Service de Médecine Interne CHU Henri Mondor, Créteil, France

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1 Service de Médecine Interne CHU Henri Mondor, Créteil, France
Purpura thrombopénique auto-immun de l’adulte: De la physiopathologie au traitement. Actualités Bertrand Godeau Centre National de Référence pour la Prise en Charge et le Traitement des Cytopénies Autoimmunes de l’Adulte Service de Médecine Interne CHU Henri Mondor, Créteil, France

2 CENTRALE CONSOMMATION Thrombopénie IMMUNOLOGIQUE SEQUESTRATION

3 PTI Comment faire le diagnostic ?
Anomalie des autres lignées ? Aspect du frottis ? (schizocytes ?) Organomégalie ? Hémostase Myélogramme (facultatif ?) BCSH, Br J Haematol 2003

4 Comment faire le diagnostic ? Nle ou insuffisance hépatocellulaire
Splénomégalie Adénopathies Hémostase Schizocytes ? Anomalie des autres lignées Myélogramme Centrale Possible Nle (ou CIVD) Non le plus souvent OUI +++ ANORMAL Consommation CIVD Oui si MAT Variable Normal Séquestration Oui (grosse rate) Nle ou insuffisance hépatocellulaire Non Immunologique Normale +++ NON +++ NORMAL

5 Quelques données importantes
Attention à la fausse thrombopénie Sang capillaire Tube citraté Médicaments ? Ancienneté de la thrombopénie ? Notion de thrombopénie familiale

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7 Examens biologiques utiles dans le cadre
du Dg d’un PTAI ? INDISPENSABLES UTILES A DISCUTER * NFS + frottis (schizocytes ?) * Ac antiphospholipides * Durée de vie Plq * Bilan hépatique * Bilan d’autoimmunité * Autres sérologies * TP, TCA, Fg * Dosage pondéral Ig * Ac antiPlq * SéroVIH, VHC, VHB * Echo abdo * Myélogramme (±) * Biopsie médullaire * TSH Dans les cas difficiles uniquement, intérêt d’un test thérapeutique: la sensibilité aux corticoïdes (voire aux IgIV) est un argument fort en faveur du mécanisme immunologique de la thrombopénie

8 Quand faire le myélogramme ?
Age > 60 ans Anomalie des autres lignées Anomalie du frottis Organomégalie Absence de réponse à un Tt de première ligne Problème de l’enfant…

9 Résumé des recommandations de l’ASH et du BCSH
Traitement non indiqué si plaquettes >30x109/L Traitement initial: cure courte de corticoïdes et/ou IgIV Traitement après échec du traitement initial: splénectomie Autres options thérapeutiques: IgIV, alkaloïdes, anti-D, danazol, azathioprine, cyclosporine Patients réfractaires: rituximab ASH = American Society of Hematology; BCSH = British Committee for Standards in Haematology.

10 Traitements de premières lignes
IVIg (2g/kg) + HDMP + platelet transfusions +/- anti-D +/- vinca alkaloids IVIg (1 to 2 g/kg) HDMP Dexamethasone Anti-D Oral PRDN Pronostic vital en jeu ? Sd hémorragique mineur

11 Percentage of patients with platelet count > 50x109/L
HDMP (n=60) IVIg (n=56) P Day 1 - Day 2 < 10% <10% Day 3 31 % 41 % 0.44 Day 4 60 % 77 % 0.07 Day 5 79 % 0.04 IgIV plus efficaces avec réponse plus rapide, plus fréquente, plus prolongée …mais pertinence clinique discutable Percentage of patients with platelet count > 50x109/L

12 results of a randomized trial comparing 0.5 and 1 g/kg b.w.
Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0.5 and 1 g/kg b.w. Godeau et al, Br J Haematol 1999, 107:716-9

13 …Mais étude non contrôlée
Réponse fréquente et prolongée Traitement peu coûteux Et bien toléré …Mais étude non contrôlée

