rituxvas - Soci©t© de n©phrologie
Transcript of rituxvas - Soci©t© de n©phrologie
Vascularites associées aux ANCA
Traitement par le RITUXIMAB
Philippe Vanhille Néphrologie Médecine Interne Hôpital de Valenciennes
Aix-‐en-‐Provence 2013
Cyclophosphamide therapy of severe systemic necrotizing vasculitis
AS Fauci, P Katz, BF Haynes, and SM Wolff
1979, Volume 301:235-238
80% survival at 8 years F/U
Therapy of AAV
• 1st generation, 1948-1992 – Glucocorticoids, cyclophosphamide
• 2nd generation, 1985-2010 – Optimisation of cyclophosphamide – Other immune suppressives
• Azathioprine, methotrexate, mycophenolate – Immunomodulators
• Plasma exchange, IVIg
Survival and ESRD in AAV EUVAS cohort: 535 patients
Patient survival Renal survival
5 years 80% 1 year 84% 5 years 73% 10 years 63%
O Flossman ARD 2011
Early pronostic factors
• Infection 1.2 p< 0.001 • Leucopenia 1.2 p< 0.001 • GFR 0.7 p= 0.002 • Cumulative cyc. dose 1.2 p= 0.04
Li/le M, ARD 2010
Other adverse outcomes
• Cumulative steroid exposure • Damage 95%-irreversible disease scars • Depressed QOL
Ø 1st generation, 1948-1992 – Glucocorticoids, cyclophosphamide
Ø 2nd generation, 1985-2010 – Optimisation of glucocorticoids and
cyclophosphamide – Methotrexate, azathioprine, mycophenolate,
plasma exchange, IVIg, antibiotics Ø New generation, 2000-
– Therapeutic antibodies • Rituximab
Therapy of AAV
• Variable regions from murine anti-CD20 antibody IDEC-2B8
• Linked to human IgG1 and kappa constant regions
• Apparent affinity: 5.2 x 10-9 M
Rituximab: Chimeric anti-CD20 monoclonal antibody
VL
Cκ
VH
Cγ1
Human constant Fc region
Human constant κ region
Murine variable regions
Rituximab for remission induction
RAVE • 197 pts • 53 y • GFR 61 • vs oral Cyc • New or relapsing AAV
RITUXVAS • 44 pts (33:11) • 68 y • GFR 17 • vs IV Cyc • New severe renal AAV
Hypothesis: Rituximab is not inferior to cyclophosphamide for remission induction
NEJM 2010
Démographics RTX n = 33
CYC n = 11
Age 68(20-85) 67(51-83)
WG 18 (55%) 4 (36%)
MPA/RLV 15 (45%) 7 (64%)
c-ANCA 20 (63%) 5 (45%)
p-ANCA 13 (37%) 6 (55%)
GFR (ml/mn/1.73m2)
20 (0-60) 12 (0-38)
Dialysis 8/33 (24%) 1/11 (9%)
Lung 17/33 (51%) 1/11 (9%)
ENT 16/33 (48%) 5/11 (45%)
BVAS 2003 18 (12-33) 19 (12-42)
PLEX 8/33 (24%) 3/11 (27%)
RITUXVAS: protocol overview and patient characteristics
Jones R, NEJM 2010
RITUXVAS: End points 0.
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250.
500.
751.
