Transcript ASH 2008 Advances in ITP Research both Basic and Clinical

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 (HPNAP) 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
HPresponde
rs
HPNon-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
②
③
④
⑤
⑥
Platelet count increase by 20 or more above baseline
Increase in platelet count by 100 or more by 24 weeks
Platelet count above 100
Platelet count increase by 20 or more above baseline
Platelet count at least 50 and double from baseline
Platelet count above 90
Viral-Associated Immune
Thrombocytopenic Purpura
(HIV &HCV)
Table 2. Prevalence of hepatitis C virus (HCV) infection in adult patients with
chronic immune thrombocytopenia (CITP)
Authors
Pawlotsly et al (1995)
Total number
139
Number of infected (%)
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 25x10 9/L.
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
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
52000 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
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.
DEXAMETHASONE PLUS RITUXIMAB VS DEXAMETHASONE
IN PREVIOUSLY UNTREATED ADULT PATIENTS WITH
IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)
Francesco Zaja M.D.
.
Clinica Ematologica
University of Udine, Italy
For internal use only
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)
For internal use only
ML18542 study
Clinica Ematologica-Udine
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
For internal use only
ML18542 study
Clinica Ematologica-Udine
STUDY TREATMENTS
ARM A: Dexamethasone
D D D D
days
1 2 3
4
7
14
21
28
ARM B: Dexamethasone + Rituximab
RTX
D D D D
RTX
RTX
RTX
days
1 2 3
4
D:
7
14
21
28
Dexamethasone 40 mg po, on days 1, 2, 3, 4
RTX: Rituximab 375 mg/m2 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=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%)
For internal use only
ML18542 study
Clinica Ematologica-Udine
EFFICACY: INITIAL RESPONSE
PLT  50 x 109/L
Initial
PLT  100 x 109/L
PLT  150 x 109/L
(Overall Response)
response
(day +30)
Dexa
Dexa
P
Dexa
+ RTX
ITT
27%
68%
Dexa
Dexa
P
+ RTX
< 0.001
23%
48%
Dexa
P
+ RTX
0.015
18%
36%
0.178
For internal use only
ML18542 study
Clinica Ematologica-Udine
EFFICACY: SUSTAINED RESPONSE
PLT  50 x 109/L
Sustained
PLT  100 x 109/L
PLT  150 x 109/L
(Sustained Response)
response,
(month +6)
Dexa
Dexa
P
Dexa
+ RTX
Dexa
Dexa
P
+ RTX
Dexa
P
+ RTX
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
For internal use only
ML18542 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
For internal use only
ML18542 study
Clinica Ematologica-Udine
PATIENTS OF ARM A “RESCUED” WITH DEXA+RTX
Sustained
response
(month +6)
PLT  50 x 109/L
(sustained response)
Patients: 27
56 %
PLT  100 x 109/L
PLT  150 x 109/L
44 %
37 %
For internal use only
ML18542 study
Clinica Ematologica-Udine
Follow up in patients who achieved sustained response
Dexa N= 11
Dexa + RTX
Dexa + RTX N= 23
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
Dexa + RTX
0.25
0.50
0.75
Dexa
2 years RFS
Dexa
Dexa + RTX
Dexa + RTX
salvage therapy
78%
94%
90%
0.00
Cumulate probability
1.00
Dexa + RTX
salvage therapy
0
10
20
Months
Salvage Therapy
Arm B
30
40
Arm A
For internal use only
TOXICITY
No toxic or hemorragic deaths observed
Dexa N= 52
Patients with any
adverse events
26 (50%)
1 (2%)
Patients with
serious adverse
events
Dexa + RTX N= 49
Dexa + RTX
salvage tx N= 27
37 (76%)
18 (67%)
3 (6%)
3 (11%)
P= 0.006
P= NS
1. Rib fracture 5
months after Dexa
1. Platelet decrease, in-pt
1. Platelet decrease, in-pt
hospitalization 18 days
hospitalization 11 days
after the 4th RTX.
after the 4th RTX.
2. SV tachycardia during the 2. Convulsion during
1st RTX (stop RTX).
the 1st RTX (stop RTX).
3. Interstitial pneumonia one 3. TIA
month after the 4th RTX.
For internal use only
ML18542 study
Clinica Ematologica-Udine
CHANGES OF IgG, IgA, IgM and CD20+LYMPHOCYTES
Therapy
Baseline
Week 24
P value
IgG, mean
Arm A
12.86
9.33
0.050
value (g/L)
Arm B
11.32
9.70
0.002
IgA, mean
Arm A
2.19
1.85
0.367
value (g/L)
Arm B
2.44
1.71
< 0.001
IgM, mean
Arm A
1.57
1.11
0.805
value (g/L)
Arm B
1.09
0.71
< 0.001
CD20+ ly mean
Arm A
0.42
0.20
0.895
value x 109/L
Arm B
0.33
0.00
< 0.001
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%)
• has increased incidence of AEs with similar incidence of SAEs
• is an active salvage therapy in 56% of patients refractory to
Dexamethasone monotherapy
For internal use only
ML18542 study
Clinica Ematologica-Udine
AKNOWLEDGEMENTS
.
.
.
.
.
.
. ...
. ..
..
.
. .
.
.
For internal use only
E. Gamba
R.
M.
P.
F.
L.
A.
F.
E.
S.
G.
E.
G.
V.
S.
G.
G.
G.
A.
G.
R.
Fanin
Baccarani
Mazza
Lauria
Gugliotta
Zaccaria
FerraraNapoli
Angelucci
Amadori
Leone
Morra
Visani
Liso
Mirto
Pizzolo
Semenzato
Rossi
Gallamini
Fioritoni
Foà
Udine
Bologna
Taranto
Siena
Reggio Emilia
Ravenna
Cagliari
Roma, Tor Vergata
Roma, Cattolica
Milano
Pesaro
Bari
Palermo
Verona
Padova
Brescia
Cuneo
Pescara
Roma, La Sapienza
M. Regazzi
Pavia (PK studies)
F. Soldano, M. Isola
Udine (Statistics)