advances in the treatment of adult immune thrombocytopenia.2016
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Advances in the Treatment of Adult Immune Thrombocytopenia
This activity is supported by an educational grant from Novartis.
Keith McCrae, MDDirector, Benign HematologyDepartments of Hematology and Medical Oncology, and Cellular and Molecular MedicineCleveland Clinic
Faculty Disclosure
Keith McCrae, MD, has no real or apparent conflicts of interest to report.
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Outline
Overview
Demographics
Insights on the Pathophysiology of ITP
Diagnosis of ITP
Clinical Manifestations
Management of ITP
– Goals of therapy
– First-line therapy
– Selection of second-line therapies
Future directions
Slide credit: clinicaloptions.com
Overview
ITP Working Group Definitions
Primary ITP– Isolated thrombocytopenia
(not caused by or associated with another disorder)
– Platelet count <100,000/µl– Increased risk of bleeding
Diagnosis of exclusion– No firm clinical or laboratory
guidelines establish this diagnosis with certainty
Best diagnostic parameter is response to therapy
Secondary ITP
– All other immune-mediated thrombocytopenia
– Infection-associated HCV, HIV, H pylori
– Immunodeficiency
– CVI, WAS– Autoimmune disorders
– SLE, others– Lymphoproliferative
– CLL, others
– Drug-induced
Rodeghiero F, et al. Blood. 2009;113:2386-2393. Slide credit: clinicaloptions.com
Accounts for estimated 20% of total ITP casesSLE 5%
APS 2%
CVID 1%
CLL 2%Evan’s 2%ALPS, post-tx 1%HIV 1%HCV 2%
H pylori 1%Postvaccine 1%
Misc systemic infection 2%
Primary80%
Cines DB, et al. Blood. 2009;113:6511-6521.
Secondary ITP Fractionated by Form
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Stages of ITP
Newly diagnosed ITP: ≤ 3 months from diagnosis Persistent ITP: 3-12 months from diagnosis
– Describes patients lacking spontaneous remission or complete response after treatment
Chronic ITP: lasting > 12 months Severe ITP: Bleeding symptoms requiring treatment
– Includes patients with new bleeding symptoms that warrant a dose escalation or treatment with a different platelet-enhancing agent
Rodeghiero F, et al. Blood. 2009;113:2386-2393. Slide credit: clinicaloptions.com
Incidence of ITP in Adults
Retrospective cohort analysis of adult pts in the UK
Abrahamson PE, et al. Eur J Haematol. 2009;83:83-89. Slide credit: clinicaloptions.com
12
10
8
6
4
2
018-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
Age, Yrs
3.6
1.6
4.9
0.6
3.5
1.3
3.01.8
4.23.0
5.5
3.9
6.4
10.5
9.29.3
10.8
8.1
FemaleMale
Rat
e pe
r 100
,000
Per
son-
Yrs
Pts with ITP
Prevalence of Primary ITP by Age/Sex
Terrell DR, et al. Am J Hematol. 2012;87:848-852.
2003 2004
Age, Yrs
Slide credit: clinicaloptions.com
4540353025201510
50
Prev
alen
ce (p
er 1
00,0
00)
0-9
10-1
920
-29
30-3
940
-49
50-5
960
-69
70-7
980
+
4540353025201510
50
Prev
alen
ce (p
er 1
00,0
00)
Age, Yrs
0-9
10-1
920
-29
30-3
940
-49
50-5
960
-69
70-7
980
+
WomenMen
Insights on the Pathophysiology of ITP
Harrington’s Classic Experiment
Harrington WJ, et al. J Lab Clin Med. 1951;38:1-10. Slide credit: clinicaloptions.com
1000
800
600
400
200
1 2 3 1 2 3 4 5 6 7 8 9
Plat
elet
s (T
hous
ands
)
Hrs Days
Epitope Spreading Leads to Diversity of Platelet Targets
Cines DB, et al. N Eng J Med. 2002;346:995-1008. Slide credit: clinicaloptions.com
Glycoprotein IIb/IIIa
autoantibody
Glycoprotein Ib/IX
Anti-glycoprotein
Ib/IX
Antiglycoprotein
IIb/IIIa
Glycoprotein Ib/IX
B-cell clone 1 T-cell clone 1Glycoprotein
IIb/IIIa
Glycoprotein Ib/IX
Activated macrophage
Glycoprotein IIb/IIIa
Antibody-coated platelet
Fcγ
CD40CD154
CD40
TCRTCRCD154
B-cell clone 2T-cell clone 2
Clearance of Antibody-Coated Platelets by Phagocyte Fcγ Receptors
1. Reprinted from The Lancet, Karpatkin S;349(9064):1531-1536, copyright (1997) with permission from Elsevier. 2. Republished with permission of American Society for Clinical Investigation from Psaila B, et al. J Clin Invest;118(8):2677-2681, copyright 2008; permission conveyed through Copyright Clearance Center, Inc.
Antibody-Coated Platelet[1] Fcγ Family of Receptors[2]
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Activ
atio
n
ITIM
inhi
bitio
n
Activ
atio
n
Activ
atio
nAc
tivat
ion
Activ
atio
n
Low to medium
Low to medium
Low to medium
Low to medium
Low to medium
HighAffinity for Fc Fragment
Cellmembrane
FcγR
IIIAFc
γRIIIB
FcγR
IIC
FcγR
IIB
FcγR
IIA
FcγR
I
Production and Survival of Platelets in ITP
1. Harker LA. Br J Haematol. 1970;19:95-104.2. Branehög I, et al. Br J Haematol. 1974; 27:127-143.3. Stoll D, et al. Blood. 1985;65:584-588.4. Ballem PJ, et al. J Clin Invest. 1987;80:33-40.
Platelet Survival, Days
Study Platelets Normal Subjects ITP Pts Turnover
(x Normal)Harker 1970[1] Allogeneic* 9.9 0.34 4.9Branehög 1974[2] Allogeneic† 6.9 0.67 2.3Stoll 1985[3] Autologous 8.0 2.9 0.9Ballem 1987[4] Autologous 9.6 2.8 0.6
*Subjects with platelet counts > 25 x 109/L received autologous platelets.†Subjects with platelet counts > 20 x 109/L received autologous platelets.
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1. McMillan R, et al. Blood. 2004;103:1364-1369. 2. Republished with permission of American Society of Hematology, from Chang M, et al. Blood;102:887-895, copyright 2003; permission conveyed through Copyright Clearance Center, Inc.
ITP Plasma Suppression of Megakaryocyte Production
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ITP-1
ITP-2
ITP-3
ITP-4
ITP-5
ITP-6
ITP-7
ITP-8
ITP-9
ITP-1
0ITP
-11
ITP-1
2
100
75
50
25
0
% C
ontr
ol
Meg
akar
yocy
tes
Cellular Immune Mechanisms in ITP
T cells
– Proinflammatory response with increased Th1/Th2 activity[1]
– Oligoclonal T-cell profiles[2]
– Platelet-reactive T cells: GPIIb/IIIa target[3]
– Cytotoxic T cells reactive with autologous platelets[4]
– Resistance of CD4+ T cells to apoptosis[5]
– Reduced number and function of CD4+CD25+ regulatory T cells[6]
Antigen presenting cells
– Splenic macrophages take up opsonized platelets and stimulate T-cell proliferation without exogenous antigen[7]
– Increased costimulatory activity on myeloid dendritic cells[8,9]
Mesenchymal stem cells
– Decreased capacity to inhibit activated T-cell proliferation[10]
1. Zhou SF, et al. J Clin Immunol. 2013;33:938-946. 2. Ishiyama M, et al. Int J Hematol. 2006;83:147-151. 3. Kuwana M, et al. Blood. 2001;98:130-139. 4. Olsson B, et al. Nat Med. 2003;9:1123-1124. 5. c6 .Liu B, et al. Eur J Haematol. 2007;78:139-143. 7. Kuwana M, et al. J Thromb Haemost. 2009;7:322-329. 8. Catani L, et al. Exp Hematol. 2006;34:879-887. 9. Zhou Z, et al. J Clin Immunol. 2010;30:814-822. 10. Zhang D, et al. Autoimmunity. 2014;47:519-529. Slide credit: clinicaloptions.com
Molecular Mimicry in ITP
Republished with permission of American Society of Hematology, from Molecular mimicry and immune thrombocytopenia, Aster RH, Blood;113:3887-3888, copyright 2009; permission conveyed through Copyright Clearance Center, Inc. Slide credit: clinicaloptions.com
HCV Prevalence in Adult ITP
Study ITP Pts, n HCV-Infected ITP Pts, n (%)Pawlotsky 1995 139 14 (10)Pivetti 1996 33 12 (36)Garcia-Suarez 2000 51 13 (22)Sakuraya 2002 79 11 (14)Zhang 2003 247 33 (13)Rajan 2005 250 76 (30)Total 799 159 (20)
Stasi R, et al. Hematol Oncol Clin North Am. 2009;23:1275-1297. Slide credit: clinicaloptions.com
Diagnosis of ITP
Initial Diagnostic Evaluation of ITP in Children and Adults
Provan D, et al. Blood. 2010;115:168-186.
