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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

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

slide10

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.

slide11

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

slide14

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.

slide15

Longer time to loss of response

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.

slide18

-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.

slide20

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.

slide22

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.

slide26

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

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.

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)
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.

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.

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)