advances in the treatment of adult immune thrombocytopenia.2016

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.

About These Slides

Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients

When using our slides, please retain the source attribution:

These slides may not be published, posted online, or used in commercial presentations without permission. Please contact [email protected] for details

Slide credit: clinicaloptions.com

mailto:[email protected]

http://www.clinicaloptions.com/oncology

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



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



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


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]


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.



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


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



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)



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


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)



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)



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



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.



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


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


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



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


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


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)


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


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


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


Study Wk

Med

ian

Plat

elet

Cou

nt

per μ

L (x

102 )

140120100

80604020

0


160

0 261 2 3 4 5 6 10 14 18 22 1 2 4


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


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)


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.


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


Win a $100 Gift CardUse anywhere Debit MasterCards are acceptedMillions of locations worldwide

Enter your email and complete the surveyusing the link belowCheck out the related CME-certified module and claim your credit:Advances in the Treatment of Adult Immune ThrombocytopeniaKeith R. McCrae, MD

Enter now:clinicaloptions.com/itpdrawing

Note: Drawing ends April 5, 2016

advances in the treatment of adult immune thrombocytopenia.2016

Health & Medicine