Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis (Journal Club)Presentation Transcript
Raj Kiran Medapalli, MD, MPH. Nephrology Fellow May 19 th , 2009 Mount Sinai School of Medicine Division of Nephrology Journal Club
Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis The “CYCLOPS” Study European Vasculitis Study Group (EUVAS) Annals of Internal Medicine 19 May 2009 Journal Club by Raj Kiran Medapalli, MD
Brief introduction to ANCA Vasculitis & CYC.
Review of key RCTs for induction & maintenance therapy for ANCA vasculitis.
Review CYCLOPS study.
Strengths, weaknesses & conclusions from CYCLOPS.
Source: Brenner & Rector's The Kidney, 8 th Edition.
Source: Jennette JC & Falk RJ. Small Vessel Vasculitis. NEJM. Nov 1997.
Incidence: 20 cases per million individuals per year
Most commonly occurs in the elderly (peak age 55–70 years).
Before CYC, 2-year survival rates were about 20%.
5-year survival rates now approach 80%.
Prevalence is over 200 cases per million individuals.
Prednisone regimen (1 mg/kg/d, tapered to 15 mg/d at 12 wks & 7.5 mg/d by 6 months, & stopped by 12 mths).
All drug treatments were gradually tapered and withdrawn by 12 months.
Followup continued to 18 months.
Primary end point was the remission rate at 6 months (noninferiority testing).
Results MTX vs CYC
6 months remission rate:
89.8% vs 93.5% (p 0.041)
MTX grp, remission delayed in pts with more extensive disease (P = 0.04) or pulm involvement (P =0.03).
Relapse rate at 18 months:
69.5% vs 46.5%
High in both. 12 mth rx not enough.
Median time to relapse:
13 mths vs 15 mths (p 0.023)
HR 1.85 [95% CI 1.06–3.25].
Median cu. dose of steroids
8.8gm vs 6.2gm (p 0.001)
2 pts from each group died.
Leucopenia less in MTX (p 0.012)
4 life threatening infxns in each grp
Liver dysfxn > in MTX grp (p 0.036)
Adjunctive Plasma Exchange or High-Dosage Solumedrol for Severe Renal Vasculitis. EUVAS RCT (MEPEX) Jayne DRW et al. JASN 2007
Background: In a RCT by Pusey et al in 1991, 10/11 pts who were initially dialysis-dependent, recovered renal fxn when rxed with PE & usual Rx as compared to only 3/8 pts who did not get PE. P = 0.041.
137 pts with renal bx proven ANCA associated vasculitis & creat > 5.8 mg/dl or RRT at presentation. Mean age 66yrs.
Randomly assigned to receive 7 plasma exchanges (n=70) or 3g of IV Solumedrol (n=67).
Both groups received daily CYC & oral prednisolone.
Results MP Vs PE
3 month renal survival
49% vs 69% (p 0.02)
Progression to ESRD at 12 mths
43% vs 19%
Risk Diff: 24% (95% CI 6.1 - 41)
1yr patient survival
76% vs 73% (NS)
Severe adverse event rates
48% vs 50% (NC)
No sig differences in freq or severity of path lesions at baseline.
Azathioprine for Maintainance Rx. (CYCAZAREM) Jayne D, et al. NEJM 2003. EUVAS RCT.
155 pts with creat <5.7mg/dl at onset, treated with cCYC and prednisolone for at least 3months.
61% pts with WG & 39% with MPA.
144 pts who achieved remission were randomly assigned to continued cCYC (n=73,1.5 mg/kg/d) or AZT (n=71, 2 mg/kg/d). Prednisolone (10mg/d) was continued in both groups.
Beginning at 12 months, both groups received AZT (1.5mg/kg/d) & prednisolone (7.5 mg/d).
Followed for 18 months
Relapse was the primary end point.
Results AZT vs cCYC
15.5% vs 13.7%. p=0.65
Lower among the patients with MPA than WG 8% vs, 18% (P=0.03)
Severe adverse effects
8 (11%) vs 7 (10%). p= 0.94
Overall 8 deaths (5%), 7 within first 3 months.
7% of AZT pts had an allergic rxn (fever, chills & rash) which lead to drug d/c.
AZT vs. MTX for Maintenance Rx. FVSG RCT (WEGENT). Pagnoux C, et al. NEJM 2008.
159 pts with WG or MPA.
pCYC (0.6 g/sqm) q2wks x3, then 0.7g/sqm qQ3wks until remission, followed by 3 additional consolidation pulses q3 wkly.
Pulse solumedrol x 3 d, followed by PO prednisone (1 mg/kg/d) for 3 wks, then progressively tapered to an avg dose of 12.5 mg/d at 6 months & 5 mg/d at 18 months and complete discontinuation after 24 mths.