Basic Initial Evaluation Patient history Family history Physical examination Complete blood count Reticulocyte count Peripheral blood film Quantitative immunoglobulins
Blood group (Rh) Direct antiglobulin test Helicobacter pylori HIV HCV Bone marrow (in select patients)
Assays of Potential Value Platelet glycoprotein-specific antibodies Antiphospholipid antibodies (including
anticardiolipin and lupus anticoagulant) Antithyroid antibodies and thyroid
function
Pregnancy test in women of childbearing potential
Antinuclear antibodies Viral PCR for parvovirus and CMV
Assays of Unproven Benefit Thrombopoietin Reticulated platelets Platelet-associated immunoglobulins
Platelet survival studies Bleeding time Serum complement
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Clinical Manifestations
Adult ITP Presenting Symptoms by Platelet Count
Neylon AJ, et al. Br J Haematol. 2003;122:966-974.
Platelet Count
Symptom, n (%)0-9 x 109/L
(n = 114)
10-19 x 109/L
(n = 51)
20-29 x 109/L
(n = 26)
30-49 x 109/L
(n =54)
Any(N = 245)
Hemorrhage 18 (16) 6 (12) 4 (15) 2 (4) 30 (12)Purpura 75 (66) 34 (67) 12 (46) 23 (43) 144 (59)
Asymptomatic 21 (18) 11 (22) 10 (38) 29 (54) 71 (29)
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Bleeding Manifestations in ITP
1. Helms AE, et al. Cutis. 2007:17:456-458. Image courtesy Stephen E. Helms, MD, University of Mississippi Medical Center, Jackson, MS2. Kline A. Foot Ankle J. 2008;1:4.3. Reproduced from Postgrad Med J, Awerbuch G, et al.;63:781-783, copyright 1987 with permission from BMJ Publishing Group Ltd. Slide credit: clinicaloptions.com
Hemorrhagic bullae[1]
Ecchymoses and petechiae[2]
CNS hemorrhage[3]
Estimated Annual Bleeding Incidence in ITP by Age
Cohen YC, et al. Arch Intern Med. 2000;160:1630-1638.
Fatal Hemorrhages Major Nonfatal Hemorrhages
Age, Yrs
Slide credit: clinicaloptions.com
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0< 40 40-60 > 60
0.130
0.0120.004
Even
ts p
er P
t-Yr
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
Even
ts p
er P
t-Yr
Age, Yrs< 40 40-60 > 60
0.0250.0725
0.719
Impact of ITP on Health-Related Quality of Life
Mathias SD, et al. Health Qual Life Outcomes. 2008;6:13.
HR-QoL Parameter, n (%)
ITP Pts(N = 15)
Signs and symptomsFatigueBleedingBruisingOther
14 (93)14 (93)8 (53)8 (53)8 (53)
Treatment EffectsSteroidsOther treatments
13 (87)13 (87)8 (53)
Emotional healthFear, stress, anxietyRelationshipsDepression, isolation, loss of controlMood, self-consciousness
11 (73)11 (73)7 (47)7 (47)
7 (47)
HR-QoL Parameter, n (%)
ITP Pts(N = 15)
Functional healthDaily activitiesSleepChanges in lifestyle
13 (87)11 (73)9 (60)7 (47)
WorkAbsencesChanges in attitudesCareer advancementProductivity
13 (87)10 (67)5 (33)3 (33)4 (27)
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Mean 10.5-yr follow-up in primary ITP pts
Portielje JE, et al. Blood. 2001;97:2549-2554.
