chronic itp presented by :f.malek under supervision of dr shamsian

In the name of God

Chronic ITP Presented by :F.Malek

Under supervision of Dr Shamsian

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

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

Abdominopelvic ultrasonographyRevealed spleen with upper limit of

normal size

normal

BMA

Cvascular tests

IGs

Virulogy

Patient had received different type ofMedications since 6 years ago such asIVIG ( 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

Chronic ITP

Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant . Texas.Hematology 2012.thrombopoietin, and other new therapeutics .

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.

Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology.

Before splenectomy, patients with ITP are divided into responders and nonresponders to the different treatment modalities.

Approximately 1/3 of children will have persistent/chronic ITP with ongoing thrombocytopenia more than 6 months after diagnosis,

5%-10% will develop severe, chronic, and/or refractory disease.

Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology

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

Chronic ITP

The primary goal of treatment is prevent of bleeding not CURE

So observation alone is an appropriate approach for many patients especially those with

minimally symptoms.

Chronic ITP Chronic ITP includes all patients who have platelet

counts less than 150 × 10 9/L persisting more than 6 months after diagnosis.

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.

2011 Clinical Practice Guideline on the Evaluation and Management of Immune Thrombocytopenia (ITP)

History:Isolated bleeding symptoms consistent with thrombocytopenia without constitutional symptoms (e.g.significant weightloss,bonepain,nightsweats).

Physicalexamination:Bleeding symptoms in the absence of hepatosplenomegaly,lymphadenopathy,or stigmata of congenital conditions.

Complete bloodcount:Isolated thrombocytopenia(platelet count<100x109 /L).

Anemia only if due to significant bleeding—otherwise normal red cell indices,whitebloodcell count and differential.

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.

Chronic ITP/Differential diagnosis

Immunedeficiency: Hypo gammaglubolinemia &

Common variable immune deficiency Lymphoprolifrative disorders:ALPS&

Hodghkine disease Colagen vascular disease:SLE Infection: HIV

Evaluation-Chronic ITP

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

Secondary ITP (H. pylori- associated)

Routine testing for H.pylori isnot recommended in asymptomatic

children with unresolved ITP.


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.

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.


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 first-line treatment if corticosteroids are contraindicated.


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+ nonsplenectomized children with recognition of the risks outlined above.

Assessment of Disease Status:Subsequent Management of ITP

o What bleeding is the patient experiencing? Determinethe timing,location,and severity of bleeding symptoms.

o Does this patient have a change in history or physical examination that requires evaluation for another diagnosis that could becausing thrombocytopenia?

o 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?

Assessment of Disease Status:Subsequent Management of ITP

Is the patient experiencing side effects from chronic

Medication use?

How is the patient coping psychologically with having a low platelet count?

o Does the patient respond intermittently to his or her

Current drug therapy?


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.


If previous treatment with corticosteroids,IVIg,or anti-D has been successful,these options may be used as needed to prevent bleeding.

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.

Special Considerations for Children 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.


Splenectomy Nearly 85% of patients undergoing splenectomy

will have an immediate platelet response and close to 70% will maintain them at 5 years.

Splenectomy is successful because it removes the primary site of platelet destruction and a site of antiplatelet Ab production

Laparoscopic splenectomy is considered safe. However, bleeding is possible, particularly if platelet counts are less than 20 × 10 at the time of surgery


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.

Special Considerations for Children 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.


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.

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.

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 5-year 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.

In addition, the majority of plasma cells are preserved in patients receiving anti-CD20 Ab therapy.


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.

previous response to corticosteroids and history of secondary ITP predicted better response


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.

Neutropenia, progressive multifocal leukoencephalopathy, hematologic malignancies, and acute respiratory distress syndrome have also been described with rituximab use.

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

Special Considerations for Children 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.


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

Special Considerations for Children Thrombopoietin Receptor

Agonists Studies are ongoing, but there are no

published data to guide the use of these agents in children.

2 Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology

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.


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

Mansoor N.Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia (ITP): results of the long-term, Blood. November 20, 2012

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.

Therefore eltrombopag does not compete with endogenous TPO and any effect it has is additive., with the half-life being 21-30 hours.

It is orally administered with the starting dose of 50 mg daily.

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.


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


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.

This interim analysis of the ongoing open-label EXTEND study

evaluates safety and efficacy of eltrombopag in 299 patients treated up to 3 years.

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.


Bleeding symptoms (WHO Grades 1–4) decreased from 56% of patients at baseline to 20% at 2 years and 11% at 3

years.

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.

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 desired range

. Pediatric Blood & Cancer Rachael F. Grace MD1,2,3

Volume 58, Issue 2, pages 221–225, February 2012

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.

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.

Treatment response was defined as a post-treatment platelet count ≥50,000/µl within 16 weeks of rituximab and 14 days of steroids. Treatment response data were captured both retrospectively at enrollment and then prospectively in children or adults.

http://onlinelibrary.wiley.com/doi/10.1002/pbc.v58.2/issuetoc

. Pediatric Blood & Cancer Rachael F. Grace MD1,2,3

Volume 58, Issue 2, pages 221–225, February 2012

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.

http://onlinelibrary.wiley.com/doi/10.1002/pbc.v58.2/issuetoc

Volume 47, Issue S5, pages 714–716, 15 October 2006. IncPediatric Blood & Cancer

About 20% of the children diagnosed with acute idiopathic thrombocytopenic purpura (ITP) will run a chronic course.

Only in a minority of these, platelet-count-enhancing treatments are indicated.

Most treatment options are directed at decreasing platelet destruction including corticosteroids, intravenous immunoglobulins, splenectomy, and other immunosuppressive or immune modulating drugs.

http://onlinelibrary.wiley.com/doi/10.1002/pbc.v47:5+/issuetoc


Volume 47, Issue S5, pages 714–716, 15 October 2006. IncPediatric Blood & Cancer

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.



Management of Immune Thrombocytopenic Purpura: An UpdateNew Orleanshe Ochsner Journal 12:221–227, 2012..Rajasekharan Warrier

Treatment Selection/ITPManagement of Immune Thrombocytopenic Purpura: An UpdateNew Orleanshe Ochsner Journal 12:221–227, 2012..Rajasekharan Warrier

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.

chronic itp presented by :f.malek under supervision of dr shamsian

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