Priporočila za zdravljenje primarne imunske trombocitopenije

Barbara Skopec

Rodeghiero F, et al. Blood 2009;113:2386–93

ITP = Idiopatična trombocitopenična purpura

ITP = primarna imunska trombocitopenija

diagnoza 12 mesecev 3 meseci

novoodkrita ITP perzistentna ITP kronična ITP

Rodeghiero F, et al. Blood 2009;113:2386–93

diagnoza 6 mesecev

akutna ITP

kronična ITP

Blood 2010;115:168–186

International consensus report on the investigation and management of primary immune thrombocytopenia Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel J.B, Chong BH, Cines DB, Gernsheimer TB, Godeau B, Grainger J, Greer I, Hunt BJ, Imbach PA, Lyons G, McMillan R, Rodeghiero F, Sanz MA, Tarantino M, Watson S, Young J and Kuter DJ

Blood 2011;117:4190–4207

The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia Neunert C, Lim W, Crowther M, Cohen A, Solberg L. Jr and Crowther MA

Basic evaluation Tests of potential utility in the

management of an ITP patient

Tests of unproven or uncertain

benefit

•Patient history •Glycoprotein-specific antibody •TPO

•Family history

•Antiphospholipid antibodies

(including anticardiolipin and lupus

anticoagulant)

•Reticulated platelets

•Physical examination •Antithyroid antibodies and thyroid

function •PaIgG

•Complete blood count and

reticulocyte count

•Pregnancy test in women of

childbearing potential •Platelet survival study

•Peripheral blood film •Antinuclear antibodies •Bleeding time

•Quantitative immunoglobulin level

measurement* •Viral PCR for parvovirus and CMV •Serum complement

•Bone marrow examination (in

selected patients; refer to text)

•Blood group (Rh)

•Direct antiglobulin test

•H pylori†

•HIV†

•HCV†

Recommendations for the diagnosis of ITP in children and adults

Provan D et al. Blood 2010;115:168–86;

Diagnostika ITP Natančna anameza in status

Celotna krvna slika

Biokemične preiskave krvi

Testi hemostaze

Presejalni testi za sistemske bolezni veziva (HEP 2, ENA)

ščitnični hormoni

imunoglobulini kvantitativno

Serologija na CMV, EBV, parvo B19, hepatitis B in C, HIV

Dihalni test ali H.pylori antigen v blatu

Punkcija kostnega mozga (pri starejših od 60 let in rezistentnih na

glukokortikoide oz. pred splenektomijo)

Cilj zdravljenja pri kronični ITP ni jasno določen in je odvisen od ravnotežja med učinkovitostjo in neželenimi učinki določenega načina zdravljenja1

Dejavniki, ki vplivajo na odločitev o načinu zdravljenja

1. Rodeghiero et al. Blood 2009;113:2386–93; 2. Neunert et al. Blood 2011;117:4190–207; 3. Provan et al. Blood 2010;115:168–86

Obsežnost krvavitev

Pridružene bolezni, ki vplivajo na možne krvavitve

Zapleti specifičnega zdravljenja Aktivnost in

življenski slog

Prenašanje neželenih učinkov

Morebitni posegi, ki lahko povzročijjo krvavitve

Dostopnost zdravniške oskrbe

Pričakovanja bolnika

Sodelovanje bolnika

Dejavniki, ki vplivajo na odločitev 2,3

Sekundarna ITP

Prvo zdravljenje ITP pri odraslih: ASH in ICR

ASH

glukokortikoidi

IVIg, če potrebujemo hiter

porast Tr

IVIg (ali anti-D), če so

glukokortikoidi

kontraindicirani

IVIg 1 g/kg v enkratnem

odmerku

ICR

glukokortikoidi

IVIg, če so glukokortikoidi

kontraindicirani ali če ni

odziva na zdravljenje

ASH, American Society of Hematology;

ICR, International Consensus Report Provan et al. Blood 2010;115:168–86

Neunert et al. Blood 2011;117:4190–207

Drugo zdravljenje ITP pri odraslih : ASH and ICR

ASH

zdravila

TPO-R agonisti za rezistentne in

neprimerne za splenektomijo

TPO-R agonisti za

nesplenektomirane, s tveganjem za

krvavitev po eni liniji zdravljenja

Rituximab za rezistentne s

tveganjem za krvavitev

Kirurško zdravljenje

splenektomija

ICR

zdravila

TPO-R agonisti

Rituximab

Ostala imunosupresivna

zdravila

ciklosporin

Kirurško zdravljenje

splenektomija

Provan et al. Blood 2010;115:168–86 Neunert et al. Blood 2011;117:4190–207

ASH, American Society of Hematology;

ICR, International Consensus Report

Second-line treatment options (1)

Treatment Time to

response Response rate

Duration of

sustained response

Azathioprine (1–2

mg/kg; max 150

mg/day)

Slow; may

need to be

continued

for 3–6

months

Up to two-thirds

of patients

Up to one-quarter

of off-therapy

patients maintain

response

Cyclosporin A

(5 mg/kg/day for 6

days, then 2.5–3

mg/kg/day; titration to

blood levels of 100–

200 ng/mL)

