Su levels before dose 7 (mean±SD; 48.3±11.2 vs. 35.1±15.3 – p=0.02) and after dose 9 (40.5±9.6 vs. 30.9±14.4 – p=0.03) in patients diagnosed with early HC (n=8) compared to those with no HC (n=31-Figure 1A, Figure 1B), respectively. Cutoff values of 49.44 and 36.28 were chosen in ROC analysis for Su levels before dose 7 and after dose 9, respectively with better sensitivity and specificity to diagnose HC (Figure 1C). Patients with Su levels above the cutoff value defined (before dose 7, 41.7 %; after dose 9 42.9 %) had higher incidence of HC compared to those below the cutoff (before dose 7, 11.0 %; after dose 9, 8.0 %) at both dose levels (Figure 2A, Figure 2B). Age and Weight were also correlated with the incidence of HC, with higher incidence in patients older than 10 years, and weighed above 30 kg. Higher levels of Su correlated with the weight and age of the patients. Out of 8 individuals diagnosed with HC, 6 were detected positive for BK virus and one patient was positive for JC virus. Conclusion Higher plasma Su levels might also explain availability of Su and its hydroxyl metabolite in bladder to cause damaging effect similar to that of acrolein. We hypothesize that formation of Su is related to the volume of liver and enzyme activity which is usually correlated with weight and age of the patient. These levels might also predict the extent for acrolein formation, and might serve as surrogate marker to identify patients predisposed to HC. A functional study to elucidate the effect of Su on bladder urothelium is underway at our laboratory to understand its role in pathogenesis of HC. Disclosures: No relevant conflicts of interest to declare.

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

AbstractAbstract 1933 Introduction:Infection by BK virus in the allo-HSCT setting is associated with the development of HC, which is a major cause of morbidity. There are few studies evaluating the impact of BK virus-associated HC on survival post allo-HSCT. Objectives:To evaluate the incidence of HC by BK virus in patients after allo-HSCT and its impact on survival. Methods:We retrospectively reviewed the medical charts of 107 patients who underwent allo-HSCT at Hospital Israelita Albert Einstein from July 2007 until November 2011. HC was defined by the presence of any degree of unexplained hematuria and positivity for BK virus in a urine sample by quantitative polymerase chain reaction (PCR) assay. CMV reactivation was defined as positivity in the antigenemia assay or greater than 165 copies in a quantitative PCR assay. Three patients were excluded because PCR results for BK virus were inconclusive, with 104 patients being analyzed in the final cohort. Cumulative incidence (CI) of HC, CMV reactivation and acute graft-versus-host disease (GVHD) were estimated taking into account the competing risk of death. Overall survival (OS) was estimated by the Kaplan-Meier method. Gray model was used for regression analysis of factors associated with the development of HC. Hazard ratios (HRs) were estimated by a Cox multivariable proportional hazards model, considering HC, CMV reactivation and acute GVHD as discrete time-varying covariates. Results:Median age was 28 years (range 6 months–76 years), and 60.5% of patients were male. About 37% had high-risk disease (refractory leukemia/lymphoma or 2nd-transplantation). Source of HSCs included matched related donors (37%), 10/10 HLA-matched unrelated donors (24%) and cord blood/haploidentical donors in 39%. The conditioning regimen was myeloablative in 81% of cases. The median follow-up of the whole cohort was 450 days (range 9–1624 days). At 1 year, the cumulative incidence of HC was 30.5% (95% confidence interval [CI] 21.8%–39.7%). The 1-year incidence of CMV reactivation and acute GVHD (all grades) was 57.1% and 39.7%, respectively. In a multivariate analysis taking into account age, sex, risk of disease, source of HSCs, intensity of conditioning, CMV reactivation and acute GVHD, only receiving cells from cord blood/haploidentical donors was associated with an increased incidence of HC (subhazard ratio 4.04, 95% CI 1.31–12.49, p = 0.015). The 1 year-OS of the whole cohort was 55% (95% CI 44–62%). Patients who developed HC had an inferior OS (1 year: 18% vs. 70%; HR= 4.40, p <0.0001; 95% CI 2.37–8.14). In the multivariate Cox analysis for OS, after adjusting for age, sex, disease risk, source of HSCs, intensity of conditioning, CMV reactivation and development of acute GVHD, development of HC was associated with an increased mortality (table). Conclusion:In this cohort, the development of CH was associated with an inferior OS in patients undergoing allogeneic HSCT. Even after adjusting for several variables, including development of acute GVHD and CMV reactivation, HC still remained an important factor associated with decreased survrival. It is possible that HC is not the direct cause of the increased mortality, but is rather a surrogate marker of a state of severe immunosuppression and increased risk of dying in the post-transplant setting. Nonetheless, our results suggest that the development of BK virus-associated HC in allo-HSCT patients is associated with inferior survival and future studies should confirm this finding and seek strategies to prevent this complication.TableCox multivariable analysis for OSCovariateHR (95% CI)PAge1.00 (0.98-1.01)0.98Male sex (yes vs. no)0.65 (0.33-1.29)0.22Myeloablative conditioning (vs. reduced-intensity conditioning)3.61 (1.41-9.26)0.007Disease risk category• Intermediate (vs. Low)1.11 (0.38-3.18)0.84• High (vs. Low)2.06 (0.77-5.46)0.14Source of Stem Cells• Matched Unrelated Donor (vs. Matched Related Donor)0.46 (0.18-1.17)0.10• Cord Blood/Haploidentical Donor (vs. Matched Related Donor)1.15 (0.53-2.51)0.71Development of BK-virus associated Hemorrhagic Cystitis4.84 (2.51-9.34)<0.0001Development of CMV reactivation1.31 (0.66-2.62)0.41Development of acute GVHD1.74 (0.86-3.51)0.11 Disclosures:No relevant conflicts of interest to declare.

