Raj Kiran Medapalli, MD, MPH. Nephrology Fellow May 19 th , 2009 Mount Sinai School of Medicine Division of Nephrology Jou...
Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis The “CYCLOPS” Study Europea...
Outline <ul><li>Brief introduction to ANCA Vasculitis & CYC. </li></ul><ul><li>Review of key RCTs for induction & maintena...
Source: Brenner & Rector's The Kidney, 8 th  Edition.
Source: Jennette JC & Falk RJ. Small Vessel Vasculitis. NEJM. Nov 1997.  <ul><li>Incidence: 20 cases per million individua...
Source: Falk RJ & Jennette JC. JASN. 1997. C-ANCA, anti-Proteinase 3 P-ANCA, anti-Myeloperoxidase Anti-neutrophil cytoplas...
Source: Xiao H, et al.  Am J of Path. Jan 2007.
 
Cyclophosphamide (Cyc) <ul><li>Alkalyting agent </li></ul><ul><li>Prodrug </li></ul><ul><li>Binds & crosslinks a variety o...
<ul><li>Bone marrow suppression </li></ul><ul><ul><li>~ 5% severe leukopenic events (WBC < 2.0/mm3) </li></ul></ul><ul><ul...
Hoffman GS et al. Annals of Int Med. March 1992. <ul><li>158 WG pts, referred to NIH during the previous 24 yrs. </li></ul...
<ul><li>Complications </li></ul><ul><li>Death due to Dz/Rx: 13% </li></ul><ul><li>Permanent disease-related morbidity occu...
Pulse Cyc in ANCA Vasculitis - EUVAS meta analysis  de Groot K et al. NDT 2001 <ul><li>A metanalyses of 3 RCTs comparing a...
CYC vs MTX for Induction - EUVAS RCT (NORAM) de Groot K et al. Arth & Rheum Aug 2005 <ul><li>100 pts with WG or MPA  </li>...
Adjunctive Plasma Exchange or High-Dosage Solumedrol for Severe Renal Vasculitis. EUVAS RCT (MEPEX)   Jayne DRW et al. JAS...
Azathioprine for Maintainance Rx. (CYCAZAREM) Jayne D, et al. NEJM 2003. EUVAS RCT. <ul><li>155 pts with creat <5.7mg/dl a...
AZT vs. MTX for Maintenance Rx. FVSG RCT (WEGENT).   Pagnoux C, et al. NEJM 2008.  <ul><li>159 pts with WG or MPA. </li></...
Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis The “CYCLOPS” Study Europea...
Study Design <ul><li>Open-label, multicenter, RCT conducted over 18 months. </li></ul><ul><li>149 patients from 42 hospita...
Intervention Pulse (IV or PO) Cytoxan Daily PO Cytoxan Induction 15 mg/kg IV Q2wkly x 3 doses 2 mg/kg/d, until remission 1...
<ul><li>Induction therapy (continued): </li></ul><ul><li>Steroids </li></ul><ul><ul><li>Both groups also received predniso...
<ul><li>Primary outcome   </li></ul><ul><li>Time to remission  </li></ul><ul><li>Secondary outcomes   </li></ul><ul><li>Pr...
Birmingham Vasculitis Activity Scores (BVAS) <ul><li>Measures manifestations of active vasculitis in the preceding 4 weeks...
Birmingham Vasculitis Activity Scores (BVAS) <ul><li>- Score range: 0 to 63 </li></ul><ul><li>Renal, GI and CNS systems gi...
 
 
 
 
Time to Remission <ul><li>131 pts achieved remission by 9 months.  </li></ul><ul><li>67 pts [88.1%] in the pulse group vs....
Main Outcome Parameters by Treatment Group <ul><li>Relapse </li></ul><ul><li>19 (14.5%) of the 131 patients who achieved r...
Main Outcome Parameters by Treatment Group <ul><li>Deaths : 14 died: 5 in the pulse group & 9 in the daily oral group (P =...
Renal Outcomes <ul><li>eGFR </li></ul><ul><ul><li>In the pulse group, the median eGFR improved from 32 to 45 mL/min/1.73 m...
Measures of disease activity <ul><li>BVAS for new or worse disease decreased promptly with rx & were similar in both group...
Cumulative dose <ul><li>Cyclophosphamide </li></ul><ul><ul><li>Daily oral group received nearly twice the dose administere...
