ASH 2008 Advances in ITP Research both Basic and Clinical Huiping Sun 26-Feb-2009

ASH Program of ITP Reports ASH 50th Anniversary Review Education Program Oral Session Poster Session Satellite Symposium

ASH 50th Anniversary Review Megakaryopoiesis and Thrombopoiesis by K Kaushansky

Education Program Helicobacter Pylori and Chronic ITP Viral-Associated Immune Thrombocytopenic Purpura The Pathophysiology of ITP Revisited: Ineffective Thrombopoiesis and the Emerging Role of Thrombopoietin Receptor Agonists in the Management of Chronic Immune Thrombocytopenic Purpura

Helicobacter Pylori and Chronic ITP Virulence factors of H pylori such as CagA and VacA play specific roles in the primary colonization and infection H pylori neutrophil-activation protein (HP- NAP) and the cell wall lopopolycacchride (LPS) induced the host immune response which caused polarized T helper 1(Th1) response of the host.

Viral-Associated Immune Thrombocytopenic Purpura (HIV &HCV)

Novel agents under clinical investigations

Clinical trials of novel agents

Eltrombopag (RAISE) Abs #400 6-month, randomized, double-blind, placebo-controlled, phase III study that evaluated the efficacy and safety of eltrombopag in previously treated adults with ITP with plt counts <30000/ul

Results: Pts n=197 (e=135,p=62) E group: 8 times more likely to achieve plt counts 50000~400000/uL (OR[95%CI]=8.2[4.32,15.38];p<0.001) Baseline median platelet counts were 16000/uL in both groups and never exceeded 30000/uL in the placebo group. E group: platelets fose to 36000/uL after 1 week and ranged from to 91000/uL for the remainder of the study. Plt counts returned to near baseline 2 weeks after stopping eltrombopag. Pts responded to eltrombopag regardless of previous therapy. Fewer pts treated with eltrombopag had any bleeding or clinically significant bleeding throughout the trial. AEs: overall incidence of AEs was similar.

Eltrobopag (EXTENT) Abs #401 An ongoing, open-label study designed to assess the long-term safety and clinical benefit of eltrobopag in patients with chronic ITP

Results: Pts n=165 （ refractory or non refractory ） 75% of refractory patients achieved plt counts ≥50000/uL and 2Xbaseline, compared to 84% of non-refractory pts (p=0.1425). Weekly median plt counts in both groups remained at or above 50000/uL from week 1 through week 39. The proportion of pts with significant bleeding in both groups was lower than baseline at any point from week 1 through week 39.

Romiplostim Abs#402 Long-term treatment with Romiplostin in patients with chronic immune thrombocytopenia purpura(ITP): 3-year update from an open-label extension study

Rituximab Treat the patients with either ITP or TTP with CD20 monoantibody. (Poster) （ Abs#2289 ， 2297 ， 3433)

Rituximab (375 mg/m2;Roche France, Paris, France was infused intravenously Once weekly for 4 weeks.

Francesco Zaja M.D. Clinica Ematologica University of Udine, Italy. DEXAMETHASONE PLUS RITUXIMAB VS DEXAMETHASONE IN PREVIOUSLY UNTREATED ADULT PATIENTS WITH IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP) For internal use only

ML18542 study Clinica Ematologica-Udine RITUXIMAB IN ITP: RATIONALE FOR STUDY DESIGN Objective: to evaluate Rituximab efficacy and safety in a prospective randomized study Selection of the patients: ITP (ASH guidelines) adults (very high probability of chronic disease) ≤ 20 x 10 9 /L platelet count (high risk disease) front line (homogeneous population) For internal use only

OBJECTIVES OF THE STUDY Primary sustained response: PLT  50 x 10 9 /L at 6 months with no additional therapy after day 30 Secondary safety profile: incidence of serious adverse events initial response: PLT  x 10 9 /L day + 30 activity of Dexamethasone + Rituximab salvage therapy identification of factors predictive of sustained response immunologic assessment pharmacokinetics ML18542 study Clinica Ematologica-Udine For internal use only

ML18542 study Clinica Ematologica-Udine STUDY TREATMENTS days DD D RTX D:Dexamethasone 40 mg po, on days 1, 2, 3, 4 D D DDD RTX days ARM A: Dexamethasone ARM B: Dexamethasone + Rituximab RTX:Rituximab 375 mg/m 2 IV, on days 7, 14, 21, 28 For internal use only

ML18542 study Clinica Ematologica-Udine ENROLLMENT Start enrollment: June 2005 Stop enrollment in June 2007, after having accrued 101 patients, when the results of the first interim analysis on 50 patients indicated a 52% advantage of sustained response for Dexamethasone + Rituximab arm (81% vs 29%). For internal use only

