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Efficacy of Cidofovir in Treatment of BK Virus–Induced Hemorrhagic Cystitis in Allogeneic Hematopoietic Cell Transplant Recipients
Accepted Manuscript Title: Efficacy of Cidofovir in Treatment of BK Virus Induced Hemorrhagic Cystitis in Post Allogeneic Hematopoietic Cell Transplant Recipients Author: Eric A. Coomes, Amanda (Jacques) Wolfe, Fotios V. Michelis, Dennis (Dong-Hwong) Kim, Santhosh Thyagu, Auro Viswabandya, Jeffrey H. Lipton, Hans A. Messner, Uday Deotare PII: DOI: Reference:
S1083-8791(18)30190-3 https://doi.org/10.1016/j.bbmt.2018.04.009 YBBMT 55094
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
3-3-2018 10-4-2018
Please cite this article as: Eric A. Coomes, Amanda (Jacques) Wolfe, Fotios V. Michelis, Dennis (Dong-Hwong) Kim, Santhosh Thyagu, Auro Viswabandya, Jeffrey H. Lipton, Hans A. Messner, Uday Deotare, Efficacy of Cidofovir in Treatment of BK Virus Induced Hemorrhagic Cystitis in Post Allogeneic Hematopoietic Cell Transplant Recipients, Biology of Blood and Marrow Transplantation (2018), https://doi.org/10.1016/j.bbmt.2018.04.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Article Type: Regular Manuscript
Title: Efficacy of Cidofovir in Treatment of BK Virus Induced Hemorrhagic Cystitis in Post Allogeneic Hematopoietic Cell Transplant Recipients Eric A. Coomes1 M.D.; Amanda Wolfe (Jacques)2 BScPharm, RPh, ACPR; Fotios V. Michelis3 M.D. Ph.D.; Dennis (Dong-Hwong) Kim3 M.D., Ph.D.; Santhosh Thyagu3 MBBS, M.D., DNB, D.M.; Auro Viswabandya3 M.D., D.M.; Jeffrey H. Lipton3 M.D., Ph.D.; Hans A. Messner3 M.D., Ulm, Ph.D.; Uday Deotare4 MBBS, M.D., D.M. 1
Department of Medicine, University of Toronto, Toronto, ON, Canada Department of Pharmacy, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 3 Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 4 Division of Hematology, Department of Medicine, London Health Sciences Centre, London, Canada 2
Corresponding Author: Eric A. Coomes, MD Department of Medicine Suite RFE 3-805 200 Elizabeth Street Toronto, Ontario Canada M5G 2C4 Email: [email protected] Telephone: 647-289-3368 Running Title: Cidofovir for BK Hemorrhagic Cystitis Keywords: BK Virus, Cidofovir, Hemorrhagic Cystitis, Allogeneic Hematopoietic Transplant Word Count: 2703 (excluding title page, abstract, tables, references) Word Count Abstract: 264 Word Count Total: 4158 Tables: 2 Conflicts of Interest: The authors declare no conflict of interest. Sources of Funding: No funding was obtained specifically for this article. Contributions: Eric Coomes and Amanda Wolfe extracted the retrospective case series. Eric Coomes and Uday Deotare performed the literature search. All authors collaborated to write the manuscript and revised it critically for important intellectual content. 1
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HIGHLIGHTS
Twelve transplant recipients received cidofovir for BK virus hemorrhagic cystitis Mean hemorrhagic cystitis severity decreased significantly after cidofovir Two-thirds achieved partial response, similar between intravenous and intravesical One-third experienced renal toxicity, including two receiving intravesical therapy
ABSTRACT
Background: BK virus associated hemorrhagic cystitis (BK-HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HCT), with incidence up to 70%. Cidofovir is an antiviral agent with growing evidence as a therapeutic intervention. Objective: To assess the safety profile and efficacy of intravenous and intravesical cidofovir in allo-HCT patients with BK-HC. Methods: Retrospective study of the allo-HCT cohort who received cidofovir for symptomatic BK-HC (hematuria with BK viruria or viremia) from January 2010 until March 2017 in a single transplant center in Ontario, Canada. The primary outcome measure was a reduction in BK-HC severity (graded from 1-4); secondary outcomes included overall survival, BK virus titers, and the onset of acute kidney injury. Results: Twelve allo-HCT patients received cidofovir for BK-HC, with pre-treatment clinical severity of 3 (50%) or 4 (50%). Cidofovir was administered via intravenous (33%), intravesical (58%), or both modalities (8%). After a median cumulative dose of 10 mg/kg (1-37 mg/kg), mean BK-HC grade decreased significantly by 1.8 [3.5 pre-cidofovir, 1.7 post-cidofovir, p<0.01]. 66% of patients had at least partial response to cidofovir, with similar response rates
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between intravenous (66%) and intravesical (62%) administration. 67% of patients died, and 33% of patients experienced renal toxicity, including two patients receiving intravesical therapy. Conclusion: In this retrospective series, there was a significant reduction in BK-HC severity after cidofovir administration; the majority of patients achieved at least partial response after cidofovir administration. Even with intravesical instillation, acute kidney injury remains a potential complication of cidofovir. While cidofovir may be an efficacious therapy for BK-HC, albeit with potential demonstrated toxicities, further prospective trials are needed. INTRODUCTION While allogeneic hematopoietic stem cell transplantation is potentially curative for numerous malignant and non-malignant conditions, downstream complications, including infectious diseases, are associated with high morbidity and mortality. BK virus is a nonencapsulated DNA human polyomavirus with high prevalence in healthy adults, with up to 90% seropositivity.1 Polyomavirus can persist latently in the kidneys and urothelium, reactivating once immunosuppressed.1 BK virus associated hemorrhagic cystitis (BK-HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HCT), with features including hematuria, dysuria, and classical lower urinary tract symptoms (frequency, urgency, hesitancy).2 Among bone marrow transplant recipients, BK virus (BKV) replication can be identified in over 50% of patients, with the incidence of BK-HC ranging from 7% to 70% in various reports.3,4 BKHC may cause significant morbidity and prolonged hospital stays, with severe hematuria in 8% to 27% of allo-HCT patients.5 Development of BK-HC is associated with factors related to transplant procedure (myeloablative conditioning regimen), graft source (unrelated donor, cord
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blood unit transplantation, HLA mismatching), onset of acute graft-versus-host disease, and high-level urinary BK viral replication.3,6-9 Supportive measures (bladder irrigation, blood transfusion, and symptomatic therapy) have been the standard of care for many years for this difficult-to-treat complication. Several alternative treatments have been tried, including ganciclovir, leflunomide, long-term ciprofloxacin, and hyperbaric oxygen therapy.10 Studies suggest that cidofovir could be a therapeutic alternative in BK-HC.11-15 Cidofovir is a cytosine nucleotide analog with activity against various DNA viruses, including herpesviruses and polyomaviruses.16 Cidofovir may be administered intravenously but is associated with potential nephrotoxicity. Intravesical administration has been employed to limit systemic toxicity.13,17,18 The aim of the present retrospective study is to assess the safety profile and efficacy of intravenous and intravesical cidofovir in allo-HCT patients with BK-HC.
