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IL RITUXIMAB NEL TRATTAMENTO DELLA PORPORA TROMBOTICA TROMBOCITOPENICA
Erica Daina
Centro Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele DaccòIstituto Mario Negri
22 Gennaio 2010Torino
A multisystem disease with predominant renal involvement in HUS and neurological signs in TTP, characterized by a triad of symptoms:
Definition
THROMBOTIC MICROANGIOPATHYHemolytic Uremic Syndrome - Thrombotic Thrombocytopenic Purpura
- microangiopathic hemolytic anemia- thrombocytopenia- formation of platelet-rich thrombi in the microcirculation
THROMBOTIC THROMBOCYTOPENIC PURPURA
Incidence of TTP estimated at 4 cases per 1 million/year
TTP is more frequent among women
(female/male ratio 3:2)
The most commom form of TTP is acquired ( “sporadic”)
Relapses following an initial episode of acquired TTP are described, with about one third of cases becoming recurrent
Familial TTP usually manifests in the postnatal period or during infancy, although in some cases the onset is later at 20-30 years
Patients with familial TTP tipically exhibit a relapsing course
• Deficiency of the von Willebrand Factor (VWF)-cleaving protease, ADAMTS13, has been reported in the majority of patients with TTPreported in the majority of patients with TTP
VWF-CLEAVING PROTEASE
Member of ADAMTS family (A Disintegrin-like AndMetalloprotease, with ThromboSpondin type 1 motif)
Named ADAMTS 13
1427 aa residues
Genomic DNA mapped to human chromosome 9q34
mRNA detected in liver
Zheng et al., J Biol Chem, 2001Gerritsen et al., Blood, 2001Fujikawa et al., Blood, 2001Soejima et al., J Biochem, 2001
REDUCED ADAMTS13 ACTIVITY IN HEALTH AND DISEASE
- elderly- newborns- third trimester of pregnancy
Mannucci et al., Blood, 2001
- third trimester of pregnancy- uremia- after major surgery- inflammatory states- liver cirrhosis
Family A
1054787
532753
1054787
532753
1054787
65/767
15/777
532753
532753
1054787
731 78679 8277
< 6%
1580
65576/
153777
108% 62% < 6% 67%< 6%
ADAMTS13 antigen (ng/mL)
ADAMTS13 activity (%)
Val88Met(metalloprotease) Gly1239Val (CUB1)
Heterozygous
ADAMTS13 MUTATIONS IN TTP CAUSE SEVERELY REDUCED PLASMA ADAMTS13 CONCENTRATION
ADAMTS13 activity (%) < 6%
653654
Family B
ADAMTS13 antigen (ng/mL) < 62.5
Family C
< 6% < 6%
651566
651566
651566
651566
< 62.5 < 62.5
653654
Arg1123Cys (TSP8) Arg1219Trp (CUB1)
Homozygous Homozygous
ACQUIRED IDIOPATHIC TTP
Undetectable plasma levels of ADAMTS13
The activity is normal after recovery
Furlan et al., Blood, 1998
The activity is normal after recovery
Antibodies that inhibit enzyme activity in plasma arefound in 48 to 80 % of these patients
Tsai et al., N Engl J Med, 1998Veyradier et al., Blood, 2001
• Deficiency of the von Willebrand Factor (VWF)-cleaving protease, ADAMTS13, has been reported in the majority of patients with TTP
