Continuous Intravenous Injection Of Mesna Can Reduce Acute Hemorrhagic Cystitis Occurrence Rate In Hematopoietic Stem Cell Transplantation: 359 Allo-HSCT Cases Report
Authors: Jiang Qianli , Liu Qifa , Sun Jing , Zhou Hongsheng , Fan Zhiping , Zhang Yu , Huang Fen , Xu Dan , Wei Qi , Yu Guopan , Zhao Jie , Li Xiaofang , Dai Min , Xu Na , Huang Hao , Shen Kefeng , Lu Yang , Yuan Lezhong , Chai Yanyan , Meng Fanyi 
Published: October 2019

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 preventing HC in HSCT by continuous intravenous injection of mesna using micro pump on HC in HSCT.

Methods
(1) 359 patients who underwent allogenic HSCT in Nanfang hospital from January 2003 to December 2012 were recruited into this study (227 male and 132 female). Conditioning regimens were BuCy or TBI-Cy, in which CTX were given 60mg/kg·d,d-3,-2; or GIAC, in which CTX were given 1.8g/m2, d-5, -4. Intravenous injection of mesna was used to prevent HC continuously using micro pump (continuous group, n=250) or intermittently (intermittent group, n=185). 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 High Performance Liquid Chromatography (HPLC), with the comparison of the trough concentrations and the peak concentration.

Results
(1) Within 30d after transplantation, HC occurs in 30 of the 160 (18.75%) cases in the intermittent group vs. 16 of 199(8.04%) in the continuous group (P=0.00077). Within 60d after transplantation, HC occurs in 45 of 160 (28.13%) cases in the intermittent group (17cases of I°, 18cases of II°, 8 cases of III°, 2 cases of IV°) with the mean occurrence time being +18.16d (-5-+41d); while only 24 of 199 (12.06%) cases (15 cases of I°, 6 cases of II°, 3 cases of III°, 0 cases of IV°) in the continuous group with the mean time of +26.58d (+2d-+58d). There were statistical significances of the incidence within 60d(P=0.000123) and occurrence time(P=0.018), however there was no statistical significances of grade/severity (P=0.057) of HC between the two groups. (2) Logistic regression analysis shows that within 30d after transplantation, the HC occurrences relates with the way of using mesna (P=0.004), with continuous mesna injection being a protective factor (OR=0.299, 95% CI=0.130-0.684); while age, sex, 24h mean liquid intake, 24h mean excretion, 24h mean urinary volume (each P>0.2) and HLA matching (P=0.099) were unrelated factor. Within 60d after transplantation, the HC occurrences relates with the way of using mesna (P=0.001)and GVHD (P=0.007); continuous mesna injection is a protective factor (OR=0.296, 95% CI=0.146-0.600) and HLA matching is a risk factor (OR=2.422, 95%CI=1.280-4.580). (3) Althrough 73 samples were detected by HPLC for mesna in urine, there were no significant difference of peak and trough concentration between groups.

Discussion
Early occurrence of HC is mostly related to high dose of cyclophosphamide, while late occurrence of HC can also be related with GVHD and infections. The continuous injection of mesna is a better way for the prevention of HC in HSCT patients, due to its short half-life of mesna. While injection with micro-infusion pump can reduce liquid intake, especially suitable for those who have heart or kidney dysfunctions.

Conclusion
Continuous intravenous injection of mesna is efficient to prevent HC in hematopoietic stem cell transplantation.

Disclosures:
No relevant conflicts of interest to declare.