Morbidity and Mortality in Adults With ITP
Adults With Primary ITP(N = 134)
85% (n = 114) had > 30 x 109/LOff therapyMortality risk mirroring the general population
6% (n = 8) had > 30 x 109/LOn maintenance therapyIncreased number of hospitalizations but only minimal increase in mortality risk
9% (n = 12) had < 30 x 109/LRefractory disease with severe thrombocytopenia Mortality risk of 4.2x (95% CI: 1.7-10.0)
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Causes of Maternal Thrombocytopenia
*Rare constitutional thrombocytopenias, infections, and hematologic malignancies.
Palta A, et al. J Obstet Gynaecol. 2016;36:146-152. Burrows RF, et al. Am J Obstet Gynecol. 1990;162:731-734. Slide credit: clinicaloptions.com
75%
15% to 20%
3% to 4%
1% to 2%Other*BenignITP-immuneHypertension
Maternal Management of Pregnancy-Associated ITP ITP responds in a similar fashion as in the nonpregnant patient
Corticosteroids increase risk for:
– Hypertension/preeclampsia
– Premature rupture of the fetal membranes
– Osteoporosis
IVIg less toxic, at greater cost
Safe use of anti-D reported in a small number of patients
Splenectomy (if required) should be in early 2nd trimester
Thrombopoietic agents: class C
Palta A, et al. J Obstet Gynaecol. 2015;[Epub ahead of print]. Slide credit: clinicaloptions.com
Thrombocytopenia in Offspring of ITP Mothers Incidence[1]
– 15% overall (platelets < 150 X 109/L)
– 10% severe (platelets < 50 X 109/L)
– < 5% less than 20 X 109/L
Pathogenesis[1]
– transplacental transfer of pathogenic antibody
– other factors
Cannot be predicted non-invasively[1,2]
– No correlation with any maternal parameters
– Best predictor is history of thrombocytopenia in prior offspring
– Invasive testing (PUBS) can accurately predict the birth platelet count, but associated with a complication rate of 2-3%
– There is no evidence that mode of delivery affects incidence of ICH
1. Burrows RF, et al. Obstet Gynecol Surv. 1993;48:781-788. 2. Hachisuga K, et al. Blood Res. 2014;49:259-264. Slide credit: clinicaloptions.com
Management of ITP
Goals of ITP Therapy
American Society of Hematology last published evidence-based guidance for ITP treatment in 2011[1]
– Updated recommendations are currently under development
Generally, clinicians should aim to:
– Maintain a safe platelet count with minimal toxicity
– Toxicity of therapy, particularly long-term steroid exposure, may be significant
– Individualize therapy based on bleeding risk
1. Neunert C, et al. Blood. 2011;117:4190-4207. Slide credit: clinicaloptions.com
Recommended “Safe” Platelet Ranges
British Committee for Standards in Haematology General Haematology Task Force. Br J Haematol. 2003;120:574-596.
Clinical Situation PlateletsGeneral dentistryExtractionsRegional dental block
≥ 10 x 109/L≥ 30 x 109/L≥ 30 x 109/L
SurgeryMinorMajor
≥ 50 x 109/L≥ 80 x 109/L
PregnancyVaginal deliveryCaesarean sectionSpinal/epidural anesthesia
> 50 x 109/L> 80 x 109/L> 80 x 109/L
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Therapy Options for ITP
Provan D, et al. Blood. 2010;115:168-186.
Clinical Situation Therapy Options
First line (initial treatment for newly diagnosed ITP)
Anti-DCorticosteroids: dexamethasone, methylprednisolone,
prednis(ol)oneIVIg
Second line
AzathioprineCyclosporin A
CyclophosphamideDanazolDapsone
Mycophenolate mofetilRituximab
SplenectomyTPO receptor agonists (romiplostim and eltrombopag)
Vinca alkaloids
Treatment for patients failing first- and second-line therapies
Category A*: TPO receptor agonistsCategory B†: campath-1 H, combination of first- and second-
line therapies, combination chemotherapy, HSCT*Sufficient data to support recommendation.†Minimal data to support recommendation; potential for considerable toxicity.
