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Bone Marrow Transplantation (2007) 39, 783–787 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00

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ORIGINAL ARTICLE

Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant MR Savona1, D Newton2, D Frame3, JE Levine4, S Mineishi4 and DR Kaul5 1 Division of Hematology–Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; 2Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; 3College of Pharmacy, Ann Arbor, MI, USA; 4Blood and Bone Marrow Transplant Program, Division of Hemato–Oncology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA and 5Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

In recipients of hematopoietic stem cell transplants (HSCTs), BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC). In our institution, HSCT recipients with BKV-associated HC are treated with 1 mg/kg of cidofovir weekly. We identified HSCT recipients with BKV-associated HC, treated with weekly cidofovir. Microbiological response was defined as at least a one log reduction in urinary BKV viral load; clinical response was defined as improvement in symptoms and stability or reduction in the grade of cystitis. Nineteen allogeneic HSCT patients received a mean of 4.5 weekly doses of cidofovir. HC occurred at a mean of 68.7 days after transplant. A clinical response was detected in 16/19 (84%) patients, and 9/19 (47%) had a measurable microbiological response (8/10 nonresponders had a BKV viral load above the upper limit of the assay before treatment). Fourteen out of nineteen (74%) patients had no significant increase in serum creatinine. Five patients with renal dysfunction resolved after completion of the therapy and removal of other nephrotoxic agents. We conclude that weekly low-dose cidofovir appears to be a safe treatment option for BKV-associated HC. Although the efficacy of low-dose cidofovir is not proven, a prospective trial is warranted. Bone Marrow Transplantation (2007) 39, 783–787; doi:10.1038/sj.bmt.1705678; published online 16 April 2007 Keywords: cidofovir; BK virus; hemorrhagic cystitis

Introduction

stenosis and graft failure in renal transplant recipients, and in 1986 Arthur et al.1,2 reported an association between BKV viruria and hemorrhagic cystitis (HC) in recipients of bone marrow transplants. HC complicates the course of 7–40% of recipients of hematopoietic stem cell transplants (HSCTs); early onset disease is probably secondary to the conditioning regimen and later onset disease has been associated with viral pathogens.1,3–6 Polymerase chain reaction (PCR) can detect BKV in up to 95% of patients at some point after allogeneic HSCT7 and this has been used for diagnosis and for monitoring during treatment of the disease.5,7–9 Most of these patients do not develop clinically significant HC, but patients with higher viral loads in the urine or plasma as assessed by quantitative PCR appear to be at increased risk of developing HC.6–10 Cidofovir (HPMPC) is a cytosine derivative of an acyclic nucleoside–phosphonate analogue, which has broad-spectrum activity against many DNA viruses including cytomegalovirus (CMV), adenoviruses and polyomaviruses.11,12 Low-dose cidofovir (0.25–1.5 mg/kg) has been used successfully in the management of BKV nephropathy.13–16 Although no standard treatment of BKVassociated HC exists, others have described previously the use of intravenous cidofovir at varying doses in HSCT patients with late-onset HC with variable results.4,5,17–19 Given the paucity of established treatment options, lowdose cidofovir (1 mg/kg) without probenicid has been given weekly at our institution for BKV-associated HC. In efforts to determine if further study of low-dose cidofovir therapy for BKV-associated HC is warranted, the safety profile and the microbiological and clinical outcomes with use of this regimen were investigated.

BK virus (BKV) is a human polyomavirus acquired in childhood, which remains latent in the genitourinary tract throughout life.1 BKV has been associated with ureteral

Methods

Correspondence: Dr DR Kaul, Division of Infectious Diseases, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. E-mail: [email protected] Received 13 December 2006; revised 6 March 2007; accepted 15 March 2007; published online 16 April 2007

On receipt of approval from the Institutional Review Board, we reviewed the records of all adult HSCT patients at the University of Michigan between April 2003 and May 2004. All adult patients (ageX18 years) with HC, who received at least three doses of cidofovir and had urinary qPCR BKV determinations before and less than 2 weeks

