Cidofovir Treatmenf For Hemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplantation For High Risk Hematological Malignancies
Authors: Crucitti Lara , Carrabba Matteo , Marktel Sarah , Assanelli Andrea , Salonia Andrea , Greco Raffaella , Vago Luca , Lorentino Francesca , Stanghellini Maria Teresa Lupo , Bernardi Massimo , Corti Consuelo , Peccatori Jacopo , Ciceri Fabio 
Published: October 2019

Background
Hemorrhagic cystitis (HC) is a common cause of morbidity after allogeneic stem cell transplantation (allo-SCT), and symptoms vary from asymptomatic microscopic to frank hematuria with clot formation and urinary tract obstruction. Multiple factors including toxicity of chemo-radiotherapy, BK virus reactivation seems to be involved a in post-transplant HC, nevertheless effective risk factors and treatments of this complication are currently unknown and unresolved. Cidofovir (CDV) is an acyclic nucleoside analogue with a broad range of antiviral activity, including BK virus and thus it has been proposed as treatment for HC after allo-SCT.

Methods
In this study we retrospectively evaluated 59 consecutive adult patients (median age 45 years) who received CDV for HC after allo-SCT from January 2008 to December 2012 at San Raffaele Hospital. All patients were affected by high risk hematologic malignancies and 39 had active disease at time of transplant. Donors were HLA identical sibling (n=8), family mismatched (n=39), unrelated volunteer (n=11), cord blood (n=1). All patients received a fully myeloablative conditioning regimen, infusion of donor T cells, 25 patients (43%) received also Total Body Irradiation (4 Gray) and in 51 cases (86%) was administered anti-thymocyte globulin as part of the conditioning regimen. BK viral load was determined on urine by TaqMan PCR. CDV was administered at the dose of 5mg/kg/week intravenously (i.v.) in 41 patients and intravescically in 21 patients (4 double treatments). The median dose number of CDV doses was 2 (range 1 to 8). The intravescically route was adopted in case of pending renal insufficiency or impossibility to interrupt intravenous antiviral for concomitant viral reactivations.

Results
HC occurred in median 14 days after allo-SCT (range -4 to 330). Median duration of symptoms was 34 days (range 6 to 166). At treatment onset 13 patients had grade 0-I HC, 13 grade II, 24 grade III and 9 grade IV. In 55 cases (93%) high BK viral load was detected in urine (BK virus median load 10^7 cp/ml) before treatment. After treatment the reduction of BK viruria was documented in 29 out of 33 evaluable cases (87%), with a 1-log reduction of BK viruria median load (p=0.004). Improvement of HC grade was observed in 41 patients (70%) and a complete clinical response within 7 days from last CDV dose was observed in 30 cases (51%). Worsening of HC leading to urological intervention occurred in 5 treated patients. Four patients died with an ongoing uncontrolled HC: 2 of acute Graft-versus Host Disease, 1 of pneumonia and 1 of relapse. During i.v. CDV treatment 22 out of 41 patients (54%) had a viral reactivation (Cytomegalovirus n=14, Epstein-Barr Virus n=8, Herpes Simplex-1 n=3, Herpes Simplex-6 n=4) and 2 patients developed acute renal failure requiring drug discontinuation.

Conclusions
CDV treatment after allo-SCT is associated with a reduction of BK viruria load and HC clinical responses in more than half of cases. This is in agreement with data reported in other retrospective trials. Viral reactivations under CDV treatment should be better investigated in the allo-setting, since the long-half life of the drug and its potential nephrotoxicity limits the possibility of concomitant antiviral therapy with other agents. Our data warrant prospective trials to investigate the role of CDV in allo-SCT.

Disclosures:
Off Label Use: Cidofovir is an acyclic nucleoside analogue with a broad range of antiviral activity, including BK virus and thus it has been proposed as treatment for hemorrhagic cystitis after Allogeneic Stem Cell Transplantation.