Download ITP

Chronic ITP
 Presented by :F.Malek
 Under supervision of Dr Shamsian
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A 10 year old girl known case of chronic
ITP since 6 years ago which was
admitted in our ward due to Epistaxis
and petechia and purpura
 At time of admission CBC was
 WBC 16000
 HB 12.6
 Plt 9000
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She has received Dexamethasone
 And at the time of discharge
 Which was 2 days later The CBC was
 WBC 27000
 HB 11.5
 Plt 85000
 Coombs - Reticulocyte 1.1
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Abdominopelvic ultrasonography
Revealed spleen with upper limit of normal
size
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BMA
Virulogy
normal
IGs
Cvascular
tests
Patient had received different type of
Medications since 6 years ago such as
IVIG ( she had showed sensitivity reactions
after adminstration) corticosteroids,
danazol Cyclosporin & Rituximab
Parents weren’t cooperative
They attend at follow up sessions weakly

At present time patient is candidate for
splenectomy hence was refered for
vaccination
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ITP is defined as a platelet count not
explained by any other cause.
Newly diagnosed ITP refers to the time from
onset of thrombocytopenia to 3 months
later;
persistent ITP is from 3-12 months after
diagnosis.
Chronic ITP is defined as a platelet count
that has been 100 × 10 9/L for longer than
12 months.
Refractory ITP now refers to severe ITP that
persists after splenectomy.
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Before splenectomy, patients with ITP are
divided into responders and nonresponders
to the different treatment modalities.
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Approximately 1/3 of children will have
persistent/chronic ITP with ongoing
thrombocytopenia more than 6 months
after diagnosis,
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5%-10% will develop severe, chronic, and/or
refractory disease.
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The initial step is to ensure that the diagnosis is
correct.
Second, treating physicians need to determine
whether the severity of symptoms warrants aggressive
therapy. many children with chronic disease will not
have major bleeding symptoms and will likely recover
within an additional 12-24 months.
Therefore, continued observation may be the only
therapy indicated.
The dilemma is to determine the best second-line
therapy for the symptomatic children, with the goals
being increase of platelet count, resolution of
bleeding, and increased quality of life
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The primary goal of treatment is prevent
of bleeding not CURE
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So observation alone is an appropriate
approach for many patients especially
those with minimally symptoms.
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Chronic ITP includes all patients who have
platelet counts less than 150 × 10 9/L persisting
more than 6 months after diagnosis.
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In 80% of cases, acute ITP in children
spontaneously resolves irrespective of any
treatment.
Spontanaous remmision: months to years
%5 recurrent ITP( intermittent episodes).
Of the 20% of patients who are truly chronic,
80% enter remission following splenectomy, but
a few will relapse over a period of years.
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History:Isolated bleeding symptoms consistent with thrombocytopenia
without constitutional symptoms (e.g.significant
weightloss,bonepain,nightsweats).
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Physicalexamination:Bleeding symptoms in the absence of
hepatosplenomegaly,lymphadenopathy,or stigmata of congenital
conditions.
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Complete bloodcount:Isolated thrombocytopenia(platelet
count<100x109 /L).
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Anemia only if due to significant bleeding—otherwise normal red cell
indices,whitebloodcell count and differential.
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Peripheral bloodsmear:Identifie platelet should be normal to largein
size.
Bone marrow examination:
 Is felt to be unnecessary in children with
typical ITP prior to initiation of
treatment with corticosteroids,prior to
splenectomy,or in patients who fail
intravenous immunoglobulin(IVIg)
therapy.
Immunedeficiency: Hypo
gammaglubolinemia &
Common variable immune deficiency
 Lymphoprolifrative disorders:ALPS&
Hodghkine disease
 Colagen vascular disease:SLE
 Infection: HIV
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BMA: if not previously done
 Ig level
 Collagen Vacscular testes
 Coombs test
 TFT
 Antiphospholipid Ab test
 HIV test
 Evaluation of parents CBC & smear for
familial types should be considerd
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Routine testing for H.pylori isnot
recommended in asymptomatic
children with unresolved ITP.
