Ash 2011 evidence based practice guideline for itp
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ASH 2011 evidence-based practice guideline for ITP. ITP in the adult Blood. 2011;117(16):4190-4207. Presentor: 周益聖 Instructor: 蕭樑材. 財團法人台灣癌症臨床研究發展基金會. Outline. Grade system of recommendation IWG definition Diagnosis Course Bleeding risk Treatment of fresh case

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ASH 2011 evidence-based practice guideline for ITP

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Ash 2011 evidence based practice guideline for itp

ASH 2011 evidence-based practice guideline for ITP

ITP in the adult

Blood.2011;117(16):4190-4207

Presentor: 周益聖

Instructor: 蕭樑材

財團法人台灣癌症臨床研究發展基金會


Outline

Outline

  • Grade system of recommendation

  • IWG definition

  • Diagnosis

  • Course

  • Bleeding risk

  • Treatment of fresh case

    • IVIG vs High dose MTP + prednisolone vs placebo

    • HD dexamethasone

  • Treatment of refractory/relapase cases after initial steroid

    • Splenectomy

    • TPO agonists

    • Rituximab

  • Take home massage


Grade system of recommendation

Grade system of recommendation

  • 1A, 1B, 1C, 2A, 2B, 2C

  • Number: strength of recommendation

    • 1-we recommend..

    • 2- we suggest..

  • Alphabetical: quality of evidence

    • A- RCTs or exceptionally strong observation studies

    • B- RCTs with limitation or strong observation studies

    • C-RCTs with serious flaws , weaker observations or

      indirect evidence

Blood.2011;117(16):4190-4207


International working group iwg definition

International working group(IWG) definition

  • Newly diagnosed: diagnosis to 3 months

  • Persistent: 3 to 12 months from diagnosis

  • Chronic: more than 12 months

Diagnosis

3 months

12 months

Newly diagnosed

Persistent

Chronic

Blood. 2009;113(11):2386-2393.


Diagnosis

Diagnosis

  • Recommend

    • Check HCV and HIV (1B)

  • Suggest

    • Further investigation if abnormalities other than thrombocytopenia (including IDA) in the blood count or smear (2C)

    • Bone marrow examination not necessary irrespective of age with typical ITP(2C)

  • Insufficient evidence to recommend routine check anti-platelet Ab , APA, ANA, TPO levels

Blood.2011;117(16):4190-4207


Causes of secondary itp

Causes of Secondary ITP

  • Antiphospholipid syndrome

  • Autoimmune thrombocytopenia(eg Evans syndrome)

  • Common variable immune deficiency

  • Drug administration side effect

  • Infection with CMV, Helicobacter pylori, HCV, HIV, varicella zoster

  • Lymphoproliferative disorder

  • Vaccination side effect

  • SLE

Blood.2011;117(16):4190-4207


Itp anti platelt ab

ITP & Anti-plateltAb

Flow Cytometry using donor platelets as target cells detects detects autoAb in

70 %(31/44) in ITP

SPRCA ( Solid phase red cell adherence assay)for plasma anti-platelet Ab

Sensitivity: 50% (22/44), Specificty:100%

J Chin Med Assoc 2006;69(12):569-574.


Treatment of fresh case

Treatment of fresh case

  • Suggest

    • Treat newly diagnosed patients with platelet count <30x10^9/L(2C)

    • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment (2B)

    • IVIG combined with steroid if more rapid increase in platelet count desired(2B)

    • IVIG or anti-D as first line if steroid contraindicated(2C)

    • IVIG dose : 1g/Kg as one-time dose, repeated higher doses if necessary (2B)

      Br J Haematol 1999;107(4):716-719.(1.5g/Kg)


Treatment of fresh case1

Treatment of fresh case

  • Suggest

    • Treat newly diagnosed patients with platelet count <30x10^9/L(2C)

    • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment (2B)

    • IVIG combined with steroid if more rapid increase in platelet count desired(2B)

    • IVIG or anti-D as first line if steroid contraindicated(2C)

    • IVIG dose : 1g/Kg as one-time dose, repeated if necessary (2B)

Blood.2011;117(16):4190-4207


Ash 2011 evidence based practice guideline for itp

Course of Severe ITP

72 pts : steroid only ( 1mg/ kg/ day)

9 pts: high dose IVIG (0.5-2g/kg)

28pts: combined both

5 pts: conservative

CR:>100X10^9/L

PR: 30X10^9/L ~ 100X10^9/L

Haematologica 2006;91(8):1041-1045.


Ash 2011 evidence based practice guideline for itp

Course of Severe ITP without splenectomy

Plt>30X10^9/L:

86% at 5 years

CR:>100X10^9/L

PR: 30X10^9/L ~ 100X10^9/L

PR +CR:86% @ 5 yrs

CR:61% @ 5 yrs

Haematologica 2006;91(8):1041-1045.