• ADAMTS13 deficiency may be either constitutive, due to mutations in the ADAMTS13constitutive, due to mutations in the ADAMTS13gene, or acquired due to the presence of circulating anti-ADAMTS13 autoantibodies
100
80
60
Sur
viva
l (%
)Aspirin
Plasma manipulation
OLD DAYS OF TREATMENT OF HUS/TTP
40
20
0
Sur
viva
l
1925 1964 1980 1990
Bell et al NEJM, 1991Rock et al NEJM,1991Goldenfarb et al, JAMA 1973
• Plasma exchange is the treatment of choice for patients with acquired TTP
• Congenital TTP responds to plasma infusion• Congenital TTP responds to plasma infusion
Author: Deborrah Symonettehttp://emedicine.medscape.com/article/779969-overviewUpdated: Sep 16, 2009
DIFFERENTIAL DIAGNOSIS BETWEEN TTP ASSOCIATED WITH GENETIC OR IMMUNE-MEDIATED ADAMTS13 DEFICIENCY IS
IMPORTANT TO GUIDE SPECIFIC TREATMENTS
Genetic ADAMTS13 deficiency: - replacement with plasma of the defective activity
Immuno-mediated ADAMTS13 deficiency:- plasmapheresis to remove anti-ADAMTS13 autoantibodies
and to replace the metalloprotease- inhibition of the autoantibodies production through treatment
with glucocorticoids, immunosuppressive agents, or rituximab
Bergamo
Trento
Padova
Treviso
Vicenza
ParmaGenovaTorino
Pavia
Milano
VareseMonza
Brescia
Firenze
UK
USA
Belgium
Canada
SwitzerlandGermany
DenmarkParticipating CentersPatients
HUS/TTPFamilial Sporadic
180600473/12786/19387/108
INTERNATIONAL REGISTRY OF RECURRENT AND FAMILIAL HUS/TTP
Czech R. EstoniaPolandRoma
Foggia
BariSalerno
Reggio Calabria
Palermo
Cagliari
Sassari
USA
ArgentinaIsrael
Portugal
Spain
South Africa
Turkey
Saudi Arabia
Greece Serbia Iran
http://villacamozzi.marionegri.itUAE
Malaysia Japan Australia
Chile
• A congenital deficiency of ADAMTS13 was found in 15 patients
• Undetectable ADAMTS13 activity (<6%) due to the presence of anti-ADAMTS13 inhibitors was found in 28 of 32 patients, in the acute
INTERNATIONAL REGISTRY OF RECURRENT AND FAMILIAL HUS/TTP
ADAMTS13 inhibitors was found in 28 of 32 patients, in the acute phase, and in 14 of 53 patients, during remission
• 10 patients with a severe and recurrent form of TTP showed persistence of high titers of autoantibodies in remission
RITUXIMAB, A HUMANIZED CHIMERIC ANTIBODY DIRECTED AGAINST THE CD20 ANTIGEN IN B CELLS, HAS BEEN PROVEN EFFECTIVE IN INDUCING REMISSION IN PATIENTS REFRACTORY TO ANY OTHER TREATMENT
Chemnitz et al., Am J Hematol, 2002Gutterman et al., Blood Cells Mol Dis, 2002Tsai et al., Eur J Haematol, 2003Yomtovian et al., Br J Haematol, 2004Fakhouri et al., Ann Int Med, 2004Sallah et al., J Thromb Haemost, 2004
• Found 17 studies with search of: Thrombotic Thrombocytopenic Purpura
Use of Rituximab Treatment in Addition to Standard Care for Newly Presenting TTP
Rituximab in Patients With Relapsed or Refractory TTP-HUS
http://www.clinicaltrials.gov/ct2/home
Rituximab in Patients With Relapsed or Refractory TTP-HUS
Evaluating the Effectiveness of Adding Rituximab to Standard Treatment for TTP (The STAR Study)
