ADVANCES IN THE DIAGNOSIS AND TREATMENT OF THROMBOCYTOPENIA
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ADVANCES IN THE DIAGNOSIS AND TREATMENT OF
THROMBOCYTOPENIA
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Petechiae
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Remove Antigen: Rx Inciting Agent = Fix “ITP”
HIV
Hepatitis C
Helicobacter pylori
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WHEN TO DO A BONE MARROW IN THE
THROMBOCYTOPENIC PATIENT?
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ITP: A SIMPLE DISEASE
• Patients make auto-antibodies directed against their own platelets
• These platelets are rapidly destroyed• If the platelet count becomes low enough,
bleeding symptoms may ensue• Bleeding is rarely serious, ie an intracranial
hemorrhage, even at very low counts
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ITP: A COMPLICATED DISEASE
• Anti-platelet antibodies have not been able to be measured discriminatively: the diagnosis and prognosis (outcome, risk of bleeding) remain insecure
• Patients may not make platelets well• Treatment is uncertain: who needs it, what
to treat with and in which order
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Pathophysiology of ITP
Implications for Diagnosis and Treatment
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Harrington WJ, et al. J. Lab Clin Med. 1951;38:1-10.
1000
800
600
400
200
1 2 3 1 2 3 4 5 6 7 8 9
Effect on the Platelet Count of Plasma : ITP into Normal
Hours
Dis
ease
inci
denc
e (th
ousa
nds)
Days
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ITP: what tests are helpful
• Complete CBC---not just the platelets• Bone marrow---not in all/most cases• Blood type & DAT-prognostic re hemolysis• PT-PTT, Thyroid, Ig’s, lupus, SMA• Anti-phospholipid antibodies• Platelet turnover (estimates): platelet retics,
thrombopoietin, large platelets
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Who Needs Treatment with ITP?At What Platelet Count ?
Needs to be individualized:jobphysical trauma ie sportsaccess to careanxietyeffect on fatigue
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Acute Platelet Increase
• gold standard: IVIG at 1 gm/kg• IV anti-D: as fast as IVIG at 75 mcg/kg• Steroids: IV solumedrol 30/kg, high dose
dexamethasone or Prednisone 2-4/kg• Platelet transfusions• Combinations including Steroids, IVIG, IV
anti-D and/or vincristine
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Advantages and Disadvantages of Treatment for Children with
ITP Advantages Disadvantages
• Steroids: oral, continuous so much toxicity often works with any usage• IVIG: rapid substantial blood product,
platelet increase headache, 4-6hrs• IV anti-D: 5-15 minute, at fever-chill, hemo- 75 mcg/kg=IVIG lysis, IVH, blood
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ML18542 study Clinica Ematologica-Udine
STUDY TREATMENTS
daysD D
D RTX
D: Dexamethasone 40 mg po daily x 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
ARM - B
RTX: Rituximab 375 mg/m2 IV x 4
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SPLENECTOMY
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CONCLUSION: ITP IN CHILDHOOD
• Treatment is indicated for those at risk of (serious) bleeding
• Choice of treatment needs to be appropriate for the goal: acute vs cure
• New treatments will revolutionize care• Understanding of pt pathophysiology may
allow individualization of care
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GUIDELINES FOR PLATELET TRANSFUSIONS
“SAVE ‘EM TIL YOU REALLY NEED ‘EM”
NEVER TRANSFUSE A NUMBER.ALWAYS TRANSFUSE A
PATIENT!
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Platelet Production Is Platelet Production Is Suboptimal in ITP Patients Suboptimal in ITP Patients
Autoantibodies inhibit Mk growth and promote apoptosis (Chang, McMillan)
Autologous 111In-platelet studies show platelet production < normal in 2/3 pts----same results with absolute platelet retics
TPO levels normal in 75% of ITP patients (relative TPO deficiency)
Damaged or Dysfunctional Mk in marrow (Houwerijl)
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PP
PP
PP
PP
Macrophage
Thrombo-poietin
Peripheral blood
Bone marrow
PlateletMegakaryocyte
Pathophysiology of ITP
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TPO Agonists in Thrombocytopenic States: Focus
on ITPNewer agents that will probably
revolutionize our approach to thrombocytopenia in many
conditions, not only ITP
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rhTPO and PEG-rHUMGDF
NH2
Mpl-binding domain
rhTPOrhTPO• Glycosylated• Full length
Polyethyleneglycol
COOHterminaldomain
NH2COOH
Mpl-binding domain
PEG-rHuMGDFPEG-rHuMGDF• Not glycosylated• Truncated• Additional polyethyleneglycol moiety
Kuter DJ, Begley CG, Blood 2002;100:3457.