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tion
Achi
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g Re
miss
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0 100 200 300 400Time (days)
Cyclophosphamide Rituximab
time to remission
Results RTX N=33
CYC N=11
Sustained remission at M12 (BVAS 0x2 at 6m)
76% 82%
Remission 82% 91%
eGFR at M 12 (recovery from dialysis)
51 (5/8)
33 (1/1)
ANCA neg by 6 months 89% 81%
R Jones, NEJM 2010
RITUXVAS: Primary Safety End Point
RTX CYC
Severe Adverse Events
31 (42%) 1.0 /pt/y
12 (36%) 1.1 /pt/y
Infections 21 (39%) 0.66 /pt/y
7 (21%) 0.60 /pt/y
Death 6 (18%) 2 (18%)
0.00
0.25
0.50
0.75
1.00
Pro
port
ion
Fre
e of
SA
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0 50 100 150 200 250 300 350Time (days)
CYC RTX
R Jones, NEJM 2010
RITUXVAS: conclusions
• Patients: Elderly, with severe renal failure • Efficacy
– RTX was not inferior to cyclophosphamide regimen
– RTX spares the use of cyclophosphamide • Safety
– Similar Severe Adverse Event rates with both regimens typical for this disease subgroup
RITUXVAS: 2 year follow-up results
Ritux N=33
Cyc N=11
1ry composite outcome (relapse, death, ESRF)
14 (42%) 4 (36%)
• Relapse 7/27 (26%) 2/10 (20%)
• Death 6 (18%) 3 (27%)
• ESRF 2 (6%) 0 p 0.57
Rise in GFR 20 16
SAE 61%* 36% p 0.64
* 3 cancers : breast, melanoma, basal cell carcinoma
Jones R, Chapel Hill 2011
Rituximab for remission induction
RAVE • 197 pts • 53 y • GFR 61 • vs oral Cyc • New or relapsing AAV
RITUXVAS • 44 pts (33:11) • 68 y • GFR 17 • vs IV Cyc • New severe renal AAV
Hypothesis: Rituximab is not inferior to cyclophosphamide for remission induction
NEJM 2010
RAVE trial
• Primary outcome is remission at 6 months: BVAS-WG=0 and w/o Pred. at M 6
- RTX: 64% - CyP: 53% • RTX superior in achieving remission in pts
(n=101) with severe flares at baseline (67% vs 42%, p=0.013)
JH Stone NEJM 2010
RAVE trial
• Primary outcome is remission at 6 months: BVAS-WG=0 and w/o Pred. at M 6
- RTX: 64% - CyP: 53% • RTX superior in achieving remission in pts
(n=101) with severe flares at baseline (67% vs 42%, p=0.013)
• Similar number of selected AE: RTX 31%,
CyP 33%, with no difference in rate of infection (severe inf.7%)
JH Stone NEJM 2010
RAVE: 18 months FU
RTX(99) Cyc-Aza(98) Severe flares (n) 22 23 Still in remission (%pts) 39 33
No difference between 2 arms: - rate of CR - time to CR and 1st flare - rate of flares - rate or severity of AE Severe flares are rare in the absence of B lymphocytes
U Specks Chapel Hill 2011
Relapse after RTX induction
• RAVE – New & relapsing – 18 months – 40%
• Cohort studies – Most will relapse – Further RTX
effective – Trend for Ig to fall
• RITUXVAS – New – 24 months – 26%
Maintenance strategy after RTX induction
• Conventional AZA/MTX, ± steroid • Further rituximab
– at time of relapse – guided by B cell return or ANCA – Routine, fixed interval
MAINRITSAN: results
Azathiorine (%) Rituximab (%) Major relapses 15 (25.4) 3 (5.2) SAE 4 (6.7) 1 Other drop outs 7 (11.8) 3 (5.2) Total 21/59 (35.6)* 6/58 (10.3)* *sevral causes for the same paQent
MAINRITSAN: SAE and Mortality
Azathioprine 37 in 30 pts (50.8%) infections: 9 3 deaths
Rituximab 32 in 27 pts (50.%) infections: 9 0 death
Rituximab in AAV • As effective as CYC for remission induction • Same rate of adverse events as conventional
immunosuppressive therapy
• Effective treatment of relapsing/refractory AAV
• Effective treatment for remission maintenance • Allow reduction of steroids and discontinuation of
immunosuppressants in maintenance phase
• Relapses still common – monitoring of patients
• Long term efficacy and safety remain to be determined
• (Bio)markers: for detection of relapse? – ANCA/B cells – MMP-3 – BCA-1 (CXCL 13) – Breg. (B5+cells)
• Therapy based on disease and patient specificities
Rituximab in AAV