Adverse events <ul><li>Leucopenia </li></ul><ul><li>Pts were less likely to have leukopenia in the pulse group than in the...
Strengths of the study <ul><li>Largest trial to date comparing the efficacy fo pCYC vs. cCYC.  </li></ul><ul><li>EUVAS has...
Weaknesses of the study <ul><li>Not powered to to detect differences in relapse rate which is the key question that needs ...
Conclusions <ul><li>pCYC is a reasonable alternative to cCYC for induction of remission in pts with ANCA associated vascul...
Ongoing trials at EUVAS <ul><li>MYCYC: MMF vs. cyclophosphamide for remission induction. </li></ul><ul><li>IMPROVE: Compar...
Summary of Rx options for induction <ul><li>Standard Induction </li></ul><ul><ul><li>Daily oral cyclophosphamide [2 mg/kg/...
<ul><li>Alternative induction regimens (to minimize use of Cyc) </li></ul><ul><li>IV or PO Pulse Cyclophosphamide (EUVAS -...
Rx options for maintainance <ul><li>Cyclophosphamide (Original NIH Study) </li></ul><ul><ul><li>1.5 mg/kg per day. Given f...
EUVAS Guidelines
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Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis (Journal Club)

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Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis (Journal Club)

  1. 1. Raj Kiran Medapalli, MD, MPH. Nephrology Fellow May 19 th , 2009 Mount Sinai School of Medicine Division of Nephrology Journal Club
  2. 2. 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
  3. 3. Outline <ul><li>Brief introduction to ANCA Vasculitis & CYC. </li></ul><ul><li>Review of key RCTs for induction & maintenance therapy for ANCA vasculitis. </li></ul><ul><li>Review CYCLOPS study. </li></ul><ul><li>Strengths, weaknesses & conclusions from CYCLOPS. </li></ul><ul><li>Ongoing RCTs. </li></ul>
  4. 4. Source: Brenner & Rector's The Kidney, 8 th Edition.
  5. 5. Source: Jennette JC & Falk RJ. Small Vessel Vasculitis. NEJM. Nov 1997. <ul><li>Incidence: 20 cases per million individuals per year </li></ul><ul><li>Most commonly occurs in the elderly (peak age 55–70 years). </li></ul><ul><li>Before CYC, 2-year survival rates were about 20%. </li></ul><ul><li>5-year survival rates now approach 80%. </li></ul><ul><li>Prevalence is over 200 cases per million individuals. </li></ul>
  6. 6. Source: Falk RJ & Jennette JC. JASN. 1997. C-ANCA, anti-Proteinase 3 P-ANCA, anti-Myeloperoxidase Anti-neutrophil cytoplasmic antibodies
  7. 7. Source: Xiao H, et al. Am J of Path. Jan 2007.
  8. 9. Cyclophosphamide (Cyc) <ul><li>Alkalyting agent </li></ul><ul><li>Prodrug </li></ul><ul><li>Binds & crosslinks a variety of macromolecules including DNA, RNA, & proteins </li></ul><ul><li>Impairs DNA replication and transcription </li></ul><ul><li>Wegeners was a fatal dz before CYC emerged in the 1970s. </li></ul><ul><li>Devastating toxicity, which correlates with cumulative dose. </li></ul>Source: UpToDate
  9. 10. <ul><li>Bone marrow suppression </li></ul><ul><ul><li>~ 5% severe leukopenic events (WBC < 2.0/mm3) </li></ul></ul><ul><ul><li>IV CYC: WBC nadir within 7- 14 days & BM recovery evident by 21 days. </li></ul></ul><ul><ul><li>Steroid induced demargination of neutrophils further complicates this. </li></ul></ul><ul><li>Infection </li></ul><ul><ul><li>in 45% pts; major bacterial or fungal infxn in 5-21% pts </li></ul></ul><ul><ul><li>Reactivation of dormant Varicella zoster (8-33%), TB, HPV </li></ul></ul><ul><li>Infertility </li></ul><ul><ul><li>12% in women < 26 yrs old, 27% if 26 to 30 yrs, 62% if > 30yrs. </li></ul></ul><ul><ul><li>75% of the men develop severe oligospermia or azoospermia </li></ul></ul><ul><li>Bladder toxicity </li></ul><ul><ul><li>Hemorrhagic cystitis: 50% incidence in original NIH study </li></ul></ul><ul><ul><li>Bladder Ca: 4.8% incidence after 8.5 yrs; 16% at 15 years. </li></ul></ul><ul><li>Secondary Malignancy </li></ul><ul><ul><li>Solid malignancies (9.7% incidence over 2 yrs). </li></ul></ul><ul><ul><li>Myelodysplastic syndrome (8% incidence over 7yrs, 13% if cu.dose > 100g) </li></ul></ul><ul><ul><li>Acute leukemia, non-Hodgkin lymphoma, multiple myeloma (5/119 vs 1/119 over 10yrs) </li></ul></ul><ul><li>Teratogenicity </li></ul>Source: UpToDate
  10. 11. Hoffman GS et al. Annals of Int Med. March 1992. <ul><li>158 WG pts, referred to NIH during the previous 24 yrs. </li></ul><ul><li>Mean F/u 8 yrs </li></ul><ul><li>Treatment </li></ul><ul><ul><li>133 pts CYC (2mg/kg/d) + Pred </li></ul></ul><ul><ul><li>10 pts only prednisone </li></ul></ul><ul><ul><li>8 pts only CYC </li></ul></ul><ul><ul><li>6 pts other cytotoxics & pred. </li></ul></ul><ul><li>CYC 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. </li></ul><ul><li>Pred: 1mg/kg/d x 4wks, then 60mg QOD within 1-3 mths & then tapered as tolerated. </li></ul><ul><li>Conversion to QOD pred median of 3.2 mths. </li></ul><ul><li>D/c of steroids median of 12 mths. </li></ul><ul><li>Partial Remission 91% </li></ul><ul><li>Complete Remission 75% </li></ul><ul><li>Median time to remission 12 months. </li></ul><ul><li>Relapse </li></ul><ul><ul><li>At least 1 relapse in 50% of pts. </li></ul></ul><ul><ul><li>44% with > 5 yrs of f/u had remissions > 5 yrs </li></ul></ul><ul><ul><li>18.5% with > 10 yrs of f/u had remissions > 10 yrs. </li></ul></ul><ul><li>Long term renal outcomes </li></ul><ul><ul><li>42% pts had CKD. Median creatinine level was 2.55 mg/dL. </li></ul></ul><ul><ul><li>17/158 pts (11%) eventually required dialysis. </li></ul></ul><ul><ul><li>8 of these pts underwent transplantation, once they were off immunosuppression, with a median f/u 5 yrs. Only 1 pt had recurrent WG with renal impairment. </li></ul></ul><ul><li>Pts treated with only steroids and CYC did much poorly </li></ul>
  11. 12. <ul><li>Complications </li></ul><ul><li>Death due to Dz/Rx: 13% </li></ul><ul><li>Permanent disease-related morbidity occurred in 86% pts </li></ul><ul><li>Secondary malignancies: </li></ul><ul><ul><li>2.4 fold overall increase in malignancies (791 vs 333/10000 persons/yr) </li></ul></ul><ul><ul><li>11-fold increase in lymphomas </li></ul></ul><ul><li>Bladder toxicity: </li></ul><ul><ul><li>33-fold increase in bladder ca </li></ul></ul><ul><li>Infections: </li></ul><ul><ul><li>46% pts with serious infections (req hosp and IV Rx) </li></ul></ul><ul><ul><li>50% of serious infxs occured during daily steroid Rx </li></ul></ul><ul><ul><li>21% occurred during QOD steroids. </li></ul></ul><ul><ul><li>16% after steroids were stopped </li></ul></ul><ul><ul><li>12% in periods without therapy. </li></ul></ul><ul><li>Reactivation of Herpes Zoster </li></ul><ul><ul><li>20-fold increase in Herpes zoster if on CYC and Pred and </li></ul></ul><ul><ul><li>10-fold increase in pts on CYC or Pred. </li></ul></ul><ul><li>Need for less toxic regimens of CYC and/or alternate therapeutic agents </li></ul>Hoffman GS et al. Annals of Int Med. March 1992.
