Advances in the Treatment of Adult Immune Thrombocytopenia This activity is supported by an educational grant from Novartis. Keith McCrae, MD Director, Benign Hematology Departments of Hematology and Medical Oncology, and Cellular and Molecular Medicine Cleveland Clinic
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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.
About These Slides
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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]
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
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
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
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
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.
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
Slide credit: clinicaloptions.com
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]
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
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
Slide credit: clinicaloptions.com
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