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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Effect on the Platelet Count of Plasma ITP into
Normal
1000 800 600 400 200
Disease incidence (thousands)
1 2 3 1 2 3
4 5 6 7 8 9
Hours
Days
Harrington WJ, et al. J. Lab Clin Med.
1951381-10.
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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, Igs, 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
• job
• physical trauma ie sports
• access to care
• anxiety
• effect 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/kgIVIG lysis, IVH, blood

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STUDY TREATMENTS
ARM - A
D
D
D
D
days
1 2 3 4 7
14 21
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ARM - B
D
RTX
D
D
D
RTX
RTX
RTX
days
1 2 3 4 7
14 21
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D Dexamethasone 40 mg po daily x 4
RTX Rituximab 375 mg/m2 IV x 4
ML18542 study
Clinica Ematologica-Udine
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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 TRANSFUSIONSSAVE EM
TIL YOU REALLY NEED EMNEVER TRANSFUSE A
NUMBER.ALWAYS TRANSFUSE A PATIENT!
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Platelet Production Is Suboptimal in ITP
Patients

• Autoantibodies inhibit Mk growth and promote
  apoptosis (Chang, McMillan)
• Autologous 111In-platelet studies show platelet
  production lt 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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Pathophysiology of ITP
Macrophage
P
Thrombo-poietin Peripheral blood
P
P
Bone marrow
P
Platelet
Megakaryocyte
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TPO Agonists in Thrombocytopenic States Focus on
ITP

• Newer agents that will probably revolutionize our
  approach to thrombocytopenia in many conditions,
  not only ITP

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rhTPO and PEG-rHUMGDF

• rhTPO
• Glycosylated
• Full length

• PEG-rHuMGDF
• Not glycosylated
• Truncated
• Additional polyethylene
• glycol moiety

COOH terminal domain
Polyethylene glycol
COOH
NH2
NH2
Mpl-binding domain
Mpl-binding domain
Kuter DJ, Begley CG, Blood 20021003457.
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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 TPOs 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

• No sequence homology with TPO
• Cleared endothelial FcRn
• Recycled
• Cleared RES

Bussel JB et al. N Engl J Med. 20063551672.
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Romiplostim 38 Durable Response, 79 Overall
Response
Overall Response
Number of Weeks Platelet Response
DurableResponse
100
100
78.6
80
80
12.3 (1.2)
60
60
Mean (SE) Number of Weeks With Platelet Response
Durable Platelet Response ()
Overall Platelet Response ()
38.1
40
40
20
20
0.2 (0.1)
0.0
0.0
0
0
(P 0.0013)
(P lt 0.0001)
(P lt 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
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Romiplostim (AMG 531) Summary

• In splenectomized patients
• 38 durable response, 79 overall response
• Increased and maintained platelet counts over24
  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 gt 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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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

Eltrombopag MW 442
Thrombopoietin MW 64,000
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Primary Endpoint Percentage of Patients With
Platelets 50,000/µL at Day 43 Visit
P lt0.001 OR 9.61 (3.31, 27.86)
Responders ()
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.
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Median Platelet Counts (25th and 75th
Percentiles) Baseline to Week 20
Platelet count (Gi/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 gt50,000/µL in the
  majority of patients
• Eltrombopag reduced the incidence and severity of
  bleeding

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HCV Phase II Study
250
Placebo
200
30 mg
50 mg
75 mg
150
Median Platelet Count
100
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INITIATION
MAINTENANCE
0
0
14
28
42
56
70
84
98
112
Study Day
McHutchison, NEJM 2007
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