  12. 13. Pulse Cyc in ANCA Vasculitis - EUVAS meta analysis de Groot K et al. NDT 2001 <ul><li>A metanalyses of 3 RCTs comparing at pCYC vs cCYC (2mg/kg/d). </li></ul><ul><li>Total of 143 pts (101 with WG, 42 with MPA). </li></ul><ul><li>Different pCYC doses (15mg/kg/pulse, 0.7 & 0.75g/sqm/pulse) & regimens (Q2wks x 3 then Q3wks, Q3wks, Qmonthly). </li></ul><ul><li>In one study pulse methyl-prednisolone (10mg/kg) was used instead of daily PO steroids (starting dose: 0.85mg/kg to 1mg/kg, varying regimens). </li></ul><ul><li>Mean f/u ranged from 30 to 43 months in pCYC and 25 to 42 mths in cCYC patients. </li></ul><ul><li>Results: pCYC vs cCYC </li></ul><ul><li>Failure to induce remission: OR 0.29 (0.12 to 0.73) </li></ul><ul><li>Risk of infection: OR 0.45 (0.23-0.73) </li></ul><ul><li>Leucopenia: OR 0.36 (0.17 - 0.78) </li></ul><ul><li>Relapse: OR 1.79 (0.85-3.75) </li></ul><ul><li>No differences in ESRD or Deaths. </li></ul><ul><li>Significantly lower cumulative dose in pCYC in the 2 studies that reported it - 27.8 vs 31.1g (p<0.001) & - 16.4 vs 38.4g (p<0.001) </li></ul>
  13. 14. CYC vs MTX for Induction - EUVAS RCT (NORAM) de Groot K et al. Arth & Rheum Aug 2005 <ul><li>100 pts with WG or MPA </li></ul><ul><li>Mild or no renal involvement (creat <1.7mg/dl, proteinuria <=1g/d, no RBC casts) </li></ul><ul><li>Without critical organ manifestations (hemoptysis with b/l infiltrates, cerebral infarction, GIB, pericarditis/myocarditis, rapidly progressive neuropathy). </li></ul><ul><li>~ 35% pts had renal involvement & 50% had lung involvement in both groups. </li></ul><ul><li>49 pts got oral CYC (2 mg/kg/d) & 51 pts got oral MTX (20–25 mg/wk).Unblinded. </li></ul><ul><li>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). </li></ul><ul><li>All drug treatments were gradually tapered and withdrawn by 12 months. </li></ul><ul><li>Followup continued to 18 months. </li></ul><ul><li>Primary end point was the remission rate at 6 months (noninferiority testing). </li></ul><ul><li>Results MTX vs CYC </li></ul><ul><li>6 months remission rate: </li></ul><ul><ul><li>89.8% vs 93.5% (p 0.041) </li></ul></ul><ul><ul><li>MTX grp, remission delayed in pts with more extensive disease (P = 0.04) or pulm involvement (P =0.03). </li></ul></ul><ul><li>Relapse rate at 18 months: </li></ul><ul><ul><li>69.5% vs 46.5% </li></ul></ul><ul><ul><li>High in both. 12 mth rx not enough. </li></ul></ul><ul><li>Median time to relapse: </li></ul><ul><ul><li>13 mths vs 15 mths (p 0.023) </li></ul></ul><ul><ul><li>HR 1.85 [95% CI 1.06–3.25]. </li></ul></ul><ul><li>Median cu. dose of steroids </li></ul><ul><ul><li>8.8gm vs 6.2gm (p 0.001) </li></ul></ul><ul><li>Adverse reactions </li></ul><ul><ul><li>2 pts from each group died. </li></ul></ul><ul><ul><li>Leucopenia less in MTX (p 0.012) </li></ul></ul><ul><ul><li>4 life threatening infxns in each grp </li></ul></ul><ul><ul><li>Liver dysfxn > in MTX grp (p 0.036) </li></ul></ul>
  14. 15. Adjunctive Plasma Exchange or High-Dosage Solumedrol for Severe Renal Vasculitis. EUVAS RCT (MEPEX) Jayne DRW et al. JASN 2007 <ul><li>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. </li></ul><ul><li>137 pts with renal bx proven ANCA associated vasculitis & creat > 5.8 mg/dl or RRT at presentation. Mean age 66yrs. </li></ul><ul><li>Randomly assigned to receive 7 plasma exchanges (n=70) or 3g of IV Solumedrol (n=67). </li></ul><ul><li>Both groups received daily CYC & oral prednisolone. </li></ul><ul><li>Results MP Vs PE </li></ul><ul><li>3 month renal survival </li></ul><ul><ul><li>49% vs 69% (p 0.02) </li></ul></ul><ul><li>Progression to ESRD at 12 mths </li></ul><ul><ul><li>43% vs 19% </li></ul></ul><ul><ul><li>Risk Diff: 24% (95% CI 6.1 - 41) </li></ul></ul><ul><li>1yr patient survival </li></ul><ul><ul><li>76% vs 73% (NS) </li></ul></ul><ul><li>Severe adverse event rates </li></ul><ul><ul><li>48% vs 50% (NC) </li></ul></ul><ul><li>No sig differences in freq or severity of path lesions at baseline. </li></ul>
