Incidence Of Hemorrhagic Cystitis Research Articles

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.

P1327: RUXOLITINIB COMBINED WITH GLUCOCORTICOID IN THE FIRST-LINE TREATMENT OF GRAFT-VERSUS-HOST DISEASE IN CHILDREN: A SINGLE CENTER RETROSPECTIVE STUDY

Background: Ruxolitinib has certain advantages and potential in the treatment of GVHD. It can inhibit the secretion of inflammatory factors by T cells, increase the number of regulatory T cells（Tregs）in the recipient, and then mediate immune tolerance. It can also reduce T cell surface related chemokines or chemokine receptors, and then change T cell migration. A multicenter retrospective study showed that the effective rate of ruxolitinib on glucocorticoid resistant aGVHD was 81.5%, and the effective rate of glucocorticoid resistant cGVHD was 85.4%. At present, there is no report on the first-line treatment of GVHD in children with glucocorticoid combined with glucocorticoid.Our center tried to use this combined scheme as the first-line treatment option in the early stage, in order to reduce the application time of glucocorticoid and reduce glucocorticoid related complications. Aims: To investigate the efficacy and safety of ruxolitinib combined with glucocorticoid in the treatment of graft-versus-host disease (GVHD) in children. Methods: A retrospective analysis of 17 cases of graft-versus-host disease（GVHD） after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in our center was conducted. The clinical efficacy and adverse reactions of early application of ruxolitinib combined with glucocorticoid were observed. Results: The median treatment time of 17 children was 47 (24-380) days, and the median onset time was 7 (4-90) days. The overall effective rate was 94.1% (16/17), the complete remission rate was 58.8% (10/17), the partial remission rate was 35.3% (6/17). The incidence of hemocytopenia during the combination therapy was 41.1% (7 /17).The incidence of EBV infection was 35.2% (6 /17), and the incidence infection of CMV was 29.4% (5/17).The incidence of hemorrhagic cystitis was 11.8% (2/17). The median follow-up time was 230 (74-545) days. One child died of grade IV acute graft versus host disease (aGVHD), and the other 16 children survived. The 6-month overall survival rate was 94.1%. Summary/Conclusion: Ruxolitinib combined with corticosteroid is effective and safe in the treatment of children with GVHD. It is expected to become a first-line anti GVHD therapy.

Post-Transplant Cyclophosphamide Versus Tacrolimus and Methotrexate to Prevent Graft-Versus-Host Disease in Recipients of Matched Donor Transplantation: Comparison of Sequential Cohorts in a Prospective Trial

Post-Transplant Cyclophosphamide Versus Tacrolimus and Methotrexate to Prevent Graft-Versus-Host Disease in Recipients of Matched Donor Transplantation: Comparison of Sequential Cohorts in a Prospective Trial

244 - CYP2B6 Variants in Cyclophosphamide Metabolism and the Incidence of Hemorrhagic Cystitis in Fanconi Anemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

244 - CYP2B6 Variants in Cyclophosphamide Metabolism and the Incidence of Hemorrhagic Cystitis in Fanconi Anemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

Outpatient haploidentical hematopoietic stem cell transplant using post-transplant cyclophosphamide and incidence of hemorrhagic cystitis

IntroductionHemorrhagic cystitis (HC) is a common complication of haploidentical hematopoietic stem cell transplantation (haplo-HSCT), characterized by irritative symptoms of the urinary tract and a higher morbidity and mortality rate. The worldwide incidence is reported between 10% and 70%. The use of alkylating agents and BK viral infection are the most frequent etiologies. The aim of this study was to report the HC incidence in an outpatient haplo-HCST program with a reduced intensity-conditioning (RIC) regimen, cataloguing risk factors, complications and final outcomes. MethodsThe medical database of patients who received a haplo-HSCT between January 2012 and November 2017 was retrospectively analyzed. Demographic variables, general characteristics and HC incidence were included. ResultsOne hundred and eleven patients were included, 30 (27%) of whom developed HC, most of them (70%) being grade II, with a 30-day (7–149) median time of post-transplant HC onset. The BK virus was detected in 71% of the urine samples analyzed. All HC patients responded to treatment, except two (6.6%), who died due to HC complications. ConclusionsThere was no difference in the HC incidence or severity, compared to that reported when performing haplo-HSCT in hospitalized patients, although the donor-recipient sex mismatch did relate to a higher HC incidence.

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.