Cidofovir for BK virus hemorrhagic cystitis MR Savona et al

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after treatment, were reviewed. Of these patients, only those with pretreatment quantitative BKV viral loads 4105 DNA copies/ml were included in the analysis. Preparative regimens for HSCT were as per the University of Michigan’s Blood and Bone Marrow Transplant Program Clinical Practice Guidelines and all included busulfan, cyclophosphomide or both. Similarly, all patients received prophylactic fluoroquinolone therapy at the time of transplant, which included 400 mg norfloxicin twice daily. HC grade was described as suggested by Bedi et al.:20 0 ¼ no HC, 1 ¼ microscopic hematuria, 2 ¼ macroscopic hematuria, 3 ¼ visible clots, 4 ¼ clots leading to obstruction. Cidofovir was always given as a 1-mg/kg weekly dose without probenicid and serum creatinine was obtained at least weekly. Quantitation of BKV was based on the realtime qPCR amplification and detection of BKV genomic DNA. The assay ranged from a lower limit of 200 BKV DNA copies/ml to an upper limit of 2 108 BKV DNA copies/ml. The coefficient of variation for the assay was 21% at 9 106 copies/ml with a standard deviation71.9 106 copies/ml (Focus Technologies Inc., Cypress, CA, USA). Microbiologic response was defined as at least one log reduction in BKV viral load by qPCR and was assayed within 2 weeks of completion of treatment. Clinical response was defined as (1) subjective improvement in the patient’s symptoms and (2) a reduction or stability in the grade of cystitis. Given the consequences of obstructive uropathy in this patient population, if pretreatment HC was grade 3 or 4, only patients with improvement in the grade of cystitis were counted as clinical responses. Nephrotoxicity was defined as a 0.3 mg/dl or greater increase in serum creatinine at any time during and up to 2 weeks after any treatment with cidofovir.

Table 1 Pt.

Age

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

44 55 36 43 30 64 43 29 59 33 53 49 38 27 57 51 34 26 20

Results Nineteen HSCT patients with a mean age of 42 years were included. All patients had allogeneic transplants from variable donor sources for a wide variety of malignant processes. The rate of graft-versus-host disease (GVHD) in the overall population of allogeneic HSCT at our institution was 52% (79/151) during this time period and 84% (16/19) of this cohort had documented GVHD. All patients with GVHD in this cohort were on steroids (methylprednisone 1.0–2.0 mg/kg daily) at the time of diagnosis of HC, the grade of the GVHD is reported in Table 1. The patients received a mean of 4.5 weekly doses of cidofovir (range 3–8 doses). HC developed at a mean of 68.7 days after transplant (18–215 days). In the safety analysis, 14/19 patients (74%) had no significant increase in serum creatinine (i.e., increase less than 0.3 mg/dl). The remaining five patients all had other possible causes of acute renal failure (e.g., obstructive uropathy secondary to HC, hypovolemia, sepis, other nephrotoxic agents). Renal failure resolved despite continuing the cidofovir in two patients. Two patients required hospitalization for renal failure and one was found to have obstructive uropathy from HC and the other had nephrotic syndrome felt to be secondary to GVHD of the kidney or cidofovir. The fifth patient had an increase of 0.5 mg/dl in serum creatinine after receiving three doses of cidofovir. Concurrent possible causes of renal failure for this patient included liposomal amphotericin, elevated tacrolimus levels and sepsis. In this case, renal function returned to baseline with clinical improvement after withdrawal of nephrotoxins. Nearly all patients had verifiable clinical response with use of cidofovir (16/19, 84%), but less than half of the

Characteristics of patients treated with cidofovir Gender

Disease

Preparative regimen

HSCT Source

M M M M F M M M F F M M F M F M M F F

CLL AML ALL AML AML CML MM AML NHL NHL CLL NHL AML AML AML CLL AML MDS AA

Bu-Cy-2 BAC BAC BAC BAC Flu/Bu/TLI Bu-Cy-2 BAC BEC BAC BAC Flu/Bu/TLI Bu-Cy-2 Cy-TBI Flu/Bu/TLI Flu/Bu/TLI BAC BAC Cy/ATG/TLI

URD – matched URD – mismatched URD – mismatched URD – matched URD – matched URD – matched Sibling matched Sibling matched Sibling mismatch Sibling mismatch Sibling matched URD – mismatched URD – matched URD – mismatched URD – mismatched URD – mismatched URD – matched Sibling matched URD – mismatched