  15. 16. Azathioprine for Maintainance Rx. (CYCAZAREM) Jayne D, et al. NEJM 2003. EUVAS RCT. <ul><li>155 pts with creat <5.7mg/dl at onset, treated with cCYC and prednisolone for at least 3months. </li></ul><ul><li>61% pts with WG & 39% with MPA. </li></ul><ul><li>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. </li></ul><ul><li>Beginning at 12 months, both groups received AZT (1.5mg/kg/d) & prednisolone (7.5 mg/d). </li></ul><ul><li>Followed for 18 months </li></ul><ul><li>Relapse was the primary end point. </li></ul><ul><li>Results AZT vs cCYC </li></ul><ul><li>Relapse rate </li></ul><ul><ul><li>15.5% vs 13.7%. p=0.65 </li></ul></ul><ul><ul><li>Lower among the patients with MPA than WG 8% vs, 18% (P=0.03) </li></ul></ul><ul><li>Severe adverse effects </li></ul><ul><ul><li>8 (11%) vs 7 (10%). p= 0.94 </li></ul></ul><ul><ul><li>Overall 8 deaths (5%), 7 within first 3 months. </li></ul></ul><ul><ul><li>7% of AZT pts had an allergic rxn (fever, chills & rash) which lead to drug d/c. </li></ul></ul>
  16. 17. AZT vs. MTX for Maintenance Rx. FVSG RCT (WEGENT). Pagnoux C, et al. NEJM 2008. <ul><li>159 pts with WG or MPA. </li></ul><ul><li>pCYC (0.6 g/sqm) q2wks x3, then 0.7g/sqm qQ3wks until remission, followed by 3 additional consolidation pulses q3 wkly. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>Mean f/u: 29 ± 13 months. </li></ul><ul><li>Sample size was calculated on the assumption that MTX would be less toxic than AZT. </li></ul><ul><li>Results AZT vs MTX </li></ul><ul><li>BVAS at diag: 23.6 vs. 21.2 p=0.07 </li></ul><ul><li>Lung inv: 83% vs. 67% p=0.05 </li></ul><ul><li>Renal inv: 75% in both groups. </li></ul><ul><li>Creat at entry 1.52 vs.1.4. p=0.56 </li></ul><ul><li>Relapse </li></ul><ul><ul><li>23pts vs 21pts. P=0.71 </li></ul></ul><ul><ul><li>73% had a relapse after study drug discontinuation. </li></ul></ul><ul><ul><li>? optimal duration of Rx </li></ul></ul><ul><li>Adverse events </li></ul><ul><ul><li>29 pts vs 35 pts (P = 0.29) </li></ul></ul><ul><li>Drug d/c or death </li></ul><ul><ul><li>7 pts (11%) vs.12 pts (20%). p=0.21. </li></ul></ul><ul><ul><li>1 death MTX grp 2/2 aplastic anemia. </li></ul></ul><ul><ul><li>HR for MTX: 1.65 (0.65 to 4.18) </li></ul></ul><ul><ul><li>8% in NORAM (creat <1.7). </li></ul></ul>
  17. 18. 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
  18. 19. Study Design <ul><li>Open-label, multicenter, RCT conducted over 18 months. </li></ul><ul><li>149 patients from 42 hospitals in 13 European countries & Mexico. </li></ul><ul><li>71 with MPA, 56 with WG & 22 with renal limited vasculitis. </li></ul><ul><li>Funded by the European Union. </li></ul><ul><li>Pts were enrolled by their treatment physicians. </li></ul><ul><li>Inclusion criteria : </li></ul><ul><ul><li>Newly diagnosed Wegener granulomatosis, microscopic polyangiitis, or renal-limited microscopic polyangiitis. </li></ul></ul><ul><ul><li>Renal involvement attributable to active vasculitis as defined by at least 1 of the following: </li></ul></ul><ul><ul><ul><ul><li>Serum creatinine level > 1.7 and < 5.7 mg/dL. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Biopsy demonstrating necrotizing glomerulonephritis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Erythrocyte casts </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hematuria [> 30 erythrocytes per HPF]. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Proteinuria [>1 g/d]). </li></ul></ul></ul></ul><ul><ul><li>Confirmatory histology or ANCA positivity. </li></ul></ul><ul><li>Exclusion criteria : </li></ul><ul><ul><li>Age younger than 18 or older than 80 years. </li></ul></ul><ul><ul><li>Coexistence of other multisystem autoimmune disease; hepatitis B or C virus or HIV infection </li></ul></ul><ul><ul><li>Serum creatinine level > 5.7 mg/dL. </li></ul></ul><ul><ul><li>Previous cancer. </li></ul></ul><ul><ul><li>Pregnancy. </li></ul></ul>