The Use of Rituximab in Acute Thrombotic Thrombocytopenic Purpura (TTP)
REGISTRY ANALYSES - Aims of the evaluation
• To verify if Rituximab, in patients with anti-ADAMTS13 antibodies, can induce remission of acute refractory TTP and can prevent relapses of recurrent forms
• To verify if Rituximab can restore a significant ADAMTS13 plasma activity (>10%) with no detectable inhibitorsactivity (>10%) with no detectable inhibitors
• To evaluate whether the reapparance of high titer of ADAMTS13 inhibitors may be an indicator for retreatment
Patients
• Adult patients with at least one episode of TTP
• Reduced ADAMTS13 activity (<6%) and high titers of anti-ADAMTS13 antibodies at onset in patients with refractory TTP
• Reduced ADAMTS13 activity (<6%) and high titers of anti-• Reduced ADAMTS13 activity (<6%) and high titers of anti-ADAMTS13 antibodies in at least two assays performed at least 3months apart, and at the time of prophylactic treatment
CHARACTERISTICS OF TTP PATIENTS BEFORE TREATMENT WITH RITUXIMAB
PatientSex
Age at diagnosis
(yr)
Age at 1st treatment with Rituximab (yr)
Total number of TTP
episodes
Brain/Kidney involvement
Previous treatments
01/F 23 23 1 ?/NoPlasma, steroids, vincristine,
defibrotide
02/F 57 57 1 Yes/YesPlasma, steroids, vincristine,
cyclophosphamide, cyclosporine
03/M 48 58 >10 Yes/YesPlasma, steroids, intravenous Ig, cyclosporine, splenectomy
04/M 37 42 3 Yes/YesPlasma, steroids,
intravenous Ig
05/F 32 49 10 No/YesPlasma, steroids,
intravenous Ig, azathioprine
06/M 27 31 5 No/YesPlasma, steroids, intravenous
Ig, vincristine, vinblastine
Data from the International Registry of Familial and Recurrent HUS/TTP
RITUXIMAB TREATMENT IN ACUTE REFRACTORY TTP
Patientno
Treatmentno
FOLLOW-UP
Pre 2 mo 6 mo 10 mo 12 mo 15 mo 27 mo
01 1
ADAMTS13#-activity -inhibitors
CD20%
< 62.2
11
52Neg
1
54Neg
0
55Neg
1
70Neg
nd
67Neg
ndCD20% 11 1 0 1 nd nd
02 1
ADAMTS13#-activity -inhibitors
CD20%
< 62.3
8
62Neg
1
69Neg
1
< 6Pos
Prophylactic treatment
68Neg
nd
76Neg
nd
# ADAMTS13 activity is expressed as % (normal range: 50-150%)Inhibitors are expressed as Bethesda units
Data from the International Registry of Familial and Recurrent HUS/TTP
PROPHYLAXIS WITH RITUXIMAB IN RECURRENT TTP
A patient with recurrent TTP due to high titers of ADAMTS13 inhibitors whoused to have two relapses of TTP a year
+A
TG
+C
HP
+C
HP
+C
HP
+A
TG
+A
TG
+A
TG
0
100
200
300
400
500
600
700
+Ig
Vin
+F
FP
+V
in+
Vin
Vin
Vin
Vin
Vin
Vin
##ATG
+C
yA
+Ig
+Ig
+V
in+
Vin
0
0 10 20 30 40 50 60 70 80 90 100 110 120
months
: Plasma exchange;Vin: vincristine; ATG: antiplatelet agents;CyA: cyclosporin A; CHP: cyclophosphamide;#: plasma exchange, vincristine, antiplatelet agents and corticosteroids;Ig: immunoglobulins; FFP: fresh frozen plasma;
: splenectomy;
: transient ischemic attack;
: ADAMTS13 activity <6%, anti-ADAMTS13 inhibitors present.
