Extended Infusion of Prophylactic Mesna Along with CTLA4Ig in Post-Transplantation Cyclophosphamide Based-Haploidentical Transplantation Is Associated with Reduced Incidence of BK Viruria and Hemorrhagic Cystitis

Abstract

<h3>Background & Methods</h3> Post-transplantation cyclophosphamide (PTCy)-based HCT has been associated with an increased frequency of hemorrhagic cystitis (HC), dominantly associated with BK viruria. We prospectively evaluated the incidence of BK viruria and HC in 115 patients [(median age 20 years, 2-65), malignant(87) and non-malignant(28)], undergoing PTCy-based haploidentical HCT with CTLA4Ig (n=71) or without (n=44). Conditioning was predominantly myeloablative (74%). As prophylaxis for HC, continuous infusion of Mesna was used from 30 minutes prior to PTCy at 50% of the daily dose of Cy every 8 hourly for 72 hours. Development of HC before day+15 was termed as ‘early HC' and later was referred to as ‘HC'. <h3>Results</h3> The overall incidence of BK viruria was 65.7%. None with BK viruria < 10⁴ copies/ml developed clinical symptoms (n=65). The incidence of BK viruria ≥ 10⁴ copies/ml (‘high BK viruria') was 7.1 % (n=8) and 75% developed HC. The incidence of HC was 5.4 % at a median of 30 days. Only 3.1% (events-2/66) of patients greater than 18 years of age had high BK viruria compared to 12.4% (events-6/49) in those who were younger than 18 years (p=0.05). The overall incidence of grade 2-4 acute GVHD was 16.9% (95%CI, 13.4-20.4). Overall BK viruria was higher in those with acute GVHD (92.1% vs 60.6 in those without acute GVHD, p=0.002, Figure 1A). Acute GVHD preceded the development of high BK viruria in 7 out of 8 patients with a median onset at 22 days (14-36 days). The incidence of high BK viruria in patients with acute GVHD was 36.8% (95% CI 25.7-37.9), compared to 1.1% (95% CI 0.1-2.2) in those without acute GVHD (p=0.0001). The incidence of HC in those with acute GVHD was likewise significantly higher (26.7%; 95%CI, 16.5-36.9 vs 1.1%; 95% CI 0.1-2.2, p=0.0001, Figure 1B). Overall BK viruria was significantly lower in those receiving CTLA4Ig (54.1% vs 89.4% in those without CTLA4Ig, p=0.001, Figure 2A). The incidences of both high BK viruria (4.3% with vs 11.9% without CTLA4Ig, p=0.08) and HC (2.9% with vs 9.5% without CTLA4Ig p=0.09, Figure 2B) tended to be lower in those receiving CTLA4Ig-based protocols. A higher NRM was observed in those with BK viruria ≥ 10⁴ copies/ml, related to GVHD and its complications (41.7% vs 12.6%, p=0.04). <h3>Conclusions</h3> In conclusion, our study demonstrates that extended infusion of Mesna, along with reduction in alloreactivity with the use of CTLA4Ig were probably responsible for a much lower incidence of BK viruria and resultant HC, than previously reported following PTCy-based haploidentical HCT.