  19. 20. 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%
  20. 21. <ul><li>Induction therapy (continued): </li></ul><ul><li>Steroids </li></ul><ul><ul><li>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). </li></ul></ul><ul><li>Maintainance therapy : </li></ul><ul><li>Cyclophosphamide </li></ul><ul><ul><li>Both groups continued the cyclophosphamide regimens for 3 months after remission. </li></ul></ul><ul><li>Azathioprine </li></ul><ul><ul><li>Then switched to Azathioprine, 2 mg/kg per day orally, until month 18. Max daily dose was 200 mg. </li></ul></ul><ul><li>Prophylaxis </li></ul><ul><li>PCP prophylaxis was given for all patients. </li></ul><ul><li>2-Mercaptoethanesulfonate sodium (Mesna) was optional. </li></ul><ul><li>Non-responders </li></ul><ul><li>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. </li></ul><ul><li>No patients received plasmapheresis. </li></ul>
  21. 22. <ul><li>Primary outcome </li></ul><ul><li>Time to remission </li></ul><ul><li>Secondary outcomes </li></ul><ul><li>Proportion of patients who achieved remission at 6 & 9 months </li></ul><ul><li>Proportion with major and minor relapses. </li></ul><ul><li>Death </li></ul><ul><li>Change in renal function </li></ul><ul><li>Adverse events, including leukopenia and infection </li></ul><ul><li>Cumulative dose of cyclophosphamide and prednisolone </li></ul><ul><li>Follow-up : </li></ul><ul><li>Assessed these outcomes at baseline; every 1.5 months until 9 months, then every 3 months until 18 months; and at relapse. </li></ul><ul><li>Birmingham Vasculitis Activity Score (BVAS) (measures manifestations of active vasculitis during the last 4 weeks) at every visit. </li></ul><ul><li>Vasculitis Damage Index (measures of cumulative damage from any cause since disease onset), at baseline and every 3 months. </li></ul><ul><li>Definitions </li></ul><ul><li>Remission : absence of new or worse signs of dz activity on BVAS & no more than 1 item indicating persistent disease activity (BVAS ≤1). </li></ul><ul><li>Major relapse : recurrence or first appearance of at least 1 BVAS item indicating threatened vital organ function. </li></ul><ul><li>Minor relapse : recurrence or1st appearance of at least 3 BVAS items related to nonvital organs. </li></ul>
  22. 23. Birmingham Vasculitis Activity Scores (BVAS) <ul><li>Measures manifestations of active vasculitis in the preceding 4 weeks. </li></ul><ul><li>Ref: Luqmani R.A, et al. Q J Med 1994; 87:671-678. </li></ul><ul><li>Departments of Rheumatology and Nephrology, University of Birmingham, </li></ul><ul><li>Edgbaston, West Midlands, UK. </li></ul>
  23. 24. Birmingham Vasculitis Activity Scores (BVAS) <ul><li>- Score range: 0 to 63 </li></ul><ul><li>Renal, GI and CNS systems given higher weightage. </li></ul>
  24. 29. Time to Remission <ul><li>131 pts achieved remission by 9 months. </li></ul><ul><li>67 pts [88.1%] in the pulse group vs. 64 pts [87.7%] in the daily oral group. </li></ul><ul><li>HR: 1.098 [95% CI: 0.78 to 1.55;P = 0.59]. </li></ul><ul><li>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). </li></ul><ul><li>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. </li></ul><ul><li>2 patients did not achieve remission by 9 months but remained in the study; censored becos they did not receive protocol-based treatment. </li></ul>
  25. 30. Main Outcome Parameters by Treatment Group <ul><li>Relapse </li></ul><ul><li>19 (14.5%) of the 131 patients who achieved remission by 9 months relapsed. </li></ul><ul><li>13 (7 with major and 6 with minor relapse) in the pulse group. </li></ul><ul><li>6 (3 with major and 3 with minor relapse) in the daily oral group. </li></ul><ul><li>HR: 2.01 [95% CI, 0.77 to 5.30]. But study not powered to detect this diff. </li></ul><ul><li>Similar to CYCAZAREM: used a similar cCYC regimen for induction & did </li></ul><ul><li>not have a consolidation phase. </li></ul><ul><li>Relapse rate < trials which stopped steroids @ 6(WGET) or 12 mths (NORAM). </li></ul>
