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

ASH 2008Advances 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 Thrombocytop

enic Purpura• The Pathophysiology of ITP Revisited: In

effective 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.

Table 1. Proportion of Helicobacter pylori(HP)-positive and HP-negative adult patients with ITP achieving a platelet count response. HP+

responders

HP+

Non-responders

HP-

responde

rs

HP-

Non-responders

Definition

of

response

Country

of

origin

Morimoto

2007

7 12 0 3 ① Japan

Asahi

2006

6 26 0 11 ② Japan

Inaba

2005

11 25 0 10 ③ Japan

Takahashi

2004

8 15 0 5 ④ Japan

Michel

2004

1 15 0 10 ⑤ USA

Ando

2004

10 17 0 2 ⑥ Japan

Hino

2003

12 21 0 3 ⑦ Japan

Overall

response

65(49.6%) 131 0 44

① Platelet count increase by 20 or more above baseline

② Increase in platelet count by 100 or more by 24 weeks

③ Platelet count above 100

④ Platelet count increase by 20 or more above baseline

⑤ Platelet count at least 50 and double from baseline

⑥ Platelet count above 90

⑦ Significant increase in platelet count

Table 2. Prevalence of hepatitis C virus (HCV) infection in adult patients with chronic immune thrombocytopenia (CITP) Authors Total number Number of infected (%)

Pawlotsly et al (1995) 139 14(10)

Pivetti et al (1996) 33 12(36)

Garcia-Suarez et al (2000) 51 13(22)

Sakuraya et al (2002) 79 11(14)

Zhang et al (2003) 247 33(13)

Rajan et al (2005) 250 76(30)

Total 799 159(20)

Study only included patients with platelet counts of less than 25x109/L.

Viral-Associated Immune Thrombocytopenic Purpura

(HIV &HCV)

Novel agents under

clinical investigations

Clinical trials of novel agents

Romiplostim (AMG 531)

Thrombopoietin (TPO) peptide mimetic Binds at the endogenous TPO-binding site Weekly subcutaneous administration

Eltrombopag (Promacta SB49711)

TPO non-peptide mimetic Binds at the intramembrane portion of the TPO receptor Daily oral administration

AKR-501 (YM477)

TPO non-peptide mimetic Binding remote from endogenous TPO-binding site Daily oral administration

Indications currently under investigation

Autoimmune thrombocytopenia Thrombocytopenia associated with chronic liver disease Thrombocytopenia associated with the treatment of hepatitis C virus Thrombocytopenia induced by chemotherapy for malignancy Thrombocytopenia associated with intrinsic marrow abnormalities Thrombocytopenia associated with the treatment of hematologic malignancy

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 52

000 to 91000/uL for the remainder of the study.• Plt counts returned to near baseline 2 weeks after stopping eltrombo

pag.• Pts responded to eltrombopag regardless of previous therapy.• Fewer pts treated with eltrombopag had any bleeding or clinically si

gnificant 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 ≥5

0000/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.

RomiplostimAbs#402

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

Possible adverse effects of thrombopoietic growth factor therapy

Thrombocytosis Thrombosis Tumor/leukemia cell growth Interaction with other cytokines Formation of neutralizing antibodies cross-reactive with native thrombopoietin Stem cell depletion Platelet activation and acceleration of pathophysiologic processes Increased bone marrow reticulin or collagen deposition Rebound thrombocytopenia below baseline upon sudden cessation of therapy

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

http://www.hematology.org/about/50thanniversary/

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 109/L platelet count (high risk disease)

• front line (homogeneous population)


OBJECTIVES OF THE STUDY

Primary• sustained response: PLT 50 x 109/L at 6 months with no additional

therapy after day 30

Secondary• safety profile: incidence of serious adverse events

• initial response: PLT 50-100-150 x 109/L day + 30

• activity of Dexamethasone + Rituximab salvage therapy

• identification of factors predictive of sustained response

• immunologic assessment

• pharmacokinetics




STUDY TREATMENTS

days

D D

D RTX

D: Dexamethasone 40 mg po, on days 1, 2, 3, 4

D D

D D D RTX RTXRTX

1 2 3 4 7 14 21 28

1 2 3 4 7 14 21 28

days

ARM A: Dexamethasone

ARM B: Dexamethasone + Rituximab

RTX: Rituximab 375 mg/m2 IV, on days 7, 14, 21, 28



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%).