14 Intravenous anti-D treatment of thrombocytopenic purpura: experience in 272 patients Scaradavou et al Blood 1997; 89: Etude rétrospective IV anti-D 25 µg/kg or 50 µg/kg Response to initial anti-D treatment Duration of effect of anti-D treatment Adult HIV - patients (n=52) Platelet increases < 20 31 % 20-50 37 % 51-99 11 % > 100 12 % Response rate * 69 % Adult HIV - patients (n=36) Duration of effect* < 7 d 1 % > 7 d 97 % > 14 d 93 % > 21 d 53 % > 28 d 36 % > 42 d 19 % * Platelet increase > 20x109/L * Platelet increase > 20x109/L

15 43x109/L 46 days Group 1 75 µg/kg Group 2 50 µg/kg P value 7x109/L
A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura. Newman et al. Br J Haematol. 2001;112: Group 1 75 µg/kg Group 2 50 µg/kg P value Mean platelet count at D1 43x109/L 7x109/L 0.012 Mean platelet count at D7 153x109/L 64x109/L 0.001 Mean duration of effect 46 days 21 days

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17 Traitements de premières lignes
IVIg (2g/kg) + HDMP + platelet transfusions +/- anti-D +/- vinca alkaloids IVIg (1 to 2 g/kg) HDMP Dexamethasone Anti-D Oral PRDN Pronostic vital en jeu Score hémorragique Sd hémorragique mineur

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19 Khellaf M et al Hematologica 2005; 90: 829-32
Age* Age over 65 years Age over 75 years Cutaneous bleeding* Localized petechial purpura (legs) Localized ecchymotic purpura Two locations petechial purpura Generalized petechial purpura Generalized ecchymotic purpura Mucosal bleeding* Unilateral epistaxis Bilateral epistaxis Hemorrhagic oral bullae, spontaneous Gingival bleeding or both Gastrointestinal bleeding* GI hemorrhage without anemia GI with acute anemia (> 2g Hb decrease in 24 h) and/or shock Urinary bleeding* Macroscopic hematuria without anemia Macroscopic hematuria with acute anemia Genitourinary tract bleeding* Major meno/metrorrhagia without anemia Major meno/metrorrhagia with acute anemia Central nervous system bleeding* CNS and/or life-threatening hemorrhage * For these items, only the bigest values are tacken into account Khellaf M et al Hematologica 2005; 90:

20 Bulles hémorragiques intra-buccales
4 5 + Purpura echymotique généralisé Bulles hémorragiques intra-buccales 9 = Exemple de Score hémorragique

21 Une stratégie thérapeutique basée
sur l’utilisation d’un score hémorragique permet d’éviter le recours aux IgIV dans 51% des cas Khellaf M et al Hematologica 2005; 90:

22 Abst Changing Trends in ITP Management from 1995 to 2007: An Interim Report from the UK Paediatric ITP Registry  John D. Grainger UK national paediatric ITP registry ( 114 children Severity of the disease

23 Abst Changing Trends in ITP Management from 1995 to 2007: An Interim Report from the UK Paediatric ITP Registry  John D. Grainger UK national paediatric ITP registry ( Steroids alone: 75% IVIg alone: 15% Steroids and IVIg: 10%

24 Abst3435 Health-Related Lifestyle among Adult & Pediatric Patients with Idiopathic Thrombocytopenic Purpura in the United Kingdom Ameet Sarpatwari

25 Spatwari et al Adults (n=696) Children (n=94) Male N=190 Female N=497
Have you ever been unable to go to work 26% 31% 20% 30% Have you had difficulty obtaining or been refused travel and life insurance? 18% Have you ever had surgery postponed or delayed because of a low platelet count? 34% 13% 19% Are people ever suspicious that the bruises are a result of physical violence? 5% 38% Do you try to hide your bruises? 10% 37% 42% Have you ever been refused a referral to an ITP specialist or hospital of your choice? 3% 4% Spatwari et al

26 Splénectomie et risque de rechute
Schwartz et al, Am J Hematol 2003; 72: 94-8 Fabris et al, Br J Haematol 2001; 112:

27 Complete response: 66% (follow-up 1 to 153 months)
Splenectomy for Adult Patients With Idiopathic Thrombocytopenic Purpura: a Systematic Review to Assess Long-term Platelet Count Responses, Prediction of Response, and Surgical Complications Retrospective review of 135 case series 2 623 patients Complete response: 66% (follow-up 1 to 153 months) Relapse: 15% Mortality with laparoscopy: 0.2% Kojoury K, et al. Blood. 2004;104:

