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ADVANCES IN THE DIAGNOSIS

AND TREATMENT OF
THROMBOCYTOPENIA
Petechiae
Remove Antigen: Rx Inciting
Agent = Fix “ITP”
HIV

Hepatitis C

Helicobacter pylori
WHEN TO DO A BONE
MARROW IN THE
THROMBOCYTOPENIC
PATIENT?
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
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
Pathophysiology of ITP
Implications for Diagnosis
and Treatment
Effect on the Platelet Count of
Plasma : ITP into Normal
1000
Disease incidence (thousands)

800

600

400

200

1 2 3 1 2 3 4 5 6 7 8 9
Hours Days
Harrington WJ, et al. J. Lab Clin Med. 1951;38:1-10.
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
Who Needs Treatment with ITP?
At What Platelet Count ?
Needs to be individualized:
job
physical trauma ie sports
access to care
anxiety
effect on fatigue
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
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
STUDY TREATMENTS

ARM - A
D D D D
days
1 2 3 4 7 14 21 28

ARM - B
D D D D RTX RTX RTX RTX
days
1 2 3 4 7 14 21 28

D: Dexamethasone 40 mg po daily x 4

RTX: Rituximab 375 mg/m2 IV x 4

ML18542 study Clinica Ematologica-Udine


SPLENECTOMY
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
GUIDELINES FOR PLATELET
TRANSFUSIONS

“SAVE ‘EM TIL YOU REALLY


NEED ‘EM”

NEVER TRANSFUSE A NUMBER.


ALWAYS TRANSFUSE A
PATIENT!
Platelet Production Is
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)
Pathophysiology of ITP
Macrophage

Thrombo-
poietin
P
Peripheral blood
P

Bone marrow

Platelet
Megakaryocyte
TPO Agonists in
Thrombocytopenic States: Focus
on ITP
Newer agents that will probably
revolutionize our approach to
thrombocytopenia in many
conditions, not only ITP
rhTPO and PEG-rHUMGDF

rhTPO PEG-rHuMGDF
• Glycosylated • Not glycosylated
• Full length • Truncated
COOH Polyethylene • Additional polyethylene
terminal glycol glycol moiety
domain

NH2 COOH NH2

Mpl-binding domain Mpl-binding domain

Kuter DJ, Begley CG, Blood 2002;100:3457.


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.
AMG 531
TPO Agonist
Fc Carrier Domain Peptides

• Unique platform “peptibody” • No sequence homology with TPO


• Made in E. coli • Cleared endothelial FcRn
• Molecular weight = 60,000 D  Recycled
• 4 Mpl binding sites • Cleared RES

Bussel JB et al. N Engl J Med. 2006;355:1672.


Romiplostim: 38% Durable Response,
79% Overall Response
Overall Number of Weeks
Durable
100 100 Response 20 Platelet Response
Response
Durable Platelet Response (%)

Overall Platelet Response (%)

Mean (SE) Number of Weeks


Placebo 78.6

With Platelet Response


80 80
15 12.3 (1.2)
Romiplostim

60 60
10
40 38.1 40

5
20 20

0.0 0.0 0.2 (0.1)


0 0 0
(P = 0.0013) (P < 0.0001) (P < 0.0001)
Platelet response: platelet count ≥ 50 x 109/L
Durable platelet response: platelet response for ≥ 6 weeks of final 8 weeks,
in the absence of rescue medications during 24 week trial
Overall response: either durable or transient platelet response (≥ 4 weekly platelet responses)
Error bars represent standard deviation of the mean
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
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
Eltrombopag: Oral Platelet Growth Factor
 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

Thrombopoietin Eltrombopag
MW 64,000 MW 442
Primary Endpoint: Percentage of
Patients With Platelets ≥50,000/µL at
100
Day 43 Visit†
80
P <0.001‡
Responders (%)

OR = 9.61 (3.31, 27.86)


60

40

20

0
Placebo§ Eltrombopag

†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.


Median Platelet Counts (25th and 75th
Percentiles) Baseline to Week 20
350

300

250
Platelet count (Gi/L)

200

150

100

50

Baseline 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Number of subjects:
Week

107 106 106 99 97 92 90 83 76 67 62 65 60 51 55 48 39 43 42 39 33

Splenectomized pts respond as well as non-splenectomized pts


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
HCV Phase II Study
250

Placebo
Median Platelet Count

200
30 mg
50 mg
150 75 mg

100

50

INITIATION MAINTENANCE
0
0 14 28 42 56 70 84 98 112
Study Day
McHutchison, NEJM 2007