METHODS Study Design Retrospective study of the patient cohort who underwent allo-HCT and received cidofovir as treatment for BK-HC between January 1, 2010 and March 30, 2017 in a single center in Ontario, Canada. Cidofovir was administered after patient-specific approval from the Health Canada Exceptional Access Program for its use. This study was approved by the institutional Research Ethics Board. Patients
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Patients who received at least one dose of cidofovir were identified using the pharmacy informatics database. Inclusion criteria included receipt of allo-HCT, symptomatic BK-HC, and treatment with at least one dosage of cidofovir. Symptomatic BK-HC was defined as hematuria with BK viruria or viremia. All eligible patients were included in the analysis. Patients with receipt of cidofovir for indications other than BK-HC were excluded. Data Acquisition Electronic chart records of eligible patients were reviewed for demographic, diagnostic and treatment information. Baseline data was collected for each patient: patient related (age, gender, Karnofsky Performance Score, Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI), creatinine), disease related (indication for transplant, time to development of BK-HC, grade of BK-HC, BK virus titers in blood and urine), transplant related (conditioning regimen, total body irradiation, donor type, cytomegalovirus (CMV) status of donor and recipient, ABO incompatibility, source of hematopoietic cells, date of transplant, graft versus host disease (GVHD) prophylaxis regimen, receipt of serotherapy, GVHD grade, and Epstein-Barr Virus (EBV) reactivation. Using the pharmacy informatics database, cidofovir prescription data was collected: dose, route of administration, number of doses, and duration). Outcome data, including response to therapy, overall survival, renal function, adverse events, and cause of death (if applicable), were collected from electronic chart records. Grading of BK-HC severity was performed as per Bedi et al:19 Grade 1 – microscopic hematuria on more than 2 consecutive days, Grade 2 – macroscopic hematuria, Grade 3 – macroscopic hematuria with clots, Grade 4 – macroscopic hematuria with clots and impaired renal function secondary to tract obstruction. 5
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Clinically efficacy was assessed at the end of cidofovir treatment as: complete response (CR): full symptom resolution, partial response (PR): downgrading BK-HC severity with ongoing symptoms, no response (NR): unchanged or worsened clinical status. Efficacy was assessed at follow-up within 1-month after the final dose of cidofovir. Renal toxicity was assessed by an increase in serum creatinine > 30 µmol/L from before the first dose and after the last dose of cidofovir. Dosage reductions due to renal toxicity were recorded. The primary outcome was response to cidofovir, as defined by partial or complete response. Secondary outcomes included overall survival, BK virus levels (both urine and blood), and renal toxicity. Statistical Methods Descriptive data were tabulated as percentages for categorical data and as medians with ranges for continuous data. The paired student’s t-test was used to examine the mean BK-HC grade, BK viremia, and BK viruria, and serum creatinine before and after cidofovir administration; these data were reported as mean with standard deviation. Significance was defined as a two-tailed p<0.05. Analyses were performed using Microsoft Excel 2016 (version 1801). Literature Review A systematic literature review was performed using EMBASE, OVID, and PubMed using the keywords “BK virus” or “Polyomavirus” and “Hemorrhagic Cystitis” or “Cystitis” and “Cidofovir.” Articles were included if they involved post allo-HCT patients with BK-HC treated with intravenous or intravesicular cidofovir. The last search was performed on June 21, 2017.
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The following information was collected: grade of BK-HC, treatment prescribed, cidofovir prescription, rate of CR, and toxicities.
RESULTS Patient characteristics Twelve allo-HCT patients with BK-HC were treated with cidofovir from January 1, 2010 until March 30, 2017. The patient characteristics are summarized in Table 1. The median age was 49 (range 28-59), and 50% of patients were female. Prior to transplantation, the patients had a median Karnofsky performance score 90 (range 70-100) and median HCT-CI of 1 (range 0-5). The underlying hematologic diseases were mostly malignant (83%) with two nonmalignant conditions, myelofibrosis (n=1) and aplastic anemia (n=1). Of patients with a malignant diagnosis, 80% were in complete remission (n=8) at the time of transplant while two had failed to achieve remission. Regarding the transplant, the majority were from matched related donors (58%) with 10/10 or 6/6 HLA (83%). The conditioning regimens were primarily myeloablative (92%). 7
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The post-transplant course was often complicated by GVHD (67%) and CMV viremia (58%). Concomitant with BK viruria, three patients had adenovirus viruria, two patients had EBV viremia, and one patient had bacteriuria. BK-Hemorrhagic Cystitis The median time from allo-HCT to BK-HC was 81.5 days (range 23-762 days), which was later in onset as compared to other BK-HC cohort studies.8,11 Clinical BK-HC grade at start of treatment was of median 3.5 (range 3-4). At the time of BK-HC diagnosis, all patients had BK viruria, while BK viremia was positive in 83%.
Cidofovir Treatment Intravenous cidofovir was used in four cases (33%), intravesical in seven cases (58%), and both modalities in one patient (8%). Median dose of cidofovir was 5 mg/kg per administration (range 1-5 mg/kg); median 1 mg/kg for intravenous administration (range 1-5 mg/kg) and median 5 mg/kg for intravesical administration (range 2.5-5 mg/kg). Median cumulative dose was 10 mg/kg (range 1-37 mg/kg). Median doses received was two [range 121]; four patients achieved complete response after less than or equal to two doses, and three patients received less than or equal to three doses due to lack of response and clinical deterioration to death. One patient had a dose reduction during therapy due to progressive renal dysfunction. 80% of patients treated with IV cidofovir received probenecid concomitantly, in contrast to 0% of patients treated with intravesical cidofovir. Most patients received therapies prior to cidofovir, ciprofloxacin (75%) or leflunomide (17%). Cidofovir treatment and BK-HC outcomes are summarized in Table 2. 8
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Outcome Mean BK-HC grade decreased significantly by 1.8 [3.5 pre-cidofovir (n=12), 1.7 postcidofovir (n=12), p<0.01]. Two-thirds of patients had at least partial response; one-third of patients had a complete response, one-third of patients had a partial response, and one-third of patients had no response to therapy. Achievement of at least partial response was similar amongst patients receiving intravenous therapy (66%) and intravesical therapy (62%). Despite cidofovir activity against adenovirus, the overall rates of response to cidofovir were the same between those patients with concomitant adenovirus viruria and those with isolated BK-HC. Overall, 67% (8/12) of patients died over the study period, three from liver failure, two from sepsis, one from ischemic colitis, and one from renal failure. There was no significant reduction in mean BK viruria after cidofovir administration (pre-cidofovir: 6.69*109, SD 1.33*109 v. post-cidofovir: 3.03*109, SD 6.54*109, n = 10, p = 0.41). Similarly, there was no significant reduction in mean BK viremia after cidofovir administration (pre-cidofovir: 5.79*103, SD 7.17*103 v. post-cidofovir: 1.52*105, SD 3.52*105, n = 7, p = 0.32); the trend to increase in mean BK viremia after cidofovir was primarily driven by one patient with a discordant > 103 percent increase in viremia. Comparing change in viremia and clinical response, 71% of patients had a concordant decrease in viremia with clinical response after cidofovir. Only 50% of patients had a concordant decrease in viruria with clinical response after cidofovir. Two patients relapsed after an initial response. Patient #9 had a relapse from grade 1 to grade 2 BK-HC within 9 days from discharge from cidofovir admission but died from ischemic colitis prior to receipt of further therapy. Patient #4 had a relapse from complete response to grade 4 BK-HC within 27 days from discharge from cidofovir admission. They were re-admitted 9
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to hospital with grade 4 BK-HC, worsening liver GVHD, and CMV re-activation. They were treated with increased immunosuppression, valganciclovir, and a second higher dose of cidofovir at 5 mg/kg, but soon thereafter died from RSV pneumonia with pseudomonal superinfection. They had no therapeutic response in their BK-HC prior to death. Toxicity Adverse events were experienced by four (33%) patients. Three patients had an increase in creatinine > 30 umol/L – two patients receiving intravesical cidofovir and one patient receiving both intravesical and intravenous cidofovir. Mean serum creatinine had a nonsignificant trend towards increase after cidofovir of 24 µmol/L (n = 12, p = 0.2). Additional complications affected two patients receiving prolonged courses of intravenous cidofovir and one patient receiving intravesical cidofovir. Patient #1 developed keratitis after a cumulative dose of 37 mg/kg over a 12-week period which was deemed to be secondary to cidofovir after ophthalmology assessment. Patient #5 developed progressive renal insufficiency while receiving intravenous cidofovir therapy three times weekly, requiring a dose reduction to once weekly and probenecid was started after the 4th dose. Patient #5 was assessed by nephrology for acute on chronic kidney injury with hyperchloremic non-anion gap metabolic alkalosis and electrolyte derangements and was diagnosed with Fanconi’s syndrome and tubular toxicity from cidofovir. Patient #7 received a single dose of intravesical cidofovir and developed bladder pain and the subsequent day died from overwhelming pseudomonal sepsis.