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First-line Therapies
Corticosteroids
Prednisone
– Dose: 1-2 mg/kg/day, then taper
– Clinical responses in 65-85% patients
– Responses in 4-14 days; peak in 7-28 days[1]
– Only 5-30% sustain response after discontinuation
– Toxicity: glucose intolerance, psychosis, osteoporosis, Cushingoid habitus, weight gain
Dexamethasone
– Dose: 40 mg daily x 4 days
– 1 or more cycles, every 2 wks
– Higher incidence of sustained remissions?
1. Neunert C, et al. Blood. 2011;117:4190-4207. Slide credit: clinicaloptions.com
GIMEMA: Dexamethasone in Previously Untreated ITP
Mazzucconi MG, et al. Blood. 2007;109:1401-1407. Slide credit: clinicaloptions.com
0 5 10 15 20 25
1.00
.75
.50
.25
0
CR: 87% (95% CI: 76.1% to 98.1%) at 15 mos
PR + MR: 65% (95% CI: 39.4% to 91.0%) at 15 mos
P = .050
Pts at risk CR: 58 Events: 5Pts at risk PR + MR: 19 Events: 5
Mos
Prob
abili
ty o
f Rel
apse
-Fre
e Su
rviv
al
80
High-Dose Dexamethasone vs Prednisone in Newly Diagnosed ITP
Wei Y, et al. Blood. 2016;127:296-302. Slide credit: clinicaloptions.com
100
60
40
20
00 6 12 18 24 30 36
Mos9597
6057
4045
3940
3732
2115
3124
1210
74
Pts
Res
pond
ing
(%)
Pts at Risk, nHigh-dose
dexamethasonePrednisone
High-dose dexamethasonePrednisone
Dexamethasone and Rituximab
Bussel JB, et al. Haematologica. 2014;99:1264-1271. Slide credit: clinicaloptions.com
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
720 12 24 36 48 60
720 12 24 36 48 60
720 12 24 36 48 60
720 12 24 36 48 60
59%
19% 17%
61%
47%41%
69%
14%
Mos of Response Mos of Response
Mos of Response Mos of Response
Responders: CR vs PR All pts: children vs adults
All pts: duration of ITP All pts: females vs males
Female (n = 37)Male (n = 30)
Adults (n = 41)Children (n = 26)
CR (n = 43)PR (n = 7)
< 24 mos (n = 44) Duration of > 24 mos (n = 23)
Con
tinui
ng
Res
pons
e (%
)C
ontin
uing
R
espo
nse
(%)
Con
tinui
ng
Res
pons
e (%
)C
ontin
uing
R
espo
nse
(%)
Intravenous Immunoglobulin (IVIg)
Dose: 0.5-2.0 g/kg over 2-5 days
Efficacy 65% achieve platelet count > 100,000/µl, 85% > 50,000/µ Most responses transient 30% become refractory
Toxicity
Headache Positive DAT Anaphylaxis in IgA-deficient patients Thrombosis Renal
Mechanisms
Modulation of Fc receptors Attenuation of complement mediated damage Induction of anti-inflammatory cytokines Anti-cytokine antibodies Neutralization of autoantibodies by anti-idiotypes Modulation of T-cell activity Inhibition of lymphocyte proliferation FcRn
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Intravenous Anti-Rh(D)
Creates RBC hemolysis and Fcγ receptor blockade
Initial dose: 50 µg/kg IV over 2-5 minutes
– Reduce if Hgb < 10 g/dL
> 70% responders; duration > 21 days in 50%
All patients drop Hgb (0.8 g/dL)
Recommended only for Rh-positive pts with no history of splenectomy
Rare but severe AE: intravascular hemolysis and disseminated intravascular coagulation[1]
Severe DIC in 1 in 20,232 infusions[2]
