Idiopathic Thrombocytopenic Idiopathic Thrombocytopenic PurpuraPurpura

הצגת מקרההצגת מקרה

שנים שהתקבלה עקב פריחה שנים שהתקבלה עקב פריחה 1010נ.ד ילדה בת נ.ד ילדה בת •פטכיאלית בגוף, לציין שסבלה מדלקת גרון פטכיאלית בגוף, לציין שסבלה מדלקת גרון

כעשרה ימים טרם קבלתה.כעשרה ימים טרם קבלתה.בבדיקה בקבלה : אכימוזות ופטכיות מפושטות על בבדיקה בקבלה : אכימוזות ופטכיות מפושטות על •

פני הגוף, שאר הבדיקה תקינה ללא הגדלת פני הגוף, שאר הבדיקה תקינה ללא הגדלת בלוטות לימפה וללא אורגנומגליה.בלוטות לימפה וללא אורגנומגליה.

ללא דיכוי ללא דיכוי 10.60010.600 טסיות – טסיות – ''בדיקות מעבדה : מסבדיקות מעבדה : מס•של שאר השורות.של שאר השורות.

הושלמה בדיקת פונדוסים ושתן לכללית – תקינים.הושלמה בדיקת פונדוסים ושתן לכללית – תקינים.•

המשך...המשך...

לאור ההתייצגות הקלינית והמעבדתית סוכמה לאור ההתייצגות הקלינית והמעבדתית סוכמה •.. ITPITPשקרוב לוודאי שקרוב לוודאי

הילדה שוחררה להמשך מעקב אמבולטורי ללא הילדה שוחררה להמשך מעקב אמבולטורי ללא •טיפול תרופתי.טיפול תרופתי.

טסיות נמוך טסיות נמוך ‘ ‘ כעבור שנה מהאבחנה עדיין מסכעבור שנה מהאבחנה עדיין מס•שגרם שגרם IVIGIVIG , טופלה בקורס של , טופלה בקורס של 97009700סביב סביב

לתגובה קצרת טווח, שבהמשך הופסק לאור לתגובה קצרת טווח, שבהמשך הופסק לאור הופעת כאבי ראש חזקים. הופעת כאבי ראש חזקים.

המשך....המשך....

נשלחו נוגדנים נגד טסיות לרמב"ם ???נשלחו נוגדנים נגד טסיות לרמב"ם ???•

נשלח בירור נשלח בירור Chronic ITPChronic ITPלאור תמונה של לאור תמונה של • ANAANA Anti ds DNA , Anti Anti ds DNA , Antiשכלל : שכלל :

cardiolipincardiolipin , ,

המשך...המשך...

כעבור שנתיים מהאבחנה לאור טרומבוציטופניה כעבור שנתיים מהאבחנה לאור טרומבוציטופניה • הוחלט להתחיל טיפול בסטירואידים הוחלט להתחיל טיפול בסטירואידים 70007000סביב סביב

מ"ג ליום(. מ"ג ליום(.6060)פרדנזון של )פרדנזון של טרם התחלת הסטירואידים בוצעה בדיקת לשד עצם טרם התחלת הסטירואידים בוצעה בדיקת לשד עצם •

שהראתה ריבוי מגקריוציטים .שהראתה ריבוי מגקריוציטים .לאחר התחלת סטירואידים היתה עלייה במספר לאחר התחלת סטירואידים היתה עלייה במספר •

. .40.00040.000הטסיות ל הטסיות ל הבעייתיות היתה תלות מלאה בטיפול ותגובה הבעייתיות היתה תלות מלאה בטיפול ותגובה •

שחלפה עם הורדת המינון. שחלפה עם הורדת המינון.

המשך....המשך....

ללא ללא RituximabRituximab היה ניסיון עם היה ניסיון עם 20042004בשנת בשנת • (. (.70007000הטבה )טסיות נשארו סביב הטבה )טסיות נשארו סביב

הועלתה אפשרות של הועלתה אפשרות של 07.200407.2004ב ב •SplenectomySplenectomy

20.00020.000 – – 50005000 טסיות סביב טסיות סביב 07.200107.2001מאז מאז •

– מספר טסיות סביב – מספר טסיות סביב 04.200604.2006ס"ד אחרונה ב ס"ד אחרונה ב •12.00012.000

ITPITP

100100 cases per 1 milion persons per yearcases per 1 milion persons per year . .

