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Priporočila za zdravljenje primarne
imunske trombocitopenije
Barbara Skopec
ITP = Idiopatična trombocitopenična
purpura
ITP = primarna imunska trombocitopenija
Rodeghiero F, et al. Blood 2009;113:2386–93
diagnoza
6 mesecev
kronična ITP
akutna ITP
diagnoza
novoodkrita ITP
3 meseci
12 mesecev
perzistentna ITP
kronična ITP
Rodeghiero F, et al. Blood 2009;113:2386–93
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
Recommendations for the diagnosis of ITP in children and adults
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 •Reticulated platelets
anticoagulant)
•Physical examination
•Antithyroid antibodies and thyroid
•PaIgG
function
•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
•Viral PCR for parvovirus and CMV •Serum complement
measurement*
•Bone marrow examination (in
selected patients; refer to text)
•Blood group (Rh)
•Direct antiglobulin test
•H pylori†
•HIV†
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)
Dejavniki, ki vplivajo na odločitev o načinu
zdravljenja
Cilj zdravljenja pri kronični ITP ni jasno določen in je odvisen od ravnotežja med
učinkovitostjo in neželenimi učinki določenega načina zdravljenja1
Sekundarna ITP
Sodelovanje
bolnika
Prenašanje
neželenih učinkov
Dostopnost
zdravniške oskrbe
Obsežnost
krvavitev
Dejavniki, ki vplivajo
na odločitev 2,3
Zapleti specifičnega
zdravljenja
Morebitni posegi, ki lahko
povzročijjo krvavitve
Pričakovanja bolnika
Aktivnost in
življenski slog
Pridružene bolezni, ki
vplivajo na možne krvavitve
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
Prvo zdravljenje ITP pri odraslih:
ASH in ICR
ASH
ICR
 glukokortikoidi
 glukokortikoidi
 IVIg, če potrebujemo hiter
porast Tr
 IVIg, če so glukokortikoidi
 IVIg (ali anti-D), če so
kontraindicirani ali če ni
glukokortikoidi
odziva na zdravljenje
kontraindicirani
 IVIg 1 g/kg v enkratnem
odmerku
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
ASH, American Society of Hematology;
ICR, International Consensus Report
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
Second-line treatment options (1)
Treatment
Azathioprine (1–2
mg/kg; max 150
mg/day)
Time to
response
Slow; may
need to be
continued
for 3–6
months
Response rate
Up to two-thirds Up to one-quarter
of patients
of off-therapy
patients maintain
response
Cyclosporin A
3–4-weeks Dose
(5 mg/kg/day for 6
dependent; high
days, then 2.5–3
response rate
mg/kg/day; titration to
(50–80%) in
blood levels of 100–
small series
200 ng/mL)
Provan D et al. Blood 2010;115:168–86
Duration of
sustained response
Half of responders
receiving low
doses sustain
remission (at least
2 years)
Second-line treatment options (2)
Treatment
Time to
response
Cyclophosphamide 1–16
(1–2 mg/kg orally
weeks
daily, at least 16
weeks; or 0.3–1 g/m2
IV every 2–4 weeks,
1–3 doses)
Response rate
14–85%
Duration of
sustained response
Up to 50%
Danazol (200 mg 2– 3–6 months 67% complete
4 times daily)
or partial
response
46% in remission
at median of 119
(±45) months;
mean duration of
therapy 37 months
Dapsone (75–100
mg)
Up to two-thirds of
responders off
therapy
Provan D et al. Blood 2010;115:168–86
3 weeks
Up to 50%
Second-line treatment options (3)
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
70–80%
Up to 5 years with
continual
administration of
TPO-R agonists:
2 weeks
Eltrombopag (25–75
mg
Provan
D etdaily)
al. Blood 2010;115:168–86
Second-line treatment options (4)
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 nonsplenectomised,
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
Provan D et al. Blood 2010;115:168–86
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
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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
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Z operacijo povezana morbiditeta in
mortaliteta:
– krvavitve, okužbe, peripankreatični hematom
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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
Preživetje brez ponovitve %
100
80
CR (n=180)
60
Vsi bolniki (n=206)
40
R (n=26)
20
0
0
120
240
360
Meseci po splenektomiji
CR, popolni odgovor; R, odgovor
Vianelli N et al. Haematologica 2013;98:875–80
CR = Tr > 100 x 109/L
R = Tr 30-100 x 109/L
CR+R = 88%
480
600
Dolgotrajen učinek zdravljenja z rituximabom pri
ITP
skupaj
100%
Začetni
odgovor
57%
1 leto
38%
2 leti
31%
5 let
21%
odrasli (N=376)
CR - Tr > 150 x 109/L
PR - Tr 50–150 x 109/L
Patel et al. Blood 2012;119:5989–95
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
agonisti TPO-R
•Indicirani za zdravljenje odraslih s kronično IT
•Kot druga linija zdravljenja za bolnike, pri kate
20
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???
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Kdaj splenektomija?
Kdaj TPO-A?
Kdaj rituksimab?
Kdaj ostala imunosupresivna zdravila?