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Literature Review A total of 16 articles were found that reported the use of cidofovir in post allo-HCT BKHC including a total of 255 patients with various BK-HC grades. A 2016 literature review by Philippe et al.11 reported a retrospective series of 27 cases of allo-HCT BK-HC (eight with grade 1, 13 with grade 2, three with grade 3, three with grade 4) receiving cidofovir for BK-HC, 24 intravenous, one intravesical, and two via both routes with a median dose concentration of 5 mg/kg with a median number of doses of four (range 1 to 11) with a complete response rate of 82%; no patients had received therapy prior to cidofovir. This review additionally identified 13 articles, with a total of 219 patients who had received cidofovir therapy for BK-HC in allo-HCT: 195 via IV, 19 via intravesical, and five via both IV/intravesical. Complete response was observed in 60 to 100% of cases, independent of cidofovir dose and administration route.11,12,15,17,18,20-27 Two further case series on cidofovir for BK-HC have since been published. Sakurada et al.13 reported a retrospective study including three allo-HCT patients with BK-HC (two with grade 2 and one with grade 3) treated cidofovir (two intravesical, one both intravenous and intravesical) with a median dose concentration of 2.6 mg/kg with a median of three doses (range 2-4 doses) with 100% CR rate; two patients had received previous therapy with ciprofloxacin. Two patients receiving intravesical cidofovir experienced irritation.13 The patient receiving intravenous cidofovir developed renal failure requiring hemodialysis, leading to a switch to intravesical therapy.13
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Aitken et al.14 reported a prospective pharmacokinetic and safety study including five post allo-HCT patients with BK-HC treated with single dose of intravesical cidofovir with three patients receiving 5 mg/kg and two patients receiving 2.5 mg/kg, response rate was not assessed. Two patients developed bladder pain and one patient had a greater than 50% rise in serum creatinine.14
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DISCUSSION In this retrospective institutional review, 67% of patients achieved at least partial response and 33% of patients achieved a complete response after cidofovir administration for BK-HC, with similar rates of response with either intravenous or intravesical administration. The rate of complete response is lower than previous case series. Patients in this study had severe Grade 3 or 4 BK-HC and a significant majority of patients in study had failed prior therapy (ciprofloxacin or leflunomide), in contrast to most previous series which included a significant proportion of patients with Grade 1 or 2 BK-HC. As cidofovir is not approved by Health Canada, Exceptional Access Approval is required to use cidofovir in the treatment of our patients. Consequently, supportive treatment or alternative agents are used in our institution for low-grade BK-HC. Cidofovir is reserved for patients with severe or refractory BK-HC, accounting for the high-grade BK-HC patients included in our study. Despite reflecting a subset of patients with severe refractory BK-HC, an overall significant reduction in BK-HC grading was observed after administration of cidofovir. While there was significant clinical improvement, there was no significant change in BK viremia or viruria. Amongst patients with clinical improvement with cidofovir, the majority had a concordant decrease in viremia, but only 50% had a concordant decrease in viruria. Cesaro et al. noted clearance of BK viremia in 81% of patients with complete response but only 20% clearance of BK viruria.12 Gaziev et al. likewise noted persistence of BK viruria after resolution of BK-HC.24 While a significant proportion of post allo-HCT patients develop BK viruria, up to half of these patients do not develop hemorrhagic cystitis.28 The relationship between cidofovir, BK urine viral loads and hemorrhagic cystitis has been inconsistent.28
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Previous BK-HC studies have identified renal toxicity from intravenous administration in 9-50% of cases,11 yet only one case of intravesical cidofovir administration with acute kidney injury has been identified.14 Amongst cases with intravesical instillation complications included bladder spasm and discomfort during instillation.13 In contrast to previous studies, two of three patients with significant acute kidney injury in this study had received intravesical cidofovir. Patient #12, had concurrent CMV colitis, EBV viremia, and Mycobacterium Avium Complex pneumonia and had received additional nephrotoxic therapy with foscarnet. While receiving intravesical cidofovir, the patient developed progressive pneumonia and bilateral hydronephrosis with no BK-HC response. Treatment was discontinued to allow for palliation. While the renal dysfunction coincided with the timing of intravesicular cidofovir, the renal dysfunction may have been secondary to progressive grade 4 BK cystitis and multi-organ dysfunction in the context of progressive pneumo-sepsis. Patient #7 received intravesical cidofovir followed by bladder pain and subsequent development of fatal septic shock within 24 hours secondary to Pseudomonas. While renal dysfunction closely followed intravesical instillation, a more plausible etiology for the renal dysfunction is secondary to sepsis rather than a direct nephrotoxic effect of the intravesical administration. Notwithstanding, this is an essential toxicity to highlight – if this patient had an unrecognized Pseudomonas bacteriuria and a friable urothelium secondary to BK cystitis, might have the intravesical administration promoted the development of bacteremia? Avoidance of renal toxicity is often purported as a benefit of intravesical instillation, but the possibility of systemic toxicity persists.
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Limitations While cidofovir appears to be efficacious, limitations of this study include retrospective study design, sample size, lack of control, and heterogeneous patient characteristics and treatment, preventing confirmatory demonstration that cidofovir induced BK-HC response.
