ADVANCES IN THE DIAGNOSIS AND TREATMENT OF THROMBOCYTOPENIA

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

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

in

cid

ence

(th

ou

san

ds)

Days

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:jobphysical trauma ie sportsaccess to careanxietyeffect 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

ML18542 study Clinica Ematologica-Udine

STUDY TREATMENTS

days

D 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

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 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)

PP

PP

PP

PP

Macrophage

Thrombo-poietin

Peripheral blood

Bone marrow

PlateletMegakaryocyte

Pathophysiology of ITP

TPO Agonists in Thrombocytopenic States: Focus

on ITPNewer agents that will probably

revolutionize our approach to thrombocytopenia in many

conditions, not only ITP

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 polyethylene

glycol moiety

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

• 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

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)

Du

rab

le P

late

let

Res

po

nse

(%

)

Ove

rall

Pla

tele

t R

esp

on

se (

%)

Mea

n (

SE

) N

um

ber

of

Wee

ksW

ith

Pla

tele

t R

esp

on

se

0.2 (0.1)

12.3 (1.2)

0

5

10

15

20

(P < 0.0001)0

20

40

60

80

100

Placebo

Romiplostim

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

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

Primary Endpoint: Percentage of Patients With Platelets ≥50,000/µL at

Day 43 Visit†

0

20

40

60

80

100

Res

po

nd

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.

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 33

Number of subjects:

Pla

tele

t co

un

t (G

i/L

)

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

0

50

100

150

200

250

0 14 28 42 56 70 84 98 112Study Day

Med

ian

Pla

tele

t C

ou

nt Placebo

30 mg

50 mg

75 mg

INITIATION MAINTENANCE

McHutchison, NEJM 2007