BK Virus-Hemorrhagic Cystitis Following Allogeneic Stem Cell Transplantation: Clinical Characteristics and Utility of Leflunomide Treatment

Abstract

Objective:BK virus-hemorrhagic cystitis (BKV-HC) is a potential cause of morbidity and mortality in patients having undergone allogeneic stem cell transplantation (Allo-SCT). We analyzed the clinical features of BKV-HC following Allo-SCT and reported the utility of leflunomide therapy for BKV-HC.Materials and Methods:From January 2005 to June 2014, among the 69 patients that underwent Allo-SCT in our institution, the patients who experienced BKV-HC were investigated retrospectively.Results:HC was observed in 30 patients (43.5%), and among them, 18 of the cases (26.1%) were identified as BKV-HC. The median age of the patients (12 males and 6 females) was 45 years (minimum-maximum: 13-63). Patients received Allo-SCT for acute myeloid leukemia (n=11), aplastic anemia (n=4), myelodysplastic syndrome (n=2), and non-Hodgkin lymphoma (n=1). The donor types were human leukocyte antigen (HLA)-matched sibling donor for six patients, HLA-matched unrelated donor for nine, and haploidentical familial donor for two. The median onset and duration of BKV-HC was on day 21 after transplantation (minimum-maximum: 7-97) and 22 days (minimum-maximum: 6-107). Eleven patients (62.1%) had grade I-II HC and seven patients (38.9%) had grade III-IV (high-grade) HC. Among the seven patients who had high-grade HC, one had complete response, one had partial response, and five had no response. Among the five nonresponders, one died of BKV-HC associated complications. The remaining four patients were treated with leflunomide, achieving complete response (n=2) and partial response (n=2). The median duration from the start of leflunomide therapy to response was 13 days (minimum-maximum: 8-17 days). All patients tolerated the leflunomide treatment well, with three patients having mild gastrointestinal symptoms, including anorexia and abdominal bloating.Conclusion:BKV-HC was commonly observed in patients with HC following Allo-SCT. In high-grade BKV-HC patients who do not respond to supportive care, leflunomide may be a feasible option without significant toxicity.

Investigation of BK Virus Infections in Haematopoietic Stem Cell Transplant Recipients

“…Bu sonuçlar çalışmamızdaki bulgulara benzerdir. Park ve arkadaşları (19)'nın yaptıkları çalışmada alojenik HKHT uygulanan 69 hastanın 18 (%26)'inde nakilden medyan 22 gün sonra BKV'yle ilişkili hemorajik sistit gelişmiştir. Sistit görülme süresi çalışmamızdakine (medyan 23 gün) benzer iken hemorajik sistit oranı çalışmamızdakinden daha yüksek bulunmuştur.…”

Pathogenicity of BK virus on the urinary system

“…In more advanced cases, blood clots can deposit in the urinary tract leading to acute urinary retention, obstructive uropathy and finally, renal function impairment. Clinical severity of HC can be graded according to the following criteria: grade 0 (no haematuria), grade I (microscopic haematuria), grade II (macroscopic haematuria), grade III (macroscopic haematuria with presence of blood clots), and grade IV (macroscopic haematuria with clots and renal impairment due to urinary obstruction) [11,94]. The diagnosis is often done by exclusion basing on clinical presentation and BKV viral load and urine analysis.…”

Pharmacological Options for Viral Induced Hemorrhagic Cystitis Management: A Review of the Literature

“…This drug's pharmacological effect occurs via interference with dihydroorotate dehydrogenase enzyme activity, thus preventing pyrimidine de novo synthesis (package insert). Leflunomide efficacy against BKV-associated HC treatment is well documented [58][59][60]. In grade 3 or 4 HC pediatric patients, leflunomide significantly decreased BKV viremia and improved symptoms without any major side effects [60].…”

“…In grade 3 or 4 HC pediatric patients, leflunomide significantly decreased BKV viremia and improved symptoms without any major side effects [60]. In a group of 18 adult allo-HSCT patients diagnosed with BKV-associated HC, four patients required "salvage therapy" with leflunomide due to poor response to supportive care measures [59]. In another group of 14 adult patients, seven obtained complete remission, five achieved partial remission, and two exhibited no response upon treatment with leflunomide [58].…”

“…In another group of 14 adult patients, seven obtained complete remission, five achieved partial remission, and two exhibited no response upon treatment with leflunomide [58]. Intolerance to leflunomide varies between gastrointestinal symptoms, such as abdominal bloating and diarrhea, and more severe symptoms, such as neutropenia [58,59]. In cases of neutropenia, a dosage reduction may be warranted in some patients [58].…”