PATIENTS CHARACTERISTICS

Dexa N=52 Dexa + RTX N=49

Male vs Female 37% vs 63% 45% vs 55%

Median age, years 49 49

PLT 10 x 109/L 24 (46%) 22 (45%)

PLT 11-20 x 109/L 28 (54%) 27 (55%)



EFFICACY: INITIAL RESPONSE

Initial

response

(day +30)

PLT 50 x 109/L

(Overall Response) PLT 100 x 109/L PLT 150 x 109/L

DexaDexa

+ RTXP Dexa

Dexa

+ RTXP Dexa

Dexa

+ RTXP

ITT 27% 68% < 0.001 23% 48% 0.015 18% 36% 0.178



EFFICACY: SUSTAINED RESPONSE

Sustained

response,

(month +6)

PLT 50 x 109/L

(Sustained Response)PLT 100 x 109/L PLT 150 x 109/L

DexaDexa

+ RTXP Dexa

Dexa

+ RTXP Dexa

Dexa

+ RTXP

ITT 36% 63% 0.004 33% 53% 0.019 25% 43% 0.029

PP 39% 85% <0.001 37% 77% <0.001 29% 65% 0.002


ML18542 study Clinica Ematologica-UdineML18542 study Clinica Ematologica-Udine

FACTORS PREDICTIVE OF SUSTAINED RESPONSE

Factors P

Age NS

Sex NS

Platelets < vs > 10 x 109/L NS

Baseline CD20 lymphocyte count NS

Baseline IgG serum level NS

Treatment (dexa plus rituximab vs dexa) 0.004



PATIENTS OF ARM A “RESCUED” WITH DEXA+RTX

Sustained

response

(month +6)

PLT 50 x 109/L

(sustained response)PLT 100 x 109/L PLT 150 x 109/L

Patients: 27 56 % 44 % 37 %


Follow up in patients who achieved sustained response

Dexa N= 11 Dexa + RTX N= 23Dexa + RTX

salvage therapy N= 13

Median FU, months (range) 18 (10-26) 22 (10-34) 18 (10-34)

Relapse rate (PLT < 50x109/L) 2 (18%) 2 (9%) 1 (8%)

Time to relapse, months 10, 14 18, 30 10

0.0

00.

25

0.5

00.

75

1.0

0C

um

ula

te p

roba

bilit

y

0 10 20 30 40Months

Salvage Therapy Arm A

Arm B

Dexa + RTXsalvage therapy

Dexa + RTXDexa

Dexa Dexa + RTXDexa + RTX

salvage therapy

2 years RFS 78% 94% 90%



TOXICITY

Dexa N= 52 Dexa + RTX N= 49Dexa + 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 4th RTX.

2. SV tachycardia during the

1st RTX (stop RTX).

3. Interstitial pneumonia one

month after the 4th RTX.

1. Platelet decrease, in-pt

hospitalization 11 days

after the 4th RTX.

2. Convulsion during

the 1st RTX (stop RTX).

3. TIA

No toxic or hemorragic deaths observed

P= NS

P= 0.006


Therapy Baseline Week 24 P value

IgG, mean

value (g/L)

Arm A

Arm B

12.86

11.32

9.33

9.70

0.050

0.002

IgA, mean

value (g/L)

Arm A

Arm B

2.19

2.44

1.85

1.71

0.367

< 0.001

IgM, mean

value (g/L)

Arm A

Arm B

1.57

1.09

1.11

0.71

0.805

< 0.001

CD20+ ly mean

value x 109/L

Arm A

Arm B

0.42

0.33

0.20

0.00

0.895

< 0.001

CHANGES OF IgG, IgA, IgM and CD20+LYMPHOCYTES

Clinica Ematologica-UdineML18542 study



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


R. Fanin Udine

M. Baccarani Bologna

P. Mazza Taranto

F. Lauria Siena

L. Gugliotta Reggio Emilia

A. Zaccaria Ravenna

F. Ferrara Napoli

E. Angelucci Cagliari

S. Amadori Roma, Tor Vergata

G. Leone Roma, Cattolica

E. Morra Milano

G. Visani Pesaro

V. Liso Bari

S. Mirto Palermo

G. Pizzolo Verona

G. Semenzato Padova

G. Rossi Brescia

A. Gallamini Cuneo

G. Fioritoni Pescara

R. Foà Roma, La

Sapienza

....... . .

.. ...

.

.

...

..

AKNOWLEDGEMENTS

M. Regazzi Pavia (PK studies)

F. Soldano, M. Isola Udine (Statistics)E. Gamba


Documents

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