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

AbstractAbstract 2304 Background:Hemorrhagic cystitis (HC) is a major complication after allogeneic hematopoietic stem cell transplantation (SCT), and is life-threatening in severe cases. Early onset HC is usually due to toxic effects of conditioning regimen, while late onset HC is caused by viral or bacterial infection, and GVHD. In order to find out risk factors and to analyze prognosis of late onset HC, we retrospectively reviewed data in our institution from 1996 through 2009. Patients and Methods:We analyzed 232 cases having underwent allogeneic SCT (AML; 65, MDS; 42, ALL; 44, ML; 44, others; 37), excluding 22 patients who received second allogeneic transplantation. The median age at SCT was 47 years old (range, 13–72), and median follow-up of survivors was 1529 days (range, 99–4822) after SCT. One-hundred and eleven patients received from related donor, and 121 from unrelated. Conditioning was myeloablative in 139 cases, and reduced intensity (RIC) in 93. Myeloablative regimen was cyclophosphamide (CY) plus total body irradiation (TBI) in 79 cases, and busulfan (BU) plus CY in 54, while RIC regimen was fludarabine (Flu) plus melphalan (Mel) plus BU in 52, and Flu plus Mel plus TBI in 12. Disease status at SCT was controlled (partial or complete remission) in 164 cases, and progressive in 68. Prophylaxis for acute GVHD consisted of calcineurin inhibitor (cyclosporine; 106 cases, tacrolimus; 126 cases), short term methotrexate (158 cases), and corticosteroid (73 cases). Acute GVHD occurred in 121 cases, 92 of them were grade II-IV, and 74 were treated with corticosteroid. Cytomegalovirus (CMV) antigenemia was positive in 82 cases after engraftment. Definition of late onset HC was microscopic or macroscopic hematuria with urinary symptoms occurring after 7 days from SCT. Urine culture and virological analysis (polymerase chain reaction of CMV, adenovirus [ADV], and BK virus DNA) were carried out in all cases with HC. Treatment was mainly hydration and intravenous hemostat, including intravenous immunoglobulin (IVIg) and antiviral agents. Results:HC was reported in 43 cases on a median of 36 days (range, 7–469) after SCT, and 31 of them (72.1%) recovered after a median of 21 days (range, 2–252). Cumulative incidence of HC after 1 year from SCT was 21.6% (95% confidence interval [CI] 18.3–24.7%). In univariate analysis, risk factors identified included age over 45 years old (p=0.04), progressive disease status at SCT (p=0.04), myeloablative conditioning (p=0.04), acute GVHD grade II-IV treated with corticosteroid (p=0.01), and positivity of CMV antigenemia after SCT (p<0.01). On multivariate analysis, older age (p<0.01, hazard ratio [HR] 2.63), myeloablative conditioning (p<0.01, HR 4.32), and positivity of CMV antigenemia (p<0.01, HR 3.61) remained independent predictors. Each HC case was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (grade 1; 12, grade 2; 19, grade 3; 12, grade 4 to 5; none), and we defined moderate as grade 1 or 2, and severe as grade 3 or more. In subgroup analysis of patients with HC, myeloablative conditioning (p=0.11, Odd's ratio [OR] 5.24) and positivity of ADV in urine (p=0.10, OR 3.17) tended to be associated with severe HC. Recovery rate from HC was inferior and median duration from onset to recovery was longer in severe HC (25.0%, 121 days) with significance (p<0.01) compared with moderate HC (90.3%, 17.7 days). Using of IVIg or antiviral agent (vidarabine, gancyclovir, or foscarnet) did not improve recovery rate in both groups. Overall survival (OS) at 1 year after day 35 landmark had no significance between cases with and without HC (59.7%, 56.7%, p=0.70), significantly poor in severe cases (16.7%, p<0.01) compared to cases with moderate HC and cases without HC. Treatment-related mortality (TRM) at 1 year after day 35 landmark was 25.0% with HC and 29.0% without HC (p=0.35), while 59.1% in patients with severe HC (p=0.01). Conclusion:Five significant risk factors of HC such as older age, progressive disease status, myeloablative conditioning, acute GVHD, and CMV antigenemia were found out in this study. OS and TRM of patients with all the grade of HC were equivalent to those without HC, while severe HC significantly elevated TRM and shortened OS. Severity of HC was related to myeloablative regimen and ADV in urine. Any successful attempts to prevent severe HC have not been established yet, and novel prophylactic and pre-emptive strategies are warranted. Disclosures:No relevant conflicts of interest to declare.

Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type

Hemorrhagic cystitis is a common cause of morbidity after allogeneic stem cell transplantation, frequently associated with BK virus infection. We hypothesized that patients with positive BK viruria before unrelated or mismatched related donor allogeneic hematopoietic stem cell transplantation have a higher incidence of hemorrhagic cystitis. To test this hypothesis, we prospectively studied 209 patients (median age 49 years, range 19-71) with hematologic malignancies who received bone marrow (n=78), peripheral blood (n=108) or umbilical cord blood (n=23) allogeneic hematopoietic stem cell transplantation after myeloablative (n=110) or reduced intensity conditioning (n=99). Donors were unrelated (n=201) or haploidentical related (n=8). Twenty-five patients developed hemorrhagic cystitis. Pre-transplant BK viruria detected by quantitative PCR was positive in 96 patients. The one-year cumulative incidence of hemorrhagic cystitis was 16% in the PCR-positive group versus 9% in the PCR-negative group (P=0.1). The use of umbilical cord blood or a haploidentical donor was the only significant predictor of the incidence of hemorrhagic cystitis on univariate analysis. There was also a trend for a higher incidence after myeloablative conditioning. Multivariate analysis showed that patients who had a positive PCR pre-transplant and received haploidentical or cord blood grafts with myeloablative conditioning had a significantly higher risk of developing hemorrhagic cystitis (58%) than all other recipients (7%, P<0.001). Hemorrhagic cystitis is the result of a complex interaction of donor type, preparative regimen intensity, and BK viruria.

