Cyclophosphamide-induced Haemorrhagic Cystitis

Cyclophosphamide induced haemorrhagic cystitis is bladder inflammation and bleeding from direct urothelial toxicity of acrolein, a urinary metabolite of cyclophosphamide. Ifosfamide acts the same way.

The risk depends on dose and rises with high dose conditioning regimens, up to about 40% without prophylaxis, and is lower with long term low dose oral therapy. Onset is early (within 24 hours) or late (weeks to months). Long term cyclophosphamide exposure also raises the risk of bladder cancer.

Pathophysiology. Acrolein penetrates the urothelium, causing oedema, ulceration and bleeding from damaged submucosal vessels. Thrombocytopenia from the underlying treatment worsens bleeding.

Viral infection (BK virus, adenovirus) can cause or amplify the same picture after transplantation.

Other risk factors are pelvic radiotherapy, dehydration, busulfan co-exposure, haematopoietic cell transplantation and reduced urine flow.

Severity grades:

• Grade I: microscopic haematuria.
• Grade II: macroscopic haematuria.
• Grade III: macroscopic haematuria with clots.
• Grade IV: clots causing retention or obstruction, renal impairment, or bleeding requiring transfusion or surgical intervention.

Dysuria, frequency, urgency, suprapubic pain, haematuria from microscopic to heavy with clots, clot retention and anaemia. Antidiuretic effect of cyclophosphamide causes water retention and hyponatraemia during high volume hydration.

Clot retention, hydronephrosis or rising creatinine, falling haemoglobin or transfusion need, and thrombocytopenia with ongoing bleeding need urgent escalation.

• Urinalysis, urine culture, urine and blood PCR for BK virus and adenovirus.
• Full blood count, coagulation screen, group and crossmatch, creatinine and electrolytes including sodium.
• Renal and bladder ultrasound for clot, wall thickening and hydronephrosis.
• Cystoscopy with clot evacuation once stable, to confirm the diagnosis, treat bleeding and exclude tumour. Urine cytology and later imaging are needed for persistent haematuria.

Differential diagnosis.

• BK virus or adenovirus haemorrhagic cystitis
• Radiation cystitis
• Bacterial cystitis
• Bladder tumour including cyclophosphamide related cancer
• Upper urinary tract bleeding
• Coagulopathy or thrombocytopenia
• Bladder stone

Prevention:

• Hydration: about 3 L/m2 each day intravenously from before the dose to 24 hours after high dose regimens, with frequent voiding every 2 to 3 hours, including at night. Oral therapy: morning dosing and 2 to 3 litres of fluid daily.
• Mesna: intravenous, total dose equal to 60 to 100% of the cyclophosphamide dose. In usual dosing give 20% of the cyclophosphamide dose at time zero and at 4 and 8 hours (total 60%). High dose conditioning uses 80 to 100%, as divided boluses or continuous infusion continued for 12 to 24 hours after the last dose. Monitor fluid balance, weight and sodium, and give a diuretic if urine output falls.

Established haemorrhagic cystitis:

• Stop or substitute cyclophosphamide if the course allows, and treat infection.
• Maintain platelets over 50 x 10^9/L during active bleeding, correct coagulopathy, and transfuse to keep haemoglobin acceptable.
• Catheter of 22 to 24 Fr three way with continuous saline irrigation, manual clot evacuation, and cystoscopic clot evacuation with diathermy of bleeding points.
• Intravesical alum: 1% aluminium potassium sulphate irrigated at 200 to 300 mL/h. Avoid in renal impairment because aluminium accumulates, and monitor for encephalopathy.
• Intravesical formalin 1 to 4% instilled for 10 to 15 minutes under anaesthesia, only after cystography has excluded reflux or perforation. It is a last resort because of pain, bladder fibrosis and reflux nephropathy.
• Aminocaproic acid 4 to 5 g intravenously over the first hour, then 1 g each hour until bleeding settles (maximum 30 g in 24 hours), or tranexamic acid, reduced in renal impairment. Both are contraindicated with upper tract bleeding because of clot obstruction, and evidence is limited.
• Hyperbaric oxygen at 2 to 2.5 atmospheres absolute for 90 to 120 minutes daily, 20 to 40 sessions, in refractory cases.
• Selective embolisation of the internal iliac arteries, or cystectomy with diversion, for life threatening bleeding.
• Viral causes need virus directed therapy, and BK virus disease after transplantation is managed by reducing immunosuppression where possible.

Monitoring. Haemoglobin, platelets, creatinine, sodium and urine output daily during bleeding. After exposure, any new macroscopic haematuria needs cystoscopy and imaging whatever the interval, and those with previous haemorrhagic cystitis or high cumulative dose need continued surveillance.

Referral and escalation. Refer to urology and the treating haematology or oncology team. Urgent referral for clot retention, hydronephrosis, uncontrolled bleeding or transfusion need.