Nouveautés dans le traitement des
microangiopathies thrombotiques:
Place de l’eculizumab
Chantal Loirat
Service de Néphrologie Pédiatrique,
Hôpital Robert Debré, Paris
CREUF,Chartres, 2 Octobre 2014
The various forms of TMAs according to
etiology / pathophysiology
HELLP
syndrome
HUS with coexisting disease / condition
• Bone marrow transplantation
 Solid organ transplantation
 Malignancy/ cancer chemotherapy
 Autoimmune disease (SLE, antiphospholipids syndrome,
scleroderma, dermatomyositis)
 Drugs (calcineurin inhibitors, sirolimus and anti-VEGF agents)
• Malignant hypertension
 HIV infection
 Cocaïne
Thrombotic
thrombocytopenic
purpura
ADAMTS13 < 10%
Congenital
ADAMTS13
deficiency
Infection-induced HUS
• S pneumoniae
 STEC
Cbl-C deficiency-HUS
TMA
Alternative complement
pathway dysregulation-HUS*
Mutations in CFH, CFI,
MCP, C3, CFB, THBD
AntiADAMTS13
antibodies
Unexplained HUS
Anti-FH
antibodies
HUS with DGKE mutation
* Including pregnancy- HUS
Treatment of aHUS up to 2009
Pre-eculizumab era
Plasma exchange (PE)
or plasma infusion (PI)
Poor prognosis in aHUS patients in the
pre-eculizumab era
• Mortality higher in children than in adults
• High risk of rapid progression to end stage renal disease at all ages
but higher in adults than in children
Overall renal survival (%)
100
Pediatric onset, n=89
Adult onset, n=125
80
French cohort, 214 patients
Mortality: 8% in children, 2% in adults
60
End stage renal failure or death
40
20
p<0.0001
0
0
5
10
Years
15
20
Number of aHUS patients at risk
Paediatric onset 89
34
17
13
6
Adult onset
18
7
2
0
125
Children
Adults
First episode
16%
46%
1-year follow-up
29%
56%
5-year follow-up
36%
64%
39% of children and 80% of adults
received PE/PI at first episode
Fremeaux-Bacchi et al. Clin J Am Soc Nephrol 2013
Eculizumab blocks terminal complement
Terminal
Proximal
Complement cascade2,3
C3
C3a
C3b
C5
C5a
Eculizumab
• Eculizumab binds with
high affinity to C51,2
• Terminal complement –
C5a and C5b-9 formation
blocked1,2
• Proximal functions of
complement remain intact1,2
– Weak anaphylatoxin2,4
C5b
C5b-9
– Immune complex clearance2
– Microbial opsonisation2
Eculizumab Prescribing Information. Alexion Pharmaceuticvals, Inc.; 2013
1. Eculizumab Summary of Product Characteristics. Alexion Europe SAS, 2012; 2. Rother RP et al. Nat Biotechnol 2007;25:1256–64
3. Walport MJ. N Engl J Med 2001;344:1058–66; 4. Figueroa JE, Densen P. Clin Microbiol Rev 1991;4:359–95
Efficacy of eculizumab in aHUS
180 patients (124 adults, 56 children)
100 treated within protocols, 80 outside of protocols
• aHUS in native kidneys, n=124
• Post-transplant recurrence, n=43
• Prophylaxis of post-transplant recurrence, n=13
Data from case reports
Patients treated with eculizumab
outside of protocols
Eculizumab to treat aHUS in native kidneys
in adult patients
Historical controls treated by PE (between 2004 and 2008) had a poorer
outcome compared to patients treated with eculizumab since 2009
French cohort
Features at presentation
Kidney disease outcome
Eculizumab
(n=18)
p
Female sex
28 (68)
13 (72)
0.8
Age, years
34 (1885)
27 (1953)
0.4
Complement gene
mutations
28 (68)
13 (72)
0.2
Haemodialysis
29 (71)
12 (63)
0.8
Platelet count
>150  109/L
6/36 (17)
4 (21)
0.6
Plasma exchange
24/38 (63)
15 (83)
0.1
80
Percentage of patients
Controls
(n=41)
p=0.04
63%
60
p=0.02
46%
40
25%
20
0
Fakhouri F et al. Am J Kidney Dis 2014
PE
Eculizumab
17%
ESRD within
3 months of HUS
ESRD at
1 year
Eculizumab efficacy to rescue renal function:
the earlier, the better !