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The goal of all treatment strategies for ITP is
to achieve a platelet count that is
associated with adequate hemostasis,
rather than a normal platelet count.
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The decision to treat should involve a
discussion with the patient and
consideration of the severity of bleeding,
anticipated surgical procedures,
medication side effects, and health-related
quality of life.
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Special Considerations for Adults and Children:
Adults:
Consider treatment for patients with platelet <30x10/L
Longer courses of corticosteroids are preferred over
shorter Courses of corticosteroids or IVIg.
IVIg may be used in conjunction with corticosteroids if
a
More rapid increase in platelet count is required.
Either IVIg(1g/kg for one dose,repeated as
necessary)
Anti-D(inappropriate patients)may be used as a firstline treatment if corticosteroids are contraindicated.
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Children:
A single dose of IVIg(0.8-1.0g/kg) or a
shortcourse of corticosteroids should be used
as first-line treatment.
IVIg should be used instead of corticosteroids
if a more rapid increase in platelet count is
required.
There is no evidence to support using
corticosteroids for longer courses compared to
very brief courses.
Anti-D may be considered for first-line therapy
in Rh+ non- splenectomized children with
recognition of the risks outlined above.
o
What bleeding is the patient experiencing?
Determinethe timing,location,and severity of
bleeding symptoms.
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Does this patient have a change in history or physical
examination that requires evaluation for another
diagnosis that could becausing thrombocytopenia?
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Does this patient have any contraindications to
splenectomy?
o
How is the diagnosis of ITP affecting the
patient’sability to , work,go to school,or participatein
activities?
Is the patient experiencing side effects from
chronic
 Medication use?
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How is the patient coping psychologically
with having a low platelet count?
Does the patient respond intermittently to
his or her
Current drug therapy?
o
In children:,
 splenectomy or other interventions with
potentially serious complications should
be delayed for at least 12 months,
unless warranted by severe disease
unresponsive to other measures or due
to quality of life considerations.
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If previous treatment with
corticosteroids,IVIg,or anti-D has been
successful,these options may be used as
needed to prevent bleeding.
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If previous treatment with
corticosteroids,IVIg,or anti-D has been
unsuccessful,subsequent treatment may
include
splenectomy,rituximab,thrombopoietin
receptor agonists, or more potent
immunosuppression.
Splenectomy
 Recommended for children with
significant or persistent bleeding and
lack of response or intolerance of other
therapies such as corticosteroids, IVIg,
and anti-D, and/or who have a need for
improved quality of life.
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Splenectomy
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Nearly 85% of patients undergoing splenectomy will
have an immediate platelet response and close to
70% will maintain them at 5 years.
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Splenectomy is successful because it removes the
primary site of platelet destruction and a site of
antiplatelet Ab production
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Laparoscopic splenectomy is considered safe.
However, bleeding is possible, particularly if platelet
counts are less than 20 × 10 at the time of surgery
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Splenectomy
If relapse occurs, it is generally within in the first
2 years after splenectomy.
At this point, the patient should have
evaluation for and removal of accessory
spleen.
If there is no spleen to remove, then
alternative therapies such as rituximab or TPO
receptor agonists should be considered,
because they have been shown to be equally
efficacious in splenectomized and
nonsplenectomized patients.
Rituximab
 May be considered for children with ITP
who have significant ongoing bleeding
and/or have a need for improved
quality of life despite conventional
treatment.
 Also may be considered as an
alternative to splenectomy in children
with chronic ITP or as therapy in those
who have failed splenectomy.
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Rituximab
Mechanism of action,Rituximab depletes B cells by
binding to the CD20 antigen surface markers. By removing
the autoreactive B-cell clones, autoimmunity can be
eradicated.
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In addition, rituximab has been shown to increase
numbers of T-regulatory cells and prevent the activity of
Th1-autoreactive cells specifically against GPIIb/IIIa.
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Although it is not FDA approved for the treatment of ITP,
more than 5 years of experience in the use of rituximab as
a second-line option and numerous additional reports of
its safety and efficacy in malignant and rheumatologic
diseases is reported.