28 Nouveaux traitements de seconde ligne ?
Treatments Number of Studies Number of Patients (Splenectomised Patients) Percentage of Response Cyclosporin A 4 49 (35) 45% to 84% Mycophenolate mofetil 54 (29) 39% to 83% Dapsone 3 136 (21) 40% to 62%

29 Rituximab (Anti-CD20) et AITP
700 700 700 600 600 600 500 500 500 Mean Platelet Count (× 109/L) 400 400 400 Mean Platelet Count (× 109/L) Mean Platelet Count (× 109/L) 300 300 300 200 200 200 100 100 100 10 12 16 1 2 3 4 6 8 10 12 16 1 2 3 4 6 8 10 12 16 1 2 3 4 6 8 Weeks of Study Weeks of Study Weeks of Study Rituximab infusions Three distinct patterns of complete response in adults treated with rituximab, 375 mg/m2 weekly for 4 weeks Cooper N, et al. Br J Haematol. 2004;125:

30 Contributing Reports, n
Systematic Review: Efficacy and Safety of Rituximab for Adults With Immune Thrombcytopenic Purpura Platelet Count Response (x 109/L) Pooled Estimate, % (95% CI) Contributing Reports, n (Patients, n) Overall response (>50) 62 (53–72) 19 (313) Complete response (>150) 46 (29–57) 13 (191) Partial response (50–150) 24 (15–33) 16 (284) CI = confidence interval. Arnold DM, et al. Ann Intern Med. 2007;146:25-33.

31 Rituximab et AITP Questions non résolues
Effet à très long terme (guérison …) ? Tolérance ? Avant splénectomie ? Dose (s) ? Injections répétées ? Facteurs prédictifs de réponse ? Mécanisme(s) d’action

32 Godeau et al, Blood 2008, in press

33 Multicenter controlled phase 3 study
Abst 1 A Prospective Randomized Study Comparing Rituximab and Dexamethasone Vs Dexamethasone Alone in ITP: Results of Final Analysis and Long Term Follow up Francesco Zaja et al Multicenter controlled phase 3 study

34 Primary objective: compare the sustained response (SR), PLT count 50G/L at month + 6 of treatment
Zaja et al

35 Primary outcome Response at 6 mths (intent to treat)
Arm A (DXM) Arm B (DXM + ritux) P Valuable pts (n) 52 49 Plt 50 G/L 36% 63% 0.004 Plt 100G/L 33% 53% 0.019 Plt 150 G/L 0.029 Zaja et al

36 Long term response 24 mths(range ?)
Arm A (DXM) Arm A with salvage (DXM + ritux) Arm B (DXM + ritux) P Valuable pts (n) 12 27 19 Plt 50 G/L 78 % 90% 94% 0.004 - No predictive factors of response - No severe side effects except >1 pneumoniae Zaja et al

37 Weeks From Initial Rituximab Infusion
Duration of Response to Rituximab in Patients With Chronic ITP With Response Duration >1 Year Duration of Response to Rituximab in 44 Patients With Chronic ITP With a Response Greater Than 1 Year 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Year 1 Year 3 Year 5 52 100 150 200 250 300 Weeks From Initial Rituximab Infusion 14/31 relapsed during follow-up; 5-year response rate = 55% 11/14 relapsed within 2.5 years of first infusion 14/17 with ongoing responses had follow-up >2.5 years Patel V, et al. Blood. 2006;108(11 part 1):145a.

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42 PTI: défaut de production ?
TPO inadaptée Inhibition de la pousse mégacaryocytaire par autoAc Anomalies morphologique Médullaire (para-apoptose) Total megacaryocytes Suppression of megakaryocyte production by IgG from ITP plasma

43 Subcutaneous injection
Nouvelle perspective dans le traitement du PTAI Les agonistes du récepteur de la TPO AMG 531 (Amgen®) Peptide Subcutaneous injection No homology with native TPO Eltrombopag (GlaxoSmithKline®) Small molecule Orally available The subject of my talk is the interesest of TPO agonists that could perheaps represent a new strategy in the treatment of ITP. I focused my presentation on adults because to my knowledge, there is no data in children.