Median duration from HUS onset
and eculizumab initiation: 6 days (1–60)
eGFR at last follow-up 9.5 months (4–22)
>60 mL/min/1.73m2
<60 mL/min/1.73m2
Haemodialysis
Eculizumab initiation
Bars: PE treatment duration
Patient
Eculizumab
ongoing at 3 m
2
3
10
12
1
15
11
18
19
9
4
7
14
8
5
16
13
17
6
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
0
10
20
30
40
50
Time after aHUS onset (days)
60
Haemodialysis
Median
Screatinine
(non-dialysed
patients)
µmol/L (range)
At
eculizumab
initiation
At last
follow-up
47%
16%
251
(145–655)
89
(55–340)
Patients who received eculizumab within
6 days of onset (n=10) tended to have lower
Screatinine at last follow-up compared to
those treated after 6 days of onset (n=9)
(p=0.5)
90
Fakhouri et al. Am J Kidney Dis 2014
Eculizumab was successful to treat aHUS on native kidneys
in 19 children, including 14 who failed to improve under PE/PI
Median age: 1.5 years (11 days -11 y) (≤ 1 year in 9)
Complement mutation identified 15/18 (83%)
PE/PI resistant 12, dependent 2;1st line Eculizumab 5
Median duration from current HUS onset to eculizumab
initiation (range)
19 days
(<1- 225)
Hematological remission under eculizumab
19 (100%)
Dialysis required at baseline, n (%)
Dialysis required at last follow-up, n (%)
Median Screatinine, µmol/L (range)
 At baseline (6 non-dialysed patients)
 At last follow-up (18 non-dialysed patients)
Screatinine <50 µmol/L at last follow-up, n (%)
(18 non-dialysed patients)
Median follow-up, months ( range)
13 (68)
1 (6)
99 (20-264)
43 (20-90)
13 (72)
13 (2.5-42)
Zuber et al, Nat Rev Nephrol 2012 (pooled analysis of 7 cases reported in 2009-2012); Vilalta et al, Pediatr Nephrol 2012 ; Cayci et al, Pediatr Nephrol 2012 ;
Giordano et al, Pediatrics 2012; Besbas et al, Pediatr Nephrol 2012; Gulleroglu et al, Pediatr Nephrol 2013; Malina et al, Pediatrics 2013; Gilbert et al, Pediatr
Nephrol 2013; Vaisbich et al, J Bras Nefrol 2013; Hu et al, Pediatr Nephrol 2013; Christmann et al, Pediatrics 2014; Michaux et al, Pediatr Nephrol 2014
Eculizumab for extra-renal
manifestations of thrombotic
microangiopathy
Eculizumab rescues distal ischaemic
manifestations of aHUS
Ariceta et al. AJKD 2012
28-day-old child, 3.6 kg
• No mutation
• Leg skin necrosis, intestinal perforation
• Eculizumab  remission within 3 days
• Recovery of skin lesions and renal function
• Follow-up 18 months,
Screatinine 23 µmol/L, remission
Malina et al. Pediatrics 2013
2-month-old child
• ESRD, multiple relapses despite plasma
infusions
• C3 gain of function mutation
• At 9 months, acute ischaemia of feet and
hands, resistant to PE
• Eculizumab  immediate reversal of distal
ischaemia
• Follow-up 22 months, remission
Right hand
Left hand
Day 5
Day 8
Day 11
Day 120
Eculizumab
Day 21, then every 3 weeks
Day 360
Ulcerative-necrotic skin lesions in aHUS
Recovery under eculizumab
Before eculizumab
After eculizumab
19-year-old man (no mutation)
• On dialysis
• Skin lesions for 10 months + thrombocytopenia
• Skin biopsy: TMA lesions
• Recovery after one dose of eculizumab
19-year-old man (factor H mutation)
• Functioning kidney graft under PE/PI
• Skin lesions for several months
•  Switch from PE to eculizumab
• Improvement of skin lesions after first dose
with further complete reversal
Ardissino G et al. Am J Kidney Dis 2013
Eculizumab appears efficient to rescue CNS involvement in aHUS
9 case reports (PE resistant :7; 1st line eculizumab:2)
Author
Age
(years)
Neurological
manifestations
MRI
Time to
eculizumab
initiation
(days)
Outcome
Pu
2013
85
Seizures, mental
disturbances
ND
18
Improvement over 2 weeks
Full recovery
Salem
2012
66
Seizures, mental
