Higher Incidence Of Hemorrhagic Cystitis Research Articles

Association Between Cytomegalovirus and Epstein-Barr Virus Co-Reactivation and Hematopoietic Stem Cell Transplantation.

The co-reactivation of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in patients undergoing hematopoietic stem cell transplantation (HSCT) has been found. Research has shown that the reactivation of CMV or EBV is closely related to poor HSCT outcomes. In this study, we describe the clinical characteristics of HSCT patients with co-reactivation of CMV and EBV. We retrospectively reviewed the medical records of 327 patients who underwent HSCT at the Peking University People’s Hospital Institute of Hematology. Co-reactivation of CMV and EBV was observed in a total of 75 patients (22.9%) who also had a higher incidence of hemorrhagic cystitis (P=0.000). HSCT patients with CMV and co-reactivation of CMV and EBV had a significantly lower 1-year overall survival (OS; P=0.050). Further, COX regression analysis showed that viral infection was a risk factor for 1-year OS (HR, 12.625 for co-reactivation vs. no reactivation, p=0.021, and HR 13.580 for CMV reactivation vs. no reactivation, P=0.013). In conclusion, the patients with CMV reactivation had poorer outcome after HSCT regardless of EBV reactivation.

AML-025: Post-Transplant Cyclophosphamide versus Methotrexate-Based Regimen as Graft Versus Host Disease Prophylaxis after Allogeneic Haematopoietic Stem Cell Transplantation in Patients with Acute Leukemia

Calcineurin inhibitor (CNI) and methotrexate are used as standard GVHD prophylaxis in HSCT. Trials using high dose post-transplant cyclophosphamide (PT-Cy) with or without immunosuppressive agents (IS) have shown success. Further studies are needed. To compare clinical outcomes of allo-HSCT using PT-Cy versus MTX as GVHD prophylaxis, we enrolled 80 patients (Pts) with acute leukaemia (53 males, 27 females) aged 18 to 60, who underwent matched and haplo allo-HSCT using reduced intensity chemotherapy at Maadi Armed Forces Hospital from 2014 to 2018. Median follow-up was 50 months after informed consent. Pts were randomized into 2 groups. The 1st group (40 patients) received MTX in the following doses: day +2 (15 mg), day +4 (10 mg), day +6 (10 mg) with cyclosporine (5 mg/kg) from day −3 till day +90 and mycophenolate (MMF) (2 −3gm/day) from day +1 till day +30. The 2nd group received PT-Cy (45 mg/kg/day) on days +3 and +4 with cyclosporine (5mg/kg) from day +5 till day +30 and MMF: (2-3 g/day) from day +5 till +30. At median 1-year post-allo, PT-Cy was associated with less incidence of chronic GVHD compared to MTX group (20%, 55%) respectively (P=0.002). Incidence of acute GVHD at day +100 was (40%, 32.5%) in group 1, 2 respectively (P=0.48). MTX group had higher incidence of renal & liver toxicity when compared to PT-Cy group (P=0.018, P=0.013) respectively. PT-Cy group had higher incidence of hemorrhagic cystitis when compared to MTX (P=0.006). In MTX group, renal toxicity caused mortality of 1 patient, hepatotoxicity caused mortality of 3 patients and HC caused mortality of 1 patient. In PT-Cy group, renal & hepatic toxicity caused no mortality while HC caused mortality of 3 patients. 87.5% of patients in group 1 and 90 % of patients in group 2 had full donor chimerism on day +30 (P=0.72). The cumulative incidence of relapse at 2 years post-allo was 17.5% for group 1 and 30% for group 2 (P >0.05). Cumulative 4 years disease free survival & overall survival (OS) in PT-Cy group was 45.7%, and 46.9%, respectively and for the MTX group, 43.4%, and 43.7%, respectively (P > 0.05). PT-Cy with addition of IS drugs has statistically significant difference in reducing the incidence of cGVHD compared with MTX based regimen without affecting engraftment, relapse, PFS & OS.