44 AMG 531, a Thrombopoiesis-Stimulating Protein, for Chronic ITP
10 000 Baseline Dose 1 Peptide receptor-binding domain Dose 2 1 000 Fc carrier domain 450 100 50 Peak Platelet Count (× 10-3/mm3) 10 1 A novel thrombopoiesis-stimulating peptibody Structurally unrelated to thrombopoietin Dipeptide linked to the Fc fragment of IgG Targets thrombopoietin Increases platelet production 1 g/kg 3 g/kg 6 g/kg 10 g/kg Dose of AMG 531 Peak Individual Platelet Counts in Phase 1. The baseline platelet count and the peak platelet count after dose 1 and dose 2 are shown. There were 4 patients in each dose cohort. Three patients did not receive a second dose. The shaded area shows the targeted platelet range. Platelet counts associated with the use of rescue medication have been excluded. Bussel JB, et al. N Engl J Med. 2006;355:

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48 Mean number weeks of response 12
Results of weekly AMG531 administration for 24 weeks In 63 splenectomized patients with chronic ITP Placebo (n=21) AMG531 (n=42) P Durable response 0% 38% 0.001 Overall response 78% < 0.001 Rescue medication 57% 26% 0.02 Mean number weeks of response 12 Gernsheimer et al, ASH 2007

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50 Mean number weeks of response 1 15
Results of weekly AMG531 administration for 24 weeks In 63 non-splenectomized patients with chronic ITP Placebo (n=21) AMG531 (n=42) P Durable response 5% 61% < 0.001 Overall response 14% 88% Rescue medication 62% 17% 0.02 Mean number weeks of response 1 15 Kutter et al, ASH 2007

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54 Bussel et al, NEJM 2007

55 Bussel et al, NEJM 2007

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58 Agonistes du récepteur de la TPO: Indications potentielles?
Patients réfractaires? Utilisation transitoire avant acte invasif ? Traitement « d’attente » après la phase aiguë? Mais coût et sécurité d’emploi ?

59 Autres Traitements? Eradication de Helicobacter pylori Anti-D IVIg
Prednisone, dexamethasone Alemtuzumab Anti-TNF Anti-CD154 Anti–IL-2 Anti-FCIII …

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61 Abst 3413 The Efficacy of H. pylori Eradication Therapy in H. pylori-Infected and Uninfected Patients with Immune Thrombocytopenic Purpura: A Systematic Review  Donald M. Arnold  et al. Revue de la littérature portant sur 10 séries considérées comme méthodologiquement satisfaisantes par les auteurs. Charateristics Number Number of patients 333 patients Mean platelet count (G/L) 42 ± 26 G/L Splenectomy (%) 11 %

62 Response of ITP to HP eradication according to the HP status
54% (n=59) HP- 3% P < Arnold et al

63 Conclusion (provisoire…)
La fin de la splénectomie ?

64 Stratégie thérapeutique au cours du PTI
IVIg MPRDN Dexaméthasone Anti-D Oral PRDN Immunosup. Splénectomie Rituximab Diagnostic 6 mois à 1 an

65 Stratégie thérapeutique au cours du PTI
IVIg MPRDN Dexaméthasone Anti-D Oral PRDN Plt < 30 giga/L et saigt Immunosup. Splénectomie Rituximab Diagnostic 6 mois à 1 an

66 Stratégie thérapeutique au cours du PTI
IVIg MPRDN Dexaméthasone Anti-D Oral PRDN Immunosup. Splénectomie Rituximab Diagnostic 6 mois à 1 an

67 Stratégie thérapeutique au cours du PTI
Agoniste TPO-r IVIg MPRDN Dexaméthasone Anti-D Oral PRDN Rituximab Splénectomie Diagnostic 6 mois à 1 an

68 Conclusions Recours à la splénectomie plus rare ?
Vers une révolution des pratiques ? Recours à la splénectomie plus rare ?