CYCLOPS

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de Groot K, et al. "Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial". Annals of Internal Medicine. 2009. 150(10):670-680.
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Clinical Question

Among patients with newly-diagnosed ANCA-associated vasculitis with renal involvement, is pulse cyclophosphamide superior to daily oral cyclophosphamide for the induction of remission?

Bottom Line

Among patients with newly-diagnosed ANCA-associated vasculitis with renal involvement, there was no difference in rates of, or time to remission when comparing pulse cyclophosphamide to daily oral cyclophosphamide. Those receiving pulse cyclophosphamide required a lower cumulative dose and had a lower risk of leukopenia.

Major Points

ANCA-associated vasculitis was almost uniformly fatal until the introduction cyclophosphamide and glucocorticoid therapy was first demonstrated by Fauci and colleagues in the 1970s.[1] The optimal dosing of these medications was unclear. While several small studies suggested that pulse cyclophosphamide was likely equivalent to daily oral cyclophosphamide for the induction of remission in patients with ANCA-associated vasculitis, no large trial had been performed.

Published in 2009, CYCLOPS randomized 149 patients with newly-diagnosed ANCA vasculitis to pulse cyclophosphamide or daily oral cyclophosphamide. Both groups received corticosteroids and azathioprine. Despite its lower cumulative cyclophosphamide dose, pulse cyclophosphamide resulted in similar rates of remission as daily oral cyclophosphamide. Pulse cyclophosphamide was associated with a significantly lower risk of leukopenia but a non-significant trend towards higher risk of relapse. In 2012 the authors published follow-up results (median 4.3 years), showing a higher relapse in the pulse cyclophosphamide group than the daily oral group (39.5% vs. 20.8%; P=0.029) with mean follow-up of 4.3 years.[2]

Of note, the 2010 RITUXVAS[3] and RAVE trials compared cyclophosphamide to rituxamab in patients with ANCA vasculitis with and without renal involvement.

Guidelines

KDIGO Glomerulonephritis (2012, adapted)[4]

  • Recommended treatments for ANCA vasculitis with glomerulonephritis:
    • Cyclophosphamide 0.75 g/m2 IV q3-4 weeks, decrease dose to 0.5 g/m2 if age >60 or GFR <20 mL/min/1.73 m2, adjust following doses to achieve 2-week WBC nadir >3,000 cells/mm3
      • Alternative dose of 15 mg/kg q2 weeks for 3 ulses then 15 mg/kg every 3 weeks for 3 months beyond remission, with dose reductions for age and GFR as above
      • Plus pulse and oral steroids
    • Cyclophosphamide 1.5-2 mg/kg/day PO, with reduced dose if age >60 or GFR <20 mL/min/1.73 m2, adjust following doses to achieve WBC nadir >3,000 cells/mm3
    • Methylprednisolone 500 mg IV daily x3 days as a pulse
    • Prednisone 1 mg/kg/day PO for 4 weeks to a maximum dose of 60 mg/day, tapering down over 3-4 months
    • Rituximab 375 mg/m2 IV weekly x4 weeks
      • Plus pulse and oral steroids
    • Plasmapheresis, 60 mL/kg volume replacement:
      • Vasculitis without anti-GBM Ab:
        • No pulmonary hemorrhage: 7 treatments over 14 days
        • Diffuse pulmonary hemorrhage: Daily treatment until the bleeding stops then q48 hours for a total of 7-10 treatments
      • Vasculitis with anti-GBM Ab: Daily for 14 days or until anti-GBM Abs are no longer detectable

Design

  • Multicenter, open-label, parallel-group, randomized, controlled trial
  • N=149 (160 screened)
    • Pulse cyclophosphamide (n=76)
    • Daily oral cyclophosphamide (n=73)
  • Setting: 42 centers in Europe and Mexico
  • Median follow-up: 18 months
  • Analysis: Intention-to-treat
  • Primary outcome: Time to remission

Population

Inclusion Criteria

Details are from the protocol published elsewhere.[5]

  • Age 18-80 years
  • Newly diagnosed ANCA-associated vasculitis, including any of the following:
    • Granulomatosis with polyangiitis (previously referred to as "Wegener's granulomatosis")
    • Microscopic polyangiitis
    • Renal-limited vasculitis
  • Renal involvement of the disease, defined by ≥1 of the following:
    • Creatinine >150 umol/L (1.69 mg/dL) but <500 umol/L (5.6 mg/dL)
    • Biopsy showing necrotizing glomerulonephritis
    • RBC casts
    • Urine showing >30 RBC/high-powered field and proteinuria (>1 gram/day)
  • Confirmatory histology or ANCA positive serology

Exclusion Criteria

  • >2 weeks of prior cyclophosphamide or other cytotoxic drug therapy in the prior year or corticosteroids for >4 weeks
  • Other multisystem autoimmune disease
  • Hepatitis Be Ag+, HCV Ab+, or known HIV
  • Creatinine >500 umol/L (5.6 mg/dL)
  • Life-threatening organ dysfunction
  • Prior malignancy
  • Pregnancy or lack of appropriate contraception in women
  • Anti-GBM Ab+

Baseline Characteristics

From the pulse cyclophosphamide group.

