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 diagnoza akutna ITP 3 meseci kronična ITP 12 mesecev novoodkrita ITP 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 anticoagulant) Reticulated platelets Physical examination Complete blood count and reticulocyte count Antithyroid antibodies and thyroid function Pregnancy test in women of childbearing potential PaIgG 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 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 zdravljenja 1 Sekundarna ITP Obsežnost krvavitev Zapleti specifičnega zdravljenja Sodelovanje bolnika Morebitni posegi, ki lahko povzročijjo krvavitve Dejavniki, ki vplivajo na odločitev 2,3 Prenašanje neželenih učinkov Dostopnost zdravniške oskrbe Aktivnost in življenski slog Pridružene bolezni, ki vplivajo na možne krvavitve Pričakovanja bolnika 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 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 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
Second-line treatment options (1) Treatment Time to response Response rate Duration of sustained response Azathioprine (1 2 mg/kg; max 150 mg/day) 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) Slow; may need to be continued for 3 6 months Up to two-thirds of patients 3 4-weeks Dose dependent; high response rate (50 80%) in small series Up to one-quarter of off-therapy patients maintain response 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 Cyclophosphamide (1 2 mg/kg orally daily, at least 16 weeks; or 0.3 1 g/m 2 IV every 2 4 weeks, 1 3 doses) Danazol (200 mg 2 4 times daily) Dapsone (75 100 mg) Provan D et al. Blood 2010;115:168 86 Time to response 1 16 weeks Response rate Duration of sustained response 14 85% Up to 50% 3 6 months 67% complete or partial response 46% in remission at median of 119 (±45) months; mean duration of therapy 37 months 3 weeks Up to 50% Up to two-thirds of responders off therapy
Second-line treatment options (3) Treatment Mycophenolate mofetil (1000 mg twice daily, at least 3 4 weeks) Rituximab (375 mg/m 2 weekly, 4 doses; lower doses [100 mg/m 2 ] may also be effective) TPO-R agonists: Eltrombopag (25 75 mg daily) Provan D et al. Blood 2010;115:168 86 Time to response Response rate 4 6 weeks Up to 75% of patients, complete response in 40% 1 8 weeks 60% of patients; complete response in 40% Duration of sustained response Sustained for short time after discontinuation Sustained response >3 5 years in 15 20% of responders, may require retreatment months to years later 2 weeks 70 80% Up to 5 years with continual administration of
Second-line treatment options (4) Treatment TPO-R agonists: Romiplostim (1 10 µg/kg subcutaneously weekly) Splenectomy Time to response Response rate 1 4 weeks 79 88% (splenectomised and nonsplenectomised, respectively) Two-thirds of patients achieve lasting response Duration of sustained response Up to 5 years with continual administration of the drug 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 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
Preživetje brez ponovitve % Dolgotrajni učinek splenektomije 233 bolnikov (povprečna starost 33 let) >10 let spremljanja 100 80 60 CR (n=180) Vsi bolniki (n=206) 40 20 0 R (n=26) CR = Tr > 100 x 10 9 /L R = Tr 30-100 x 10 9 /L CR+R = 88% 0 120 240 360 480 600 Meseci po splenektomiji CR, popolni odgovor; R, odgovor Vianelli N et al. Haematologica 2013;98:875 80
Dolgotrajen učinek zdravljenja z rituximabom pri ITP skupaj Začetni odgovor 1 leto 2 leti 5 let 100% 57% 38% 31% 21% odrasli (N=376) CR - Tr > 150 x 10 9 /L PR - Tr 50 150 x 10 9 /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 50x10 9 /L v času pri 85% bolnikov romiplostim Tr 50x10 9 /L v času študije pri 95% bolnikov
Naša priporočila??? Kdaj splenektomija? Kdaj TPO-A? Kdaj rituksimab? Kdaj ostala imunosupresivna zdravila?