Influence Of Busulfan/Cyclophosphamide And Busulfan/Fludar-abine Conditioning Regimens On Severe Hemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplantation And Multivar-iate Analysis Of Risk Factors

Objective To compare the influence of Busulfan-Cycophosphamide(BU-CY) and Busulfan-Fludarabine(BU-FDR) conditioning regimens on overt hemorrhagic cystitis(HC) after allogeneic hematopoietic stem cell transplantation,and explore the independent risk factors and the pathogenesis of HC.Methods We retrospectively analyzed 181 transplant patients conditioned with BU-CY(119 patients) and BU-FDR(62 patients) conditioning regimens from April 1997 to December 2008.The time of follow-up began from the day of initiating conditioning to day 180 post-transplant.The 7 clinical parameters were selected for univariate analysis using a Cox regression:sex,age,underlying disease,donor type, disease status at transplant,aGVHD and use of ATG.Factors that were significant at the 0.1 level on univariate analysis were evaluated by multivariate analysis using a Cox regression.Results 31 out of 119 patients conditioned with BU-CY regimen developed HC (26.1%),and HC occurred in 15 patients of 62 patients conditioned with BU-FDR regimen(24.2%)(P=0.785).The Median time to HC onset in the BU-CY group was day +44(range between day -1 to day +165),and day +55(range between day +30 to day +154) in the BU-FDR group(P=0.246).Symptom of HC lasted median time of 22.5 days(range,7～60 days) in BU-CY group,compared to 15 days(range,6～65 days) in BU-FDR group(P=0.030).There were 12 patients with gradeⅡHC out of 119 patients who received BU-CY regimen(10.1%),as compared with 12 patients of 62 patients who received BU-FDR regimen(19.4%)(P=0.071);However,19of 119 patients developed gradeⅢ～ⅣHC in the BU-CY group(16.0%),and only 3 of 62 patients developed gradeⅢ～ⅣHC in the BU-FDR group(4.8%)(P=0.004)。The following factors were associated with an increased risk of HC by univariate analysis: BU-CY group:male(RR=2.885,P=0.021),younger than 25 years(RR=3.265,P =0.002),unrelated donor(RR=4.347,P=0.000),advanced disease(RR=2.668, P=0.009);BU-FDR group:gradeⅡ～ⅣaGVHD(RR=3.199,P=0.072),unrelated donor(RR=4.439,P=0.066) and use of ATG(RR=3.477,P=0.069).These risk factors were entered into a multivariate model,only male(RR=2.993,95%CI 1.218-7.358;P=0.017) and unrelated donor(RR=4.478,95%CI 2.049-9.786;P= 0.000) in BU-CY group and gradeⅡ～ⅣaGVHD(RR=4.111,95%CI 1.339-12.624, P=0.014) and unrelated donor(RR=4.897,95%CI 1.051-22.819;P=0.043) in BU-FDR group were identified as being significantly associated with the occurrence of hemorrhagic cystitis.Conclusion BU may play a major role in the pathogenesis of HC,compared to CY,and CY increased degree of severity of HC,but has no effect on the incidence of HC.Patients were at increased risk of HC if they had received graft from unrelated donor or developed gradeⅡ～ⅣaGVHD,suggesting that HC possibly represents the clinical manifestation of aGVHD involving the bladder epithelial cells,and the bladder may be a target organ of acute graft-versus-host-disease.