disturbances, coma
Focal lesions
3
Awoke and verbal after 8 weeks
Nearly complete recovery
Beye
2013
64
Status epilepticus, focal
defects, nystagmus,
confusion
Normal CTS
9
Improvement within 24 hours
Full recovery
Ohanian
2011
50
Seizures,
unresponsiveness
Right parietal infarction
3
Improvement after 1 week
Full recovery
Chaudhary
2014
20
Seizures, lethargy
ND
42
Slow initial improvement
(subtherapeutic doses)
Full recovery after dose increase
Gulleroglu
2013
11
Seizures, visual loss,
confusion
Bilateral occipital and
posterior parietal
hyperdensities/oedema
2
Improvement after 4 days
Full recovery after 1 month
Gulleroglu
2013
6
Seizures, visual loss
Bilateral occipital and
posterior parietal
hyperdensities
<1
Normal vision within 24 hours
Full recovery after 5 weeks
Diamante
Chiodini
2014
8
Confusion, delirium
Persistant
psychocognitive
impairment under PE/PI
Multifocal hypersignals
20
Full recovery within 2 weeks
1.7
Seizures, hemiparesis,
lethargy,
unresponsiveness
Subtle bilateral
anomalies
<1
Improvement over 3 weeks
Full recovery with residual
weakness of right thumb/index
Hu
2013
Eculizumab appears efficient to rescue
ischemic cardiomyopathy in aHUS
Author
Age
(yrs)
Cardiac
manifestations
Response to PE
Time to
eculizumab
initiation
(days)
80
Vilalta
2012
1.5
Day 60 under PE:
Dilated
cardiomyopathy
Cardiorespiratory
arrest
Resistance to PE
Hu
2013
1.6
Day 0: Dilated
cardiomyopathy
EF 30%
Cardiovascular
instability,
hypotension
First line
eculizumab
Day 20 under PE:
Dilated
cardiomyopathy
EF 37%
Repolarization
anomalies
High troponine level
Resistance to
daily PE +
plasma
intolerance
Diamante
Chiodini
2014
8
< 12 hours
37
Outcome
Improvement of cardiac
function over 6 days.
Subsequent full recovery.
Recovery over 9 days
Normalization of LV volume
and function over 2 weeks
Eculizumab in aHUS
Prospective trials in adult / adolescent
patients under prior plasmatherapy
Results at 26 and 64 weeks
Legendre CM et al. N Engl J Med 2013
Results at 2 years
Greenbaum L et al. ASH; Atlanta, USA; 8–11 Dec 2012. Abstract and Poster 2084
Legendre CM et al. WCN; Hong Kong; 31 May–4 Jun 2013. Abstract and Poster MO065
Prospective trials of eculizumab
C08-002: 17 patients with progressing TMA
(≥4 PE/PI in the week prior to screening)
C08-003: 20 patients with a long duration of aHUS
and chronic kidney disease under long-term PE/PI
1200 mg every 2 weeks through 26 weeks
C08-002:
no OP
900 mg/week
C08-003:
8-week OP
Wk 1
Plasma exchange/
infusion removed
OP, observation period
Wk 5
All patients offered to
continue into long-term
extension study:
86% (32/37) continued
eculizumab treatment,
median duration
100 weeks (002) and
114 weeks (003)
Prospective trials
Patients’ baseline characteristics
C08-002
Progressing
TMA
(N=17)
C08-003
Long disease
duration
(N=20)
28 (17–68)
28 (13–63)
Identified complement mutations or anti-CFH Ab, %
76
70
Prior kidney transplant, %
41
40
Median time from onset of current aHUS manifestation to
screening, months (range)
0.8 (0.2-3.7)
8.6 (1.2-45.0)
Median platelet count, x109/L (range)
118 (62-161)
218 (105-421)
22.9 (14.5)
30.8 (19.0)
35
10
6 (0-7)*
1.5 (1-3)
Median age, years (range)
Mean baseline eGFR, mL/min/1.73 m2 (SD)
Dialysis at baseline, %
Median number of PE/PI 7 days prior to first eculizumab dose
(range)
* One patient had no PE/PI 7 days prior to eculizumab due to severe allergic reaction after 2 sessions
Patients with progressing TMA under PE/PI C08-002
Hematologic normalization after the switch to eculizumab
Mean increase
73x109/L
p<0.001
Significant increase in platelet count
as early as day 7 (p=0.027)
53% of patients with abnormal