  26. 31. Main Outcome Parameters by Treatment Group <ul><li>Deaths : 14 died: 5 in the pulse group & 9 in the daily oral group (P = 0.79). </li></ul><ul><li>Median time to death did not differ: 3.5 mths in pCYC vs 4 in cCYC grp </li></ul><ul><li>Death associated with active dz or rx in 3 pts in pCYC grp & 7 in cCYC grp </li></ul><ul><li>Death 2/2 sepsis in 5 of the daily oral group pts & 1 of the pulse group pts. </li></ul><ul><li>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]. </li></ul>
  27. 32. Renal Outcomes <ul><li>eGFR </li></ul><ul><ul><li>In the pulse group, the median eGFR improved from 32 to 45 mL/min/1.73 m2 (P= 0.010). </li></ul></ul><ul><ul><li>In the daily oral group, the median eGFR improved from 29 to 45 mL/min/1.73 m2 (P = 0.010). </li></ul></ul><ul><ul><li>GFR did not differ between study groups at any time point. </li></ul></ul><ul><li>ESRD </li></ul><ul><ul><li>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. </li></ul></ul><ul><ul><li>The 2 groups did not differ in the development of ESRD (P = 0.105). </li></ul></ul>
  28. 33. Measures of disease activity <ul><li>BVAS for new or worse disease decreased promptly with rx & were similar in both groups at all time points. </li></ul><ul><li>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. </li></ul><ul><li>CRP levels similar in both treatment groups at study start and decreased </li></ul><ul><li>rapidly in both groups after initiation of induction therapy. </li></ul>
  29. 34. Cumulative dose <ul><li>Cyclophosphamide </li></ul><ul><ul><li>Daily oral group received nearly twice the dose administered to the pulse group (15.9 g vs. 8.2 g; P < 0.001). </li></ul></ul><ul><li>Prednisolone </li></ul><ul><ul><li>The groups did not differ in prednisolone dose at any time point, with a mean cumulative dose of about 7.5g in both grps. </li></ul></ul>
  30. 35. Adverse events <ul><li>Leucopenia </li></ul><ul><li>Pts were less likely to have leukopenia in the pulse group than in the daily oral group 26% vs. 45%. P = 0.016. </li></ul><ul><li>Median time to 1st episode: 219 days vs 68 days. HR: 0.41 (0.23-0.71). </li></ul><ul><li>Infections </li></ul><ul><li>Median time to 1st infection: 147 (pCYC) vs 68 days. HR 0.88 (0.42-1.83). </li></ul>
  31. 36. Strengths of the study <ul><li>Largest trial to date comparing the efficacy fo pCYC vs. cCYC. </li></ul><ul><li>EUVAS has the largest experience with RCTs in ANCA-Vasculitis. </li></ul><ul><li>Funded by the European Union. </li></ul><ul><li>Used clinically relevant inclusion & exclusion criteria. Renal involment was necessary to be included in the trial. </li></ul><ul><li>Used a consensus Rx regimen. </li></ul>
  32. 37. Weaknesses of the study <ul><li>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. </li></ul><ul><li>18 month f/u not be enough to determine the optimal duration for therapy (Rx was continued until month 18 in all pts). </li></ul><ul><li>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). </li></ul><ul><li>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. </li></ul>
  33. 38. Conclusions <ul><li>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). </li></ul><ul><li>AZT is a reasonable alternative for maintainace rx after induction with pCYC or cCYC. </li></ul><ul><li>No difference in rate of remission or time to remission. </li></ul><ul><li>Cumulative dose was reduced by approximately 50% in the pCYC grp. </li></ul><ul><li>Fewer episodes of leukopenia and possibly lesser infections, but other side effects not significantly different. </li></ul><ul><li>pCYC is simpler to monitor, better compliance and also permits pre-hydration and administration of Messna. </li></ul><ul><li>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. </li></ul><ul><li>3-month consolidation phase seems to have little effect on relapse in 18 months and can probably be eliminated, especially in cCYC group. </li></ul><ul><li>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. </li></ul>