About half of these cases occur in childrenAbout half of these cases occur in children . .

Primary vs SecondaryPrimary vs Secondary . .

Acute vs Chronic ( >6 months)Acute vs Chronic ( >6 months) . .

The The etiologyetiology is still unknown and the is still unknown and the pathogenesis is complex and possibly pathogenesis is complex and possibly depends on disturbed antigen depends on disturbed antigen presentation, T cell activation and presentation, T cell activation and signaling, disregulated B cell stimulation signaling, disregulated B cell stimulation and antibodies, unbalanced activation / and antibodies, unbalanced activation / suppression of complementsuppression of complement..

Affected children are young (Affected children are young (peak age peak age ~ 5~ 5 yrsyrs) and previously healthy, and ) and previously healthy, and they typically present with the they typically present with the sudden onset of petechiae or purpura sudden onset of petechiae or purpura a few days or weeks after an a few days or weeks after an infectious illnessinfectious illness..

Boys and girls are equally affectedBoys and girls are equally affected..

In more than 70% of children, the In more than 70% of children, the illness resolves illness resolves within six monthswithin six months, , irrespective of whether they receive irrespective of whether they receive therapytherapy..

By contrastBy contrast, ITP in adults is generally , ITP in adults is generally chronicchronic . .

The bone marrow in patients with ITPThe bone marrow in patients with ITP

contains normal or increasedcontains normal or increased numbers numbers ofof

megakaryocytesmegakaryocytes..

http://mmserver.cjp.com/images/image/2574001.jpg

PathophysiologyPathophysiology

ITPITP is mediated by IgG autoantibodies is mediated by IgG autoantibodies..

GlycoproteinGlycoprotein IIb/IIa, Ib/Ix, Ia/IIa, IV and IIb/IIa, Ib/Ix, Ia/IIa, IV and VV... ...

Accelerated clearanceAccelerated clearance through through FcFcүү receptors that are expressed by tissue receptors that are expressed by tissue macrophages (spleen & liver)macrophages (spleen & liver) . .

GeneticsGenetics

Monozygotic twinsMonozygotic twins..

An increased prevalence of An increased prevalence of HLA-DRw2HLA-DRw2 and and DRB1*0410DRB1*0410 alleles alleles..

HLA-DR4 and DRB1*0410 allelesHLA-DR4 and DRB1*0410 alleles have have been associated with unfavorable and been associated with unfavorable and favorable response to corticosteroids, favorable response to corticosteroids, respectivelyrespectively..

DiagnosisDiagnosisThe diagnosis of ITP remains one of exclusionThe diagnosis of ITP remains one of exclusion . .

Secondary formsSecondary forms of the disease occur in of the disease occur in association with SLE, the antiphospholipid association with SLE, the antiphospholipid syndrome, immunodeficiency states (IgA syndrome, immunodeficiency states (IgA deficiency and common variable deficiency and common variable hypogammaglobulinemia), Lymphoproliferative hypogammaglobulinemia), Lymphoproliferative disorders (CLL, Large granular lymphocytic disorders (CLL, Large granular lymphocytic leukemia, and lymphoma), infection with HIV leukemia, and lymphoma), infection with HIV and hepatitis c virus, and therapy with drugs and hepatitis c virus, and therapy with drugs

such as heparin and quinidinesuch as heparin and quinidine . .

The guidelines of the American The guidelines of the American Society of Hematology state that a Society of Hematology state that a bone marrow examination is bone marrow examination is not not requiredrequired in adults younger than 60 in adults younger than 60 yrs of age if the presentation is yrs of age if the presentation is typical but is appropriate before typical but is appropriate before splenectomy is performedsplenectomy is performed..

Marrow examination Marrow examination is necessary in the is necessary in the presence of atypical features (e.g., presence of atypical features (e.g., those with additional cytopenias, those with additional cytopenias, protracted fever, bone or joint pain, protracted fever, bone or joint pain, unexplained macrocytosis ), or in unexplained macrocytosis ), or in patients who do not have a brisk or patients who do not have a brisk or robust response to therapyrobust response to therapy..