Itp persistent thrombocytopenia fatal bleeding

ITP – persistent thrombocytopenia & fatal bleeding

47.8% in aged >60 yrs @ 5 yrs

Plt<30x10^9/L

Fatal bleeding

2.2% in aged <40 yrs @ 5 yrs

76% in aged >60 years at 2 years

Non-fatal bleeding

Arch Intern Med 2000;160(11):1630-1638.


Treatment of fresh case2

Treatment of fresh case

  • Suggest

    • Treat newly diagnosed patients with platelet count <30x10^9/L(2C)

    • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment (2B)

    • IVIG combined with steroid if more rapid increase in platelet count desired(2B)

    • IVIG or anti-D as first line if steroid contraindicated(2C)

    • IVIG dose : 1g/Kg as one-time dose, repeated if necessary (2B)

Blood.2011;117(16):4190-4207


Ash 2011 evidence based practice guideline for itp

IVIG Vs. HDMP for ITP

Plt<20x10^9/L

HDMP 15mg/Kg/day

D1-3

Daily dose<1g

IVIG 0.7g/Kg/day

D1-3

Prednisolone

(10mg) 1mg/Kg/day

D4-21

Lancet 2002;359(9300):23-29.


Ash 2011 evidence based practice guideline for itp

Longer time to loss of response

Lancet 2002;359(9300):23-29.


Ash 2011 evidence based practice guideline for itp

Lancet 2002;359(9300):23-29.


High dose dexamethasone for itp

High dose Dexamethasone for ITP

Dex

40mg/day

D1-4

-Dex

40mg/day

D1-4

-Pred 15mg maintian

N Engl J Med 2003;349(9):831-836.


Ash 2011 evidence based practice guideline for itp

-Plt at D10<90X10^9/L->70% relapse

-36% required additional treatment

-42% had plt >50X10^9/L at 6 months

N Engl J Med 2003;349(9):831-836.


High dose dexamethasone for itp1

High dose Dexamethasone for ITP

  • Dexamasone 40mg IVA QD x4 days

  • Every 28 days for 6 cycles

  • Prednisone at 0.25 mg/kg/day PO

    • Plt < 20X10^9 /L

    • Bleeding symptoms related to thrombocytopenia

  • CR - >150X10^9/L

  • PR - 50X10^9/L ~ 150X10^9/L

  • MR( minimal response)

    • 20X10^9/L ~ 50X10^9/L (Monocenter: 1996 and June 2000 at the Haematology Department of the University La Sapienza of Rome,Hospital Policlinico Umberto I Italy)

    • 30X10^9/L ~ 50X10^9/L (GIMEMAmulticenter pilot study)

  • NR( no response)

    • <20X10^9/L (Monocenter)

    • <20X10^9/L (GIMEMAmulticenter pilot study)

  • Blood 2007;109(4):1401-1407.


    Ash 2011 evidence based practice guideline for itp

    Monocenter trial

    RFS:

    97% at 6 months

    90% at 15 months

    58% at 50 months

    RFS

    RFS:

    Cycle 6 : 94% at 15 months

    Cycle 3-4-5: 84% at 15 months

    RFS according to cycles

    Blood 2007;109(4):1401-1407.


    Ash 2011 evidence based practice guideline for itp

    Blood 2007;109(4):1401-1407.


    Ash 2011 evidence based practice guideline for itp

    GIMEMAmulticenter pilot study

    RFS:

    <18y/o: 96% at 15 ms

    >=18y/o: 60% at 15 ms

    RFS:

    CR : 87% at 15ms

    PR+MR:65% at 15ms

    Blood 2007;109(4):1401-1407.


    Treatment of unresponsive or relapse cases after initial steroid

    Treatment of unresponsive or relapse cases after initial steroid

    • Recommend

      • Splenectomy for patients failing steroid (1B)

      • The only treatment for sustained remission off all treatment at 1 year and beyond in a high proportion of patients

      • Deferred for at least 6 months after diagnosis

        Blood. 2010;115(2):168-186.

    • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L (1C)

    Blood.2011;117(16):4190-4207


    Chronic itp post splenectomy

    Chronic ITP post splenectomy

    Br J Haematol 2003;120(6):1079-1088.


    Ash 2011 evidence based practice guideline for itp

    Br J Haematol 2003;120(6):1079-1088.


    Ash 2011 evidence based practice guideline for itp

    Truly refractory cases post splenectomy : 5/183(2.7%)

    Br J Haematol 2003;120(6):1079-1088.


    Ash 2011 evidence based practice guideline for itp

    Br J Haematol 2003;120(6):1079-1088.


    Chronic itp after splenectomy failure

    Chronic ITP after splenectomy failure

    Gooup 0: spontaneous remission

    Group 1: response to steroid,danazol,colchicine, vinblastin, rituximab,interferon

    Group 2:response to oral cyclophosphmide, azathioprine,cyclosproine

    Group 3: response to IV cyclophosphmide or C/T

    Blood 2004;104(4):956-960.


