What is the recommended management of hemorrhagic cystitis, including chemotherapy‑induced (cyclophosphamide/ifosfamide), radiation‑induced, and BK‑virus‑associated cases?

Management of Hemorrhagic Cystitis

For chemotherapy-induced hemorrhagic cystitis (cyclophosphamide/ifosfamide), mandatory mesna prophylaxis with extended infusion (30 minutes prior and 48 hours post-chemotherapy) combined with aggressive hydration is the standard of care, while BK virus-associated cases require primarily supportive management with consideration of cidofovir for severe refractory disease. 1, 2

Prevention of Chemotherapy-Induced Hemorrhagic Cystitis

Mesna Prophylaxis (Mandatory)

• Mesna (2-mercaptoethanesulfonate sodium) is mandatory for all IV pulse cyclophosphamide to prevent hemorrhagic cystitis, which occurs in 6% of patients without protection. 1
• Administer mesna as continuous infusion starting 30 minutes prior to cyclophosphamide and continuing for 48 hours post-chemotherapy. 2
• Mesna binds to acrolein (the toxic metabolite responsible for bladder toxicity) and directly reduces urinary tract complications. 1

Hydration and Bladder Emptying

• Implement forced diuresis with intravenous fluids (as clinically warranted) and frequent bladder emptying to reduce frequency and severity of bladder toxicity. 3
• Continuous bladder irrigation with 3,000 mL of saline per day is an alternative effective method, though more invasive. 4
• Mesna and forced diuresis are equally effective in abrogating urothelial toxicity when used appropriately. 5

Ongoing Surveillance

• Perform periodic urinalysis for the duration of follow-up to screen for microscopic hematuria and bladder cancer risk. 1
• Monitor urinary sediment regularly for presence of erythrocytes and other signs of toxicity during cyclophosphamide administration. 3

Management of Established Hemorrhagic Cystitis

Initial Assessment and Grading

• Document onset, duration, severity (microscopic vs. gross hematuria), presence of clots, and associated symptoms (dysuria, urgency, suprapubic pain). 5, 6
• Obtain urine culture to exclude bacterial infection and urine PCR for BK virus in all cases, as BK viruria is present in 50-65% of post-transplant patients and strongly correlates with hemorrhagic cystitis. 5, 2
• Check complete blood count to assess for anemia requiring transfusion support. 3

BK Virus Testing and Interpretation

• Hemorrhagic cystitis after BMT or high-dose cyclophosphamide is virtually always associated with persistent BK viruria (≥2 consecutive positive samples). 5
• BK viruria <10⁴ copies/mL rarely causes clinical symptoms and does not require specific antiviral therapy. 2
• BK viruria ≥10⁴ copies/mL is strongly associated with hemorrhagic cystitis (75% develop HC) and warrants consideration of antiviral treatment. 2
• Temporal correlation between BK virus shedding and HC onset is extremely strong (r = 0.95). 5

Supportive Care (Mainstay for All Cases)

• Supportive care remains the mainstay of management for BK virus-associated hemorrhagic cystitis. 3
• Maintain aggressive hydration and consider continuous bladder irrigation for severe cases with clot formation. 4
• Provide analgesics for bladder spasm and dysuria (avoid NSAIDs if thrombocytopenic). 3
• Transfuse packed red blood cells as needed for symptomatic anemia. 6

Antiviral Therapy for BK Virus-Associated Cases

• Cidofovir demonstrates effectiveness for BK virus but carries significant renal toxicity risk. 3
• Consider intravenous cidofovir for severe, refractory BK virus-associated hemorrhagic cystitis with BK viruria ≥10⁴ copies/mL and persistent gross hematuria despite supportive measures. 6
• One case series showed resolution of both BK viruria and hematuria following cidofovir treatment, though definitive efficacy data require clinical trials. 6
• There is currently insufficient data to support routine recommendations on antiviral treatment of BK virus. 3

Duration and Prognosis

• BK virus-positive hemorrhagic cystitis typically has more prolonged hematuria (14-16 weeks) compared to BK-negative cases (10 weeks). 6
• HC may necessitate chemotherapy delays and prolonged supportive care. 6
• Higher non-relapse mortality is observed in patients with BK viruria ≥10⁴ copies/mL (41.7% vs 12.6%), primarily related to GVHD and its complications. 2

Radiation-Induced Hemorrhagic Cystitis

Management Approach

• Apply similar supportive care principles as chemotherapy-induced cases with aggressive hydration and bladder irrigation. 3
• Radiation-induced cases may require more prolonged management due to ongoing mucosal injury throughout fractionated radiotherapy. 3
• Consider hyperbaric oxygen therapy for late radiation-induced hemorrhagic cystitis (not addressed in provided guidelines but standard practice).

Special Populations

Transplant Recipients

• Allogeneic transplant recipients have similar HC incidence (27.2%) compared to autologous transplant (22.9%). 5
• Acute GVHD is strongly associated with both BK viruria ≥10⁴ copies/mL and hemorrhagic cystitis (p < 0.001). 2
• CTLA4Ig-based regimens may reduce alloreactivity and preserve antiviral immunity, resulting in lower BK viruria and HC incidence. 2

Pediatric Oncology Patients

• BK virus-associated HC occurs in non-transplant pediatric patients receiving high-dose oxazophosphorine chemotherapy. 6
• HC may present early and be more prolonged in pediatric patients with BK viruria. 6
• Patients with HC after cyclophosphamide or ifosfamide with negative bacterial cultures should be routinely tested for BK virus. 6

Key Pitfalls to Avoid

• Never delay or omit mesna prophylaxis for IV cyclophosphamide—this is mandatory, not optional. 1
• Do not assume all hemorrhagic cystitis is purely chemical; always test for BK virus, as 50-65% of cases have viral etiology. 5, 2
• Avoid using cidofovir empirically without documented high-level BK viruria (≥10⁴ copies/mL) due to significant nephrotoxicity risk. 3, 2
• Do not discontinue mesna prematurely; extended infusion for 48 hours post-chemotherapy is critical. 2
• Recognize that BK viruria <10⁴ copies/mL does not require antiviral therapy and will not cause clinical HC. 2