Hemorrhagic Cystitis after Allogeneic or Autologous Hematopoietic Cell Transplantation in Pediatric Patients: Continuous Versus Intermittent Mesna

Introduction

Hemorrhagic cystitis (HC) is a complication of hematopoietic cell transplantation (HCT) which may result from conditioning regimens that utilize the alkylating agent cyclophosphamide. Incidence varies by conditioning regimen and other transplant-related factors but HC has been estimated to occur in approximately 15% of pediatric hematopoietic cell transplants. Cyclophosphamide-induced HC is characterized by dysuria, bladder spasms, and hematuria, as a result of urothelial damage from acrolein, a toxic metabolite, and can lead to life-threatening hemorrhage. Preventative strategies include intravenous fluids to increase diuresis and coadministration of sodium 2-mercaptoethanesulfonate (mesna) with cyclophosphamide doses to bind acrolein and prevent urothelial damage. While mesna was historically given as an intermittent infusion 3-5 times a day, new studies have suggested that continuous infusion of mesna may provide more sustained therapeutic levels in the bladder, potentially enhancing its efficacy in the prevention of HC.

Methods

This single center retrospective study (n=333) compared intermittent (n=179) versus continuous infusion (n=154) mesna in pediatric patients age 0-18 who underwent allogeneic or autologous HCT with a cyclophosphamide-containing conditioning or graft-vs-host-disease (GVHD) prophylaxis regimen between 2013 to 2023 to evaluate an institutional change in practice in 2018. The primary endpoint was the incidence of HC at day 100. Secondary endpoints included early onset HC by day 30, CTCAE-graded severity of HC and association of BK virus with cystitis. Additional subgroup analyses compared incidences of HC by mesna administration approach in patients with DNA breakage disorders, such as Fanconi Anemia, and by low- vs high- total cyclophosphamide dose.

Results

Of 333 patients treated with cyclophosphamide-containing conditioning or GVHD prophylaxis regimens, 92% (n=306) were allogeneic HCTs. Median age was 8 years and there were no significant differences between the intermittent and continuous mesna cohorts in age, sex, stem cell source, donor type, or cumulative cyclophosphamide dose. More patients received post-transplant cyclophosphamide for GVHD prophylaxis in the continuous mesna cohort (21%, n=33) than the intermittent mesna cohort (6%, n=10).

Cumulative incidence of HC by day 100 in the study population was 14% (n=48), 11% (n=17) in the continuous mesna cohort compared to 17.3% (n=31) in the intermittent mesna cohort (p=0.11). Severity of HC in the continuous group was favorable compared to intermittent as assessed by CTCAE grading (Grade III-IV HC – 5 (3.2%) in continuous cohort, 11 (6.1%) in intermittent cohort) and evaluation of therapeutic interventions such as catheterization/irrigation, percutaneous nephrostomy tubes or intravenous analgesics. Incidence of coinciding BK viruria or viremia within 2 weeks of HC onset was high and similar in both cohorts – 82% (14/17) of continuous cohort and 74% (23/31) of intermittent cohort.

In subgroups of patients with DNA breakage disorders and those who received cumulative doses >100 mg/kg, the continuous mesna cohorts had lower cumulative incidence of HC at both 30- and 100-days post-transplant, although these differences also did not reach statistical significance. Patients who received doses </=100 mg/kg had similar cumulative incidence of HC at both time points.

Discussion

To date, studies of continuous mesna administration with cyclophosphamide-containing conditioning or GVHD prophylactic regimens are limited to adult populations but have demonstrated significant benefits in reduction of post-HCT hemorrhagic cystitis compared to intermittent administration. Although the primary endpoint did not reach statistical significance, this study suggests that those benefits are also likely true among a broad pediatric HCT population. There appears to be particular benefit among patients with DNA breakage disorders such as Fanconi Anemia and in patients receiving cumulative cyclophosphamide doses >100mg/kg.