    Ash 2011 evidence based practice guideline for itp

    Blood 2004;104(4):956-960.


    Ash 2011 evidence based practice guideline for itp

    Blood 2004;104(4):956-960.


    Laprascopic vs open splenectomy

    Laprascopic vs. open splenectomy

    • Both offer similar efficacy (1C)

      Blood 2004;104(9):2623-2634 Surg Endosc 2006;20(8):1208-1213.

    • 2010 CDC recommend

      • pneumococcal and meningococcal vaccination for elective splenectomy

      • One dose of H influenzae type b is not contraindicated before splenectomy

    Blood 2007;109(4):1401-1407.


    Treatment of unresponsive or relapse cases after splenectomy

    Treatment of unresponsive or relapse cases after splenectomy

    • Recommend

      • TPO agonists for risk of bleeding who relapse after splenectomy or who have contraindication to splenectomy failing at least one other therapy (1B)

    • Suggest

      • TPO for risk of bleeding who failed one line of therapy (steroid or IVIG) and s/p no splenectomy (2C)

      • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy) (2C)


    Ash 2011 evidence based practice guideline for itp

    Blood.2011;117(16):4190-4207


    Eltrombopag itp

    Eltrombopag & ITP

    50 mg or placebo PO once daily for

    6 weeks

    Increased from 50 mg to

    75 mg after 3 weeks in patients with platelet counts less than 50 000 per μL

    Lancet 2009;373(9664):641-648.


    Ash 2011 evidence based practice guideline for itp

    Lancet 2009;373(9664): 641-648.


    Ash 2011 evidence based practice guideline for itp

    Lancet 2009;373(9664):641-648.


    Romiplostim itp

    Romiplostim & ITP

    Lancet 2008;371(9610): 395-403.

    Splenectomised:3ug/Kg

    Non-splenectomised:2ug/Kg

    SC QW for 24 weeks

    To keep Plt 50×10⁹/L to 200×10⁹/L.


    Ash 2011 evidence based practice guideline for itp

    Lancet 2008;371(9610): 395-403.


    Ash 2011 evidence based practice guideline for itp

    Lancet 2008;371(9610): 395-403.


    Tpo agonists

    TPO agonists

    • US FDA approval: chronic ITP with insufficient response to steroid, IVIG , or splenectomy

    • Thrombocytopenia recurs or worsen if suddenly abrupted

    • Increased risk of portal venous thrombosis in chronic liver disease

      Hematol 2010;47(3):289-298.

    • Increased marrow reticulin fibrosis in 10/271 in the romiplostin trials

      Blood 2009;114(18):3748-3756.


    Rituximab itp

    Rituximab & ITP

    • Weekly infusion of 375mg/m2 for 4 weeksin 16/19 studies

    Ann Intern Med 2007;146(1):25-33.


    Rituximab response

    Rituximab response

    • 30% at one year

      J Support Oncol 2007;5 4 suppl 2:82-84. 2007.

    • 9/26 (35%) had long-term response

      • median follow-up of 57 months (range 39–69)

      • 11/26 (42%) did not necessitate further therapy

        Eur J Haematol 2008;81(3):165-169.


    Take home masage

    Take home masage

    • Treat newly diagnosed patients with platelet count <30x10^9/L

    • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment

    • Splenectomy for patients failing steroid

    • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L

    • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy

    • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)


    Take home masage1

    Take home masage

    • Treat newly diagnosed patients with platelet count <30x10^9/L

    • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment

    • Splenectomy for patients failing steroid

    • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L

    • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy

    • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)


    Take home masage2

    Take home masage

    • Treat newly diagnosed patients with platelet count <30x10^9/L

    • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment

    • Splenectomy for patients failing steroid

    • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L

    • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy

    • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)


    Take home masage3

    Take home masage

    • Treat newly diagnosed patients with platelet count <30x10^9/L

    • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment

    • Splenectomy for patients failing steroid

    • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L

    • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy

    • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)


    Take home masage4

    Take home masage

    • Treat newly diagnosed patients with platelet count <30x10^9/L

    • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment

    • Splenectomy for patients failing steroid

    • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L

    • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy

    • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)


    Take home masage5

    Take home masage

    • Treat newly diagnosed patients with platelet count <30x10^9/L

    • Longer courses of steroid are preferred than short courses of steroid or IVIG as first-line treatment

    • Splenectomy for patients failing steroid

    • Against further treatment in asymptomatic patients after splenectomy with platelet count >30x10^9/L

    • TPO agonists for risk of bleeding who relpase after splenectomy or who have contraindication to splenectomy failing at least one other therapy

    • Rituximab for risk of bleeding who failed one line of therapy (steroid , IVIG or splenectomy)


    Ash 2011 evidence based practice guideline for itp

    • Thanks for your attention!


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