Continuous intravenous injection of Mesna can effectively prevent Hemorrhagic cystitis in hematopoietic stem cell transplantation and retain the Mesna's concentration in urine: 394 cases reported within 11 years

BACKGROUND: 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.

OBJECTIVE: Our previous work proved that the continuous intravenous injection of Mesna using micro pump can help prevent HC in HSCT. This study expanded the sample size to research further,Mesna concentration in urine or serum were detected to explore the mechanism of action.

METHODS: (1) 394 patients who underwent allogenic HSCT in Nanfang hospital from January 2003 to June 2014were recruited into this study (247male and 147 female). All patients received BuCy or TBI-Cy basedconditioning regimens, in which CTX were given 60mg/kg·d, d-3,-2: or GIAC regimen, 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=234) or intermittently (intermittent group, n=160). (2) Patients in two groups received the same daily dose of Mesna. 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 of the 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 and serum of the continuous group was detected by High Performance Liquid Chromatography (HPLC), with the test of the mean concentration at four time points. As all the patients were changed from the intermittent to the continuous group since 2009, hence, we are now testing for the Mesna concentration in the continuous group only. Patients in other hospitals will be involved in trials for future research.

RESULTS: (1) Within 30d after transplantation, HC occurs in 30 of the 160 (18.75%) cases in the intermittent group vs. 17 of 234(7.26%) in the continuous group (P=0.001). Within 60d after transplantation, HC occurs in 45 of 160 (28.13%) cases in the intermittent group (17 cases of I°, 18 cases of II°, 8 cases of III°, 2 cases of IV°) with the mean occurrence time being +19.77d (-5-+42d); while only 30 of 234 (12.82%) cases (17 cases of I°, 9 cases of II°, 4 cases of III°, 0 cases of IV°) in the continuous group with the mean time of +27.20d (-3d-+58d). There were statistical significances of the incidence within 60d (P=0.000123) and occurrence time (P=0.037), however there was no statistical significances of grade/severity (P=0.063) of HC between the two groups. (2) Logistic regression analysis shows that within 30d after transplantation, the HC occurrences were related with the procedure of Mesna infusion (P=0.001), with continuous Mesna injection being a protective factor (OR=0.270, 95% CI=0.121-0.599); while age, sex, 24h mean liquid intake, 24h mean excretion, 24h mean urinary volume (each P>0.2) and HLA matching (P=0.093) were unrelated factors. Within 60d after transplantation, the HC occurrences relate with with the procedure of Mesna infusion (P<0.001)and GVHD (P=0.001); continuous Mesna injection is a protective factor (OR=0.266, 95% CI=0.135-0.524) and GVHD occurrence is a risk factor (OR=2.951, 95%CI=1.598-5.451). 3) As the half-life of Mesna is 70mins, therefore, we must maintain the Mesna concentration at a certain level at all times. The five observation points were the first day before and after CTX use, the second day before and after CTX use and the third day morning. The mean concentration of Mesna were as follows: 0±0, 298.06±299.76, 317.08±234.22, 415.18±463.75, 271.40±265.02 in urine,and 0±0, 75.04±56.93, 62.93±47.04, 57.39±39.14, 55.84±34.97 in serum.

CONCLUSION: Continuous intravenous injection of Mesna is efficient in the prevention of HC in HSCT. Maintaining the Mesna concentration at a certain level in urine or serum is the key factor in reducing the incidence rate of HC significantly.