  • Demographics: Age 57 years, male 54%
  • Diagnosis:
    • Granulomatosis with polyangiitis: 33%
    • Microscopic polyangiitis: 50%
    • Renal limited vasculitis: 17%
  • Diagnostics:
    • +biopsy, +ANCA: 79%
    • +biopsy, -ANCA: 0%
    • -biopsy, +ANCA: 21%
  • BVAS score 20
  • Labs: Creatinine 223 umol/L (2.52 mg/dL), PR3+ 39%, MPO+ 50%, PR3+ and MPO+ 5%, PR3- and MPO- 5%, CRP 524 nmol/L

Interventions

  • Randomized to a group:
    • Pulse cyclophosphamide: 15 mg/kg IV pulses every 2 weeks for 6 weeks, then 15 mg/kg IV pulses very 3 weeks until remission and then for 3 months following remission, adjusted for WBC level, age, and renal function
      • Weeks 7-25 could be be administered orally as 5 mg/kg/day for 3 days per week
    • Daily oral cyclophosphamide: 2 mg/kg/day until remission (generally about 3 months), then 1.5 mg/kg/day for 3 months following remission, adjusted for WBC count, age, and renal function
  • Additional immunosuppression (administered to both groups):
    • Prednisolone 1 mg/kg/day oral, tapered to 0.4 mg/kg/day by month 3 and 5 mg/kg/day by month 15
    • Azathioprine 2 mg/kg/day starting 3 months after remission, continued until the end of the study

Outcomes

Comparisons are pulse cyclophosphamide vs. daily oral cyclophosphamide.

Primary Outcomes

Median time to remission
3 months (range 0.5-8) vs. 3 months (range 1-7.5)
Hazard ratio 1.098 (95% CI 0.78-1.55; P=0.59)

Secondary Outcomes

Proportion in remission at 9 months
88.1% vs. 87.7%
Relapses
Of the 78.9% of patients who achieved remission by 9 months.
Any: 13 vs. 6 patients (HR 2.01; 95% CI 0.77-5.30)
Major: 7 vs. 3 patients
Minor: 6 vs. 3 patients
Any adverse events
77% vs. 77%
Severe or life-threatening: 19 vs. 31 patients
All-cause mortality
6.5% vs. 12.3% (P=0.79)
Changes in renal function (improvement in eGFR)
5 ml/min/1.73 m2 vs. 8 ml/min/1.73 m2 (P=0.36)
Leukopenia
26% vs. 45% (P=0.016)
Multiple bouts: 4 vs. 15 patients
Time to first event: 219 vs. 68 days (HR 0.41; 95% CI 0.23-0.71)
Infection
20 vs. 21 patients
Time to first event: 147 days vs. 68 days (HR 0.88; 95% CI 0.42 to 1.83)
Life threatening: 7 vs. 10 events
Cumulative dose of cyclophosphamide
8.2 grams vs. 15.9 grams (P<0.001)
Cumulative dose of prednisolone
7587 mg vs. 7586 mg

Additional Analyses

BVAS score
Similar at all points (see table 2 on pg. 676-677 and figure 4 on pg. 678)

Criticisms

  • Unclear how patients would do with this protocol in areas with endemic TB; pulse cyclophosphamide may be lead to worse outcomes in patients with latent TB[6]
  • Daily oral therapy may have been more effective than pulse therapy for renal function recovery[6]
  • Contrary to the author's comments, pulse therapy is not likely more convenient[6]
  • No report of proteinuria[6]

Funding

  • CYCLOPS was funded by the European Union (European Community Systemic Vasculitis Trial project) and the Associated Vasculitis European Randomised Trial (AVERT) project
  • The authors had no reported financial conflicts of interest

Further Reading

  1. Fauci AS, et al. "Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years." Ann Intern Med. 1983 Jan;98(1):76-85.
  2. Harper L, et al. "Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up." Annals of the Rheumatic Diseases. 2012;71(6):955-960.
  3. Jones, Rachel B., et al. "Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis." New England Journal of Medicine. (2010):363)211-220.
  4. Eckard KU, Kasiske BL, et al. "KDIGO clinical practice guideline for glomerulonephritis." Kidney International. 2012;2(sup 2):259-274.
  5. Vasculitis.org CYCLOPS protocol
  6. 6.0 6.1 6.2 6.3 Multiple authors. "Letters: Pulse verus daily oral cyclophosphamide in ANCA-associated vasculitis." Annals of Internal Medicine. 2010;152(1):64-66.