CONCLUSION In this retrospective series, there was a significant reduction in BK-HC severity after cidofovir administration, with the majority of patients achieving at least partial response after cidofovir administration. Similar response rates were seen with intravenous and intravesical therapy. However, even with intravesical instillation, acute kidney injury remains a potential complication of cidofovir. The precise role of cidofovir in BK-HC management, the severity at which to intervene, and the optimal route and dosing protocol remain to be defined. Further prospective randomized controlled trials are needed.
REFERENCES 1. Bennett SM, Broekema NM, Imperiale MJ. BK polyomavirus: Emerging pathogen. Microbes Infect. 2012;14(9):672-683.
2. Dropulic LK, Jones RJ. Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplant. 2008;41(1):11-18.
3. Hirsch HH. BK virus: Opportunity makes a pathogen. Clin Infect Dis. 2005;41(3):354-360.
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4. Shakiba E, Yaghobi R, Ramzi M. Prevalence of viral infections and hemorrhagic cystitis in hematopoietic stem cell transplant recipients. Exp Clin Transplant. 2011;9(6):405-412.
5. Cesaro S, Facchin C, Tridello G, et al. A prospective study of BK-virus-associated haemorrhagic cystitis in paediatric patients undergoing allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant. 2008;41(4):363-370.
6. El-Zimaity M, Saliba R, Chan K, et al. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: Donor type matters. Blood. 2004;103(12):4674-4680.
7. Rorije NM, Shea MM, Satyanarayana G, et al. BK virus disease after allogeneic stem cell transplantation: A cohort analysis. Biol Blood Marrow Transplant. 2014;20(4):564-570.
8. Uhm J, Hamad N, Michelis FV, et al. The risk of polyomavirus BK-associated hemorrhagic cystitis after allogeneic hematopoietic SCT is associated with myeloablative conditioning, CMV viremia and severe acute GVHD. Bone Marrow Transplant. 2014;49(12):1528-1534.
9. Gilis L, Morisset S, Billaud G, et al. High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2014;49(5):664-670.
10. Harkensee C, Vasdev N, Gennery AR, Willetts IE, Taylor C. Prevention and management of BK-virus associated haemorrhagic cystitis in children following haematopoietic stem cell transplantation--a systematic review and evidence-based guidance for clinical management. Br J Haematol. 2008;142(5):717-731.
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11. Philippe M, Ranchon F, Gilis L, et al. Cidofovir in the treatment of BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22(4):723-730.
12. Cesaro S, Hirsch HH, Faraci M, et al. Cidofovir for BK virus-associated hemorrhagic cystitis: A retrospective study. Clin Infect Dis. 2009;49(2):233-240.
13. Sakurada M, Kondo T, Umeda M, Kawabata H, Yamashita K, Takaori-Kondo A. Successful treatment with intravesical cidofovir for virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: A case report and a review of the literature. J Infect Chemother. 2016;22(7):495-500.
14. Aitken SL, Zhou J, Ghantoji SS, et al. Pharmacokinetics and safety of intravesicular cidofovir in allogeneic HSCT recipients. J Antimicrob Chemother. 2016;71(3):727-730.
15. Ganguly N, Clough LA, Dubois LK, et al. Low-dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: A retrospective analysis of an algorithmic approach. Transpl Infect Dis. 2010;12(5):406-411.
16. Snoeck R, De Clercq E. Role of cidofovir in the treatment of DNA virus infections, other than CMV infections, in immunocompromised patients. Curr Opin Investig Drugs. 2002;3(11):1561-1566.
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17. Bridges B, Donegan S, Badros A. Cidofovir bladder instillation for the treatment of BK hemorrhagic cystitis after allogeneic stem cell transplantation. Am J Hematol. 2006;81(7):535537.
18. Rascon J, Verkauskas G, Pasauliene R, Zubka V, Bilius V, Rageliene L. Intravesical cidofovir to treat BK virus-associated hemorrhagic cystitis in children after hematopoietic stem cell transplantation. Pediatr Transplant. 2015;19(4):E111-4.
19. Bedi A, Miller CB, Hanson JL, et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol. 1995;13(5):1103-1109.
20. Gorczynska E, Turkiewicz D, Rybka K, et al. Incidence, clinical outcome, and management of virus-induced hemorrhagic cystitis in children and adolescents after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2005;11(10):797-804.
21. Savona MR, Newton D, Frame D, Levine JE, Mineishi S, Kaul DR. Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant. Bone Marrow Transplant. 2007;39(12):783-787.
22. Faraci M, Cuzzubbo D, Lanino E, et al. Low dosage cidofovir without probenecid as treatment for BK virus hamorrhagic cystitis after hemopoietic stem cell transplant. Pediatr Infect Dis J. 2009;28(1):55-57.
23. Rao KV, Buie LW, Shea T, et al. Intravesicular cidofovir for the management of BK virusassociated cystitis. Biol Blood Marrow Transplant. 2009;15(3):391-392. 18
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24. Gaziev J, Paba P, Miano R, et al. Late-onset hemorrhagic cystitis in children after hematopoietic stem cell transplantation for thalassemia and sickle cell anemia: A prospective evaluation of polyoma (BK) virus infection and treatment with cidofovir. Biol Blood Marrow Transplant. 2010;16(5):662-671.
25. Koskenvuo M, Dumoulin A, Lautenschlager I, et al. BK polyomavirus-associated hemorrhagic cystitis among pediatric allogeneic bone marrow transplant recipients: Treatment response and evidence for nosocomial transmission. J Clin Virol. 2013;56(1):77-81.
26. Kwon HJ, Kang JH, Lee JW, Chung NG, Kim HK, Cho B. Treatment of BK virus-associated hemorrhagic cystitis in pediatric hematopoietic stem cell transplant recipients with cidofovir: A single-center experience. Transpl Infect Dis. 2013;15(6):569-574.
27. Gilis L, Morisset S, Billaud G, et al. High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2014;49(5):664-670.
28. Mackey MC. Intravesicular cidofovir for the treatment of polyomavirus-associated hemorrhagic cystitis. Ann Pharmacother. 2012;46(3):442-446.