1. WinRho [package insert]. 2. Gaines AR. Blood. 2005;106:1532-1537.
Patients should be closely monitored in a health care setting for at least 8 hrs after administration
Dipstick urinalysis should be performed at baseline, 2 hrs, 4 hrs post administration and prior to end of monitoring period
FDA Black Box Warning
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Second-Line Therapies
Second-Line Therapies
Rituximab Splenectomy Thrombopoietin receptor
agonists
– Romiplostim
– Eltrobopag
Mycophenylate mofetil Vinca alkaloids
Azathioprine Cyclosporine A Cyclophosphamide Danazol Dapsone
Provan et al. Blood. 2010;115:168-186. Slide credit: clinicaloptions.com
Splenectomy
Vianella N, et al. Haematologica. 2013;98:875-880. Slide credit: clinicaloptions.com
80
100
60
40
20
00 120 240 360 480 600
Mos From Splenectomy
Rel
apse
-Fre
e Su
rviv
al (%
)
CR (n = 180)
All pts (n = 206)
R (n = 26)
CR R = pts who responded
120 144 168
VTE and Sepsis After Splenectomy in ITP
Boyle S, et al. Blood. 2013;121:4782-4790. Slide credit: clinicaloptions.com
0.25
0.20
0.15
0.10
0.05
00 24 48 72 96
Mos After Splenectomy
Inci
denc
e of
Sep
sis
0.03
0.02
0.01
00
Mos After Splenectomy24 48 72 96 120 In
cide
nce
of A
bdom
inal
VTE
Log-rank P = .0544
SplenectomizedNonsplenectomized
0
0.010.02
0.030.040.05
0.070.06
Log-rank P < .0001
Inci
denc
e of
VTE
0 24 48 72 96 120
SplenectomizedNonsplenectomized
SplenectomizedNonsplenectomized
Mos After Splenectomy
Rituximab Efficacy in Adult ITP: Systematic Analysis
Arnold DM, et al. Ann Intern Med. 2007;146:25-33.
Platelet Count Response, x 109/L
Pooled Estimate, % (95% CI)
Contributing Reports, n
Pts, n
Overall response (> 50)
62.5 (52.6-72.5) 19 313
CR (> 150) 46.3 (29.5-57.7) 13 191
PR (50-150) 24.0 (15.2-32.7) 16 284
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At 5 yrs, 21% to 26% of adults and children demonstrate sustained response to rituximab
Durable ITP Remissions After Rituximab
Patel VL, et al. Blood. 2012;119:5989-5995.
n = 38 n = 72
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100
80
60
40
20
0
100
80
60
40
20
0350300250200150100500 350300250200150100500
Children Adults
Wks From Initial Treatment Wks From Initial Treatment
Pts
in C
ontin
uing
Res
pons
e (%
)
Pts
in C
ontin
uing
Res
pons
e (%
)26%
21%
RITP: Rituximab vs Placebo in ITP Relapse Rituximab used as a
second-line treatment in randomized, double-blind, multicenter, placebo-controlled trial
Ghanima W, et al. Lancet. 2015;385:1653-1661. Slide credit: clinicaloptions.com
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
0 20 40 60 80
0 20 40 60 80Wks of CR
Wks of Response
Prob
abili
ty o
f an
Even
tPr
obab
ility
of a
n Ev
ent
Log-rank P = .1951
Log-rank P = .0143
PlaceboRituximab
Rituximab generally well tolerated with no grade 4 AEs reported
RITP: Safety Data
Ghanima W, et al. Lancet. 2015;385:1653-1661.
AE, n (%) Rituximab (n = 55)
Placebo (n = 54)
Main safety outcomesDeathBleedingInfectionsVTE‡
021 (38)*22 (40)†
2 (4)
1 (2)27 (50)*13 (24)†
0
Grade 3Abdominal painPneumoniaAppendicitisBack painOvarian cystPelvic pain
01 (2)1 (2)1 (2)
00
2 (4)1 (2)
01 (2)1 (2)1 (2)
*Log-rank P = 0.08. †Log-rank P = 0.09. ‡1 pulmonary embolism, 1 deep venous thrombosis.
AE, n (%) Rituximab (n = 55)
Placebo (n = 54)
Grade ≤ 2AnemiaPyrexiaInfluenzaBronchitisURTIHeadacheThroat irritationCoughRashAbdominal painBack pain
2 (4)4 (7)
8 (15)4 (7)3 (5)5 (9)
8 (5)1 (2)3 (5)
2 (4)0
3 (6)2 (4)4 (7)2 (4)2 (4)2 (4)
1 (2)3 (6)2 (4)
1 (2)1 (2)
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TPO Receptor Agonists
1. Bussel JB, et al. N Engl J Med. 2006;355:1672-1781. 2. Bussel JB, et al. N Engl J Med. 2007;357:2237-2247. Slide credit: clinicaloptions.com
Fc Carrier DomainPeptide Receptor-Binding
Domain
Eltrombopag[2,3]
Peptidomimetic PO bioavailableBinds to transmembrane portion of TPO receptor
Romiplostim[1]
Unique platform peptibodyBinds to ligand binding site of TPO receptorSC injection
H0
0
H0
0
HN
N
NN CH3
H3C
H3C
Romiplostim in Chronic ITP
0
38.1
(P = .0013)
Dur
able
Pla
tele
t Res
pons
e (%
)
0
20
40
60
80
100
4.8
61.0
(P < .0001)
Splenectomized Non-splenectomized
0
78.6
Ove
rall
Plat
elet
Res
pons
e (%
)14.3
87.8
Placebo Romiplostim
Kuter DJ, et al. Lancet. 2008;371:395-403.