There is consensus, that bone marrow There is consensus, that bone marrow examination is not necessary in children examination is not necessary in children if management involves observation or if management involves observation or IVIGIVIG..

Although it is not mandatory, many Although it is not mandatory, many pediatric hematologists recommend that pediatric hematologists recommend that an aspiration be performed before an aspiration be performed before starting corticosteroids to rule out the starting corticosteroids to rule out the rare case of acute leukemiarare case of acute leukemia..

The direct assay for the measurement The direct assay for the measurement of platelet-bound AB’s has an of platelet-bound AB’s has an estimated sensitivity of 49-66%, an estimated sensitivity of 49-66%, an estimated specificity of 78-92%, and estimated specificity of 78-92%, and an estimated PPV of 80-83%an estimated PPV of 80-83%..

The decision to treat ITP is based on The decision to treat ITP is based on thethe platelet count, the degree of platelet count, the degree of bleeding, and the patient’s lifestylebleeding, and the patient’s lifestyle

..

ManagementManagementThe incidence of intracranial The incidence of intracranial hemorrhageis ~ between 0.2-1%hemorrhageis ~ between 0.2-1%..

Almost all intracranial hemorrhages occur Almost all intracranial hemorrhages occur at platelet counts below 20.000/mmat platelet counts below 20.000/mm3, 3, and generally below 10.000/mm3and generally below 10.000/mm3..

Risk factorsRisk factors : head trauma and : head trauma and exposure to antiplatelet drugsexposure to antiplatelet drugs . .

Most intracranial hemorrhagrs occur Most intracranial hemorrhagrs occur within within four weeks after four weeks after presentation with ITP, often presentation with ITP, often within the first weekwithin the first week..

Most children with typical acute ITP Most children with typical acute ITP recover completely within a few recover completely within a few weeks without treatment and that weeks without treatment and that there is no proof that therapy there is no proof that therapy prevents intracranial hemorrhageprevents intracranial hemorrhage..

ITP in many children – certainly those ITP in many children – certainly those without hemorrhage –is managed on without hemorrhage –is managed on an outpatient basis with minimal an outpatient basis with minimal investigation, short-term therapy in investigation, short-term therapy in select cases, and the avoidance of select cases, and the avoidance of activities that predispose the patient activities that predispose the patient to trauma and of medications that to trauma and of medications that impair platelet functionimpair platelet function..

American Society of HematologyAmerican Society of Hematology

((ASHASH ) )recommends drug therapy forrecommends drug therapy for

children with platelet counts of children with platelet counts of lessless

than 10.000/mm3 with little or no than 10.000/mm3 with little or no purpurapurpura..

The UK guidelines state : only The UK guidelines state : only patients who experience patients who experience significant mucous membrane significant mucous membrane bleeding receive treatmentbleeding receive treatment..

TreatmentTreatment

Watch & WaitWatch & Wait strategy strategy..

CCorticosteroidsorticosteroids (high, standard or low (high, standard or low dose)dose)..

IVIGIVIG (high or low dose, 2 day or 1 day) (high or low dose, 2 day or 1 day)..

IV IV anti-D immunoglobulinanti-D immunoglobulin in Rh(D) positive in Rh(D) positive patients (high or low dose)patients (high or low dose)..

Randomized clinical trials have demonstrated that Randomized clinical trials have demonstrated that therapy with IVIG shortens the duration of severe therapy with IVIG shortens the duration of severe thrombocytopenia ( platelet < 20.000 /mm3)thrombocytopenia ( platelet < 20.000 /mm3). .

Adverse reactions : headache, fever, nausea, and Adverse reactions : headache, fever, nausea, and aseptic meningitisaseptic meningitis..

The response to IVIG is more rapid than the The response to IVIG is more rapid than the response to IV anti-Dresponse to IV anti-D..

The average decrease in the hemoglobin level is The average decrease in the hemoglobin level is 1.3 g per deciliter, and intravascular hemolysis is 1.3 g per deciliter, and intravascular hemolysis is rarerare..

Urgent treatmentUrgent treatment

Neurologic symptoms, internal bleeding, Neurologic symptoms, internal bleeding, or emergency surgery demands or emergency surgery demands immediate interventionimmediate intervention..

IV.Methylprednisone (30 mg/Kg/d; max 1 IV.Methylprednisone (30 mg/Kg/d; max 1 gr/d for 2-3 days) / 20-30min + IVIG (1 gr/d for 2-3 days) / 20-30min + IVIG (1 gr/kg/d for 2-3 days) + infusion of gr/kg/d for 2-3 days) + infusion of platelets that is 2-3 times the usual platelets that is 2-3 times the usual amount infused; Vincristine may be amount infused; Vincristine may be consideredconsidered..

SplenctomySplenctomy should be considered if it has should be considered if it has not yet been performednot yet been performed..

PlasmapheresisPlasmapheresis is of limited benefit is of limited benefit..

Antifibrinolytic therapyAntifibrinolytic therapy (e.g. Aminocaproic (e.g. Aminocaproic acid) may reduce mucosal bleeding, and acid) may reduce mucosal bleeding, and recombinant factor VIIarecombinant factor VIIa should be should be consideredconsidered..

Management of first relapseManagement of first relapse

Approximately 25%Approximately 25% of children with ITP of children with ITP have a relapse after initial treatmenthave a relapse after initial treatment..

One third of childrenOne third of children have spontaneous have spontaneous remission and remission and only 5%only 5% still have severe still have severe thrombocytopenic requiring therapy thrombocytopenic requiring therapy one year after diagnosisone year after diagnosis..

Guidelines from the American Society of Guidelines from the American Society of HematologyHematology recommended that recommended that splenctomy be considered for children splenctomy be considered for children who have had ITP for at least one year who have had ITP for at least one year with symptomatic, severe with symptomatic, severe thrombocytopeniathrombocytopenia..

In children, the rate of complete remission In children, the rate of complete remission after splenectomy is 70-80%after splenectomy is 70-80%..

Bacterial sepsisBacterial sepsis ( ( ~ ~ 3%)3%) !!!!!!!!

Chronic refractory ITPChronic refractory ITP

AchallengeAchallenge is posed by the occasional is posed by the occasional symptomatic child in whom symptomatic child in whom splenectomy fails or is containdicated splenectomy fails or is containdicated and in whom the platelet count cannot and in whom the platelet count cannot be sustained with acceptable doses of be sustained with acceptable doses of corticosteroids, anti-D immune globulincorticosteroids, anti-D immune globulin..

American Soceity of Hematology guidelinesAmerican Soceity of Hematology guidelines recommend treatment for such children if recommend treatment for such children if they have symptomatic thrombocytopenia they have symptomatic thrombocytopenia and platelet counts of less than and platelet counts of less than 30.000/mm330.000/mm3..

No regimen is universally effectiveNo regimen is universally effective..

Vincristine, azathioprine, cyclophosphamide Vincristine, azathioprine, cyclophosphamide or cyclosporineor cyclosporine..

Childhood ITP in the nordic Childhood ITP in the nordic countriescountriesActa paediatrica 2005;94Acta paediatrica 2005;94

A A prospective registrationprospective registration 1998 – 2000 1998 – 2000..

Ninety eight paediatric departmentsNinety eight paediatric departments..

506506 children with newly ITP aged 0-14 yr children with newly ITP aged 0-14 yr and at least one platelet count <30.000and at least one platelet count <30.000. .

423423 of the children followed for 6 monthsof the children followed for 6 months..

The platelet count < 10.000 in 58%The platelet count < 10.000 in 58%..

Chronic ITP developed in 25% : Chronic ITP developed in 25% : thrombocytopenia < 150.000 persisting thrombocytopenia < 150.000 persisting after 6 monthsafter 6 months . .

Cont’dCont’d

Most cases in the Most cases in the winterwinter months from months from October to MarchOctober to March..

About 57.7% of the children have various About 57.7% of the children have various infections in the 4 wk preceding infections in the 4 wk preceding diagnosisdiagnosis..

The majority had viral URI, flu-like diseases The majority had viral URI, flu-like diseases or unspecified feveror unspecified fever..

Some patients developed ITP following a Some patients developed ITP following a bacterial infection like sinusitis, otitis bacterial infection like sinusitis, otitis media or tonsillitismedia or tonsillitis..