3–4-weeks Dose

dependent; high

response rate

(50–80%) in

small series

Half of responders

receiving low

doses sustain

remission (at least

2 years)

Provan D et al. Blood 2010;115:168–86

Second-line treatment options (2) Treatment

Time to

response Response rate

Duration of

sustained response

Cyclophosphamide

(1–2 mg/kg orally

daily, at least 16

weeks; or 0.3–1 g/m2

IV every 2–4 weeks,

1–3 doses)

1–16

weeks

14–85% Up to 50%

Danazol (200 mg 2–

4 times daily)

3–6 months 67% complete

or partial

response

46% in remission

at median of 119

(±45) months;

mean duration of

therapy 37 months

Dapsone (75–100

mg)

3 weeks Up to 50% Up to two-thirds of

responders off

therapy

Provan D et al. Blood 2010;115:168–86

Provan D et al. Blood 2010;115:168–86

Treatment Time to

response Response rate

Duration of

sustained response

Mycophenolate

mofetil (1000 mg

twice daily, at least

3–4 weeks)

4–6 weeks Up to 75% of

patients,

complete

response in

40%

Sustained for short

time after

discontinuation

Rituximab (375

mg/m2 weekly, 4

doses; lower doses

[100 mg/m2] may

also be effective)

1–8 weeks 60% of patients;

complete

response in

40%

Sustained

response >3–5

years in 15–20% of

responders, may

require retreatment

months to years

later

TPO-R agonists:

Eltrombopag (25–75

mg daily)

2 weeks 70–80% Up to 5 years with

continual

administration of

the drug

Second-line treatment options (3)

Provan D et al. Blood 2010;115:168–86

Treatment Time to

response Response rate

Duration of

sustained response

TPO-R agonists:

Romiplostim (1–10

µg/kg

subcutaneously

weekly)

1–4 weeks 79–88%

(splenectomised

and non-

splenectomised,

respectively)

Up to 5 years with

continual

administration of

the drug

Splenectomy Two-thirds

of patients

achieve

lasting

response

1–24 days Response

sustained in more

than two-thirds of

patients over 5–10

years with no

additional

treatment

Second-line treatment options (4)

Probability of first CR according to the type of onset (insidious or acute).

Ghanima W et al. Blood 2012;120:960-969

©2012 by American Society of Hematology

Priporočila za splenektomijo

• Splenektomija ima med zdravljenji 2. reda najvišji delež uspešnosti(80%) in remisije (60–70% po 5–10 letih)

• ICR in ASH jo priporočata kot zdravljenje 2.reda

• ICR priporoča odlog splenektomije do kronične faze (>12 mesecev)

• ASH predlaga zdravljenje s TPO-R agonisti in rituksimabom pred splenektomijo

Ghanima W et al. Blood 2012;120:960–9; Provan D et al. Blood 2010;115:168–86; Neunert C et al. Blood 2011;117:4190–207

Zapleti splenektomije

• Z operacijo povezana morbiditeta in mortaliteta:

– krvavitve, okužbe, peripankreatični hematom

• Povečano tveganje za nastanek VT

• Doživljenjsko povečano tveganje za sepso povzročeno z enkapsuliranimi bakterijami (pneumococci, meningococci, Haemophilus influenzae)

Ghanima W et al. Blood 2012;120:960–9

Dolgotrajni učinek splenektomije 233 bolnikov (povprečna starost 33 let) >10 let spremljanja

CR = Tr > 100 x 109/L

R = Tr 30-100 x 109/L

CR+R = 88%

Pre

žive

tje

bre

z p

on

ovi

tve

%

100

80

60

40

20

0

Meseci po splenektomiji

0 120 240 360 480 600

CR (n=180)

Vsi bolniki (n=206)

R (n=26)

CR, popolni odgovor; R, odgovor Vianelli N et al. Haematologica 2013;98:875–80

31% 100% 57% 38% 21%

odrasli (N=376)

5 let skupaj Začetni odgovor

1 leto 2 leti

Patel et al. Blood 2012;119:5989–95

Dolgotrajen učinek zdravljenja z rituximabom pri ITP

CR - Tr > 150 x 109/L

PR - Tr 50–150 x 109/L

Kaplan-Meier response duration curves after month 6 in patients who achieved sustained response

(SR) after dexamethasone monotherapy, dexamethasone plus rituximab, and dexamethasone plus

rituximab salvage therapy.

Zaja F et al. Blood 2010;115:2755-2762

20

•Indicirani za zdravljenje odraslih s kronično ITP po splenektomiji, ki so odporni na druga zdravljenja (glukokortikoidi, IvIG)

•Kot druga linija zdravljenja za bolnike, pri katerih je splenektomija kontraindicirana

agonisti TPO-R

dolgotrajno zdravljenje s TPO agonisti

eltrombopag Tr ≥50x109/L v času pri 85% bolnikov

romiplostim Tr≥50x109/L v času študije pri 95% bolnikov

Naša priporočila???

• Kdaj splenektomija?

• Kdaj TPO-A?

• Kdaj rituksimab?

• Kdaj ostala imunosupresivna zdravila?