platelet count at baseline had normal
platelet count at day 7
Median delay before 1st normal value
Platelets (≥150X109/L): 7days (1-218)
LDH: 14 days (0-56)
C08-002
Patients with progressing TMA under PE/PI
Eculizumab allowed rapid improvement in eGFR, that
was sustained under ongoing treatment over 2 years
p<0.001
Mean increase in eGFR
from baseline,
mL/min/1.73m2 (SD)
• Week 26: 33.1 (33.3); p=0.001
• Week 100: 36.6 (29.8); p=0.006
p=NS p<0.001 p=0.03
1
2
3
eGFR mean change from baseline
Slope
Mean eGFR,
mL/min/1.73 m2 (SD)
•Baseline: 22.9 (14.5)
•Week 26: 55.9 (40.2)
•Week 100: 55.8 (30.0)
4/5 patients (80%) eliminated the
need for dialysis and remained
dialysis free through week 100
At median 100 weeks, only 2*/17
patients (12%) on dialysis
*One patient started dialysis at week 64
(baseline eGFR 19 mL/min/1.73m2 )
Patients 5 5 6 17 1716151515151515151315
15 14 13 12 11 12 11 13 12 13 13 12 9 12 12 10 9
9
9
Shorter time from clinical manifestation predicted greater eGFR gain (p=0.009)
C08-003
Patients with long duration of aHUS
Eculizumab allowed rapid improvement in eGFR, that was
sustained under ongoing treatment over 2 years
p=0.007
p=NS
p=0.001 p=NS
Mean increase in eGFR
from baseline,
mL/min/1.73 m2 (95% CI)
•Week 26: 6.1 (3.3–8.8); p=0.0001
•Week 104: 7.2 (0.76–13.6); p<0.05
Slope
1
2
3
Mean eGFR,
mL/min/1.73 m2 (SD)
• Baseline: 30.8 (18.9)
• Week 104: 40.1 (17.5)
2 patients on dialysis at
baseline remained on
dialysis at week 104 (10%).
No patient not on dialysis
at baseline initiated dialysis
Patients
20 20 20
20
20
19
17
18
17
18
18
13
17
17
15
Shorter time from clinical manifestation predicted greater eGFR gain (p<0.0001)
21
C08-002 and C08-003
Conclusions
These data suggest early switch to eculizumab or
eculizumab as first line therapy may be warranted to offer
patients the best chance of full recovery of renal function
The new prospective trials in pediatric
and adult patients with aHUS,
with or without prior plasmatherapy
Presented at Am Soc Nephrol, Atlanta USA; 5–9 Nov 2013
Paediatric trial: Greenbaum L et al. Abstract 5579 and Poster SA-PO849
Adult trial: Fakhouri F et al. Abstract 5593 and Presentation FR-OR057
Early/first line eculizumab initiation as adopted by
pediatricians may offer the best chance of full renal recovery
C10-003, children, n=22
Median delay before eculizumab: 6 d (<1 d–4.3 m)
12/22 (55%) without prior PE
Mean eGFR at baseline: 33±30 mL/min/1.73 m2
eGFR mean increase at week 27
64 mL/min/1.73m2
• 11/22 (50%) on dialysis at baseline
• 9/11(82%) discontinued dialysis
• 0/11 not on dialysis at baseline initiated dialysis
• 2/22 (9%) on dialysis at 6 months
C10-004, adults, n=41
Median delay before eculizumab: 15 d (<1 d–19.2 m)
6/41 (15%) without prior PE
Mean eGFR at baseline: 17±12 mL/min/1.73m2
eGFR mean increase at week 26
29.3 mL/min/1.73m2
• 24/41 (58%) on dialysis at baseline
• 20/24 (83%) discontinued dialysis
• 4/17 (24%) not on dialysis at baseline initiated dialysis
(2 short course)
• 6/41 (15%) on dialysis at 6 months
In practice
Proposals from
1. The French Study Group for aHUS and C3G (Zuber et al, Nat Rev Nephrol
2012)
Coordinated by V Fremeaux-Bacchi, F Fakhouri, J Zuber and C Loirat
Working group: M Buchler, S Burtey, D Chauveau, Y Delmas,
G Deschenes, A Garnier, A Karras, B Knebelmann, Y Lebranchu,
B Legallicier, C Legendre, M Lequintrec, B Moulin, P Niaudet,
C Pouteil-Noble, F Provot, B Ranchin, E Rondeau
2. HUS International (Loirat et al, Pediatr Nephrol 2014, in press)
Is it necessary to know whether the patient with a first
episode of aHUS has a complement anomaly and
which one it is before starting eculizumab?