Higher Incidence of Hemorrhagic Cystitis Following Haploidentical Related Donor Transplantation Compared with Matched Related Donor Transplantation

Hemorrhagic cystitis (HC) is a common and important complication of allogeneic hematopoietic cell transplantation (HCT). Reactivation of BK virus is its most common cause. The more intense immunosuppressive regimens administered to recipients of grafts from alternative donors have been reported to account for the increased susceptibility to HC in this population. This study compares patients undergoing HCT with either a haploidentical donor or a matched related donor, all of whom received identical immunosuppression with a post-transplantation cyclophosphamide-based regimen. The incidence of HC was significantly higher in the patients receiving a haploidentical graft (P = .01). The higher incidence of HC in haploidentical graft recipients is therefore directly related to the inherent immune deficiency that follows HLA-mismatched transplantation, independent of the intensity of pharmacologic immunosuppression. This finding carries significant clinical impact for the prevention and treatment of HC in haploidentical graft recipients.

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.

Ultrasonography in the diagnosis of hemorrhagic cystitis - a complication of bone marrow transplantation in pediatric oncology patients.

ObjectiveThe aim of this study was to evaluate the usefulness of ultrasonography in the diagnosis of hemorrhagic cystitis following bone marrow transplantation in children.Material and methodsThe study involved an analysis of clinical material and the results of imaging tests performed in 334 patients who underwent hematopoietic cell transplantation. Ultrasonographic findings in 42 patients with hemorrhagic cystitis were analyzed in detail. The ultrasound images served to assess the severity of hemorrhagic cystitis and the results were compared with the clinical assessment of the disease on the Droller scale, as well as the laboratory and endoscopic tests.ResultsIn the studied group of patients hemorrhagic cystitis following allogeneic transplantation was diagnosed in 12.5% cases. 73.8% patients received transplants from unrelated donors, 26.2% – from compatible siblings. The study revealed a higher incidence of hemorrhagic cystitis in children above 10 years of age. Grade 3 according to the Droller was diagnosed in 42.9%, grade 2 – in 30.9%, grade 4 – in 14.3%, and grade 1 – in 11.9% patients. The number of ultrasound examinations depended on the clinical symptoms, severity, duration and co-occurrence of other complications following the transplantation and was within the 1–15 range (average: 4.6). Grades 3 and 4 were related to the poor clinical condition of the patients and to their longer hospitalization. During this period there was an increased risk of renal malfunction and acute renal failure, post-inflammatory narrowing of the ureters, hydronephrosis, and in grade 4 the fibrosis of the bladder with reduced bladder capacity. Analyses demonstrated a significant correlation between the ultrasound image of the bladder wall and the clinical severity.ConclusionsUltrasound with Doppler options remains the primary diagnostic tool in the evaluation of hemorrhagic cystitis, and is useful in terms of its diagnosis, determination of the severity, and monitoring of the treatment.

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.

Incidence of Adenovirus and BK Virus Reactivation and Diseases Following Reduced-Intensity Cord Blood Transplantation for Adult Patients.

Background Late-onset hemorrhagic cystitis (HC) is a common viral infections after allogeneic hematopoietic stem cell transplantation (HSCT). Most cases of HC occurring after HSCT are self-limited, but they can cause pain, pollakiuria, and prolonged hospitalization. In cases with progression of HC, ureteral stenosis has occurred and occasionaly resulted in obstructive renal failure. Several risk factors associated with HC after bone marrow transplantation(BMT) and peripheral blood stem cell transplantation(PBSCT) have been reported in several studies. However, most of these risk factors for HC after cord blood transplantation(CBT) have not been observed in detail.Subjects and methods We retrospectively analyzed the clinical records of 461 patients who underwent HSCT at Toranomon Hospital between November 2002 and December 2006. Median age of the patients was 53 years (range 17– 79). Source of HSCT was peripheral blood (PB) in 79 patients (17%), cord blood (CB) in 281 patients (61%), bone marrow (BM) in 101 patients (22%). Underlying diseases were AML(n= 146), ALL(n=61), MDS(n=68), ATL(n=34), CML(n=8), NHL (n=109), other(n=35). The most frequently used conditioning regimens were fludarabine (Flu), alkylating agent (melphalan, busulfan or cyclophosphamide) with total body irradination (TBI).The most frequently used prophylaxis regimens for graft-versus-host disease (GVHD) were calcineurin inhibitor (CI) alone or CI plus methotrexate. HC was defined as the presence of sustained microscopic hematuria for more than 7 days at least 10 days after HSCT in the absence of other conditions such as gynecologic-related bleeding, multiple organ dysfunction, or sepsis. HC was graded according to the following criteria: grade0 = no HC, grade1 = microscopic hematuria, grade2 = macroscopic hematuria, grade3 = macroscopic hematuria with clots, grade4 = macroscopic hematuria requiring instrumentation for clot evacuation or causing urinary retention. BK virus and adenovirus were detected by PCR on urinary samples in all patients who developed HC.Results Overall, 73 patients (16%) developed HC. The median day of presentation was 55 days (range 10 to 505 days). HC cases were graded as follows: grade 1 (8%), grade 2 (64%), grade 3 (24%), grade 4 (4%). The following variables were associated with a higher incidence of HC: CB source vs BM vs PB (14.2% vs 19.8% vs 16.5%, p<0.01). Adenovirus was detected in 27 patients (ADV type11 in 16 patients). BK virus was detected in 42 patients. Both virus was detected in 9 patients. The incidence of HC was significantly associated with grade II to IV acute GVHD in CBT (p<0.01).Conclusion We concluded that there is no significant disparity in the rate of HC among CBT and other HSCT, and immune reconstitution in parallel with BK and adenovirus viruria after CBT stand comparison with other HSCT.