GVHD grade 4 3 0 1 0 3 0 3 2 2 2 2 3 4 4 2 3 1 4

Cortico-steroids use

CMV in urine

Adenovirus in urine

Yes Yes No Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

No No No No No No No

a

b

No No a

No a a a

No

a

b

a

No No No No Yes

No No a

No No

b

a

No No

No No

b

a

Abbreviations: AA ¼ aplastic anemia; AML ¼ acute myelocytic leukemia; ATG ¼ anti-thymocyte globulin; BAC ¼ busulfan, cytosine arabinoside; BEC ¼ carmustine, etoposide, cytoxan; Bu ¼ busulfan; CLL ¼ chronic lymphocytic leukemia; CML ¼ chronic myelocytic leukemia; CMV ¼ cytomegalovirus; Cy ¼ cytoxan; flu ¼ fludarabine; GVHD ¼ graft-versus-host disease; HD ¼ hodgkin’s disease; HSCT ¼ hematopoietic stem cell transplant; MDS ¼ myelodysplastic syndrome; MM ¼ multiple myeloma; NHL ¼ non-hodgkin’s lymphoma; Pt ¼ patient; TLI ¼ total lymphocyte irradiation; URD ¼ unrelated donor. a Adenovirus was not measured in the urine in these patients. b CMV was not measured in the urine in these patients. Bone Marrow Transplantation


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patients developed a measurable microbiologic response (9/19, 47%). Of those who had no measurable microbiologic response, 8/10 had more than 2.0 108 DNA copies/ml (the upper limit of detection with the assay used) both before and after therapy. Two patients had worsening of quantitative BKV viral loads while on therapy, yet

Table 2

Microbiological and clinical response to cidofovir

Pt

Day post- CDV Duration of Platelet count transplant doses symptoms at onset of CDV

1 37 2 150 3 90 4 60 5 70 6 73 7 99 8 36 9 65 10 18 11 22 12 104 13 28 14 72 15 54 16 41 17 39 18 32 19 215 Avg7(s.d.) 68.7748.5

4 3 4 5 3 4 4 4 4 4 7 3 4 4 8 4 4 8 4 4.5

19 129 61 35 7 20 113 21 23 29 a

41 a a

11 35 63 68 24 43.7738.2

89 14 37 64 200 39 45 92 38 26 23 80 17 26 31 115 16 22 121 58748.3

resolution of symptoms and hematuria. All patients with a microbiological response had a clinical response (Table 2). Of note, five patients treated with cidofovir who had grade 3 HC with symptoms and BKV greater than 105 copies/ml were not included in the analysis as post-therapy

Platelet count at completion of CDV

HC grade pre-CDV/ symptoms

31 54 137 100 221 54 179 18 88 43

2/+ 3/+ 3/+ 2/+ 2/+ 2/+ 2/+ 1/+ 1/+ 1/+ 3/+ 3/+ 1/+ 1/ 1/+ 3/+ 3/+ 3/+ 2/+

b

78 b b

16 70 32 122 17 79763.0

HC grade Urine BKV post-CDV/ pre-CDV symptoms (copies/ml) 0/ 0/ 1/ 0/ 0/ 0/ 0/ 1/ 0/ 0/ 4/+ 0/ 3/+ 1/ 0/ 0/ 0/ 0/ 0/

2.7 105 7.7 107 1.4 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 4.4 105 4.0 106

Urine BKV Clinical success/ post-CDV micro success (copies/ml) o200 1.1 106 1.1 103 520 o200 4.2 105 1.2 106 2.5 106 5.8 105 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 2.0 108 1.7 108

Yes/yes Yes/yes Yes/yes Yes/yes Yes/yes Yes/yes Yes/yes Yes/yes Yes/yes Yes/no No/no Yes/no No/no Noc Yes/no Yes/no Yes/no Yes/no Yes/no

Abbreviations: BKV ¼ BK virus; CDV ¼ cidofovir; Pt ¼ patient; s.d. ¼ standard deviation. a Duration of symptoms unknown. b Platelet count not measured at the end of CDV therapy. c Unknown.

Table 3

Literature review: intravenous cidofovir treatment of BKV-associated hemorrhagic cystitis

Study

Year

Comments

Cidofovir dose

BKV monitoring

Outcome

Gonzalez-Fraile et al.4

2001

Single case report

Standard dosing regimen,a four doses

qPCR and electron microscopy

Resolution of symptoms and BKV viruria

Gorczynska et al.5

2005

19 children with 4grade II HC

Standard dosinga until resolution of symptoms (median three treatments)

qPCR

15/19 clinical resolution 1/19 progression then resolution day 80 3/19 died with persistent hematuria 6/19 with eradication in urine

Held et al.19

2000

Single case report

Standard dosinga (three doses)

Daily EM and qPCR Hematuria resolved after 20 days BKV viruria declined after two doses of cidofovir

Palandri et al.18

2005

Single case report

5 mg/kg given 21 days apart

PCR

No improvement after two doses Success with superselective vesical artery embolization