: corticosteroids;
Galbusera et al., Blood 2005
30
35
(BU
)
15
18
13 a
ctiv
ity
(%)
PROPHYLAXIS WITH RITUXIMAB IN RECURRENT TTP
-Rituximab caused progressive disappearance of inhibitors and increase of protease activitythat lasted 14 months
-A second course of rituximab induced a prompt recovery of ADAMTS13 activity anddisappearance of inhibitor
- Plasmapheresis had a small transient effect on ADAMTS13 activity and on inhibitor titer
6
10
15
20
25
30
-25 -20 -15 -10 -5 0
Inh
ibit
or
tite
r (
BU
)
0
3
6
9
12
15
0 100 200 300 400 500 600 700 800AD
AM
TS
-13
acti
vity
3 courses of plasmapheresis 4 rituximab doses
days
: anti ADAMTS13 IgG titer: 1:1600
: anti ADAMTS13 IgG titer: negative
Galbusera et al., Blood 2005
PROPHYLAXIS WITH RITUXIMAB IN RECURRENT TTP
Patientno
Treatmentno
FOLLOW-UP
Day 0 3 mo 6 mo 12 mo 18 mo 24 mo 30 mo 40 mo
03 1 ADAMTS13#-activity -inhibitors
CD20%
< 62.3
9
15Neg
1
21 Neg
3
14Neg
6
< 66.5
Prophylactic retreatment
32Neg
1
10Neg
4
< 64.4
Relapse10 mo later
04 1 ADAMTS13#-activity < 6 55 74 91 70 84 56 45-activity -inhibitors
CD20%
< 61.9
7
55Neg
0
74Neg
0.2
91Neg
3
70Neg
3.2
84Neg
7.5
56Neg
nd
45Neg
nd
05 1 ADAMTS13#-activity -inhibitors
CD20%
< 63.4
nd
59Neg
1
64Neg
1
50Neg
nd
24Neg
nd
23Neg
nd
< 6Pos
Prophylactic retreatment1 infusion
25Neg
4.1
Data from the International Registry of Familial and Recurrent HUS/TTP
# ADAMTS13 activity is expressed as % (normal range: 50-150%)Inhibitors are expressed as Bethesda units
TTP PATIENT TREATED WITH RITUXIMAB BOTH IN ACUTE AND REMISSION PHASES
Patientno
Treatmentno
FOLLOW-UP
Day 0 2 mo 3 mo 6 mo 9 mo 12 mo
06acute
1ADAMTS13#
-activity-inhibitors
< 6+
33Neg
56Neg
46Neg
< 63.6
Prophylactictreatment
ADAMTS13#
06remission
2-activity-inhibitors
< 63.6
75Neg
78Neg
< 6+/-
< 62.5
Mild disease relapse
06acute
3ADAMTS13#-activity-inhibitors
< 62.5
60Neg
53 Neg
16Neg
# ADAMTS13 activity is expressed as % (normal range: 50-150%)Inhibitors are expressed as Bethesda units
Data from the International Registry of Familial and Recurrent HUS/TTP
Our observations confirmed that Rituximab as adjunctive therapy in patients with TTP not responding to conventional therapies induced remission
• Rituximab can be used as preventive therapy in patients at high risk of relapses
• ADAMTS13 activity and inhibitors should be monitored
CONCLUSIONS
• ADAMTS13 activity and inhibitors should be monitored during follow-up
• Trials are needed to evalute:
- parameters that should be used to predict relapse and indicate retreatment
- response rate and long term side effects
In a 10-year-old girl with high levels of anti-CFH autoantibodies, plasmaexchange combined with prednisone and azathioprine only transientlydecreased the antibody titer.
Rituximab (375 mg/m2/week x 4 weeks) led to a complete B celldepletion and maintained anti-CFH antibody at low levels during thefollowing 4 months.
RITUXIMAB FOR TREATMENT OF aHUS WITH ANTI-CFH ANTIBODIES
following 4 months.
In a 7 year old boy, combined treatment with FFP and Rituximabresulted in reduction in CFH autoantibody levels and induced clinicalremission.
Kwon et al, Nephrol Dial Transplant , 2008
Wigger et al, Pediatric Nephrol 2008
Laboratory ClinicalMarina Noris
Roberta Donadelli
Chiara Mossali
Chiara Fenili
Annalisa Sorosina
Jessica Caprioli
Rossella Piras
Giuseppe Remuzzi
Piero Ruggenenti
Erica Daina
Elena Bresin
Sara Gamba
Collaborations
Caterina Mele
Erica RuraliPeter Zipfel
Matthew Pickering
Veronique Fremeaux-Bacchi
Tim Goodship
John Atkinson
Santiago Rodriguez DeCordoba
Grants