Incidence and Risk Factors for Hemorrhagic Cystitis in Adult Patients Undergoing Allogeneic Stem-Cell Transplantation.
Authors: Montesinos Pau , Paciello Mari-Liz , Cantero Susana , Sanz Jaime , Lorenzo Ignacio , Moscardo Federico , Martin Guillermo , Senent Leonor , Puig Noemi , Blanes Margarita , Algarra Lorenzo , de la Rubia Javier , Sanz Miguel , Sanz Guillermo 
Published: October 2019

Abstract
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.