Outcome of Canine Multicentric Lymphoma after Single or Divided Treatment with Cyclophosphamide in Multidrug Chemotherapy

Cyclophosphamide is commonly used in combination chemotherapy to treat dogs with lymphoma. The metabolite of cyclophosphamide, acrolein, can irritate urinary bladder and cause sterile hemorrhagic cystitis. Dividing the administration of cyclophosphamide across multiple days may reduce the concentration of this metabolite in urinary bladder and reduce the possibility of cystitis. However, the impact of the therapeutic effect of this modification is not evaluated and compared to traditional single maximum-tolerated dose regimen. Seventy-two dogs with multicentric lymphoma received either bolus doses or divided doses of cyclophosphamide were included in this study. The incidence of hemorrhagic cystitis between 2 cyclophosphamide treatment groups was not significantly different (P = .357). There was no statistical difference in progression-free survival and survival time between 2 groups (P = .267 and P = .346). This modification of cyclophosphamide administration did not reduce the side effect of cystitis or affect remission and survival times in lymphoma dogs.

PF762 EFFECTS OF TWO DOSES OF ANTITHYMOCYTE GLOBULIN IN CONDITIONING REGIMENS FOR HAPLOIDENTICAL PERIPHERAL BLOOD STEM CELL TRANSPLANTATION

Background:Antithymocyte globulin (ATG), an important in vivo T‐cell depletion strategy, has been used for graft‐versus‐host disease (GVHD) prophylaxis and shown significant clinical benefit. However, the optimal ATG dose remains unclear.Aims:To assess the effectiveness of ATG at a total dose of 10.0 mg/kg and 7.5 mg/kg for haploidentical peripheral blood stem cell transplantation (PBSCT).Methods:We retrospectively analyzed patients who underwent haploidentical PBSCT, receiving myeloablative conditioning and standard GVHD prophylaxis. ATG (rabbit thymoglobulin) at a total dose of 10.0 mg/kg (2.5 mg/kg on days −5 to −2) and 7.5 mg/kg (2.5 mg/kg on days −4 to −2) were used in the two groups.Results:40 and 35 patients were enrolled in the ATG‐10 and ATG‐7.5 groups, respectively. No significant difference was observed regarding the cumulative incidence of 100‐day grade II‐IV acute GVHD (20.0% vs 14.3%; p = 0.53) and 3‐year chronic GVHD (13.7% vs 15.7%; p = 0.83). The 3‐year probability of overall survival (OS) was 72.6% vs 74.4% (p = 0.81) and the 3‐year probability of GVHD‐free/relapse‐free survival (GRFS) was 69.0% vs 53.0% (p = 0.16). The incidence of relapse in the ATG‐7.5 group (30.9%) was higher compared with the ATG‐10.0 group (17.1%), but this difference was not statistically significant (p = 0.20). In multivariate analysis, the ATG dose was not associated with relapse, while no further respond to therapy (NR) before PBSCT predicted relapse (HR 1.19, p = 0.04). There were 5 patients (12.5%) and 8 patients (22.9%) in NR in the ATG‐10 and ATG‐7.5 groups, respectively (p = 0.19). Additionally, the ATG‐7.5 group had a trend for lower 300‐day incidence of EBV reactivation (92.5% vs 80.0%; p = 0.14) and CMV reactivation (90.5% vs 80.0%; p = 0.16), and lower 100‐day incidence of hemorrhagic cystitis (42.5% vs 28.6%; p = 0.15).Summary/Conclusion:7.5 mg/kg ATG led to lower incidence of EBV reactivation, CMV reactivation and hemorrhagic cystitis without compromising control of grade II‐IV acute GVHD, chronic GVHD and OS when compared with 10.0 mg/kg ATG. Therefore, ATG at a dose of 7.5 mg/kg could be considered for further study.

HLA- haploidentical donor hematopoietic transplantation for severe aplastic anemia achieved comparable outcomes with HLA- unrelated donor transplantation

目的评价亲缘半相合造血干细胞移植（Haplo-HSCT）治疗重型再生障碍性贫血（SAA）的疗效，并且与同期进行的无关供者造血干细胞移植（UD-HSCT）进行比较。方法回顾性分析2012年9月至2014年7月接受替代供者造血干细胞移植的50例SAA患者临床资料；其中24例接受Haplo-HSCT, 26例接受UD-HSCT。结果中位随访时间9(2~26)个月，总生存（OS）率为91.3%。UD-HSCT组和Haplo-HSCT组OS率分别为96.1%和86.0%（P=0.30）。3例（6%）患者原发植入失败。Haplo-HSCT组患者Ⅱ~Ⅳ度急性移植物抗宿主病、慢性移植物抗宿主病、CMV血症、EBV血症发生率分别为37.5%、37.5%、78.2％及43.1%，均明显高于UD-HSCT组（3.83%、15.3%、46.1％及16.0%）（P值分别为0.003、0.030、0.005、0.040）；出血性膀胱炎发生率差异无统计学意义（39.1％对23.0%，P=0.120）。结论Haplo-HSCT治疗SAA OS率较高，疗效与UD-HSCT相近。

Clinical significance of high-dose cytarabine added to cyclophosphamide/total-body irradiation in bone marrow or peripheral blood stem cell transplantation for myeloid malignancy.