129 pts (79%) who achieved were randomized to AZT (2mg/kg/d) or MTX (0.3mg/kg/d, increased in 2.5 mg increments each wk, if tolerated, to a dose of 20 - 25 mg/wk) for 12 months , 2 to 3 weeks after the last pCYC dose.
Mean f/u: 29 ± 13 months.
Sample size was calculated on the assumption that MTX would be less toxic than AZT.
Results AZT vs MTX
BVAS at diag: 23.6 vs. 21.2 p=0.07
Lung inv: 83% vs. 67% p=0.05
Renal inv: 75% in both groups.
Creat at entry 1.52 vs.1.4. p=0.56
23pts vs 21pts. P=0.71
73% had a relapse after study drug discontinuation.
? optimal duration of Rx
29 pts vs 35 pts (P = 0.29)
Drug d/c or death
7 pts (11%) vs.12 pts (20%). p=0.21.
1 death MTX grp 2/2 aplastic anemia.
HR for MTX: 1.65 (0.65 to 4.18)
8% in NORAM (creat <1.7).
Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis The “CYCLOPS” Study European Vasculitis Study Group (EUVAS) Annals of Internal Medicine 19 May 2009
Open-label, multicenter, RCT conducted over 18 months.
149 patients from 42 hospitals in 13 European countries & Mexico.
71 with MPA, 56 with WG & 22 with renal limited vasculitis.
Funded by the European Union.
Pts were enrolled by their treatment physicians.
Inclusion criteria :
Newly diagnosed Wegener granulomatosis, microscopic polyangiitis, or renal-limited microscopic polyangiitis.
Renal involvement attributable to active vasculitis as defined by at least 1 of the following:
Coexistence of other multisystem autoimmune disease; hepatitis B or C virus or HIV infection
Serum creatinine level > 5.7 mg/dL.
Intervention Pulse (IV or PO) Cytoxan Daily PO Cytoxan Induction 15 mg/kg IV Q2wkly x 3 doses 2 mg/kg/d, until remission 15 mg/kg IV or 5 mg/kg PO on 3 consecutive days, q3wkly, until remission (physician discretion) Initial maintenance Continue above for 3 months 1.5 mg/kg/d for 3 months Max dose 1.2 g per pulse 200 mg/d Age 60-70 Reduce by 2.5 mg/kg per pulse Reduce by 25% Age >70 Reduce by 5 mg/kg per pulse Reduce by 50% Creat 3.4 to 5.7 Reduce by 2.5 mg/kg per pulse - CBC checks Day 0,10,14 Q wkly x 1 month, Q2wkly x 1 month, then monthly 3 - 4 x 10 9 /L - Withhold dose and resume at a dose reduced by 25 mg/d when WBC > 4 x 10 9 /L 2 - 3 x 10 9 /L Reduce dose by 20% 1 - 2 x 10 9 /L Reduce dose by 40%
Induction therapy (continued):
Both groups also received prednisolone, 1 mg/kg orally, tapered to 12.5 mg at the end of month 3 and to 5 mg at the end of the study (month 18).
Maintainance therapy :
Both groups continued the cyclophosphamide regimens for 3 months after remission.
Then switched to Azathioprine, 2 mg/kg per day orally, until month 18. Max daily dose was 200 mg.
PCP prophylaxis was given for all patients.
2-Mercaptoethanesulfonate sodium (Mesna) was optional.
Pts who did not achieve remission at 9 months were treated according to local practice. Data was collected on these pts but they were censored during survival analysis.
No patients received plasmapheresis.
Time to remission
Proportion of patients who achieved remission at 6 & 9 months
Proportion with major and minor relapses.
Change in renal function
Adverse events, including leukopenia and infection
Cumulative dose of cyclophosphamide and prednisolone
Assessed these outcomes at baseline; every 1.5 months until 9 months, then every 3 months until 18 months; and at relapse.
Birmingham Vasculitis Activity Score (BVAS) (measures manifestations of active vasculitis during the last 4 weeks) at every visit.
Vasculitis Damage Index (measures of cumulative damage from any cause since disease onset), at baseline and every 3 months.
Remission : absence of new or worse signs of dz activity on BVAS & no more than 1 item indicating persistent disease activity (BVAS ≤1).
Major relapse : recurrence or first appearance of at least 1 BVAS item indicating threatened vital organ function.
Minor relapse : recurrence or1st appearance of at least 3 BVAS items related to nonvital organs.
Birmingham Vasculitis Activity Scores (BVAS)
Measures manifestations of active vasculitis in the preceding 4 weeks.
Ref: Luqmani R.A, et al. Q J Med 1994; 87:671-678.
