Management of itp

ADVANCES IN
MANAGEMENT OF ITP
Dr. M SAITEJ REDDY
GANDHI MEDICAL COLLEGE
SECUNDERABAD

ITP – AT A GLANCE
 Primary immune thrombocytopenia (ITP, also called idiopathic
thrombocytopenic purpura, immune thrombocytopenic purpura)
is an acquired thrombocytopenia caused by autoantibodies
against platelet antigens.

TERMINOLOGY
International working group on ITP published in 2009
 Primary ITP –is acquired ITP due to autoimmune mechanisms
leading to platelet destruction and platelet underproduction that
is not triggered by an associated condition.
 Secondary ITP –is ITP associated with another condition (eg,
HIV, HCV, SLE, chronic lymphocytic leukemia [CLL]).
 Drug-induced immune thrombocytopenia – Drug-induced
immune thrombocytopenia (DITP) is thrombocytopenia due to
drug-dependent platelet antibodies that cause platelet
destruction.

 Newly diagnosed – Up to 3 months since diagnosis
 Persistent – 3 to 12 months since diagnosis
 Chronic –>12 months since diagnosis
 Severe ITP – Severe ITP refers to ITP with bleeding symptoms
sufficient to require treatment, this typically occurs when
platelet counts are below 20,000/microL.
 Refractory ITP – Refractory ITP refers to ITP that has failed to
respond to (or relapsed after) splenectomy and is severe (ie,
associated with bleeding or bleeding risk that requires therapy).

PATHOGENESIS
 The pathogenesis of ITP is incompletely understood.
 Reduced platelet lifespan due to antibody-mediated destruction
is the predominant hypothesis
 Other mechanisms are likely important, including autoreactive
cytotoxic T cells, as well as humoral and cellular autoimmunity
directed at megakaryocytes, causing impaired platelet
production.
 The principal mechanism is thought to involve specific
immunoglobulin G (IgG) autoantibodies produced by the
patient's B cells, most often directed against platelet membrane
glycoproteins such as GPIIb/IIIa.

Clearance of Antibody-Coated Platelets by
Phagocyte Fcγ Receptors

Initial Diagnostic Evaluation of ITP in Adults
.
Basic Initial Evaluation
 Patient history  Blood group (Rh)
 Family history Direct antiglobulin test
 Physical examination  Helicobacter pylori
 Complete blood count  HIV
 Reticulocyte count  HCV
 Peripheral blood film Bone marrow (in select patients)
Assays of Potential Value
Platelet glycoprotein-specific antibodies
Antiphospholipid antibodies (including
anticardiolipin and lupus anticoagulant)
Antithyroid antibodies and thyroid function
Pregnancy test in women of childbearing
potential
Antinuclear antibodies
Viral PCR for parvovirus and CMV
Assays of Unproven Benefit
Thrombopoietin
Reticulated platelets
Platelet-associated immunoglobulins
Platelet survival studies
Bleeding time
Serum complement

Clinical Situation Therapy Options
First line (initial treatment for
newly diagnosed ITP)
Corticosteroids: dexamethasone, methylprednisolone, prednis(ol)one
Anti D
IVIg
Azathioprine
Cyclosporin A
Cyclophosphamide
Danazol
Second line Dapsone
Mycophenolate mofetil
Rituximab
Splenectomy
TPO receptor agonists (romiplostim and eltrombopag)
Vinca alkaloids
Treatment for patients failing first-
and second-line therapies
Category A*: TPO receptor agonists
Category B†: campath-1 H, combination of first- and second- line therapies,
combination chemotherapy, HSCT
*
Category A:
treatment options
with sufficient
data
Category B: treatment options
with minimal data and
considered to have potential
for considerable toxicity

1A, 1B, 1C, 2A, 2B, 2C
Number: strength of recommendation
1-we recommend..
2- we suggest..
Alphabetical: quality of evidence
A-RCTsor exceptionally strong observation studies
B- RCTswith limitation or strong observation studies
C-RCTswith serious flaws ,weaker observations or indirect evidence
Blood.2011;117(16):4190-4207

Suggest
Treat newly diagnosed patients with platelet count
<30,000/cu.mm(2C)
Longer courses of steroid are preferred than short courses of
steroid or IVIGas first-line treatment (2B)
IVIGcombined with steroid if more rapid increase in platelet count
desired(2B)
IVIgor anti-D as first line if steroid
contraindicated(2C)
IVIgdose :1g/Kg as one-time dose, repeated higher doses if necessary
(2B)

Recommend
TPOagonists for risk of bleeding who relapse after splenectomy or
who have contraindication to splenectomy or failing at least one
other therapy (1B)
Suggest
TPOfor risk of bleeding who failed one line of therapy (steroid or
IVIG)and had no splenectomy (2C)
Rituximab for risk of bleeding who failed one line of therapy (steroid ,
IVIGor splenectomy)(2C)

 Dexamethasone is a corticosteroid that has an anti-
inflammatory effect that is >6 times more potent than
prednisone with a longer halflife (36–72 h compared with 12–36
h).
 We aimed to evaluate the long-term efficacy and safety of high-
dose corticosteroids as an initial treatment for adults or children

 Methods We searched MEDLINE, Embase, Cumulative Index of
Nursing and Allied Health Literature, and the Cochrane Library
Database for papers published from 1970 to July 2016, and
abstracts from American Society of Hematology annual meetings
published from 2004 to 2015 for randomised trials comparing
different corticosteroid regimens for patients with previously
untreated immune thrombocytopenia who achieved a platelet count
response.
 The primary endpoint was overall (platelets >30 × 10⁹/L) and
complete (platelets >100 × 10⁹/L) platelet count response at 6
months with high-dose dexamethasone compared with standard-
dose prednisone.

Results
 9RCTs(n=1138) were included. Of those, 5 (n=533) compared one
to three cycles of dexamethasone (40 mg per day for 4 days) with
prednisone (1 mg per kg) for 14–28 days followed by dose tapering
in adults.
 We found no difference in overall platelet count response at 6
months (pooled proportions 54% vs 43%, relative risk [RR] 1.16,
95% CI 0.79–1.71; p=0.44). At 14 days, overall platelet count
response was higher with dexamethasone (79% vs 59%, RR 1.22,
95% CI 1.00–1.49; p=0.048). The dexamethasone group had fewer
reported toxicities.
 Long-term response rates were similar when the data were
analysed by cumulative corticosteroid dose over the course of

 In summary, we found that durable platelet count responses
were not different with high-dose dexamethasone or standard-
dose prednisone in adults with previously untreated immune
thrombocytopenia.
 High-dose dexamethasone was associated with improved
platelet count responses by 14 days in adults, fewer bleeding
events, and less toxicity than prednisone over the course of
treatment.
 Another advantage is that the regimen is short, lasting only 4
days, as opposed to prednisone, which is often continued as a
protracted course of therapy resulting in high corticosteroid

 High-dose dexamethasone might be preferred over prednisone
for patients with severe immune thrombocytopenia who require
a rapid rise in platelet count (eg, for severe bleeding) in
conjunction with other treatments that work even faster such as
intravenous immunoglobulin.

Intravenous Anti-Rh(D)

Creates RBC hemolysis and Fcγ
receptor blockade
Initial dose: 50 µg/kg IV over 2- 5
minutes



– Reduce if Hgb < 10 g/dL
> 70% responders; duration > 21 days
in 50%
All patients drop Hgb (0.8 g/dL)
Recommended only for Rh- positive
pts with no history of splenectomy
 



Patients should be closely monitored in
a health care setting for at least 8 hrs
after administration
Dipstick urinalysis should be performed at
baseline, 2 hrs, 4 hrs post administration
and prior to end of monitoring period
Rare but severe AE: intravascular
hemolysis and disseminated
intravascular coagulation
Severe DIC in 1 in 20,232
infusions
FDA Black Box Warning

 Corticosteroids are the mainstay of therapy and though 60–70
% of patients show an initial response to corticosteroids,
majority of responders relapse leading to a sustained response
in only 15– 40 %.
 Thus needs second line drugs
 Eltrombopag is a small-molecule, oral, nonpeptide,
thrombopoietinreceptor-agonist (TPO-RA) widely approved for
treatment of patients with chronic ITP who are older than 1
year.
 Eltrombopag increases platelet production by binding to the
transmembrane domain of the TPO-R and activating
proliferation of megakaryocytes from bone marrow progenitors.

AIM: to compare the response to once daily eltrombopag versus
placebo in patients with chronic immune thrombocytopenia
during a 6-month period.

 Study done between Nov 2006 and July 2007, from 75 sites in
23 countries.
 double-blind, placebo-controlled study in adults with previously
treated immune thrombocytopenia of more than 6 months’
duration who had baseline platelet counts lower than 30 000
per μL.
 Patients were randomly allocated (in a 2:1 ratio) treatment with
local standard of care plus 50 mg eltrombopag or matching
placebo once daily for 6 months.

 Patients were assessed for response to treatment (defined as a
platelet count of 50 000–400 000 per μL) weekly during the first
6 weeks and at least once every 4 weeks thereafter; the
primary endpoint was the odds of response to eltrombopag
versus placebo.

Interpretation
 On the basis of these findings, eltrombopag seems to be
beneficial for patients who have refractory immune
thrombocytopenia, who have not responded to splenectomy, or
who have had temporary or negligible responses to treatments
such as corticosteroids, immunoglobulins, or rituximab and
continue to have bleeding symptoms.
 Less effective in splenectomised patients than in non-
splenectomised patients

 EXTEND (Eltrombopag EXTENded Dosing) was a phase 3,
openlabel, long-term extension study of the safety, tolerability,
and efficacy of eltrombopag in patients with ITP of at least 6 to
12months’ duration who had completed a previous eltrombopag
study.

EXTEND: STUDY DESIGN
1. Eltrombopag initiated at 50 mg OD adjusted to
keep plt. ≥ 50,000/µL
2. Reduce concomitant ITP medications, keep plt. ≥ 50,000/µL
3. Identify the minimal dose to maintain plt. ≥ 50,000/µL (25-75
mg OD or less frequently) ± minimal concomitant medication
4. Evaluate safety and efficacy of long-term dosing ± minimal
concomitant medication

 For the 302 patients enrolled, median duration of eltrombopag
treatment was 2.37 years (2 days-8.76 years).
 Median platelet counts increased to 50,000 or more by week 2
and were sustained throughout the treatment period.
 Overall, 259 patients (85.8%) achieved a response (platelet
count ‡50,000L at least once), and 133 (52%) of 257 patients
achieved a continuous response of 25 weeks or longer.
 Responses in patients with platelet counts lower than 15,000,
more previous therapies, splenectomy were somewhat lower.

 Thirty-four (34%) of 101 patients receiving concomitant ITP
medication discontinued 1 or more medication.
 In patients with assessments, bleeding symptoms decreased
from 57% at baseline to 16% at 1 year.

 Forty-one patients (14%) withdrew because of adverse events.
Hepatobiliary adverse events (n 57), cataracts (n 54), deep
vein thrombosis (n 53), cerebral infarction (n 52), headache (n
5 2), and myelofibrosis (n 5 2) occurred in more than 1 patient;
the remaining adverse events occurred only once.
 Rates of thromboembolic events (6%) and hepatobiliary
adverse events (15%) did not increase with treatment duration
past 1 year.

Median platelets
during EXTEND
Efficacy end points n = 299
 Platelet count ≥ 50,000/µL at least once
 Splenectomized
 Nonsplenectomized
 Baseline plt. < 30,000/µL
85%
80%
88%
80%
 Median no. of cumulative wk with plt. ≥ 50,000/µL 44

CONCLUSION
 Eltrombopag increased platelet counts in most patients with ITP
in a consistent fashion to adequate levels, was well-tolerated,
and appeared safe, with a low frequency of Severe adverse
effects and BM fibrosis.
 It was effective in essentially all patient subgroups, although
less effective in splenectomized and heavily pretreated patients
and in those with very low baseline platelet counts.

AIM
 To assess the long-term administration of romiplostim in
splenectomised and non-splenectomised patients with ITP.

Methods
 In two parallel trials, 63 splenectomised and 62 non-
splenectomised patients with platelet counts <30,000 were
randomly assigned 2:1 to subcutaneous injections of
romiplostim (n=42 in splenectomised study and n=41 in non-
splenectomised study) or placebo (n=21 in both studies) every
week for 24 weeks.
 The primary objectives were to assess the efficacy of
romiplostim as measured by a durable platelet response
(platelet count ≥50×10⁹/L during 6 or more of the last 8 weeks
of treatment) and treatment safety.

 The starting dose of study drug (romiplostim or placebo) was 1
μg/kg.
 To achieve the target platelet count of 50,000 to 2 lakhs, doses
could be increased according to the following algorithm: 2 μg/kg
every week if the count was 10,000 or less and 2 μg/kg every 2
weeks if 11,000 to 50,000.
 Once platelets reached more than 50×10⁹/L, the maintenance
algorithm was used: dose was increased by 1 μg/kg every week if
10×10⁹/L or less; increased by 1 μg/kg after 2 weeks if 11×10⁹/L to
50×10⁹/L; reduced by 1 μg/kg after 2 consecutive weeks at
201×10⁹/L to 400×10⁹/L; withheld if more than 400×10⁹/L and
subsequent doses reduced by 1 μg/kg and given after count was
less than 200×10⁹/L.

Findings
 A durable platelet response was achieved by 16 of 42
splenectomised patients given romplostim versus none of 21 given
placebo (difference in proportion of patients responding 38% [95%
CI 23.4–52.8], p=0.0013), and by 25 of 41 non-splenectomised
patients given romplostim versus one of 21 given placebo (56%
[38.7–73.7], p<0.0001).
 The overall platelet response rate (either durable or transient
platelet response) was noted in 88% (36/41) of non-
splenectomised and 79% (33/42) of splenectomised patients
given romiplostim compared with 14% (three of 21) of non-
splenectomised and no splenectomised patients given placebo
(p<0.0001).

Interpretation
 Romiplostim was well tolerated, and increased and maintained
platelet counts in splenectomised and non-splenectomised
patients with ITP.
 Many patients were able to reduce or discontinue other ITP
medications.
 Stimulation of platelet production by romiplostim may provide a
new therapeutic option for patients with ITP.

Background
 Despite the absence of supporting evidence, rituximab is
frequently used off -label in patients with immune
thrombocytopenia.
 We aimed to assess the efficacy of rituximab as compared with
placebo as a splenectomy-sparing treatment in patients who
were previously treated with corticosteroids.

Multicenter, randomized, double-blinded, placebo-controlled trial
Inclusion criteria: corticosteroid unresponsive primary ITP pts with
plt < 30,000/µL
Primary outcome: rate of treatment failure within 78 weeks
Splenectomy or meeting criteria for splenectomy after week 12
Secondary outcome: response rate, relapse rate and duration of
response
study period - Aug 2006 and June 30 2011

STUDY DESIGN
1:1 randomization to receive rituximab or placebo in a
double-blinded fashion
Treatment: 4 weekly infusion of rituximab 375 mg/m2
or placebo
Corticosteroid use with dose tapering to keep plt
count >20,000/µL was allowed
Follow up visit q 6 wks during the study for 78 wks or
for 12 wks after splenectomy
Lancet 2015;385:1653-1661

Rituximab Placebo p value
(n=55) (n=54)
 Treatment failure 32 (58%) 37 (68%) 0.65
Splenectomy 8 (15%) 14 (26%) 0.12
 Overall response 40 (73%) 36 (67%) 0.15
Loss of overall response 27 (68%) 28 (78%) 0.01
Median duration of OR, wk 36 (13-not reached) 7 (5-69) 0.01
 Complete response 28 (51%) 21 (39%) 0.12
Loss of complete response 14 (50%) 13 (62%) 0.19
Median duration of CR,wk 76 (32-not reached) 49 (20-95) 0.19
 Bleeding 21 (38%) 27 (50%) 0.08
 Infection 22 (40%) 13 (24%) 0.09
RESULTS
Lancet 2015;385:1653-1661

RITP STUDY: SUMMARY
First double-blinded, placebo-controlled study to assess the long-term efficacy
(78 weeks) of rituximab as second-line treatment in ITP
Rituximab does not significantly reduce the rate of long-term treatment failure
compare with placebo
A small benefit of rituximab cannot be ruled out
A longer duration of response and higher response rate was observed in the
rituximab group

Patients and methods
 This was a retrospective analysis of all patients with ITP with
platelet counts <50,000, treated at our center with dapsone
between June 1996 and July 2002.

 Dapsone was used at a dose of 1–2 mg/kg/d for at least 3
months.
 Response to treatment with dapsone was classified as partial
response (PR) if the increase in the platelet count was between
50,000 to 1lakh and complete response (CR) if the increase in
the platelet count was >1 lakh
 No response (NR) was defined as a platelet count remaining
below 50,000
 Continuous CR (CCR) was defined as CR maintained for >6
months with or without dapsone therapy.

 The only factor, which had an influence on the response rate,
was the platelet count prior to therapy, which was higher in the
CR group when compared with the group with no response.
 The duration of symptoms prior to therapy did not affect the
response.

Summary
 Present data show that dapsone provides an inexpensive and
well tolerated therapy for chronic ITP that is effective in both
children and adults, who have had an inadequate response to
steroids or other immunosuppressive therapy.
 The high response rates with low adverse effects raises the
possibility of its use as second-line therapy in patients who are
steroid-refractory or -dependent.
 Further studies are needed to determine the optimal duration
of treatment as also a randomized comparison with other drugs
that are used in the treatment of ITP.

Results
 106 (79%) patients in the eltrombopag group responded to
treatment at least once during the study, compared with 17
(28%) patients in the placebo group.
 37 (59%) patients receiving eltrombopag reduced concomitant
treatment versus ten (32%) patients receiving placebo
(p=0.016).
 24 (18%) patients receiving eltrombopag needed rescue
treatment compared with 25 (40%) patients receiving placebo
(p=0.001).

