Daina Erica Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità...

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


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

(%)


-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


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



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



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

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Daina Erica Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità...

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Transcript of Daina Erica Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità...