advances in the diagnosis and treatment of thrombocytopenia
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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