Rituximab
 In children, nearly 60% of the initial
responders maintained platelet counts
> 50 × 10 9/L for longer than 1 year & had
a greater than 80% chance of maintaining
the response at 2 years.
 An estimated 26% of children will have a 5year durable response.
 O ne theory for the lack of sustained
response to rituximab is the persistence of
autoreactive B cells in the germinal centers
and the BM.
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Rituximab
 The median time to response was 3
weeks with a median duration of
response of 12.8 months.
 Although the most frequently
administered dose remains 375 mg/m 2
for 4 consecutive weeks, there are small
series of children who had similar
response rates with a single dose of 375
mg/m 2 or after lower doses regimens of
100 mg/dose for 4 weeks.
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Due to the risk of hypogammaglobulinemia, it is
recommended to check baseline Igs before
administration of rituximab and then yearly. If levels are
abnormal, supplemental IVIg is indicated.
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Neutropenia, progressive multifocal
leukoencephalopathy, hematologic malignancies, and
acute respiratory distress syndrome have also been
described with rituximab use.
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Most reports of toxicity are not in ITP patients, but in older
adults and in young children with autoimmune hemolytic
anemia, combined variable immunodeficiency, and other
disorders requiring additional immunosuppressive agents
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High-Dose Dexamethasone
May be considered for children or adolescents
with ITP who have significant ongoing bleeding
and/or have a need for improved quality of life
despite conventional treatment. Also may be
considered as an alternative to splenectomy in
children with chronic ITP or in those who have
failed splenectomy.
Immunosuppression
Multiple agents have been reported; however
data for any one specific agent remain
insufficient for specific recommendations.
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Other agents
There are multiple studies of other immunosuppressive
agents used in chronic refractory ITP in both children
and adults. Although they are not new, these agents
include azathioprine, cyclophosphamide, danazol,
dapsone, cyclosporine, sirolimus, and
mycophenolate mofetil. These have been used as
single agents or in combination. However, the
published evidence for their efficacy, particularly in
children, is controversial and limited and their use
should be reserved for patients refractory to all other
therapies, including splenectomy
Thrombopoietin Receptor Agonists
 Studies are ongoing, but there are no
published data to guide the use of these
agents in children.
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Recombinant TPO and TPO receptor agonists
Endogenous TPO regulates platelet production by
increasing the number, ploidy, and maturation of BM
megakaryocytes
TPO is made in the liver
TPO receptor activation on megakaryocyte
precursors leads to increased number and
maturation of cells and prevents apoptosis, thereby
increasing platelet production.
This antiapoptotic effect of TPO likely plays an
important role in ITP, in which BM megakaryocytes
and precursors are increased in number but undergo
apoptosis mediated by antiplatelet IgG.
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In 1994, cloned and purified TPO
1995, 2 first generation recombinant human
TPO agents entered clinical trials.
Both products had half-lives of 40 hours
and increased platelet counts in humans
Romiplostim :
FDA approved since 2008, and the majority
of patients have had a very good response
with an initial dose of 1 g/kg given
subcutaneously each week
Eeltrombopag:
is a small, nonpeptide TPO mimetic that has no homology to
endogenous TPO so it is not immunogenic.
 It binds to the transmembrane region of the TPO receptor rather
than the TPO-binding site.
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Therefore eltrombopag does not compete with endogenous
TPO and any effect it has is additive., with the half-life being 2130 hours.
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It is orally administered with the starting dose of 50 mg daily.
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Polyvalent cations such as calcium, aluminum, magnesium, and
zinc also reduce the absorption of eltrombopag, so this drug
cannot be given within 4 hours of any foods or medications
containing these minerals.
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Thromboembolic events is recommended that the
target platelet range be limited to 50-100 × 109 /L to
minimize risk.
Myelofibrosis
Liver toxicity,
Cataract
The main concern for the practical use of TPO
receptor agonists is the indefinite duration of
treatment required and the need to see patients
frequently to titrate the dose. Relapse rates are high in
patients who have interruption of therapy
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Patients with chronic ITP may have bleeding resulting from low
platelet counts.