  34. 39. Ongoing trials at EUVAS <ul><li>MYCYC: MMF vs. cyclophosphamide for remission induction. </li></ul><ul><li>IMPROVE: Compares MMF with azathioprine for remission therapy in renal vasculitis. Completed recruitment. </li></ul><ul><li>RITUXVAS: Rituximab based regimen vs. standard cyclophophamide/ azathioprine regimen in the treatment of active, ‘generalised’ ANCA associated vasculitis. Completed recruitment. </li></ul><ul><li>REMAIN: Long-term low dose immunosuppression vs. treatment withdrawal for renal vasculitis. </li></ul><ul><li>STAVE: Meta-analysis of the effect of different corticosteroid dosing regimens on relapses. </li></ul>
  35. 40. Summary of Rx options for induction <ul><li>Standard Induction </li></ul><ul><ul><li>Daily oral cyclophosphamide [2 mg/kg/d] </li></ul></ul><ul><ul><li>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] </li></ul></ul><ul><ul><li>Prophylactics: </li></ul></ul><ul><ul><li>Bactrim SS daily or Bactrim DS q MWF for PCP prophylaxis. </li></ul></ul><ul><ul><li>In pts allergic to Bactrim: Dapsone (100 mg/day), Atovaquone (1500 mg/day), or monthly aerosolized Pentamidine. </li></ul></ul><ul><ul><li>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). </li></ul></ul><ul><ul><li>Nystatin swish and swallow orally: 600,000 units 4 times/day </li></ul></ul><ul><ul><li>Sperm cryopreservation + Testosterone 100 mg IM every 15 days in males. </li></ul></ul><ul><ul><li>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. </li></ul></ul><ul><ul><li>Calcium 1200mg and Vitamin D 800mg, while on steorids. </li></ul></ul><ul><ul><li>Pepcid 20mg QD, while on steroids. </li></ul></ul>
  36. 41. <ul><li>Alternative induction regimens (to minimize use of Cyc) </li></ul><ul><li>IV or PO Pulse Cyclophosphamide (EUVAS - CYCLOPS) </li></ul><ul><ul><li>15 mg/kg IV Q2wkly x 3 doses </li></ul></ul><ul><ul><li>Then 15 mg/kg IV Q3wkly or 5 mg/kg PO on 3 consecutive days Q3wkly until remission </li></ul></ul><ul><ul><li>? Continue for 3 more months after remission (consolidation phase) </li></ul></ul><ul><li>Methotrexate (EUVAS – NORAM) </li></ul><ul><ul><li>In pts with mild or no renal dysfunction (creat <1.7, prot,1g, no RBC casts) and without other critical organ inv. </li></ul></ul><ul><ul><li>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. </li></ul></ul><ul><ul><li>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. </li></ul></ul><ul><li>7 plasma exchanges, in addition to cCYC & steroids (EUVAS - MEPEX) </li></ul><ul><ul><li>In patients with severe renal failure (creat > 5.8 or dialysis dependent at presentation) or concomitant anti-GBM abs or pulmonary hemorrhage </li></ul></ul>
  37. 42. Rx options for maintainance <ul><li>Cyclophosphamide (Original NIH Study) </li></ul><ul><ul><li>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. </li></ul></ul><ul><li>Azathioprine (EUVAS – CYCAZAREM & CYCLOPS) </li></ul><ul><ul><li>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). </li></ul></ul><ul><ul><li>Prednisolone was given at 10mg/d until 1yr, then 7.5mg/d until month 18 in CYCAZAREM. </li></ul></ul><ul><ul><li>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 </li></ul></ul><ul><li>Methotrexate (EUVAS -NORAM & FVSG-WEGENT) </li></ul><ul><ul><li>As previously described. </li></ul></ul><ul><ul><li>Leukovorin 10mg Qweekly given 24 hours after MTX. </li></ul></ul>
  38. 43. EUVAS Guidelines
  39. 44. Thank You.

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