BackgroundAddition of high-dose cytarabine (HDCA) to the conventional cyclophosphamide/total-body irradiation (CY/TBI) regimen significantly improved prognosis after cord blood transplantation (CBT) for adult acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The efficacy of HDCA in bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT), however, has not yet been elucidated.FindingsWe conducted a cohort study to compare the prognosis of HDCA/CY/TBI (N = 435) and CY/TBI (N = 1667) in BMT/PBSCT for AML/MDS using a Japanese transplant registry database. The median age was 38 years, and 86.0 % of the patients had AML. Unrelated donors comprised 54.6 %, and 63.9 % of donors were human leukocyte antigen (HLA)-matched. Overall survival (OS) was not improved in the HDCA/CY/TBI group (adjusted hazard ratio (HR), 1.14; p = 0.13). Neutrophil engraftment was inferior (HR, 0.80; p < 0.01), and the incidence of hemorrhagic cystitis and thrombotic microangiopathy increased in HDCA/CY/TBI (HR, 1.47 and 1.60; p = 0.06 and 0.04, respectively), leading to significantly higher non-relapse mortality (NRM; HR, 1.48; p < 0.01). Post-transplant relapse and tumor-related mortality were not suppressed by the addition of HDCA.ConclusionsThis study indicated the inefficacy of HDCA/CY/TBI in BMT/PBSCT for AML/MDS. Our results should be validated in large-scale prospective studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0201-x) contains supplementary material, which is available to authorized users.

SAT0538 Cyclophosphamide Induced Bladder Toxicity and Protective Effect of 2-Mercaptoethane Sulfonate (MESNA) in Systemic Autoimmune Disorders

BackgroundTo assess bladder toxicity of Cyclophosphamide (CYC) treatment and preventive effect of 2-mercaptoethane sulfonate (Mesna) in systemic autoimmune disorders.MethodsSix hundred fifty-six patients (F/M:479/177) with various systemic autoimmune disease who were...

Polymorphisms in the CYP450 Genes Influences Regimen Related Toxicity and Outcome in Patients with Beta Thalassaemia Major Undergoing HSCT.

Abstract 869Polymorphisms in drug metabolizing enzymes are known to contribute to inter-individual differences in the pharmacokinetics (PK) of the two most commonly used drugs for conditioning for hematopoietic stem cell transplantation (HSCT), busulfan (Bu) and cyclophosphamide (Cy) and their metabolites in plasma. We have previously reported the impact of CYP genes on the PK of Cy, [Blood (ASH Annual Meeting Abstracts), Nov 2004; 104: 99] and the influence of Cy PK on transplant outcome [Blood (ASH Annual Meeting Abstracts), Nov 2004; 104: 1820]. We have now extended this study to evaluate a total of 19 polymorphisms in 11 genes that are known to be involved in the metabolism of Bu and Cy. 180 of the 276 patients with thalassemia major who underwent HSCT between March 1991 and Dec 2008 and for who genomic DNA was available were included in the study. The following polymorphisms were screened using PCR followed by RFLP and/ or gel electrophoresis: GSTA1*B, GSTM1 and GSTT1 deletion, GSTP1*B, CYP2B6*2, *3, *4, *5 and *6, CYP2C9*2, *3 and *4, CYP2C19*2, *3, CYP3A4*1B, CYP3A5*3, *6 and ALDH1A1*2 and ALDH3A1*2. Polymorphism frequencies were associated with regimen related toxicities, other transplant related complications using Fischer's Exact test and Cox-proportional hazard's model.. Significant associations are shown in the Table. On univariate analysis, CYP2B6*4 variant genotype was associated with incidence of hemorrhagic cystitis (HC); CYP2C9*3 variant genotype was associated with the severity of HC; CYP2C19*3 and 2C9*2 genotypes were associated with overall and even-free survival (OS and EFS) and CYP2C9*2 and CYP2C9*3 genotype was associated with transplant related mortality (TRM). Multivariate analyses performed adjusting for known clinical risk factors still showed these genotypes to be significantly associated with outcome parameters. Variant genotypes of polymorphisms that result in decreased metabolism of Cy are protective against regimen related toxicities while these polymorphisms were risk factors for EFS and OS in the present study. This is the first report on the influence of common GST, CYP and ALDH polymorphisms on outcome of HSCT in patients with thalassaemia major. Screening for these polymorphisms in patients with beta thalassaemia undergoing HSCT can help identify patients at higher risk of complications.Table:EndpointGenotypeRelative risk (95% CI)P- valueHCCYP2B6*4 variant0.3 (0.13-0.889)0.028HC grade 1 vs. HC grade 2-4CYP2C9*3 variant0.2 (0.073-0.962)0.043TRM2C9*2 variant2.7 (1.08-6.77)0.0342C9*3 variant2.3 (1.0-5.7)0.049OS and EFS2C19*3 variant3.3 (1.2-9.3)0.0182C9*2 variant1.3 (0.93-2.03)0.070 Disclosures:No relevant conflicts of interest to declare.