Eltrombopag increases and maintains hemostatic platelet
counts; however, to date, outcome has been reported only for
treatment
 ≤ 6 months.
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This interim analysis of the ongoing open-label EXTEND study
 evaluates safety and efficacy of eltrombopag in 299 patients
treated up to 3 years.
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Splenectomized and non-splenectomized patients achieved
platelets
 ≥ 50,000/µL at least once (80% and 88%, respectively). Platelets ≥
50,000/µL and 2x baseline were maintained for a median of 73
of 104 and 109 of 156 cumulative study weeks.
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Bleeding symptoms (WHO Grades 1–4) decreased from
 56% of patients at baseline to 20% at 2 years and 11% at 3 years.
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One hundred (33%) patients were receiving concomitant
treatments at study entry, 69 of whom attempted to reduce them;
65% (45/69) had a sustained reduction or permanently stopped ≥ 1
concomitant treatment.
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Thirty-eight patients (13%) experienced ≥ 1 adverse events leading
to study withdrawal, including patients meeting protocol-defined
withdrawal criteria (11 [4%] thromboembolic events, 5 [2%]
exceeding liver enzyme thresholds).
No new or increased incidence of safety issues was identified.
 Long-term treatment with eltrombopag was generally safe, well
tolerated, and effective in maintaining platelet counts in the
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Background
 Treatment choice in pediatric immune thrombocytopenia
(ITP) is arbitrary, because few studies are powered to
identify predictors of therapy response. Increasingly,
rituximab is becoming a treatment of choice in those
refractory to other therapies.
 Methods
 The objective of this study was to evaluate univariate and
multivariable predictors of platelet count response to
rituximab.
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565 patients with chronic ITP enrolled and met criteria for
this study in the longitudinal, North American Chronic ITP
Registry (NACIR) between January 2004 and October
2010.
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Treatment response was defined as a post-treatment
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Results
Eighty (14.2%) patients were treated with rituximab with an
overall response rate of 63.8% (51/80).
Univariate correlates of response to rituximab included the
presence of secondary ITP and a positive response to steroids.
In multivariable analysis, response to steroids remained a strong
correlate of response to rituximab, OR 6.8 (95% CI 2.0–23.0,
P = 0.002).
Secondary ITP also remained a strong predictor of response to
rituximab, OR 5.6 (95% CI 1.1–28.6, P = 0.04). Although 87.5% of
patients who responded to steroids responded to rituximab, 48%
with a negative response to steroids did respond to rituximab.
Conclusion
Response to steroids and presence of secondary ITP were strong
correlates of response to rituximab, a finding not previously
reported in children or adults.
About 20% of the children diagnosed with
acute idiopathic thrombocytopenic
purpura (ITP) will run a chronic course.
 Only in a minority of these, platelet-countenhancing treatments are indicated.
 Most treatment options are directed at
decreasing platelet destruction including
corticosteroids, intravenous
immunoglobulins, splenectomy, and other
immunosuppressive or immune modulating
drugs.
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In children, rituximab seems to have similar
efficacy as in adults with a lasting continuous
remission rate of 30–35%.
Toxicity includes fever, pruritus, throat tightness,
and serum sickness that may be reason to
discontinue rituximab treatment.
No increased frequency of infections is noted.
We conclude that rituximab should be given to
those symptomatic ITP patients who would
otherwise be referred for splenectomy; only
those who fail rituximab treatment should
proceed to surgery.
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The factors that influence the selection of a
treatment regimen in a given patient are:
quality-of life impact, adverse events, likelihood of
response, bleeding risk, patient/parent anxiety, and
economic issues.
A detailed clinical history and thorough physical
examination are vital.
The clinical history has important implications not only
in diagnosing the disease but also for selecting the
treatment regimen.
Based on the clinical history, patients can be
subclassified into the following groups:
emergent, acute responsive, acute refractory,
chronic persistent, and chronic refractory.