Cont’dCont’d

In 6.9%In 6.9% cases, cases, ITPITP occured after occured after vaccinations, particularly vaccinations, particularly the MMR the MMR vaccination (DTP, Oral polio, Hepatitis A vaccination (DTP, Oral polio, Hepatitis A & B)& B)..

Cont’dCont’d

Factors associated with chronic ITPFactors associated with chronic ITP: :

Insidious onset of symptomsInsidious onset of symptoms . .

A bsence of preceding infection and/or A bsence of preceding infection and/or vaccinationvaccination..

Age 8-14 yrsAge 8-14 yrs..

Female genderFemale gender..

Treatment soon after diagnosis did not Treatment soon after diagnosis did not appear to influence the risk of appear to influence the risk of developing chronic diseasedeveloping chronic disease..

The frequency of mucosal bleeding was The frequency of mucosal bleeding was related to the initial platelet count related to the initial platelet count (<15000)(<15000)..

3/153/15 patients with severe haemorrhage patients with severe haemorrhage had platelet count between 16 – 24.000had platelet count between 16 – 24.000 . .

Corticosteroids versus IVIG forCorticosteroids versus IVIG for thethe treatment of acute ITP in childrentreatment of acute ITP in children

J Pediatr 2005; 147J Pediatr 2005; 147

A systematic review and meta-analysis A systematic review and meta-analysis of randomized controlled trials of randomized controlled trials comparing corticosteroids with IVIGcomparing corticosteroids with IVIG..

1010 studies were includedstudies were included..

The primary outcome was the number The primary outcome was the number of patients with a platelet count of patients with a platelet count >20.000, 48 hrs after treatment >20.000, 48 hrs after treatment initiationinitiation..

Cont’dCont’d

25%25% of patients treated with of patients treated with corticosteroids and 18% of patients corticosteroids and 18% of patients treated with IVIG developed chronic ITPtreated with IVIG developed chronic ITP..

Children treated with corticosteroids for Children treated with corticosteroids for acute ITP are 26% less likely to have a acute ITP are 26% less likely to have a platelet count > 20.000 after 48 hrs of platelet count > 20.000 after 48 hrs of therapy, when compared with children therapy, when compared with children treated with IVIGtreated with IVIG..

Single dose of anti-D immune globulin at 75 µg/Kg Single dose of anti-D immune globulin at 75 µg/Kg is as effective as intravenous immune globulin.is as effective as intravenous immune globulin.The journal of pediatrics .April 2006The journal of pediatrics .April 2006..

Randomised prospectiveRandomised prospective trial of immune globulin trial of immune globulin treatments for 105 Rh+ children with newly treatments for 105 Rh+ children with newly diagnosed ITP and a platelet count<20.000diagnosed ITP and a platelet count<20.000..

Nine study sites in the USANine study sites in the USA..Age range 1-16 yrsAge range 1-16 yrs..Patients received either a single IV dose of 50 µg/kg Patients received either a single IV dose of 50 µg/kg anti-D, 75 µg/kg anti-D, or 0.8 g/kg IVIGanti-D, 75 µg/kg anti-D, or 0.8 g/kg IVIG..

By 24 hrs after treatment 50%, 72%, 77% of patients By 24 hrs after treatment 50%, 72%, 77% of patients in the anti-D50, anti-D75, and IVIG groups, in the anti-D50, anti-D75, and IVIG groups, respectively, had achieved a platelet count > respectively, had achieved a platelet count > 20.00020.000. .

Cont’dCont’d

A singleA single 75 µg/kg dose of 75 µg/kg dose of anti-Danti-D raised raised the platelet count in children with the platelet count in children with newly diagnosed immune newly diagnosed immune thrombocytopenia more rapidly than thrombocytopenia more rapidly than standard dose standard dose anti-Danti-D and as effectively and as effectively as as IVIGIVIG..

•The presence of wet purpura at study The presence of wet purpura at study entryentry

•affected the response to treatment, in affected the response to treatment, in all andall and

•in each groupin each group..

Rituximab treatment for symptomatic Rituximab treatment for symptomatic chronic ITP. Pediatr blood cancer chronic ITP. Pediatr blood cancer 2006;472006;47

Monoclonal antibody against CD20+ B Monoclonal antibody against CD20+ B cellscells..

Rapid depletion of B-cells for 6-12 Rapid depletion of B-cells for 6-12 monthsmonths..

