Effect of Cyclophosphamide on Hemorrhagic Cystitis Following Haploidentical Related Compared to Matched Related/Unrelated Donor Hematopoietic Stem Cell Transplantation: A 7-Year Tertiary Center Analysis
Authors: Cengiz Seval Guldane , Ozturk Nergis , Civriz Bozdag Sinem , Yuksel Meltem Kurt , Topcuoglu Pervin , Arslan Onder , Özcan Muhit , Demirer Taner , Gurman Gunhan , Ilhan Osman , Akan Hamdi , Beksac Meral , Toprak Selami Kocak 
Published: November 2019

Introduction: Hemorrhagic cystitis (HC) is a serious and common complication of hematopoietic cell transplantation (HCT) affecting both allogeneic (alloHCT) and haploidentical HCT recipients. Early urinary bleeding after transplant is usually attributed to toxic effects of cyclophosphamide (Cy) or other agents used in the conditioning regimen or for graft-versus-host disease (GVHD) prevention. HC occurring beyond 3 to 4 weeks after HCT is usually attributed to BK polyoma virus or other viruses, e.g. cytomegalovirus or adenovirus.
The aims of this study were to determine the incidence, risk factors, severity, morbidity pattern and toxicity of treatment, and outcome of HC in recipients of HSCT at a single tertiary transplant center.
Methods: We analyzed all patients undergoing haploidentical (haploHCT) or MRD/MUD alloHCT at our bone marrow transplant unit from September 2012 through June 2019. In alloHCT group, 70% (n=205) of the patients received myeloablative conditioning consisted of Cy and only six patients (2%) received identical GVHD prevention with a post-transplant Cy-based regimen. Conversely; in haploHCT group, use of Cy-containing preparative regimen was not often (22.9 % (n=8)) but 77.1% (n=27) of the patients received post-transplant Cy. Grading of HC was based on the system used by Droller et al. and classified as grade I if the hematuria was microscopic and grade II if macroscopic. The presence of clots in the urine was regarded as grade III and obstructive uropathy with or without renal impairment as grade IV HC, respectively. All patients with a clinical diagnosis of HC had urine and blood analyzed for presence of BK virus by PCR.
Results: A total of 328 HSCTs were performed during the study period, of which 169 (51.5%) alloHSCT from MUD, 124 (37.8%) alloHCT from MRD and 35 (10.7%) haploHCT. Baseline characteristics of the patients were similar among two groups with regarding to age, diagnosis, disease status and intensity of conditioning (Table 1). Hemorrhagic cystitis was diagnosed in 78 of 328 patients (23.8%) with a median follow up 7.4 months. Disease status at transplant, recipient age, cytomegalovirus antigenemia and the intensity of conditioning regimen were not associated with the development of HC. In addition, use of bone marrow versus peripheral blood had no influence on development of hemorrhagic cystitis (p=0.16). The incidence of HC was significantly higher in patients who received grafts from haploidentical donors compared to those receiving grafts from MRD/MUDs (54.3% (n=19) vs 20.1% (n=59), p<0.001). Interestingly, the incidence of Grade III-IV HC was higher in the alloHCT compared to the haploHCT groups (37.2% vs 2.1%, p<0.001). In multivariate analysis of risk factors associated with HC, receiving conditioning regimen including Cy and the use of a haploidentical donor was not significantly associated with HC. The incidence HC with BK viruria at the time of diagnosis of HC was higher in the cohort of patients receiving grafts from MRD/MUD donors (61% vs 47%, p=0.04). and BK viruria was not associated with HC severity. We identified no significant association between adenovirus, HHV-6 or CMV in HC patients comparing the onset and resolution of HC. Neither HC nor grades III-IV HC was associated with overall survival.
Conclusion: Conditioning regimen is an important factor in the development of HC and its mechanism has been well described. In our study, we could not demonstrate the increased HC risk of conditioning regimens including cyclophosphamide. We also showed that cyclophosphamide in MAC had similar HC risk compared with RIC containing cyclophosphamide. BK virus was frequently found to be a risk factor for HC. In this retrospective analysis, BK virus was detected 45 patients out of 78 patients with HC and BK viruria was not associated with HC severity.
Table 1

Disclosures
Özcan: Amgen: Honoraria, Other: Travel support; Novartis: Research Funding; Celgene Corporation: Research Funding, Travel support; MSD: Research Funding; AbbVie: Other: Travel support, Research Funding; Jazz: Other: Travel support; Janssen: Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; Archigen: Research Funding; Roche: Other: Travel support, Research Funding; Bayer: Research Funding; Sanofi: Other: Travel support; Abdi Ibrahim: Other: Travel support; BMS: Other: Travel support. Beksac:Celgene: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.