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Why Are We Not Using the 1st Generation Thrombopoietins?
Initial use of MGDF (and also rhuTPO) resulted in the development of antibodies to exogenous (administered) 1st generation TPO’s that cross-reacted with endogenous TPO (native eTPO): a number of multiply-dosed recipients developed a lasting thrombocytopenia.
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AMG 531
• Unique platform “peptibody”• Made in E. coli • Molecular weight = 60,000 D• 4 Mpl binding sites
Bussel JB et al. N Engl J Med. 2006;355:1672.
• No sequence homology with TPO• Cleared endothelial FcRn
Recycled• Cleared RES
Fc Carrier DomainTPO Agonist
PeptidesFc Carrier DomainTPO Agonist
Peptides
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Romiplostim: 38% Durable Response, 79% Overall Response
DurableResponse
Overall Response
Number of Weeks Platelet Response
Platelet response: platelet count ≥ 50 x 109/LDurable platelet response: platelet response for ≥ 6 weeks of final 8 weeks,in the absence of rescue medications during 24 week trialOverall response: either durable or transient platelet response (≥ 4 weekly platelet responses)Error bars represent standard deviation of the mean
0.0
38.1
(P = 0.0013)0.0
78.6
0
20
40
60
80
100
(P < 0.0001)
Dur
able
Pla
tele
t Res
pons
e (%
)
Ove
rall
Plat
elet
Res
pons
e (%
)
Mea
n (S
E) N
umbe
r of W
eeks
With
Pla
tele
t Res
pons
e
0.2 (0.1)
12.3 (1.2)
0
5
10
15
20
(P < 0.0001)0
20
40
60
80
100
PlaceboRomiplostim
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Romiplostim (AMG 531): Summary
In splenectomized patients:• 38% durable response, 79% overall response • Increased and maintained platelet counts over
24 weeks• Significantly decreased the use of rescue medications• All romiplostim patients discontinued or reduced
concurrent ITP therapy (corticosteroids, azathioprine, danazol)
• Romiplostim appeared to be well tolerated
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Romiplostim: Summary of Long-term Dosing
Efficacy Data Summary• The majority of patients achieved long-term platelet counts >
50 x 109/L and double the baseline value– Mean platelet count maintained between 50 and 250 x
109/L over 2 years• Use of concomitant and rescue medications was substantially
reduced over time• No trend in this study for adverse events to increase in
frequency with longer drug exposure• One patient had neutralizing antibodies to AMG 531; negative
on retesting
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Small molecule, non-peptide thrombopoietin receptor (TPO-R) agonist
Does not compete with TPO for binding to TPO-R Low immunogenic potential Active only in humans, chimps Stimulates megakaryocyte proliferation and
differentiation Orally bioavailable Increases platelet counts in normal volunteers
ThrombopoietinMW 64,000
EltrombopagMW 442
Eltrombopag: Oral Platelet Growth Factor
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Primary Endpoint: Percentage of Patients With Platelets ≥50,000/µL at
Day 43 Visit†
0
20
40
60
80
100
Res
pond
ers
(%)
Placebo§ Eltrombopag
P <0.001‡ OR = 9.61 (3.31, 27.86)
†Last observation carried forward.‡Indicates significance at 5% (2-sided) level of significance.§1 patient received IVIg on Day 1.Logistic regression analysis adjusted for randomization stratification variables.
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Median Platelet Counts (25th and 75th Percentiles) Baseline to Week 20
1Baseline 2 3 64 5 87 119 10 1312 1614 15 1817 19 20
0
50
100
150
200
250
300
350
Week
106107 106 99 9097 92 7683 6567 62 5160 3955 48 4243 39 33Number of subjects:
Plat
elet
cou
nt (G
i/L)
Splenectomized pts respond as well as non-splenectomized pts
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Conclusions• The EXTEND data suggest that oral
eltrombopag was well tolerated and safe• Eltrombopag up to 75 mg/day increased and
sustained platelet counts >50,000/μL in the majority of patients
• Eltrombopag reduced the incidence and severity of bleeding
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HCV Phase II Study
0
50
100
150
200
250
0 14 28 42 56 70 84 98 112Study Day
Med
ian
Plat
elet
Cou
nt Placebo30 mg50 mg75 mg
INITIATION MAINTENANCE
McHutchison, NEJM 2007
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