Departments of Rheumatology and Nephrology, University of Birmingham,
Edgbaston, West Midlands, UK.
Birmingham Vasculitis Activity Scores (BVAS)
- Score range: 0 to 63
Renal, GI and CNS systems given higher weightage.
Time to Remission
131 pts achieved remission by 9 months.
67 pts [88.1%] in the pulse group vs. 64 pts [87.7%] in the daily oral group.
HR: 1.098 [95% CI: 0.78 to 1.55;P = 0.59].
Median time to remission was 3 months for both groups (pulse group range: 0.5 to 8 months; daily oral group range: 1 to 7.5 months).
Of the 18 pts who did not achieve remission, 5 pts in the daily oral group died, 3 in the pulse group died, and 4 pts in each group withdrew or were lost to f/u.
2 patients did not achieve remission by 9 months but remained in the study; censored becos they did not receive protocol-based treatment.
Main Outcome Parameters by Treatment Group
19 (14.5%) of the 131 patients who achieved remission by 9 months relapsed.
13 (7 with major and 6 with minor relapse) in the pulse group.
6 (3 with major and 3 with minor relapse) in the daily oral group.
HR: 2.01 [95% CI, 0.77 to 5.30]. But study not powered to detect this diff.
Similar to CYCAZAREM: used a similar cCYC regimen for induction & did
not have a consolidation phase.
Relapse rate < trials which stopped steroids @ 6(WGET) or 12 mths (NORAM).
Main Outcome Parameters by Treatment Group
Deaths : 14 died: 5 in the pulse group & 9 in the daily oral group (P = 0.79).
Median time to death did not differ: 3.5 mths in pCYC vs 4 in cCYC grp
Death associated with active dz or rx in 3 pts in pCYC grp & 7 in cCYC grp
Death 2/2 sepsis in 5 of the daily oral group pts & 1 of the pulse group pts.
Early deaths before remission similar to CYCAZAREM, but more late deaths after remission [? 2/2 higher % MPA pts (48% vs 39%) who have more chronic lesions than WG, poorer eGFR @entry 37 vs 50ml/min; & more men (59% vs 47%) who have been shown to have greater dz extent in the past].
In the pulse group, the median eGFR improved from 32 to 45 mL/min/1.73 m2 (P= 0.010).
In the daily oral group, the median eGFR improved from 29 to 45 mL/min/1.73 m2 (P = 0.010).
GFR did not differ between study groups at any time point.
6 pts (5 in the pulse group & 1 in the daily oral group) developed ESRD, 3 pts in the context of uncontrolled disease during induction.
The 2 groups did not differ in the development of ESRD (P = 0.105).
Measures of disease activity
BVAS for new or worse disease decreased promptly with rx & were similar in both groups at all time points.
All-cause damage [Vasculitis Damage Index (VDI)], increased in both groups from a median of 0 at entry to 2 at months 6 & 18. NS btwn groups.
CRP levels similar in both treatment groups at study start and decreased
rapidly in both groups after initiation of induction therapy.
Daily oral group received nearly twice the dose administered to the pulse group (15.9 g vs. 8.2 g; P < 0.001).
The groups did not differ in prednisolone dose at any time point, with a mean cumulative dose of about 7.5g in both grps.
Pts were less likely to have leukopenia in the pulse group than in the daily oral group 26% vs. 45%. P = 0.016.
Median time to 1st episode: 219 days vs 68 days. HR: 0.41 (0.23-0.71).
Median time to 1st infection: 147 (pCYC) vs 68 days. HR 0.88 (0.42-1.83).
Strengths of the study
Largest trial to date comparing the efficacy fo pCYC vs. cCYC.
EUVAS has the largest experience with RCTs in ANCA-Vasculitis.
Funded by the European Union.
Used clinically relevant inclusion & exclusion criteria. Renal involment was necessary to be included in the trial.
Used a consensus Rx regimen.
Weaknesses of the study
Not powered to to detect differences in relapse rate which is the key question that needs to be answered. Sample size was determined based on clinical (rare dz: 12/million) & monetary limitations (funding was for 5 yrs only), rather than statistical calculations.
18 month f/u not be enough to determine the optimal duration for therapy (Rx was continued until month 18 in all pts).
Not placebo controlled & outcomes were measured by a subjective tool (BVAS), which can lead to bias. (But, no objective bio markers of dz remission & same tools used in all previous trials).
The addition of a 3-month consolidation phase to the daily oral cyclophosphamide regimen might bias the results against that group by increasing the risk for hematologic toxicity without improving efficacy.
pCYC is a reasonable alternative to cCYC for induction of remission in pts with ANCA associated vasculitis & moderate renal dysfunction/ involvement (creat<5.7& no RRT at onset).