High incidence of adeno- and polyomavirus-induced hemorrhagic cystitis in bone marrow allotransplantation for hematological malignancy following T cell depletion and cyclosporine.

Nine of 56 (20% actuarial) patients receiving a T cell-depleted, HLA-identical sibling BMT for hematological malignancy developed hemorrhagic cystitis (HC) 15-368 days post BMT. Hematuria was severe and prolonged (median duration 18 days). In eight patients (89%), a viral etiology was confirmed (four adenovirus, four polyomavirus). HC was associated with significant morbidity, with all patients requiring continuous bladder irrigation and transfusion support for blood loss and thrombocytopenia. HC occurring before day 100 was significantly associated with a reduction in long-term survival: 1/7 (14.3%) patients developing HC before day 100 became long-term survivors vs 21/49 (42.8%) without HC by day 100 (P = 0.034). In univariate analysis, HC was associated with a diagnosis of multiple myeloma (P = 0.02). There was a trend towards a higher incidence of HC in patients reactivating cytomegalovirus (CMV) compared with those remaining CMV negative (18.4 vs 5.5% respectively, P = 0.17). HC was not associated with graft-versus-host disease, or with the transplant dose of CD34+ progenitors or CD3+ cells, patient age or sex. Life-threatening, viral-induced HC and the unusually high incidence of adenovirus-induced HC may have been caused by immune deficiency associated with T cell depletion in this series.

Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung: a randomized trial of the Bristol Lung Cancer Study Group.

A total of 353 patients with previously untreated small-cell lung cancer (SCLC) were accrued in this multicenter trial. Patients were randomly assigned to receive one of the following three regimens: cyclophosphamide 1,000 mg/m2 intravenously (IV) day 1, vincristine 1.4 mg/m2 IV day 1, and etoposide 50 mg/m2 IV day 1, followed by etoposide 100 mg/m2/day orally days 2 through 5 (CEV); cyclophosphamide 1,000 mg/m2 IV day 1, vincristine 1.4 mg/m2 IV day 1, and doxorubicin 50 mg/m2 IV day 1 (CAV); cyclophosphamide 2,000 mg/m2 day 1 and vincristine 1.4 mg/m2 IV day 1 (CV). Cycles were repeated every 3 weeks. Treatment groups were comparable with respect to extent of disease, age, sex, performance status, and metastatic sites. No significant differences in response rates, response duration, or survival could be detected in limited disease, although there appeared to be a trend favoring CEV. Among extensive-disease patients, response duration on the CEV regimen was longer than on the CV regimen or the CAV program (P less than .001). The superiority of the CEV regimen was also demonstrated in the survival analysis in which differences attained statistical significance (P = .01). In this group the median survival was increased from 29 weeks on CV to 31 weeks on CAV and 39 weeks on CEV. Myelosuppression was the most frequent toxicity. It was more severe with CV than CEV or CAV. Most nonhematologic side effects were comparable among the three treatment groups. However, the high doses of cyclophosphamide in the CV regimen produced a higher incidence of hemorrhagic cystitis than in the CEV or CAV programs (P less than .001). Cardiotoxicity only occurred in the CAV group (P = .05). The addition of etoposide to the CV regimen resulted in significantly longer response duration and survival without increased toxicity. Similarly, the substitution of etoposide for the doxorubicin in the CAV regimen was associated with prolonged survival and reduced cardiotoxicity.