Hatakeyama et al.17

2003

Single case report, BKV 1 mg/kg three times a week with and adenovirus present probenicid for 14 doses

BKV by PCR adeno by PCR and culture

Adenovirus resolved after nine doses BKV resolved after 14 doses Clinical improvement after nine doses

Abbreviations: BKV ¼ BK virus; EM ¼ electron microscopy; qPCR ¼ quantitative polymerase chain reaction. a 5 mg/kg weekly for 2 weeks, then 5 mg/kg with probenicid every other week. Bone Marrow Transplantation


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viral titers were not assessed. All five of these patients had complete resolution of their HC after four doses of cidofovir without renal compromise as defined previously. Coinfection with other viruses, known to lead to HC after HCST, was also investigated. There were no cases of adenovirus in the urine in the 9/19 patients who were tested for adenovirus. CMV in the urine was assayed in 15/19 patients. The one patient with CMV in the urine had a clinical response from BKV-associated HC, but died of systemic CMV disease.

Discussion Most patients in our study with BKV-associated HC tolerated low-dose cidofovir without probenicid without renal compromise or worsening of BKV-associated HC. Low-dose cidofovir appears to be generally safe in this population, but may have contributed to renal failure in three of 19 (16%) of patients. In addition, all patients with a successful microbiological response had a successful clinical response. However, patients treated with low-dose cidofovir may fail, as evidenced by two patients without clinical improvement of their HC despite four or seven doses of cidofovir. The pharmacokinetics of cidofovir have been evaluated in patients with CMV infection.21–25 After 1 h infusions of 1, 3, 5, 7.5 and 10 mg/kg, the drug demonstrated doseindependent pharmacokinetics both with and without probenecid. Without probenecid, in patients with normal renal function, approximately 80–100% of the cidofovir dose was recovered unchanged in urine within 24 h, whereas approximately 70–85% of cidofovir was excreted within 24 h in patients who were also given probenicid. Thus, withholding probenicid may achieve higher urinary concentrations of cidofovir. The rapid clearance of cidofovir from the urine raises the question of whether more frequent dosing of intravenous or intravesicular instillation would be effective. Two studies describing intravesicular instillation of cidofovir for HC caused by BKV or adenovirus have been reported. Bridges et al.26 describe a single patient with severe HC who improved with two weekly doses of 5 mg/kg intravesicularly administered cidofovir in 60 ml of normal saline with clamping of the foley catheter for 1 h after administration. A similar strategy has been used to treat successfully adenovirusassociated HC.27 The outcome of BKV-associated HC is poorly understood; however, cases of spontaneous recovery with only supportive treatment have been described.3,5 It is possible that some of the patients in this study would have improved clinically without treatment. The upper limit of detection of the assay was 2 108 copies/ml. Peak BKV viral loads in the urine as high as 1 1014 copies/ml have been reported in other studies.7 As eight of our patients, who were considered microbiologic failures by the criteria listed above, had pre- and post-treatment BKV viral load beyond the upper limit of detection of our assay, the true microbiological response rate may be underestimated. As mentioned above, there is some evidence that cidofovir has activity against other viral etiologies of HC. Bone Marrow Transplantation

Ideally, we would prefer to study the urine before and after treatment for CMV or adenovirus. The prevalence of these viruses among those assayed, however, seem to indicate that they did not contribute substantially to the etiology of HC in this study. No standard treatment for BKV-associated HC is available. In addition to intravenous low-dose cidofovir, reported treatments include hyperhydration, intravesicular prostaglandins, continuous bladder irrigation, embolization of the vesicular artery and vidarabine.1,3,7,18 To our knowledge, five reports of intravenous cidofovir for BKVassociated HC have been published (Table 3).4,5,17–19 Four are single case reports and the case series did not include adults or quantitative BKV viral monitoring of the urine. No report used low-dose cidofovir and probenicid was used in each case. Three of the four case reports describe clinical and microbiological success; one describes worsening after two doses. Our report is the largest available and the only using the 1 mg/kg dose without probenicid with serial microbiological monitoring. BKV may play a substantial role in late-onset HC in the HSCT patient population. Low-dose cidofovir without probenecid is an attractive treatment option, as it may reduce the renal toxicity of standard dose cidofovir in these patients. The presence of GVHD, multiple comorbidities (e.g., thrombocytopenia) and the variable natural history of BKV-associated HC complicate the conduct of clinical trials. Our results do suggest, however, that proceeding to a prospective trial of low-dose cidofovir for the treatment of BKV-associated HC is warranted.

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