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Table 1: Patient and Transplant Characteristics, n=12 Age, median years [range] Gender, no. (%) Diagnosis, no. (%)
HLA Match, no. (%)
ABO Mismatch, no. (%)
Karnofsky Performance Score, median [range] HCT-CI, median [range] CMV (Donor / Recipient), no. (%)
Conditioning Regimen, no. (%)
Serotherapy, no. (%) Total Body Irradiation, no. (%) Stem Cell Source, no. (%) GVHD, no. (%) GVHD Grade, no. (%)
Adenovirus viruria, no (%) CMV viremia, no. (%) EBV viremia, no. (%) Bacteriuria, no (%) Percent chimerism at 60+ days post alloHCT, median [range] Time to BK-HC, median days [range]
49 (28-59) Male – 6 (50%) Female – 6 (50%) Acute Myeloid Leukemia – 8 (67%) Acute Lymphoblastic Leukemia – 1 (8%) Mantle Cell Lymphoma – 1 (8%) Myelofibrosis – 1 (8%) Aplastic Anemia – 1 (8) 10/10 – 7 (58%) 6/6 – 3 (25%) 9/10 – 2 (17%) Major – 1 (8%) Minor – 5 (42%) Bidirectional – 1 (8%) None – 4 (33%) Unknown – 1 (8%) 90 (Range 70-100) 1 (0-5) +/+ – 9 (75%) +/- – 1 (8%) -/+ – 1 (8%) -/- – 1 (8%) Fludarabine / Busulfan / TBI – 8 (67%) TBI / Cyclophosphamide – 2 (17%) Busulfan / Cyclophosphamide – 1 (8%) Fludarabine / Cyclophosphamide – 1 (8%) 5 (42%) 10 (83%) Peripheral Blood - 11 (92%) Bone Marrow – 1 (8%) GVHD – 8 (67%) Grade 4 – 3 (25%) Grade 3 – 3 (25%) Grade 2 – 1 (8%) Grade 1 – 1 (8%) 3 (25%) 7 (58%) 2 (17%) 1 (8%) 97.9% (Range 84.6-99.2) 81.5 (23-762) 20
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Table 2: BK-HC Treatment, Response, and Toxicity Treatment Cidofovir route, no. (%)
Dose of cidofovir, median mg/kg [range] Cumulative dose of cidofovir, median mg/kg [range] No. cidofovir injections per patient, median [range] Prior BK-HC Treatment, no (%)
Response BK Titer Urine, mean copies/mL [SD] BK Titer Blood, mean copies/mL [SD] BK Blood post-CDV: Grade of BK-HC, mean score (SD) Response, no. (%) [n=12]
Death, no (%) [n=12]
Toxicity Serum creatinine, mean µmol/L [SD] [n=12] Increased creatinine > 30umol/L, no. (%)
n=12 Intravenous only: 4 Intravesical only: 7 Both: 1 5 [1,5] 10 [1-37] IV 2 [1-21] Intravesical 2 [1-4] Ciprofloxacin: 9 (75%) Leflunomide: 2 (17%) None: 3 (25%) Pre-CDV (n=12): 6.10*109 [1.72*1010] Post-CDV (n=10): 3.03*109 [6.2E*109] Pre-CDV (n=12): 3.28*106 [1.13*107] Post-CDV (n=7): 1.52*105 [3.52*105] Pre-CDV (n=12): 3.5 [0.5] Post-CDV (n=12): 1.7 [1.7] PR or greater: 8 (67%) CR: 4 (33%) PR: 4 (33%) NR: 4 (33%) All cause: 8 (67%) Liver failure: 3 (25%) Sepsis: 2 (17%) Ischemic Colitis: 1 (8%) Renal Failure: 1 (8%) Unspecified: 1 (8%) Pre-CDV: 77 [37] Post-CDV: 101 [67] 3 (25%)
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S1083-8791(18)30190-3 https://doi.org/10.1016/j.bbmt.2018.04.009 YBBMT 55094
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
3-3-2018 10-4-2018
Please cite this article as: Eric A. Coomes, Amanda (Jacques) Wolfe, Fotios V. Michelis, Dennis (Dong-Hwong) Kim, Santhosh Thyagu, Auro Viswabandya, Jeffrey H. Lipton, Hans A. Messner, Uday Deotare, Efficacy of Cidofovir in Treatment of BK Virus Induced Hemorrhagic Cystitis in Post Allogeneic Hematopoietic Cell Transplant Recipients, Biology of Blood and Marrow Transplantation (2018), https://doi.org/10.1016/j.bbmt.2018.04.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Article Type: Regular Manuscript
Title: Efficacy of Cidofovir in Treatment of BK Virus Induced Hemorrhagic Cystitis in Post Allogeneic Hematopoietic Cell Transplant Recipients Eric A. Coomes1 M.D.; Amanda Wolfe (Jacques)2 BScPharm, RPh, ACPR; Fotios V. Michelis3 M.D. Ph.D.; Dennis (Dong-Hwong) Kim3 M.D., Ph.D.; Santhosh Thyagu3 MBBS, M.D., DNB, D.M.; Auro Viswabandya3 M.D., D.M.; Jeffrey H. Lipton3 M.D., Ph.D.; Hans A. Messner3 M.D., Ulm, Ph.D.; Uday Deotare4 MBBS, M.D., D.M. 1
Department of Medicine, University of Toronto, Toronto, ON, Canada Department of Pharmacy, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 3 Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 4 Division of Hematology, Department of Medicine, London Health Sciences Centre, London, Canada 2
Corresponding Author: Eric A. Coomes, MD Department of Medicine Suite RFE 3-805 200 Elizabeth Street Toronto, Ontario Canada M5G 2C4 Email: [email protected] Telephone: 647-289-3368 Running Title: Cidofovir for BK Hemorrhagic Cystitis Keywords: BK Virus, Cidofovir, Hemorrhagic Cystitis, Allogeneic Hematopoietic Transplant Word Count: 2703 (excluding title page, abstract, tables, references) Word Count Abstract: 264 Word Count Total: 4158 Tables: 2 Conflicts of Interest: The authors declare no conflict of interest. Sources of Funding: No funding was obtained specifically for this article. Contributions: Eric Coomes and Amanda Wolfe extracted the retrospective case series. Eric Coomes and Uday Deotare performed the literature search. All authors collaborated to write the manuscript and revised it critically for important intellectual content. 1
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HIGHLIGHTS
Twelve transplant recipients received cidofovir for BK virus hemorrhagic cystitis Mean hemorrhagic cystitis severity decreased significantly after cidofovir Two-thirds achieved partial response, similar between intravenous and intravesical One-third experienced renal toxicity, including two receiving intravesical therapy
ABSTRACT
Background: BK virus associated hemorrhagic cystitis (BK-HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HCT), with incidence up to 70%. Cidofovir is an antiviral agent with growing evidence as a therapeutic intervention. Objective: To assess the safety profile and efficacy of intravenous and intravesical cidofovir in allo-HCT patients with BK-HC. Methods: Retrospective study of the allo-HCT cohort who received cidofovir for symptomatic BK-HC (hematuria with BK viruria or viremia) from January 2010 until March 2017 in a single transplant center in Ontario, Canada. The primary outcome measure was a reduction in BK-HC severity (graded from 1-4); secondary outcomes included overall survival, BK virus titers, and the onset of acute kidney injury. Results: Twelve allo-HCT patients received cidofovir for BK-HC, with pre-treatment clinical severity of 3 (50%) or 4 (50%). Cidofovir was administered via intravenous (33%), intravesical (58%), or both modalities (8%). After a median cumulative dose of 10 mg/kg (1-37 mg/kg), mean BK-HC grade decreased significantly by 1.8 [3.5 pre-cidofovir, 1.7 post-cidofovir, p<0.01]. 66% of patients had at least partial response to cidofovir, with similar response rates
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between intravenous (66%) and intravesical (62%) administration. 67% of patients died, and 33% of patients experienced renal toxicity, including two patients receiving intravesical therapy. Conclusion: In this retrospective series, there was a significant reduction in BK-HC severity after cidofovir administration; the majority of patients achieved at least partial response after cidofovir administration. Even with intravesical instillation, acute kidney injury remains a potential complication of cidofovir. While cidofovir may be an efficacious therapy for BK-HC, albeit with potential demonstrated toxicities, further prospective trials are needed. INTRODUCTION While allogeneic hematopoietic stem cell transplantation is potentially curative for numerous malignant and non-malignant conditions, downstream complications, including infectious diseases, are associated with high morbidity and mortality. BK virus is a nonencapsulated DNA human polyomavirus with high prevalence in healthy adults, with up to 90% seropositivity.1 Polyomavirus can persist latently in the kidneys and urothelium, reactivating once immunosuppressed.1 BK virus associated hemorrhagic cystitis (BK-HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HCT), with features including hematuria, dysuria, and classical lower urinary tract symptoms (frequency, urgency, hesitancy).2 Among bone marrow transplant recipients, BK virus (BKV) replication can be identified in over 50% of patients, with the incidence of BK-HC ranging from 7% to 70% in various reports.3,4 BKHC may cause significant morbidity and prolonged hospital stays, with severe hematuria in 8% to 27% of allo-HCT patients.5 Development of BK-HC is associated with factors related to transplant procedure (myeloablative conditioning regimen), graft source (unrelated donor, cord
3
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blood unit transplantation, HLA mismatching), onset of acute graft-versus-host disease, and high-level urinary BK viral replication.3,6-9 Supportive measures (bladder irrigation, blood transfusion, and symptomatic therapy) have been the standard of care for many years for this difficult-to-treat complication. Several alternative treatments have been tried, including ganciclovir, leflunomide, long-term ciprofloxacin, and hyperbaric oxygen therapy.10 Studies suggest that cidofovir could be a therapeutic alternative in BK-HC.11-15 Cidofovir is a cytosine nucleotide analog with activity against various DNA viruses, including herpesviruses and polyomaviruses.16 Cidofovir may be administered intravenously but is associated with potential nephrotoxicity. Intravesical administration has been employed to limit systemic toxicity.13,17,18 The aim of the present retrospective study is to assess the safety profile and efficacy of intravenous and intravesical cidofovir in allo-HCT patients with BK-HC.