Overall Platelet Response
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0
20
40
60
80
100
(P < .0001) (P < .0001)
Splenectomized Non-splenectomized
Durable Platelet Response
Long-term Romiplostim: Efficacy
Kuter DJ, et al. Br J Haematol. 2013;161:411-423.
12
10
8
6
4
2
0
Mea
n D
ose
(μg/
kg)
2721 8 16 24 32 40 48 56 64 72 80 88 96 104112120128136144152160168176184192200208216224232240248256264n = 291 9279272262254244230227206162136118111108103100 97 95 89 87 83 78 68 58 51 41 28 22 22 23 21 19 16 15
350
300
250
200
150
100
0
Med
ian
(Q1,
Q3)
Plat
elet
Cou
nt x
109 /L
2720 8 16 24 32 40 48 56 64 72 80 88 96 104112120128136144152160168176184192200208216224232240248256264
n = 291 11257242233227228210210194156129110100 95 92 85 83 81 82 80 75 74 67 57 45 41 31 26 22 23 19 17 13 14Study Wk
50
Slide credit: clinicaloptions.com
Long-Term Romiplostim: Safety Data
Cines DB, et al. Int J Hematol. 2015;102:259-270. Slide credit: clinicaloptions.com
RAISE: Eltrombopag in Chronic ITP
Cheng G, et al. Lancet. 2011;377:393-402.
PlaceboEltrombopag
Placebo, splenectomizedPlacebo, not splenectomized Eltrombopag, splenectomizedEltrombopag, not splenectomized
Pts at Risk, nPlacebo
Eltrombopag61135
60134
59131
58129
59123
59128
58128
4396
4495
4391
53110
54110
55118
58119
46101
Med
ian
Plat
elet
Cou
nt
per μ
L (x
103 )
140120100
80604020
0
On treatment Post-treatment
Pts at Risk, n Placebo
Eltrombopag61
13561134
60133
59133
60131
60134
59134
47108
48112
47113
58132
54110
55118
58119
50114
Pts
Res
pond
ing
to tr
eatm
ent
(%)
605040302010
0
On treatment Post-treatment
Study Wk
Med
ian
Plat
elet
Cou
nt
per μ
L (x
102 )
140120100
80604020
0
On treatment Post-treatment
160
0 261 2 3 4 5 6 10 14 18 22 1 2 4
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PlaceboEltrombopag
EXTEND: Eltrombopag in Chronic ITP
Saleh MN, et al. Blood. 2013;121:537-545.
200
150
100
50
0
Med
ian
Plat
elet
Cou
nt
(x 1
09 /L)
156BL 1 2 3 4 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152
Pts at Risk, nWks
n = 253 n = 218 n = 147 n = 32
10290
285
272
272
243
166
128
107 94 68 77 78 71 72 61 50 43 31 12 12 15 12 11299
60
50
40
30
0
Pts
(%)
156BL 1 2 3 4 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152
Pts at Risk, nWks
9
290
284
270
270
238
160
121 99 89 63 73 78 68 68 59 50 41 31 12 12 15 12 11299
20
10
Grades 1-4
Grades 2-4
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EXTEND: Adverse Events Leading to Withdrawal from Study
Saleh MN, et al. Blood. 2013;121:537-545.
