What is the recommended cyclophosphamide (CYC) regimen for induction in ANCA-associated vasculitis (AAV)?

Cyclophosphamide Regimen for Induction in ANCA-Associated Vasculitis

For remission-induction in organ-threatening or life-threatening AAV, use cyclophosphamide combined with glucocorticoids, with either intravenous (15 mg/kg at weeks 0,2,4,7,10,13) or oral (2 mg/kg/day, maximum 200 mg/day) administration, both achieving similar remission rates but with different toxicity profiles. 1

Route of Administration: IV vs Oral

Choose intravenous cyclophosphamide for:

• Patients with prior moderate cumulative cyclophosphamide exposure 1
• Lower baseline white blood cell counts 1
• Ready access to infusion centers 1
• Concerns about oral medication adherence 1

Choose oral cyclophosphamide for:

• Cost-sensitive situations 1
• Limited infusion center access 1
• Patients who can reliably self-administer oral regimens 1

The CYCLOPS trial demonstrated that IV cyclophosphamide reduces total cumulative dose and lowers leukopenia risk compared to oral administration, though a trend toward more relapses during long-term follow-up was observed with IV dosing. 1

Specific Dosing Regimens

Intravenous cyclophosphamide:

• Standard dose: 15 mg/kg at weeks 0,2,4,7,10, and 13 1, 2
• Dose reductions required for age and renal function 1:
  • Age <60 years with creatinine <300 μmol/L: 15 mg/kg/pulse
  • Age 60-70 years with creatinine <300 μmol/L: 12.5 mg/kg/pulse
  • Age >70 years with creatinine <300 μmol/L: 10 mg/kg/pulse
  • Further reductions for creatinine 300-500 μmol/L 1

Oral cyclophosphamide:

• 2 mg/kg/day (maximum 200 mg/day) 1
• Continue for 3-6 months until remission achieved 3

Recent evidence suggests that cumulative cyclophosphamide doses of 2.5-3 g may be sufficient for remission induction while reducing infectious complications, particularly in elderly patients. 4

Combination Glucocorticoid Therapy

Initial glucocorticoid dosing:

• Oral prednisolone: 1 mg/kg/day (maximum 80 mg/day) 1
• IV methylprednisolone pulses (1-3 g) for severe presentations 1

Structured tapering schedule (PEXIVAS protocol): 1

• Week 1: 50-75 mg (weight-based)
• Week 2: 25-40 mg
• Weeks 3-4: 20-30 mg
• Progressive taper to 5 mg/day by week 20-22
• Maintain 5 mg/day through week 52

Special Considerations for Severe Renal Disease

For patients with serum creatinine >4 mg/dL (>354 μmol/L):

• Cyclophosphamide is preferred over rituximab due to limited data supporting rituximab in this population 1, 2
• Consider combination therapy: rituximab plus 2 IV cyclophosphamide pulses 1
• Consider plasma exchange for creatinine >3.4 mg/dL, dialysis requirement, or rapidly increasing creatinine 1, 2

Essential Supportive Measures

Uroprotection:

• Encourage high fluid intake or provide IV fluids on infusion days 1
• MESNA (2-mercaptoethanesulfonate sodium) oral or IV with pulse cyclophosphamide 1
• MESNA may benefit patients on continuous oral cyclophosphamide 1

Infection prophylaxis:

• Trimethoprim/sulfamethoxazole 800/160 mg on alternate days or 400/80 mg daily for Pneumocystis jirovecii prophylaxis 1, 2
• Alternatives if contraindicated: dapsone or atovaquone 1
• Inhaled pentamidine is not cost-effective for routine use 1

Antiemetic therapy:

• Routinely administer with IV cyclophosphamide 1

Monitoring Requirements

During cyclophosphamide therapy:

• Regular complete blood counts for leukopenia monitoring 1
• Dose adjustment or discontinuation if acute leukopenia develops 1
• Urinalysis at each visit and throughout follow-up for hemorrhagic cystitis and bladder cancer surveillance 1, 2
• Renal function, inflammatory markers, and ANCA levels 2

Critical Pitfalls to Avoid

Bladder toxicity risk:

• Cyclophosphamide metabolites cause hemorrhagic cystitis and long-term bladder cancer risk 1
• Tobacco smokers develop cancer at lower doses and earlier 1
• Persistent unexplained hematuria requires investigation even years after cyclophosphamide discontinuation 1

Cumulative dose concerns:

• Long-term cyclophosphamide maintenance is no longer recommended due to toxicity 1
• Switch to azathioprine, methotrexate, or leflunomide for maintenance after remission induction 1
• Lower cumulative doses (2.5-3 g) may maintain efficacy while reducing infectious complications 4

Evidence Quality Considerations

The recommendation for cyclophosphamide has Level 1A evidence for GPA and MPA, but only Level 3 evidence for EGPA, as no RCTs have been published for EGPA. 1 The RAVE and RITUXVAS trials established rituximab as equally effective to cyclophosphamide for most AAV presentations, with rituximab showing superiority in relapsing PR3-ANCA disease. 1, 5 However, for severe renal impairment (creatinine >4 mg/dL), cyclophosphamide remains preferred based on the most recent KDIGO 2024 guidelines. 1