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

Background: BK virus infection has been associated with development of HC after HSCT, but most studies detected the virus at the time of bleeding, therefore not allowing estimation of the risk imposed by asymptomatic infection. We hypothesized that viruria prior to HSCT increased the risk of HC, and sought to investigate this hypothesis in a cohort of consecutive patients receiving HSCT from donors other than HLA-identical siblings in our institution from 09/2005 and 08/2007.Patients and Methods: We prospectively performed a quantitative PCR on urine samples collected before admission to transplant and on day 30 after transplant. The quantitative BK virus assay was performed at Focus Diagnostics, Inc., Cyprus, CA with a commercially available kit. A set of quantitative standards are run in parallel and assay is linear through 39 million copies/mL. Risk factors for the development of HC were evaluated on univariate and multivariate analysis using Cox's regression model. The cumulative incidence (CI) of HC was estimated considering death without HC as a competing event.Results: 209 pts were studied (132 males). Median age was 49 years (range, 19–71). Diagnoses included leukemias (n=161, 77%), lymphoma and myeloma (n=46, 22%) and others (n=2, 1%). Donors were unrelated (n=178), haploidentical (n=8) and unrelated cord blood (CB) (n=23). Stem cell source was bone marrow (BM, n=78), peripheral blood (PB; n=108), and CB (n=23). . Conditioning regimen was myeloablative in 110 pts and reduced intensity (RIC) in 99 pts; 38 pts (18%) received cyclophosphamide-containing regimens. GVHD prophylaxis was tacrolimus and mini-methotrexate. Median time to platelet engraftment was 20 days (range, 0–164). Pre transplant BK viruria was detected in 96 patients (46%). The number of viral copies ranged from 300 to > 200 million copies. Twenty five patients (11%) developed HC within one year after HSCT at a median of 59 days (range, 8–225). In 6 pts, HC was diagnosed before platelet engraftment. The severity of HC was grade 1 in 3 pts, grade 2 in 11, grade 3 in 8, an grade 4 in 3. On univariate analysis, donor type was the most significant predictor of the incidence of HC within a year of HSCT, with recipients of haploidentical or CB transplant having the highest incidence rate (HR=3.1, p=0.009). There was also a trend for higher HC incidence in patients who received a myeloablative conditioning (HR=2.3, p=0.06), and in those who had a positive PCR before transplant (HR=2, p =0.095). Because of the small number of HC cases in pts who received a RIC (n=7/99, CI of HC 7%) we could not perform a multivariate analysis adjusting for the type of conditioning. In patients who received a myeloablative conditioning multivariate analysis showed a significantly higher incidence of HC in pts who received a haploidentical or CB transplant (HR=3.8, p=0.006); and in pts with a positive PCR before transplant (HR=2.9, p=0.03). The cumulative incidence of HC in pts who had both adverse factors was 58%, compared with 11% and 13% in those who had either one or none of these factors, respectively. There was no significant association between the incidence of HC and grade II-IV acute GVHD, considered as a time dependent variable, patient age, stem cell type (BM vs. PB), use of cyclophosphamide in conditioning, BK viral load, or PCR positivity on day 30 post HSCT. With a median follow-up among survivors of 11 months (range 4–32), HC, considered as time dependent variable, did not have a significant impact on survival.Conclusion: BK viruria pre-HSCT may be a predict factor for development of HC, especially for those receiving haploidentical or CB transplants using a myeloablative regimen.Cumulative incidence of HC as a function of preparative regimen intensity and BK virus PCR status pre transplant [Display omitted] Incidence of HCVariable (n)No patients with HC (%)Total (209)25 (12%)Age≤ 50 years (99)12 (12%)> 50 years (110)13 (12%)SexM/F 132/7716(12%)/9(12%)DiagnosisLeukemia (161)18 (11%)Lymphoma (40)7 (17.5%)ConditioningAblative (110)18 (16%)Non-ablative (99)7 (7%)Donor TypeMUD(169)17 (10%)Haplo/cords (31)8 (25%)acute GVHDI – II (88)10 (12%)III – IV (26)4 (15%)Pre SCT PCRPositive (96)16 (17%)Negative (111)9 (8%)

Incidence and Risk Factors for Hemorrhagic Cystitis in Adult Patients Undergoing Allogeneic Stem-Cell Transplantation.