 The treatment of choice in steroid-resistant immune
thrombocytopenia is still controversial due to the recent advent
of new drugs (anti-CD20 antibodies and thrombopoietin
mimetics) that have encouraged a generalized tendency to
delay splenectomy.
 Consequently, it is extremely importance to define the efficacy
and safety of splenectomy in the long term.

Study design
 This was a retrospective, multicenter study that analyzed the
outcome of 233 consecutive ITP patients who underwent open
splenectomy between 1959 and 2001 in six European
Hematology Centers and who were observed for a minimum of
ten years.

Resuts
 Of the 233 patients, 180 (77%) achieved a complete response
and 26 (11%) a response.
 Sixty-eight of 206 (33%) responsive patients relapsed, mostly
(75%) within four years from first response.
 In 92 patients (39.5%), further treatment was required after
splenectomy that was effective in 76 cases (83%).
 In 138 patients (59%), response was maintained free of any
treatment at last contact.
 No significant association between baseline characteristics and
likelihood of stable response was found.

 A stable response to splenectomy was associated with a lower
rate of infections (P=0.004) and hemorrhages (P<0.0001).
 Splenectomy achieved a long-term stable response in
approximately 60% of cases.

 Although studies comparing splenectomy and medical
treatments second-line are lacking, our retrospective data
indicate that splenectomy should be still considered the
therapeutic treatment of choice with the higher curative
potential in eligible patients with chronic disease.

 The purpose of this research is to study the outcomes of
splenectomy for chronic and persistent immune
thrombocytopenia (ITP).
 This study is a retrospective analysis of 254 patients with
chronic or persistent ITP who underwent splenectomy at CMC,
Vellore, India between 1995 and 2009.

 167adults and 87 children with a median age of 29 years
(range 2–64) with persistent (n = 103) or chronic ITP (n = 151)
was studied.
 Response was seen in 229 (90.2 %) including CR in 74.4 % at
a median time of 1 day (range 1– 54).
 Infections following splenectomy were reported in 16 %.
 Deaths related to post splenectomy sepsis occurred in 1.57 %
and major bleeding in 0.78 %.

 Splenectomy is an effective treatment modality for patients with
chronic ITP, who have failed to achieve durable remissions with
steroid therapy or who are steroid dependent.
 Female sex, steroid sensitivity and higher platelet count at
splenectomy are factors that predict response to splenectomy.
 Splenectomy is associated with low morbidity and mortality, and
a significant proportion of patients undergoing splenectomy for
chronic and persistent ITP achieve long-term control of their
disease

SECOND-LINE TREATMENT OF ADULT ITP
Treatment Dose Time to initial
response
Time to peak
response
• Rituximab 375 mg/m2/dose iv (4 weekly dose) 7-56 d 14-180 d
• Splenectomy 1-56 d 7-56 d
• Vincristine Up to 2 mg/dose iv (4-6 weekly doses) 7-14 d 7-42 d
• Vinblastine 0.1 mg/kg/dose iv (6 weekly doses) 7-14 d 7-42 d
• Danazol 400-800 mg po OD 14-90 d 28-180 d
• Azathioprine 2 mg/kg po OD 30-90 d 30-180 d
• Romiplostim 3-10 µg/kg weekly SC 5-14 d 14-60 d
• Eltrombopag 25-75 mg po OD 7-28 d 14-90 d

Splenectomy Rituximab TPO-RA
Efficacy High cure rate, Long- Initial response Maintenance treatment
term response 60%-
70% at 5-10 y
50%-60%, sustained
response 20% at 3-5 y
response rate 60%-80%
Safety Surgery related
morbidty, infection
Infusion-related side
effects, neutropenia, viral
reactivation, serum
sickness
BM reticulin fibrosis,
thrombosis, rebound
thrombocytopenia
Contraindication Unfit for surgery,
Immunodeficiency,
Active hepatitis B, allergy
e.g. Serum sickness
Pregnancy, lactation
secondary ITP
ASH 2011
recommendation
1B after failure of
Steroids
Recommended for
adults who have failed
corticosteroid therapy,
with
similar efficacy with open
or laparoscopic
procedures.
2C after failure of steroids
May be considered for
adults at risk of bleeding
who have failed one
line of therapy such as
corticosteroids, IVIg, or
splenectomy.
1B after failure of
Steroids
Recommended for
adults at risk of bleeding
who relapse after
splenectomy or who have
a contraindication to
splenectomy and who
have
failed at least one other
therapy.

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