NO
Eculizumab is efficacious and thus can be administered to
patients with aHUS and
 Any type of complement mutation
 No mutation identified (However, uncertain efficacy in patients with
DGKE mutation)
However
 Obtain anti-factor H antibody results rapidly
 Genetic screening is recommended for further decisions
First episode of aHUS
Which first-line treatment?
PE or eculizumab?
In children
 Eculizumab first-line, within 24 hours, to avoid PE/central catheter
In adults
Diagnosis of aHUS needs confirmation
Diagnosis of aHUS unequivocal
(e.g. eliminate cancer, TTP…)
(e.g. familial history, relapse of HUS,
post-transplant recurrence)
 PE first
 Switch to eculizumab if
• plasma resistance*
• relapse at PE tapering or cessation
 Eculizumab first-line, within 24 hours
* Definition of plasma resistance: no constant upward trend of platelet count ( particularly if still <
150x109/l) or no constant downward trend of LDH (particularly if still >ULN) or no significant decrease
of Screatinine (at a minimum ≥25% decrease) after 5 daily PE
Conclusion
• Eculizumab offers aHUS patients the best chance of
sustained remission and full rescue of renal function
if started early
• Prospective studies are now required to establish
whether treatment withdrawal is safe, in whom and
when.
Prevention of meningococcal infections
Risk of invasive meningococcal infection in PNH patients under eculizumab
0.5/year /100 patients
One aHUS patient out of approximately 65 outside of protocoles* and 2
patients out of 100 within trials** had invasive meningococcal infection
(favourable outcome).
Anti-meningococcal vaccine mandatory
 Quadrivalent conjugate vaccines (anti-A, C, W, Y) (Menveo® (≥2y) or Nimenrix® (≥1y))
should be used
 Anti-B vaccine available in France since Dec 11, 2013 and recommended.
However, further data on its clinical efficacy and duration of protection are still pending.
 The bactericidal activity of immune response after vaccination is uncertain in patients
with complement deficiency and/or receiving eculizumab and/or immunosuppressive therapy.
This justifies immediate antibioprophylaxis allowing prompt initiation of eculizumab.
 Repeated information to the patient, his family and family doctor
 Information card
Continuous antibioprophylaxis obligatory in some countries (France, UK)
 Oral methyl penicillin (full dose, twice daily)
To our opinion, should be recommended for children
*Struijik et al, AJT 2013 ; ** Fakhouri et al, ASN, Nov 5-10 2013, FR-OR057, Atlanta
Complications of plasma exchanges in children
with aHUS
71 children from 11 European countries and North America
with aHUS between 1 July 2009 to 31 Dec 2010
Audit of the 2009 Guidelines for initial therapy of aHUS (Ariceta et al, Pediatr Nephrol 2009)
Central venous catheters n = 51
• 17 complications in 16 children (31%)
• Infection n= 8, thrombosis n=3, limb ischemia n=1,
haemorrhage n= 2, chylothorax n= 1.
Plasma hypersensitivity n=8, leading to withdrawal of therapy in 1
Johnson S et al, for the European Paediatric Study Group for HUS, Pediatr Nephrol 2014
Eculizumab treatment
Which duration?