METHODS Study Design Retrospective study of the patient cohort who underwent allo-HCT and received cidofovir as treatment for BK-HC between January 1, 2010 and March 30, 2017 in a single center in Ontario, Canada. Cidofovir was administered after patient-specific approval from the Health Canada Exceptional Access Program for its use. This study was approved by the institutional Research Ethics Board. Patients
4
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Patients who received at least one dose of cidofovir were identified using the pharmacy informatics database. Inclusion criteria included receipt of allo-HCT, symptomatic BK-HC, and treatment with at least one dosage of cidofovir. Symptomatic BK-HC was defined as hematuria with BK viruria or viremia. All eligible patients were included in the analysis. Patients with receipt of cidofovir for indications other than BK-HC were excluded. Data Acquisition Electronic chart records of eligible patients were reviewed for demographic, diagnostic and treatment information. Baseline data was collected for each patient: patient related (age, gender, Karnofsky Performance Score, Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI), creatinine), disease related (indication for transplant, time to development of BK-HC, grade of BK-HC, BK virus titers in blood and urine), transplant related (conditioning regimen, total body irradiation, donor type, cytomegalovirus (CMV) status of donor and recipient, ABO incompatibility, source of hematopoietic cells, date of transplant, graft versus host disease (GVHD) prophylaxis regimen, receipt of serotherapy, GVHD grade, and Epstein-Barr Virus (EBV) reactivation. Using the pharmacy informatics database, cidofovir prescription data was collected: dose, route of administration, number of doses, and duration). Outcome data, including response to therapy, overall survival, renal function, adverse events, and cause of death (if applicable), were collected from electronic chart records. Grading of BK-HC severity was performed as per Bedi et al:19 Grade 1 – microscopic hematuria on more than 2 consecutive days, Grade 2 – macroscopic hematuria, Grade 3 – macroscopic hematuria with clots, Grade 4 – macroscopic hematuria with clots and impaired renal function secondary to tract obstruction. 5
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Clinically efficacy was assessed at the end of cidofovir treatment as: complete response (CR): full symptom resolution, partial response (PR): downgrading BK-HC severity with ongoing symptoms, no response (NR): unchanged or worsened clinical status. Efficacy was assessed at follow-up within 1-month after the final dose of cidofovir. Renal toxicity was assessed by an increase in serum creatinine > 30 µmol/L from before the first dose and after the last dose of cidofovir. Dosage reductions due to renal toxicity were recorded. The primary outcome was response to cidofovir, as defined by partial or complete response. Secondary outcomes included overall survival, BK virus levels (both urine and blood), and renal toxicity. Statistical Methods Descriptive data were tabulated as percentages for categorical data and as medians with ranges for continuous data. The paired student’s t-test was used to examine the mean BK-HC grade, BK viremia, and BK viruria, and serum creatinine before and after cidofovir administration; these data were reported as mean with standard deviation. Significance was defined as a two-tailed p<0.05. Analyses were performed using Microsoft Excel 2016 (version 1801). Literature Review A systematic literature review was performed using EMBASE, OVID, and PubMed using the keywords “BK virus” or “Polyomavirus” and “Hemorrhagic Cystitis” or “Cystitis” and “Cidofovir.” Articles were included if they involved post allo-HCT patients with BK-HC treated with intravenous or intravesicular cidofovir. The last search was performed on June 21, 2017.
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The following information was collected: grade of BK-HC, treatment prescribed, cidofovir prescription, rate of CR, and toxicities.
RESULTS Patient characteristics Twelve allo-HCT patients with BK-HC were treated with cidofovir from January 1, 2010 until March 30, 2017. The patient characteristics are summarized in Table 1. The median age was 49 (range 28-59), and 50% of patients were female. Prior to transplantation, the patients had a median Karnofsky performance score 90 (range 70-100) and median HCT-CI of 1 (range 0-5). The underlying hematologic diseases were mostly malignant (83%) with two nonmalignant conditions, myelofibrosis (n=1) and aplastic anemia (n=1). Of patients with a malignant diagnosis, 80% were in complete remission (n=8) at the time of transplant while two had failed to achieve remission. Regarding the transplant, the majority were from matched related donors (58%) with 10/10 or 6/6 HLA (83%). The conditioning regimens were primarily myeloablative (92%). 7
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The post-transplant course was often complicated by GVHD (67%) and CMV viremia (58%). Concomitant with BK viruria, three patients had adenovirus viruria, two patients had EBV viremia, and one patient had bacteriuria. BK-Hemorrhagic Cystitis The median time from allo-HCT to BK-HC was 81.5 days (range 23-762 days), which was later in onset as compared to other BK-HC cohort studies.8,11 Clinical BK-HC grade at start of treatment was of median 3.5 (range 3-4). At the time of BK-HC diagnosis, all patients had BK viruria, while BK viremia was positive in 83%.