Introduction: Hemorrhagic cystitis (HC) is a major cause of morbidity in patients submitted to allogeneic stem-cell transplantation (SCT). HC is characterized by a late onset, and it has been related with viral infections, such as cytomegalovirus (CMV), adenovirus, or BK virus (BKV). However, incidence and risk factors for HC are not established so far.Objectives: Analyze incidence and risk factors for HC in a large cohort of adult patients undergoing allogeneic SCT in a single institution.Material and methods: Between 1996 and 2006, 366 adult patients (median age 39 years, range 14 to 63 years) received allogeneic SCT, 251 (69%) from related donor and 115 (31%) from unrelated donor. Source of SCT was peripheral blood (PB) in 219 patients (60%), cord blood (CB) in 95 (26%) and bone marrow (BM) in 52 (14%). Graft was manipulated using CD34+ selection or T-cell depletion in 81 (22%) and 16 patients (4%), respectively. The most frequent underlying diseases were AML (36%), ALL (20%) and CML (15%). Conditioning regimens consisted of busulfan plus cyclophosphamide (BUCY) in 28% of patients, BUCY plus tiotepa (BUCYTT) in 14%, BUCYTT plus thymoglobulin (BUCYTTATG) in 22%, reduced intensity conditioning (RIC) in 12%, and other regimens in 24%. Immunosuppressive therapy consisted of cyclosporine plus methotrexate (52%), cyclosporine plus prednisone (39%) and other (9%). HC was graded according to NCI-CTC modified criteria. In the presence of HC shell-vial urine culture for CMV and adenovirus were performed. Since 2002 VBK viruria using qualitative RT-PCR analysis was also assessed.Results: Overall, 92 patients (25%) developed HC. The median day of presentation was +32 days (range −1 to +680 days). Cystitis cases were graded as follows: grade 1 (4%), grade 2 (40%) and grade 3–4 (56%). Etiology was unknown in 61% of patients, chemotherapy-related in 4% (all from days −1 to +3) and viral-related in 35% (16 VBK, 7 CMV, 6 adenovirus, and 2 HSV). Cumulative incidence (CI) of HC at 3 years was 23%. The following variables were associated with a higher CI of HC: unrelated-donor vs mismatched related donor vs matched related-donor (41% vs 31% vs 16%, p<0.01), CB source vs BM vs PB (47% vs 21% vs 18%, p<0.01), myeloablative regimens vs RIC (29% vs 4%, p<0.01), T-cell depletion vs CD34+ selection (37% vs 17%, p=0.03), BUCYTTATG vs BUCYTT vs BUCY (46% vs 38% vs 13%, p<0.01), age <30 years (41% vs 18%, p<0.01), donor age <30 years (39% vs 14%, p<0.01) and acute GVHD grade 3–4 vs grade 0 (31% vs 15%, p=0.01). In multivariate analysis unrelated-donor and myeloablative regimens were related to a higher CI of HC (both p<0.01). In patients with a matched-related donor CI of HC was higher among these subsets: age <30 years (p<0.01), acute GVHD grade 3–4 vs grade 0 (p=0.02), myeloablative regimens (p=0.02), donor age <30 years (p=0.03), and BUCYTT vs BUCY (p<0.01). In patients with an unrelated donor only age <30 years (p=0.02) was related to a higher CI of HC.Conclusion: In this cohort of adult patients submitted to SCT, the cumulative incidence of HC was 23%. Myeloablative and immunosuppressive conditioning regimens, as well as unrelated-donor, young recipients and young donors are related to an increased risk of HC.

Hemorrhagic Cystitis in Adults after Unrelated Cord Blood Transplantation: A Single-Institution Experience in Japan

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.