ML18542 study Clinica Ematologica-Udine PATIENTS CHARACTERISTICS Dexa N=52Dexa + RTX N=49 Male vs Female37% vs 63%45% vs 55% Median age, years49 PLT  10 x 10 9 /L 24 (46%)22 (45%) PLT x 10 9 /L28 (54%)27 (55%) For internal use only

ML18542 study Clinica Ematologica-Udine EFFICACY: INITIAL RESPONSE Initial response (day +30) PLT  50 x 10 9 /L (Overall Response) PLT  100 x 10 9 /LPLT  150 x 10 9 /L Dexa Dexa + RTX P Dexa Dexa + RTX P Dexa Dexa + RTX P ITT27%68% < %48% %36% For internal use only

ML18542 study Clinica Ematologica-Udine EFFICACY: SUSTAINED RESPONSE Sustained response, (month +6) PLT  50 x 10 9 /L (Sustained Response) PLT  100 x 10 9 /LPLT  150 x 10 9 /L Dexa Dexa + RTX P Dexa Dexa + RTX P Dexa Dexa + RTX P ITT36%63% %53% %43% PP39%85% < %77% < %65% For internal use only

ML18542 study Clinica Ematologica-Udine ML18542 study Clinica Ematologica-Udine FACTORS PREDICTIVE OF SUSTAINED RESPONSE FactorsP AgeNS SexNS Platelets 10 x 10 9 /LNS Baseline CD20 lymphocyte countNS Baseline IgG serum levelNS Treatment (dexa plus rituximab vs dexa)0.004 For internal use only

ML18542 study Clinica Ematologica-Udine PATIENTS OF ARM A “RESCUED” WITH DEXA+RTX Sustained response (month +6) PLT  50 x 10 9 /L (sustained response) PLT  100 x 10 9 /LPLT  150 x 10 9 /L Patients: 2756 %44 %37 % For internal use only

Follow up in patients who achieved sustained response Dexa N= 11Dexa + RTX N= 23 Dexa + RTX salvage therapy N= 13 Median FU, months (range)18 (10-26)22 (10-34)18 (10-34) Relapse rate (PLT < 50x10 9 /L) 2 (18%)2 (9%)1 (8%) Time to relapse, months10, 1418, 3010 Dexa + RTX salvage therapy Dexa + RTX Dexa Dexa + RTX Dexa + RTX salvage therapy 2 years RFS78%94%90% For internal use only

ML18542 study Clinica Ematologica-Udine TOXICITY Dexa N= 52Dexa + RTX N= 49 Dexa + RTX salvage tx N= 27 Patients with any adverse events 26 (50%)37 (76%)18 (67%) Patients with serious adverse events 1 (2%)3 (6%)3 (11%) 1. Rib fracture 5 months after Dexa 1. Platelet decrease, in-pt hospitalization 18 days after the 4 th RTX. 2. SV tachycardia during the 1 st RTX (stop RTX). 3. Interstitial pneumonia one month after the 4 th RTX. 1. Platelet decrease, in-pt hospitalization 11 days after the 4 th RTX. 2. Convulsion during the 1 st RTX (stop RTX). 3. TIA No toxic or hemorragic deaths observed P= NS P= For internal use only

TherapyBaselineWeek 24P value IgG, mean value (g/L) Arm A Arm B IgA, mean value (g/L) Arm A Arm B < IgM, mean value (g/L) Arm A Arm B < CD20+ ly mean value x 10 9 /L Arm A Arm B < CHANGES OF IgG, IgA, IgM and CD20+LYMPHOCYTES Clinica Ematologica-Udine ML18542 study For internal use only

ML18542 study Clinica Ematologica-Udine CONCLUSIONS The results of this randomized study indicate that Rituximab plus a single course of Dexamethasone vs a single course of Dexamethasone monotherapy: improves the rate of initial response (68% vs 27%) improves the rate of sustained response (63% vs 36%) is an active salvage therapy in 56% of patients refractory to Dexamethasone monotherapy has increased incidence of AEs with similar incidence of SAEs For internal use only

R. FaninUdine M. Baccarani Bologna P. Mazza Taranto F. LauriaSiena L. Gugliotta Reggio Emilia A. Zaccaria Ravenna F. FerraraNapoli E. Angelucci Cagliari S. Amadori Roma, Tor Vergata G. Leone Roma, Cattolica E. Morra Milano G. VisaniPesaro V. LisoBari S. MirtoPalermo G. PizzoloVerona G. SemenzatoPadova G. RossiBrescia A. GallaminiCuneo G. FioritoniPescara R. FoàRoma, La Sapienza AKNOWLEDGEMENTS M. RegazziPavia (PK studies) F. Soldano, M. IsolaUdine (Statistics) E. Gamba For internal use only