Outcome after eculizumab discontinuation in 20 patients
Relapse of HUS
after eculizumab
withdrawal
Delay between
eculizumab
withdrawal and
relapse (m)
Screatinine
at relapse
(µmol/l)
Screatinine
at last f-up
(µmol/l)
F-up after
eculizumab
withdrawal or
re-initiation
(m)
Age
(y)
Complement
anomaly
Eculizumab
treatment
duration until
withdrawal
20 (PP)
CFH
9m
Yes
6
Normal  451
(3 weeks dialysis )
ND (off
dialysis)
ND
26 (PP)
CFH + CFI
18 m
No
NA
NA
70
18
4.3
CFH
5.5 m
Yes
1.5
71  248
71
25
37.7
CFH
14 m
Yes
0.9
124203
115
10
11
CFI
2w
No
NA
NA
48
11
52.7
CFI
1.5 m
No
NA
NA
88.5
22
34.8
CFI
11.5 m
No
NA
NA
221
10
2.6
CFI
5.5 m
No
NA
NA
35
15.5
6
MCP
5w
No
NA
NA
Normal
9
22
MCP
8w
No
NA
NA
84
11
5.4
MCP
0.5 m
No
NA
NA
44
13.5
49
Anti-CFH
8w
No
NA
NA
88.5
10
19.1
Anti-CFH
5.5 m
No
NA
NA
106
14.5
13.3
Anti-CFH
2.5 m
No
NA
NA
53
8.5
10.9
Anti-CFH
(high titer)
0.4 m
Yes
1
62 301
53
5
85
None
3m
No
NA
NA
Normal
12
64
ND
13 w
No
NA
NA
60
6
32 (PP)
None
6m
No
NA
NA
88.5
12
20
None
9m
No
NA
NA
70.8
≈9
1.3
None
13.5 m
No
NA
NA
26
6.5
Cayci 2012; Beye 2013; Canigral 2013; Carr 2013; Delmas 2013; Pu 2013; Fakhouri 2014; Ardissino 2014; Chaudhary 2014
The specific subgroup of anti- factor H antibodyassociated aHUS
First described in 2005 : 3 cases in children1
Approximately 200 cases reported currently2-4, mainly in childhood
Frequency 6-10% (up to 25%) of aHUS in European children, 50% in Indian children
Ref 2
All patients (n = 45)
mean : 9 years (8 months – 52 years)
Children (n = 38)
9 years (8 months – 14 years)
Adults (n=7)
41 years (28 - 52 years)
7
Number of cases
6
5
4
females
males
3
2
1
1 Dragon-Durey
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 28 30 35 41 45 50 52
Age at onset (Years)
et al, JASN 2005
Dragon-Durey et al JASN 2010
3 Hofer et al, CJASN 2013
4 Sinha et al, KI 2013
2
Anti-CFH antibody-associated HUS
Benefit from early PE+ immunosuppression with subsequent maintenance
immunosuppression guided by anti-CFH antibodies titer
92%
76%
Combined PE+IS
71%
69%
Maintenance IS
87%
P= 0.010
P<0.0001
46%
41%
No maintenance IS
33%
No combined therapy
Probability of renal survival with
respect to induction combined
therapy with plasma exchanges
and immunosuppression
Probability of relapse free survival
with respect to maintenance
immunosuppression
Renal survival free of adverse outcome: alive with eGFR ≥ 30 ml/min/1.73m2
Sinha et al, KI 2013
New prospective trials in paediatric and adult patients:
Haematologic normalisation in most patients
41 adults
C10-004
95%
82%
98%
88%
(95% CI 77–100)
(95% CI 60–95)
(95% CI 88–100)
(95% CI 74–96)
Haematologic
normalisation
Platelet count
normalisation
Haematologic
normalisation
55 (1–153)
8 (0–84)
55 (2–146)
100
100
80
80
Percentage
Percentage
22 children
C10-003
60
40
60
40
20
20
0
0
Platelet count
normalisation
Median
days to
endpoint
(range)
7 (1–80)
Haematologic normalisation: platelet count ≥150 x 109/L and LDH ≤ULN for at least 2 consecutive measurements over ≥4 weeks
Clinical characteristics at first episode according to age
French cohort
Children (n=89)
Trigerring event
Diarrhea
Upper respiratory tract
infection
Pregnancy
(post-partum )
47%
39%
8%
Adults (n=125)
33%
15%
1%
19% of women
Complete triad
Platelets > 150G/L
Hb>10g/dl
74%
15%
6%
83%
16%
11%
CNS involvement
16%
8%
Dialysis required
59%
81%
Fremeaux-Bacchi et al, CJASN 2013
The late 2000s: Recommended schedule for PE/PI
for aHUS at presentation and during the first month
•
•
PE with plasma for restitution (or PI if PE not possible) within 24 hours
of onset
