Continuous Intravenous Injection of Mesna Is Powerful in Preventing Acute Hemorrhagic Cystitis in Hematopoietic Stem Cell Transplantation: 108 Cases report
Authors: Jiang Qian-li , Liu Qi-Fa , SUN Jing , Fan Zhiping , Zhou Hongsheng , Zhang Yang , Chai Yan-yan , Xu Dan , Wei Qi , Yu Guo-pan , Zhao Jie , Li Xiao-fang , Yu Guan-nan , Huang Qin , Meng Fan-Yi 
Published: October 2019

Abstract
Abstract 3015FN2

Objective:
Acute hemorrhagic cystitis (HC), a severe complication of hematopoietic stem cell transplantation (HSCT), being considered mainly as a result of cyclophosphamide (CTX), seriously affects the quality of life of patients. Mesna, whose half-life is about 70min, is widely used to prevent HC. Aim of this research is to explore the effect of continuous intravenous injection of mesna on HC in HSCT.

Methods:
(1) 108 patients who underwent HSCT in Nanfang hospital from July 2008 to December 2010 were recruited into this study (70 male and 38 female, the median age is 35.00); 106 cases were allogenic HSCT, 2 cases were auto-HSCT. Conditioning regimens were BuCy or TBI-Cy, in which CTX were given 60mg/kg·d, d−3, −2. Intravenous injection of mesna was used to prevent HC continuously (continuous group, n=68) or intermittently (intermittent group, n=40). Graft versus host disease (GVHD) prevention regimen was cyclosporine A+MTX for HLA-matched sibling donors and cyclosporine A+MTX+ATG for unrelated donors or HLA partial-matched related donors. (2) Both groups received the same daily dose of mesna, which is about 150% of CTX daily dosage. In the intermittent group, 25% of mesna's daily dosage was injected at 0h, 3h, 6h and 9h after the use of CTX at each time-point; while in the continuous group, 25% of mesna's daily dosage was injected before the use of CTX, with the rest dosage being continuously injected intravenously for 24hs using micro-infusion pump (25% daily dosage of mesna dissolved in 40ml 0.9% sodium chloride lasting for 8h was given, q8h), from the first dose of CTX till 48hs after the last injection of CTX. Incidences and grades of HC in the two groups were followed up and analyzed. (3) The mesna concentration in urine of two groups was detected by HPLC, with the comparison of trough concentrations being presented by comparing the average peak concentration.

Results:
(1) Within 30d after transplantation, HC occurs in 13 of the 40 (32.5%) cases in the intermittent group (6 cases of II°, 4 cases of III°, 3 cases of IV°) with none (0%) in the continuous group. Within 60d after transplantation, HC occurs in 16 of 40 (40.0%) cases in the intermittent group (8 cases of II°, 5 cases of III°, 3 cases of IV°) with the mean occurrence time being +14.6d (-1d - +44d); while only 7 of 68 (10.3%) cases (5 cases of I°and 2 of II°) in the continuous group with the mean time of +43.0d (+33d–+54d). There were statistical significances of the incidence (P =0.000), grade/severity (P =0.007) and occurrence time (P =0.005) of HC between the two groups. (2) Logistic regression analysis shows that the HC occurrences relates with the way of using mesna(P =0.025), with continuous mesna injection being a protective factor(OR=0.114, 95% CI=0.017–0.764); while age, sex, 24h mean liquid intake, 24h mean excretion, 24h mean urinary volume (each P >0.1) and HLA matching (P =0.063) were unrelated factors. (3) The urine mesna trough concentration/average peak concentration was 0.219 (0.043–0.399) and 0.643 (0.153–0.868) in the intermittent group and the continuous group, respectively(P =0.031, n=4).

Discussion:
Early occurrence of HC is mostly related to high dose of cyclophosphamide, while late occurrence of HC can also be related with infection and GVHD, etc. The continuous injection of mesna seems to be a better way for the prevention of HC in HSCT patients, due to its short half-life of mesna. Injection with micro-infusion pump can reduce the liquid intake, especially suitable for those who have heart or kidney dysfunctions. More tests of mesna and acrolein concentration will help to reveal the mechanism.

Conclusion:
Continuous intravenous injection of mesna is a more efficient method in prevention of HC in hematopoietic stem cell transplantation than routine intermittent intravenous injection.

Disclosures:
No relevant conflicts of interest to declare.