AE, n (%) N = 299Any 38 (13)
Tromboembolic 11 (4)
Hepatobiliary 6 (2)
Cataract 4 (1)
Headache 2 (<1)
Angina pectoris 1 (<1)
Death NOS 1 (<1)
Ectopic pregnancy 1 (<1)
Epistaxis 1 (<1)
Fatigue 1 (<1)
Hypertension 1 (<1)
Lung neoplasm 1 (<1)
Lymphoma 1 (<1)
AE, n (%) N = 299Mouth hemorrhage 1 (<1)
Multi-organ failure 1 (<1)
Muscle spasms 1 (<1)
Myelofibrosis 1 (<1)
Optic neuritis 1 (<1)
Palpitations 1 (<1)
Petechiae 1 (<1)
Pneumonia 1 (<1)
Renal failure 1 (<1)
Retinal pigment epitheliopathy 1 (<1)
Road traffic accident 1 (<1)
Subarachnoid hemorrhage 1 (<1)
Toxic neuropathy 1 (<1)
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TPO Receptor Agonists
Characteristic Romiplostim EltrombopagClassification Peptibody Non-peptide small molecule
Indications Chronic ITP
Chronic ITPSevere aplastic anemiaHepatitis C-associated
thrombocytopeniaPediatric chronic ITP > 6 yrs of
age
Delivery/dosing SC, weekly PO, daily
TPO-R binding site Ligand-binding domain Transmembrane domain
Rebound thrombocytopenia 4-10% 4-10%
Elevated transaminases -- 3-7%
Myalgias 10% 5%
Marrow fibrosis MF2: 10-70%, MF3: 1-3%. Rare collagen
MF2: 10-70%, MF3: 1-3%. Rare collagen
Kuter DJ. Semin Hematol. 2010;47:243-248. Slide credit: clinicaloptions.com
Choosing Second-line Therapy in ITP
Republished with permission of American Society of Hematology, from Ghanima W, et al. Blood;120:960-969, copyright 2012; permission conveyed through Copyright Clearance Center, Inc.
Slide credit: clinicaloptions.com
ITP unresponsive or relapsed after first-line therapy
Choose a second-line treatment based on the following factors
Restrictions on use of TPO receptor agonist/rituximab by health funding authorities
1. Contraindication to splenectomy, eg, comorbidity2. No restrictions on use of TPO receptor agonist/rituximab
Other factors:1. Old age (> 60-70 yrs depending on physical condition)2. Mixed/hepatic platelet sequestration on radioisotope study3. Newly diagnosed (0-3 mos) or persistent (3-12 mos) ITP4. Exposure to malaria, babesia, or other infections cleared by the spleen
Other factors:1.Chronic ITP (> 1 yr)2.Pt prefers Tx with high cure rate and/or no maintenance therapy3.Wish to become pregnant
1. Pt refuses splenectomy but prefers Tx with curative intent
2. High risk of thrombosis3. Anticipated poor compliance4. Inability to meet dietary
restrictions (eltrombopag)
Pt/physician seeks Tx with high response rate
Splenectomy Rituximab TPO-RA
Future Directions: Current Phase III Trials
Trial NCT#rhTPO Combining Cyclosporin A vs Cyclosporin A in Steroid-Resistant/Relapsed ITP NCT02203422
2 Cycles Rituximab vs Standard Regimen in Management of Steroid-Resistant/Relapsed ITP NCT02137681
Multicenter Open-Labeled Pilot Study on rhTPO in Management of ITP in Pregnancy NCT02391272
Efficacy and Safety of Different Doses and Frequencies of rhTPO in Primary ITP NCT02139501
Study of Fostamatinib Disodium in the Treatment of Persistent/Chronic ITP NCT02076412
Safety and Efficacy of Eltrombopag at Escalated Doses Up to 150 mg in Patients With Persistent and Chronic ITP Not Responsive to 75 mg
NCT01880047
ClinicalTrials.gov Slide credit: clinicaloptions.com
Conclusions
ITP is a common hematologic disorder with a complex pathogenesis involving accelerated platelet destruction, impaired platelet production, and humoral/cellular immunity abnormalities
Viral and other pathogens play important roles in development of secondary ITP Multiple therapeutic strategies exist for the treatment of ITP and should be
individualized for each patient– First-line
– Corticosteroids: effective, but usually do not provide long-term responses
– Second-line– Splenectomy: remains an effective long-term therapy
– Rituximab: may potentially provide long-term remissions in a subset of patients
– Thrombopoietic agents: provide an important new treatment option
The role of aggressive management in newly-diagnosed ITP is uncertain The choice of a second line therapy depends on patient characteristics and
desired outcomes
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