Daily for at least 5 days and until normalisation of platelet count and
LDH, and improvement of renal function
– Then five sessions per week during 2 weeks followed by three sessions
per week for 2 weeks
– Followed by empirical treatment schedule (modality and interval)
per patient
Ariceta G et al. for the European Pediatric Study Group for HUS. Pediatr Nephrol 2009;
Taylor CM et al. for the Renal Association, the British Committee for Standards in Hematology and the British Transplantation Society. Br J Hematol 2010
The risk of meningococcal infection in patients with
terminal complement factors deficiency or blockade
• Immunity against Neisseria meningitis is mainly mediated by the lytic terminal
complement complex C5b-9
• Walport MJ, NEJM 2001: « The risk of meningococcal disease for a person with
a complement deficiency …can be calculated to be 0.5 percent per year. This is
a relative risk of 5000, as compared with … persons without a complement
deficiency » .
• Invasive meningococcal infection in PNH patients under eculizumab:
0.5 / year / 100 patients (Hillmen et al, 2013)
• Invasive meningococcal infection in aHUS patients under eculizumab :
-1 patient out of 80 treated outside of trials (Struijk 2013) and 2 patients out of
100 within trials (Fakhouri, ASN 2013) (favourable outcome).
Prevention of meningococcal infections
Obligatory anti-meningococcal vaccine + antibioprophylaxis for 2 weeks
• Conjugate tetravalent vaccines protect against serogroups A, C, W135 and Y, not
against serogroup B
• Anti-B vaccine now available (since Dec 11, 2013 in France) must be
associated
• Education/information to the patient, his family and family doctor
• Information card
Continuous antibioprophylaxis obligatory in some countries (France, UK)
• Oral methyl penicillin (full dose, twice daily)
• To our opinion, should be recommended for children
Early initiation of eculizumab as adopted in children seems
to offer the best chance of renal function full recovery
C10-003, Children, N=22
Median delay before eculizumab: 6d (<1d-4.3m)
12/22 (55%) without prior PE
Mean eGFR at baseline : 33±30 ml/min/1.73 m2
C10-004, Adults, N=41
Median delay before eculizumab: 15d (<1d-19.2m)
6/41 (15%) without prior PE
Mean eGFR at baseline : 17±12 ml/min/1.73m2
eGFR mean Increase at Week 27
64 ml/min/1.73m2
11/22 (50%) on dialysis at baseline
9/11(82%) discontinued dialysis
0 not on dialysis at baseline initiated dialysis
2/22 (9%) on dialysis at 6 months
eGFR mean Increase at Week 26
29.3 ml/min/1.73m2
24/41 (58%) on dialysis at baseline
20/24 (83%) discontinued dialysis
4/17not dialysed at baseline initiated dialysis (short course in 2)
6/41 (15%) on dialysis at 6 months
C10-003
The new prospective trials in pediatric and adult patients
Hematologic normalization in most patients
22 Children
C10-003
41 Adults
C10-004
(95% CI: 77-100 )
21/22
Median
days to
endpoint
(range)
7 (1-80)
18/22
55 (1-153)
14/22
8 (0–84)
60.0
(7.0–153.0)
55 (2-146)
Hematologic normalization: platelet count ≥150x109/l and LDH ≤ ULN for at least 2 consecutive measurements over ≥ 4 weeks
43
Conclusion
• Eculizumab offers aHUS patients the chance of
sustained remission and full rescue of renal function
if started early
• Let’s make the best use of this revolution through:
– registries
– treatment duration studies
C10-003
C10-003 and C10-004
Conclusions
The results of the two current studies support the
recommendation of eculizumab as first line treatment in
pediatric patients and also in adults once unequivocal
diagnosis of aHUS is made.
45