Mechanism in ITPMechanism in ITP???? ????

Cont’dCont’d

About 1/3 of children has acontiuous About 1/3 of children has acontiuous responseresponse..

Side effects : chills, fever, urticaria Side effects : chills, fever, urticaria and serum sickness (12%)and serum sickness (12%)..

The time to platelet counts> 50.000 The time to platelet counts> 50.000 ranged from 1 – 7 weeksranged from 1 – 7 weeks..

No increased frequency of infectionsNo increased frequency of infections..

ITP in childrenITP in childrenPediatr Blood Cancer 2006 ;47Pediatr Blood Cancer 2006 ;47

Children’s hospital “Bambino Gesu” RomeChildren’s hospital “Bambino Gesu” Rome..Jan 1995 – Dec 2005Jan 1995 – Dec 2005..

265265 children with ITPchildren with ITP..Diagnosis was made, excluding other Diagnosis was made, excluding other haematological disorders by BM aspirate haematological disorders by BM aspirate showing normal to increased megakaryocytesshowing normal to increased megakaryocytes..None of the 265 children had been pretreated or None of the 265 children had been pretreated or received any steroid treatment for at least 2 received any steroid treatment for at least 2 months before the observationmonths before the observation..Children with a platelet count >= 10.000 and no Children with a platelet count >= 10.000 and no significant cutaneous or mucosal bleeding have significant cutaneous or mucosal bleeding have been observed without any treatment (wait & been observed without any treatment (wait & see)see)..

Cont’dCont’d

208208 out of 265 children were treatedout of 265 children were treated..

CR – persistent plt count >= 100.000 for CR – persistent plt count >= 100.000 for at least 3 months without further at least 3 months without further therapytherapy..

PR – a plt count 30-100.000 for at least 3 PR – a plt count 30-100.000 for at least 3 monthsmonths..

Splenectomy in children withSplenectomy in children with chronic ITPchronic ITPPediatr Blood Cancer 2006;47Pediatr Blood Cancer 2006;47

The aim of the study was to determine The aim of the study was to determine whether the response to whether the response to splenectomy is related to the splenectomy is related to the

response to previous treatmentsresponse to previous treatments??? ???

Cont’dCont’d

Retrospective studyRetrospective study..

9090 children that were splenctomized for children that were splenctomized for chronic ITP in 11 Italian centers and chronic ITP in 11 Italian centers and previously treated with several previously treated with several treatments including IVIGtreatments including IVIG..

Chronic ITP – PLT count < 50.000 Chronic ITP – PLT count < 50.000 persistng for a minimum of 6 monthspersistng for a minimum of 6 months..

The mean age was 8±3.9 yrsThe mean age was 8±3.9 yrs..

Cont’dCont’d

The mean follow up after splenectomy The mean follow up after splenectomy was 2.4 yrswas 2.4 yrs..

Plt count were constantly > 50.000 in Plt count were constantly > 50.000 in 75% of patients75% of patients..

The success of splenectomy was strongly The success of splenectomy was strongly correlated with a good response to correlated with a good response to previous treatmentprevious treatment..

A negative response to any of the prior A negative response to any of the prior treatments had no predictive valuetreatments had no predictive value..

AMG 531 For chronic ITPAMG 531 For chronic ITPNEJM OCT 19:2006NEJM OCT 19:2006

AMG 531 – Amgen : Thrombopoiesis-AMG 531 – Amgen : Thrombopoiesis-Stimulating ProteinStimulating Protein..

There is evidence that platelet production is There is evidence that platelet production is suboptimal in a substantial proportion of suboptimal in a substantial proportion of patients with ITPpatients with ITP..

Cont’dCont’d

Thrombocytopenia occurs in patients with ITP Thrombocytopenia occurs in patients with ITP when the rate of plt destruction exceeds the when the rate of plt destruction exceeds the ability of the bone marrow to increase platelet ability of the bone marrow to increase platelet productionproduction..Kinetic data show that plt production, as Kinetic data show that plt production, as measured by plt turnover, is reduced in 2/3 of measured by plt turnover, is reduced in 2/3 of patients with ITPpatients with ITP..Plasma level of endogenous thrombopoietin are Plasma level of endogenous thrombopoietin are not elevated in patients with ITP, as they are not elevated in patients with ITP, as they are in patients with thrombocytopenia due to in patients with thrombocytopenia due to chemotherapy or aplastic anemiachemotherapy or aplastic anemia..