AZT is a reasonable alternative for maintainace rx after induction with pCYC or cCYC.
No difference in rate of remission or time to remission.
Cumulative dose was reduced by approximately 50% in the pCYC grp.
Fewer episodes of leukopenia and possibly lesser infections, but other side effects not significantly different.
pCYC is simpler to monitor, better compliance and also permits pre-hydration and administration of Messna.
More relapses with pCYC (NS, but study not powered to detect differences). However, overall the relapse rate was similar to CYCAZAREM which used cCYC and Azathioprine for maintainance.
3-month consolidation phase seems to have little effect on relapse in 18 months and can probably be eliminated, especially in cCYC group.
Higher relapse rate in trials that discontinued steroids at 6 months (WGET) & 12 months (NORAM) than in trials that continued steroids for 18 months (CYCLOPS & CYCAZAREM). Optimum duration of Rx remains unclear.
Ongoing trials at EUVAS
MYCYC: MMF vs. cyclophosphamide for remission induction.
IMPROVE: Compares MMF with azathioprine for remission therapy in renal vasculitis. Completed recruitment.
RITUXVAS: Rituximab based regimen vs. standard cyclophophamide/ azathioprine regimen in the treatment of active, ‘generalised’ ANCA associated vasculitis. Completed recruitment.
REMAIN: Long-term low dose immunosuppression vs. treatment withdrawal for renal vasculitis.
STAVE: Meta-analysis of the effect of different corticosteroid dosing regimens on relapses.
Summary of Rx options for induction
Daily oral cyclophosphamide [2 mg/kg/d]
PO Prednisone (1 mg/kg/day, max 60mg/d) x 4 weeks. If significant improvement then taper to 0.25 mg/kg/d by 12 weeks & further as tolerated. Median duration of steroid Rx is 6-12 months, but in CYCOPS & CYCAZAREM continued until 18 months, with better results]
Bactrim SS daily or Bactrim DS q MWF for PCP prophylaxis.
In pts allergic to Bactrim: Dapsone (100 mg/day), Atovaquone (1500 mg/day), or monthly aerosolized Pentamidine.
Mesna: Binds and detoxifies acrolein. Dose same as the dose of CYC. Give at 0 & 2 hrs (either IV or PO; for PO use, the IV formulation is diluted in soda).
Nystatin swish and swallow orally: 600,000 units 4 times/day
Sperm cryopreservation + Testosterone 100 mg IM every 15 days in males.
Leuprolide 3.75 mg IM monthly in females. Emergency in vitro fertilization can be performed, but requires significant hormonal manipulation and can lead to a three to five week delay in therapy.
Calcium 1200mg and Vitamin D 800mg, while on steorids.
Pepcid 20mg QD, while on steroids.
Alternative induction regimens (to minimize use of Cyc)
IV or PO Pulse Cyclophosphamide (EUVAS - CYCLOPS)
15 mg/kg IV Q2wkly x 3 doses
Then 15 mg/kg IV Q3wkly or 5 mg/kg PO on 3 consecutive days Q3wkly until remission
? Continue for 3 more months after remission (consolidation phase)
Methotrexate (EUVAS – NORAM)
In pts with mild or no renal dysfunction (creat <1.7, prot,1g, no RBC casts) and without other critical organ inv.
Start PO MTX @ 15 mg/week, if tolerated increase in 2.5mg increments each week to 20–25 mg/week by 12 weeks. Maintain until month 10 & if remission sustained taper by 2.5mg each month until discontinuation.
In another study by FVSG (WEGENT), MTX was studied for maintainance only and was started as above after induction with IV pCYC + 3 consolidation doses & tapered after 12 mths (of maintainance rx) and d/c.
7 plasma exchanges, in addition to cCYC & steroids (EUVAS - MEPEX)
In patients with severe renal failure (creat > 5.8 or dialysis dependent at presentation) or concomitant anti-GBM abs or pulmonary hemorrhage
Rx options for maintainance
Cyclophosphamide (Original NIH Study)
1.5 mg/kg per day. Given for at least 1 yr after remission. Then tapered by 25-mg decrements every 2 - 3 mths until d/c or dz recurrence required a dose increase.
Azathioprine (EUVAS – CYCAZAREM & CYCLOPS)
Start at 2 mg/kg/d for 18 months (reduced to 1.5 mg/kg/d at 1 yr from the time of initiation of cCYC induction therapy in CYCAZAREM).
Prednisolone was given at 10mg/d until 1yr, then 7.5mg/d until month 18 in CYCAZAREM.
Prednisolone, 1 mg/kg orally, tapered to 12.5 mg at the end of month 3 and to 5 mg at month 18 in CYCLOPS