What is the cyclophosphamide dose and schedule in the European Vasculitis Study Group (EUVAS) induction protocol for severe ANCA-associated vasculitis, including adjustments for impaired renal function or elderly patients and the subsequent maintenance regimen?

Cyclophosphamide Dosing in ANCA Vasculitis: EUVAS Protocol

Standard Intravenous Cyclophosphamide Regimen

The EUVAS protocol for intravenous cyclophosphamide in severe ANCA-associated vasculitis uses 15 mg/kg administered at weeks 0,2,4,7,10, and 13, with additional doses at weeks 16,19,21, and 24 if disease activity persists. 1

Dosing Schedule

• Initial intensive phase: 15 mg/kg every 2 weeks for the first 3 doses (weeks 0,2,4) 1, 2
• Maintenance phase: 15 mg/kg every 3 weeks (weeks 7,10,13) 1, 2
• Extended protocol: Additional doses at weeks 16,19,21,24 if required for refractory disease 1, 2
• Maximum dose cap: 1500 mg per infusion 2, 3
• Total duration: 3-6 months for remission induction 1, 2

This pulse regimen achieves equivalent remission rates to daily oral cyclophosphamide (88.1% vs 87.7% at 9 months) while delivering significantly lower cumulative doses (median 8.2 g vs 15.9 g) and reducing leukopenia risk by 59% 4.

Mandatory Dose Adjustments

Age-Based Reductions

Elderly patients require substantial dose reductions to minimize toxicity while maintaining efficacy:

• Age >60 years: Reduce to 12.5 mg/kg per dose 1
• Age >70 years: Reduce to 10 mg/kg per dose 1

Renal Function Adjustments

For patients with severe renal impairment (GFR <30 ml/min/1.73 m²): Reduce dose by 2.5 mg/kg from the calculated dose 1

These adjustments are critical as elderly patients are particularly susceptible to infectious complications, and lower cumulative doses (2.5-3 g) maintain efficacy while reducing leukopenia and infection rates 5.

Alternative Oral Cyclophosphamide Regimen

For patients without access to infusion centers or preferring oral administration: 2 mg/kg/day for 3 months, continuing up to a maximum of 6 months if ongoing disease activity persists 1

Age-Based Oral Dose Reductions

• Age >60 years: 1.5 mg/kg/day 1
• Age >70 years: 1.0 mg/kg/day 1

Renal Function Adjustment for Oral Dosing

• GFR <30 ml/min/1.73 m²: Reduce by 0.5 mg/kg/day 1

The oral regimen delivers higher cumulative doses and increased leukopenia risk compared to pulse IV therapy, making the IV route preferable when feasible 4.

Mandatory Concomitant Glucocorticoid Therapy

Cyclophosphamide must always be combined with glucocorticoids using a structured tapering protocol based on body weight: 1, 2

Weight-Based Prednisolone Dosing (mg/day)

Week	<50 kg	50-75 kg	>75 kg
1	50	60	75
2	25	30	40
3-4	20	25	30
5-6	15	20	25
7-8	12.5	15	20
9-10	10	12.5	15
11-12	7.5	10	12.5
13-14	6	7.5	10
15-16	5	5	7.5
19-20	5	5	5
23-52	5	5	5

1

This reduced-dose glucocorticoid regimen from the PEXIVAS trial achieves comparable outcomes to higher-dose protocols while minimizing steroid toxicity 1.

Essential Protective Measures

Hemorrhagic Cystitis Prevention

MESNA (sodium 2-mercaptoethanesulfonate) is mandatory with each cyclophosphamide infusion to prevent hemorrhagic cystitis, which occurs in 6% of patients without protection 2, 3, 6.

Pneumocystis Prophylaxis

All patients must receive trimethoprim/sulfamethoxazole 800/160 mg on alternate days or 400/80 mg daily throughout cyclophosphamide treatment and for several months after completion 1, 2, 3, 6.

Special Considerations for Severe Disease

Plasma Exchange Indications

Consider plasma exchange for patients with:

• Serum creatinine >3.4 mg/dl (>300 µmol/L) 1
• Dialysis requirement or rapidly increasing creatinine 1
• Diffuse alveolar hemorrhage with hypoxemia 1, 2

Combination Rituximab-Cyclophosphamide Protocol

For severe organ-threatening disease, consider combining rituximab 375 mg/m² weekly for 4 weeks with limited cyclophosphamide 15 mg/kg at weeks 0 and 2 only 1, 6. This combination approach demonstrates superior long-term outcomes with reduced death risk (HR 0.29), ESRD risk (HR 0.20), and relapse risk (HR 0.49) compared to cyclophosphamide alone 7.

Transition to Maintenance Therapy

After achieving remission (typically 3-6 months), switch to maintenance therapy with either:

• Rituximab: 500 mg × 2 at complete remission, then 500 mg at months 6,12, and 18 (MAINRITSAN scheme) 1
• Azathioprine: 1.5-2 mg/kg/day plus low-dose glucocorticoids 1

Optimal maintenance duration: 18 months to 4 years after remission induction 1, 6

Switching to azathioprine after only 3-6 months of cyclophosphamide (rather than 12 months) may increase relapse risk, though this remains uncertain 8.

Critical Safety Monitoring

Hematologic Monitoring

Monitor leukocyte counts regularly and adjust doses for acute leukopenia or gradual decline 2. Lower cumulative cyclophosphamide doses (2.5-3 g) significantly reduce leukopenia rates (HR 2.73) and infectious episodes 5.

Fertility Considerations

Gonadal toxicity is substantial: amenorrhea occurs in 20-85% of menstruating women and azoospermia in men 2, 3. Discuss fertility preservation before initiating treatment, particularly in younger patients 2.

Malignancy Risk

Limit total cumulative cyclophosphamide exposure to reduce bladder cancer and myelodysplasia risk 2, 3. The pulse IV regimen's lower cumulative dose (median 8.2 g vs 15.9 g oral) provides a significant safety advantage 4.

Key Clinical Pitfalls to Avoid

• Never omit age and renal function dose adjustments—elderly patients with reduced GFR require both adjustments applied sequentially 1
• Never use cyclophosphamide without MESNA protection for IV pulses—hemorrhagic cystitis risk is 6% without prophylaxis 2, 3
• Never skip Pneumocystis prophylaxis—infection risk is substantial throughout treatment 1, 2
• Never exceed 1500 mg per IV pulse—this cap applies regardless of calculated weight-based dose 2, 3