Cont’dCont’d99 U.S. Centers enrolled patients with chronic U.S. Centers enrolled patients with chronic

ITP in two sequential trialsITP in two sequential trials..

Inclusion criteriaInclusion criteria : :

Age 18 - 65 yrsAge 18 - 65 yrs..

A history of ITP for at least 3 monthsA history of ITP for at least 3 months..

One or more prior treatments for ITPOne or more prior treatments for ITP..

A mean platelet count < 30.000/mm3 for A mean platelet count < 30.000/mm3 for patients not receiving corticosteroids or < patients not receiving corticosteroids or < 50.000 /mm3 for patients receiving 50.000 /mm3 for patients receiving corticosteroidscorticosteroids..

Cont’dCont’d

The followingThe following intervals since the last intervals since the last administration of therapy for administration of therapy for ITPITP were were required : 2 weeks for required : 2 weeks for IVIGIVIG, 8 weeks for , 8 weeks for alkylating agentsalkylating agents, 16 weeks for , 16 weeks for rituximabrituximab, and 4 weeks for all other , and 4 weeks for all other treatmentstreatments..

Cont’dCont’d

Exclusion criteriaExclusion criteria: :

AnyAny known risk factor for known risk factor for thromboembolic events, a history of thromboembolic events, a history of cardiovascular disease, active cardiovascular disease, active cancer, and a history of a bone cancer, and a history of a bone marrow disordermarrow disorder..

This study was a multicenter, trial consisting of two This study was a multicenter, trial consisting of two phases, with no overlap between patients in phases, with no overlap between patients in phase 1 and those in phase 2phase 1 and those in phase 2..

Phase 1 (July 2002 - Oct 2003)Phase 1 (July 2002 - Oct 2003): :

.1.1Safety and tolerability of two injections of AMG Safety and tolerability of two injections of AMG 531 in patients with ITP531 in patients with ITP..The dose that would result in platelet count that was The dose that would result in platelet count that was within the targeted range (50.000 to within the targeted range (50.000 to 450.000/mm3)450.000/mm3)

Phase 1 cont’dPhase 1 cont’d

AMG 531 was administered by SC. Injection on day 1, AMG 531 was administered by SC. Injection on day 1, followed by 14 days of observationfollowed by 14 days of observation..Health status, CBC, and blood chemical values were Health status, CBC, and blood chemical values were monitored throughout the studymonitored throughout the study..Assays to detect anti-AMG 531 antibodies were Assays to detect anti-AMG 531 antibodies were performed before treatment, at the end of performed before treatment, at the end of treatment, and at the end of the studytreatment, and at the end of the study..If plt <50.000 on day 15, a second identical dose was If plt <50.000 on day 15, a second identical dose was administered. If plt>=50.000 on day 15, the administered. If plt>=50.000 on day 15, the second dose was delayed until day 22, if second dose was delayed until day 22, if plt>=50.000 the second dose was not givenplt>=50.000 the second dose was not given..Follow up for 8 weeks after the studyFollow up for 8 weeks after the study..

Phase 2Phase 2

Oct 2003 – June 2004Oct 2003 – June 2004..

Double blind, placebo controlledDouble blind, placebo controlled..

Patients were randomly assigned to Patients were randomly assigned to receive AMG 531 at one of three doses receive AMG 531 at one of three doses (1,3 or 6 µg/kg) or placebo once a week (1,3 or 6 µg/kg) or placebo once a week for 6 weeksfor 6 weeks..

Doses were withheld if plt > 350.000/mm3Doses were withheld if plt > 350.000/mm3..

Follow up for 6 weeks after the last doseFollow up for 6 weeks after the last dose..

Cont’dCont’d

AMG 531 does not appear to affect the AMG 531 does not appear to affect the ongoing rate of platelet destruction; ongoing rate of platelet destruction; in all patients receiving the drug, the in all patients receiving the drug, the platelet count returned to the platelet count returned to the baseline value after the baseline value after the discontinuation of short term discontinuation of short term treatmenttreatment . .