Cidofovir Treatment Intravenous cidofovir was used in four cases (33%), intravesical in seven cases (58%), and both modalities in one patient (8%). Median dose of cidofovir was 5 mg/kg per administration (range 1-5 mg/kg); median 1 mg/kg for intravenous administration (range 1-5 mg/kg) and median 5 mg/kg for intravesical administration (range 2.5-5 mg/kg). Median cumulative dose was 10 mg/kg (range 1-37 mg/kg). Median doses received was two [range 121]; four patients achieved complete response after less than or equal to two doses, and three patients received less than or equal to three doses due to lack of response and clinical deterioration to death. One patient had a dose reduction during therapy due to progressive renal dysfunction. 80% of patients treated with IV cidofovir received probenecid concomitantly, in contrast to 0% of patients treated with intravesical cidofovir. Most patients received therapies prior to cidofovir, ciprofloxacin (75%) or leflunomide (17%). Cidofovir treatment and BK-HC outcomes are summarized in Table 2. 8
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Outcome Mean BK-HC grade decreased significantly by 1.8 [3.5 pre-cidofovir (n=12), 1.7 postcidofovir (n=12), p<0.01]. Two-thirds of patients had at least partial response; one-third of patients had a complete response, one-third of patients had a partial response, and one-third of patients had no response to therapy. Achievement of at least partial response was similar amongst patients receiving intravenous therapy (66%) and intravesical therapy (62%). Despite cidofovir activity against adenovirus, the overall rates of response to cidofovir were the same between those patients with concomitant adenovirus viruria and those with isolated BK-HC. Overall, 67% (8/12) of patients died over the study period, three from liver failure, two from sepsis, one from ischemic colitis, and one from renal failure. There was no significant reduction in mean BK viruria after cidofovir administration (pre-cidofovir: 6.69*109, SD 1.33*109 v. post-cidofovir: 3.03*109, SD 6.54*109, n = 10, p = 0.41). Similarly, there was no significant reduction in mean BK viremia after cidofovir administration (pre-cidofovir: 5.79*103, SD 7.17*103 v. post-cidofovir: 1.52*105, SD 3.52*105, n = 7, p = 0.32); the trend to increase in mean BK viremia after cidofovir was primarily driven by one patient with a discordant > 103 percent increase in viremia. Comparing change in viremia and clinical response, 71% of patients had a concordant decrease in viremia with clinical response after cidofovir. Only 50% of patients had a concordant decrease in viruria with clinical response after cidofovir. Two patients relapsed after an initial response. Patient #9 had a relapse from grade 1 to grade 2 BK-HC within 9 days from discharge from cidofovir admission but died from ischemic colitis prior to receipt of further therapy. Patient #4 had a relapse from complete response to grade 4 BK-HC within 27 days from discharge from cidofovir admission. They were re-admitted 9
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to hospital with grade 4 BK-HC, worsening liver GVHD, and CMV re-activation. They were treated with increased immunosuppression, valganciclovir, and a second higher dose of cidofovir at 5 mg/kg, but soon thereafter died from RSV pneumonia with pseudomonal superinfection. They had no therapeutic response in their BK-HC prior to death. Toxicity Adverse events were experienced by four (33%) patients. Three patients had an increase in creatinine > 30 umol/L – two patients receiving intravesical cidofovir and one patient receiving both intravesical and intravenous cidofovir. Mean serum creatinine had a nonsignificant trend towards increase after cidofovir of 24 µmol/L (n = 12, p = 0.2). Additional complications affected two patients receiving prolonged courses of intravenous cidofovir and one patient receiving intravesical cidofovir. Patient #1 developed keratitis after a cumulative dose of 37 mg/kg over a 12-week period which was deemed to be secondary to cidofovir after ophthalmology assessment. Patient #5 developed progressive renal insufficiency while receiving intravenous cidofovir therapy three times weekly, requiring a dose reduction to once weekly and probenecid was started after the 4th dose. Patient #5 was assessed by nephrology for acute on chronic kidney injury with hyperchloremic non-anion gap metabolic alkalosis and electrolyte derangements and was diagnosed with Fanconi’s syndrome and tubular toxicity from cidofovir. Patient #7 received a single dose of intravesical cidofovir and developed bladder pain and the subsequent day died from overwhelming pseudomonal sepsis.
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Literature Review A total of 16 articles were found that reported the use of cidofovir in post allo-HCT BKHC including a total of 255 patients with various BK-HC grades. A 2016 literature review by Philippe et al.11 reported a retrospective series of 27 cases of allo-HCT BK-HC (eight with grade 1, 13 with grade 2, three with grade 3, three with grade 4) receiving cidofovir for BK-HC, 24 intravenous, one intravesical, and two via both routes with a median dose concentration of 5 mg/kg with a median number of doses of four (range 1 to 11) with a complete response rate of 82%; no patients had received therapy prior to cidofovir. This review additionally identified 13 articles, with a total of 219 patients who had received cidofovir therapy for BK-HC in allo-HCT: 195 via IV, 19 via intravesical, and five via both IV/intravesical. Complete response was observed in 60 to 100% of cases, independent of cidofovir dose and administration route.11,12,15,17,18,20-27 Two further case series on cidofovir for BK-HC have since been published. Sakurada et al.13 reported a retrospective study including three allo-HCT patients with BK-HC (two with grade 2 and one with grade 3) treated cidofovir (two intravesical, one both intravenous and intravesical) with a median dose concentration of 2.6 mg/kg with a median of three doses (range 2-4 doses) with 100% CR rate; two patients had received previous therapy with ciprofloxacin. Two patients receiving intravesical cidofovir experienced irritation.13 The patient receiving intravenous cidofovir developed renal failure requiring hemodialysis, leading to a switch to intravesical therapy.13
11
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Aitken et al.14 reported a prospective pharmacokinetic and safety study including five post allo-HCT patients with BK-HC treated with single dose of intravesical cidofovir with three patients receiving 5 mg/kg and two patients receiving 2.5 mg/kg, response rate was not assessed. Two patients developed bladder pain and one patient had a greater than 50% rise in serum creatinine.14
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DISCUSSION In this retrospective institutional review, 67% of patients achieved at least partial response and 33% of patients achieved a complete response after cidofovir administration for BK-HC, with similar rates of response with either intravenous or intravesical administration. The rate of complete response is lower than previous case series. Patients in this study had severe Grade 3 or 4 BK-HC and a significant majority of patients in study had failed prior therapy (ciprofloxacin or leflunomide), in contrast to most previous series which included a significant proportion of patients with Grade 1 or 2 BK-HC. As cidofovir is not approved by Health Canada, Exceptional Access Approval is required to use cidofovir in the treatment of our patients. Consequently, supportive treatment or alternative agents are used in our institution for low-grade BK-HC. Cidofovir is reserved for patients with severe or refractory BK-HC, accounting for the high-grade BK-HC patients included in our study. Despite reflecting a subset of patients with severe refractory BK-HC, an overall significant reduction in BK-HC grading was observed after administration of cidofovir. While there was significant clinical improvement, there was no significant change in BK viremia or viruria. Amongst patients with clinical improvement with cidofovir, the majority had a concordant decrease in viremia, but only 50% had a concordant decrease in viruria. Cesaro et al. noted clearance of BK viremia in 81% of patients with complete response but only 20% clearance of BK viruria.12 Gaziev et al. likewise noted persistence of BK viruria after resolution of BK-HC.24 While a significant proportion of post allo-HCT patients develop BK viruria, up to half of these patients do not develop hemorrhagic cystitis.28 The relationship between cidofovir, BK urine viral loads and hemorrhagic cystitis has been inconsistent.28
13
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Previous BK-HC studies have identified renal toxicity from intravenous administration in 9-50% of cases,11 yet only one case of intravesical cidofovir administration with acute kidney injury has been identified.14 Amongst cases with intravesical instillation complications included bladder spasm and discomfort during instillation.13 In contrast to previous studies, two of three patients with significant acute kidney injury in this study had received intravesical cidofovir. Patient #12, had concurrent CMV colitis, EBV viremia, and Mycobacterium Avium Complex pneumonia and had received additional nephrotoxic therapy with foscarnet. While receiving intravesical cidofovir, the patient developed progressive pneumonia and bilateral hydronephrosis with no BK-HC response. Treatment was discontinued to allow for palliation. While the renal dysfunction coincided with the timing of intravesicular cidofovir, the renal dysfunction may have been secondary to progressive grade 4 BK cystitis and multi-organ dysfunction in the context of progressive pneumo-sepsis. Patient #7 received intravesical cidofovir followed by bladder pain and subsequent development of fatal septic shock within 24 hours secondary to Pseudomonas. While renal dysfunction closely followed intravesical instillation, a more plausible etiology for the renal dysfunction is secondary to sepsis rather than a direct nephrotoxic effect of the intravesical administration. Notwithstanding, this is an essential toxicity to highlight – if this patient had an unrecognized Pseudomonas bacteriuria and a friable urothelium secondary to BK cystitis, might have the intravesical administration promoted the development of bacteremia? Avoidance of renal toxicity is often purported as a benefit of intravesical instillation, but the possibility of systemic toxicity persists.