277: A Prospective Evaluation of the Effect of Polyoma (BK) Virus Infection on the Incidence of Hemorrhagic Cystitis (HC) after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (UD HSCT)

277: A Prospective Evaluation of the Effect of Polyoma (BK) Virus Infection on the Incidence of Hemorrhagic Cystitis (HC) after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (UD HSCT)

High Incidence of BK-Virus-Related Hemorrhagic Cystitis after Busulfan/Fludarabine Myeloablative Conditioning in Allogeneic Stem Cell Transplantation Recipients.

Busulfan (BU) and Fludarabine (F) has been reported by de Lima et al. to be a well-tolerated myeloablative conditioning regimen with 3% incidence of hemorrhagic cystitis (Blood 2004; 104:857). Between 5/2005 and 5/2006, we performed allogeneic stem cell transplantation (SCT) in 29 patients following BU+F (n=17) and other (n=12) myeloablative regimens. Nineteen (66%) patients were in remission and 10 (34%) had active disease at BMT. Twenty patients had AML, 4 ALL and 5 had other malignancies. Busulfan was given at 130mg/M2 over 3 hours on 4 successive days, along with Fludarabine 40mg/M2 on 4 successive days. Eighteen (72%) had matched-related 7 (24%) had matched-unrelated donor (MUD) transplant. GVHD prophylaxis consisted of Tacrolimus and low-dose Methotrexate. Thymoglobulin (n=4) and CAMPATH (n=3) were given along with conditioning in MUD/one-antigen mismatch transplant recipients (5 BU+F and 2 other). As of August 1st, 2006, 19 (65%) patients are alive. Of 26 evaluable patients, the incidence of bacterial (59% vs. 89%), fungal (29% vs. 11%) infections were similar between Bu+F and other group, respectively. CMV reactivation was observed in 78% in other group as compared to 35% in BU+F recipients (p=0.09). Hemorrhagic cystitis (HC) occurred in 6 patients (35%) in BU+F group and in 1 (11%) patient in other group (p=0.35). BK virus was detected by quantitative PCR in all patients with HC. Two BK(+) cases were in BU+F+CAMPATH group. Considering 18 AML patients who received transplant in remission and had at least 2 months of follow-up, 5 patients (38%) in BU+F group relapsed within 6 months of transplant. Two out of 5 patients relapsed in the other group. Our findings suggest that BU+F myeloablative conditioning appears to be associated with high incidence of BK-related hemorrhagic cystitis and may have long-term consequences. Further studies are warranted.

Safety and Cost of Hyperhydration for the Prevention of Hemorrhagic Cystitis in Bone Marrow Transplant Recipients

Hemorrhagic cystitis is a major cause of morbidity after bone marrow transplantation. Traditional methods of prevention have included mesna (2-mercaptoethane sodium sulfonate) and bladder irrigation. We report the use of hyperhydration as an alternative to these prophylactic measures. One hundred consecutive patients who underwent autologous or allogeneic bone marrow transplantation received high dose cyclophosphamide with hyperhydration using 5% dextrose normal saline at the rate of 250 ml/h and furosemide to maintain a urine output of >150 ml/h. Seventy-one of these patients also received high dose cyclophosphamide as mobilization chemotherapy. There were no episodes of hemorrhagic cystitis following mobilization chemotherapy. The incidence of hemorrhagic cystitis after transplant conditioning was 7% with 2 patients developing clinically significant hemorrhagic cystitis; one was a severe episode. The cost of hyperhydration was US$ 20 per course as opposed to US$ 1,500 per course for mesna, based on acquisition costs at our institution. We conclude that hyperhydration is a safe, inexpensive means of preventing hemorrhagic cystitis associated with high dose cyclophosphamide in bone marrow transplant recipients.