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Limitations While cidofovir appears to be efficacious, limitations of this study include retrospective study design, sample size, lack of control, and heterogeneous patient characteristics and treatment, preventing confirmatory demonstration that cidofovir induced BK-HC response.
CONCLUSION In this retrospective series, there was a significant reduction in BK-HC severity after cidofovir administration, with the majority of patients achieving at least partial response after cidofovir administration. Similar response rates were seen with intravenous and intravesical therapy. However, even with intravesical instillation, acute kidney injury remains a potential complication of cidofovir. The precise role of cidofovir in BK-HC management, the severity at which to intervene, and the optimal route and dosing protocol remain to be defined. Further prospective randomized controlled trials are needed.
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19. Bedi A, Miller CB, Hanson JL, et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol. 1995;13(5):1103-1109.
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24. Gaziev J, Paba P, Miano R, et al. Late-onset hemorrhagic cystitis in children after hematopoietic stem cell transplantation for thalassemia and sickle cell anemia: A prospective evaluation of polyoma (BK) virus infection and treatment with cidofovir. Biol Blood Marrow Transplant. 2010;16(5):662-671.
25. Koskenvuo M, Dumoulin A, Lautenschlager I, et al. BK polyomavirus-associated hemorrhagic cystitis among pediatric allogeneic bone marrow transplant recipients: Treatment response and evidence for nosocomial transmission. J Clin Virol. 2013;56(1):77-81.
26. Kwon HJ, Kang JH, Lee JW, Chung NG, Kim HK, Cho B. Treatment of BK virus-associated hemorrhagic cystitis in pediatric hematopoietic stem cell transplant recipients with cidofovir: A single-center experience. Transpl Infect Dis. 2013;15(6):569-574.
27. Gilis L, Morisset S, Billaud G, et al. High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2014;49(5):664-670.
28. Mackey MC. Intravesicular cidofovir for the treatment of polyomavirus-associated hemorrhagic cystitis. Ann Pharmacother. 2012;46(3):442-446.
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Table 1: Patient and Transplant Characteristics, n=12 Age, median years [range] Gender, no. (%) Diagnosis, no. (%)
HLA Match, no. (%)
ABO Mismatch, no. (%)
Karnofsky Performance Score, median [range] HCT-CI, median [range] CMV (Donor / Recipient), no. (%)
Conditioning Regimen, no. (%)
Serotherapy, no. (%) Total Body Irradiation, no. (%) Stem Cell Source, no. (%) GVHD, no. (%) GVHD Grade, no. (%)
Adenovirus viruria, no (%) CMV viremia, no. (%) EBV viremia, no. (%) Bacteriuria, no (%) Percent chimerism at 60+ days post alloHCT, median [range] Time to BK-HC, median days [range]
49 (28-59) Male – 6 (50%) Female – 6 (50%) Acute Myeloid Leukemia – 8 (67%) Acute Lymphoblastic Leukemia – 1 (8%) Mantle Cell Lymphoma – 1 (8%) Myelofibrosis – 1 (8%) Aplastic Anemia – 1 (8) 10/10 – 7 (58%) 6/6 – 3 (25%) 9/10 – 2 (17%) Major – 1 (8%) Minor – 5 (42%) Bidirectional – 1 (8%) None – 4 (33%) Unknown – 1 (8%) 90 (Range 70-100) 1 (0-5) +/+ – 9 (75%) +/- – 1 (8%) -/+ – 1 (8%) -/- – 1 (8%) Fludarabine / Busulfan / TBI – 8 (67%) TBI / Cyclophosphamide – 2 (17%) Busulfan / Cyclophosphamide – 1 (8%) Fludarabine / Cyclophosphamide – 1 (8%) 5 (42%) 10 (83%) Peripheral Blood - 11 (92%) Bone Marrow – 1 (8%) GVHD – 8 (67%) Grade 4 – 3 (25%) Grade 3 – 3 (25%) Grade 2 – 1 (8%) Grade 1 – 1 (8%) 3 (25%) 7 (58%) 2 (17%) 1 (8%) 97.9% (Range 84.6-99.2) 81.5 (23-762) 20
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Table 2: BK-HC Treatment, Response, and Toxicity Treatment Cidofovir route, no. (%)
Dose of cidofovir, median mg/kg [range] Cumulative dose of cidofovir, median mg/kg [range] No. cidofovir injections per patient, median [range] Prior BK-HC Treatment, no (%)
Response BK Titer Urine, mean copies/mL [SD] BK Titer Blood, mean copies/mL [SD] BK Blood post-CDV: Grade of BK-HC, mean score (SD) Response, no. (%) [n=12]
Death, no (%) [n=12]
Toxicity Serum creatinine, mean µmol/L [SD] [n=12] Increased creatinine > 30umol/L, no. (%)
n=12 Intravenous only: 4 Intravesical only: 7 Both: 1 5 [1,5] 10 [1-37] IV 2 [1-21] Intravesical 2 [1-4] Ciprofloxacin: 9 (75%) Leflunomide: 2 (17%) None: 3 (25%) Pre-CDV (n=12): 6.10*109 [1.72*1010] Post-CDV (n=10): 3.03*109 [6.2E*109] Pre-CDV (n=12): 3.28*106 [1.13*107] Post-CDV (n=7): 1.52*105 [3.52*105] Pre-CDV (n=12): 3.5 [0.5] Post-CDV (n=12): 1.7 [1.7] PR or greater: 8 (67%) CR: 4 (33%) PR: 4 (33%) NR: 4 (33%) All cause: 8 (67%) Liver failure: 3 (25%) Sepsis: 2 (17%) Ischemic Colitis: 1 (8%) Renal Failure: 1 (8%) Unspecified: 1 (8%) Pre-CDV: 77 [37] Post-CDV: 101 [67] 3 (25%)
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