KRÓNIKUS MYELOPROLIFERATIVBETEGSÉGEK,NÉHÁNY AKTUALITÁS  Udvardy Miklós  DEOEC Haematologia Tanszék  VEAB 2012
Krónikus myeloproliferativ kórképek            (WHO, 2000-es, morphologiai szemlélet)   Krónikus, klonális, proliferativ ...
Molekuláris alapok: Uj krónikus myeloproliferativ definitioszükségessége,                                               kö...
Krónikus myeloproliferativbetegségek, nemzetközi fejlemények Jak mutatio sokrétüsége, Jak haplotipus    (Andrikovics, Nah...
Jak2 pathologiás utak Jak2/Stat rendszer, V613F  MPN, CMMoL, endothelium, etc. Allel  mennyiség függő betegség fenotipus ...
Chemical series                                                                               Status of       Company     ...
© 2011 Wagner, J Carcinog. 2011; 10: 32.Figure 1Interaction between Jak2/Stat5 signaling and the PI3K/Akt1 pathway in mamm...
Fig. 1. Involvement of JAK/STAT signaling inmultiple pathways of carcinogenesis andcancer metastasis. Model highlights and...
Fig. 2. Therapeutic rationale fortargeting JAK2 for the treatment of   Cytokines the contribute to SLE include IL-12,syste...
Jak(2)/Stat út módositáspotenciális területei Onkologia, haematologia       Nem daganatos betegség MPN, V613F Jak statu...
Hazai helyzetkép Sok centrum involvált, motivált, Jak  detectio elérhető Ohurea, anagrelide elérhető, interferon  nehézk...
Thrombosis in MPN with Thrombocythemia Is Associated with Higher Platelet   3857   Count At the Time of the Event: Data Fr...
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  1. 1. KRÓNIKUS MYELOPROLIFERATIVBETEGSÉGEK,NÉHÁNY AKTUALITÁS Udvardy Miklós DEOEC Haematologia Tanszék VEAB 2012
  2. 2. Krónikus myeloproliferativ kórképek (WHO, 2000-es, morphologiai szemlélet) Krónikus, klonális, proliferativ kórképek (Szeged és Dameshek, 50-es évek eleje) Egy predomináns, de általában több „myeloid” (non-lymphoid) vonal hasonló transformatios utak (fibrosis – AML szekvencia) KLONÁLIS EVOLUCIÓ, eltérő mértékben Cytoreduktiv közös szer: hydroxyurea, interferon jó hatás + cytogenetikai válasz Klasszikus kórképek: CML és variánsai, PV, ET, MF
  3. 3. Molekuláris alapok: Uj krónikus myeloproliferativ definitioszükségessége, köz ös elem - tirozin kináz defektus Krónikus myeloid leukaemia: Novell, Hungerford, Philadelphia, bcr/abl, uj CML definitio, B lymphocyta érintett Polycythaemia, thrombocythaemia , myelofibrosis (2005) PV, ET, MF jelentős része ugyancsak tirozin kináz rendszerhez kötött JAK2 mutatio JAK-STAT rendszer , JAK haplotipus, TET2, lymphoid sejtvonal nem érintett Hypereosinophilia, Mastocytosis: Gilliland munkacsoport HES –FIP1L1-PDGRF-alfa, FGF, etc. mutatio Glivec effektiv, néha ismert mutatio nélkül is…
  4. 4. Krónikus myeloproliferativbetegségek, nemzetközi fejlemények Jak mutatio sokrétüsége, Jak haplotipus (Andrikovics, Nahajevszky és mtsai, AML, Haematologica) Egyfajta genotipus, többféle fenotipus, allel mennyiség (mérés, DEOEC) Jak inhibitorok, Jak V617F status , titer és klinikai válasz Jak+ versus Jak- kórképek klinikai különbségei (vasculáris szövódmények, transformatios hajlam) Interferon és molekuláris válasz Endothel Jak2 és a Jak/Stat rendszer ubiquiter volta
  5. 5. Jak2 pathologiás utak Jak2/Stat rendszer, V613F MPN, CMMoL, endothelium, etc. Allel mennyiség függő betegség fenotipus más mutatiok (R683G és I682F) rossz prognózis, pre B ALL Jak aktiváció tumor immunitás (DC) gátlása Stat független sejtmagbeli Jak2 aktiváció, tumorgenesist fokozza, valószinü histon demetiláció ill. c-myc uton keresztül. Jak inhibitorral gátolható
  6. 6. Chemical series Status of Company and/or lead Target Indication compounds/project compounds TofacitinibPfizer JAK3 RA Phase III CP690550 Ruxolitinib Approved Nov. 16,Incyte/Novartis Pan JAK MPN* INCB18424 2011; Jakafi®AstraZeneca AZD1480 JAK1/JAK2 MPN Cancer Phase II Phase IYM Biosciences CYT387 JAK1/JAK2 MPN Phase II LY3009104Incyte/Lilly JAK1/JAK2 RA Phase II (INCB28050) Advanced myeloidOnyx ONX0803 (SB1518) JAK2 and lymphoid Phase I/II malignanciesTargeGen TG101348 Pan JAK Myelofibrosis MPN Phase II Phase I Myelofibrosis SB1518 SB1578 myeloid andS*Bio JAK1/JAK2 Phase I Phase II SB1317 lymphoid malignanciesAmbit Biosciences AC-430 JAK2 Cancer Phase IAEgera AEG41174 JAK2/Bcr-Abl Cancer Phase IEli Lilly & Co LY 2784544 JAK2 MPN Phase IBMS BMS-911543 JAK2 Myelofibrosis Phase I/IIExelixis XL-019 JAK2 Myelofribrosis Phase I
  7. 7. © 2011 Wagner, J Carcinog. 2011; 10: 32.Figure 1Interaction between Jak2/Stat5 signaling and the PI3K/Akt1 pathway in mammary epithelial cells.Active Stat5 modifies signaling through the PI3 kinase and Akt1 by at least two distinct mechanisms in luminal epithelial cells,i.e. by binding to the regulatory subunit of the PI3 kinase and by enhancing the transcriptional activation of the Akt1 gene from a mammary-specific promoter
  8. 8. Fig. 1. Involvement of JAK/STAT signaling inmultiple pathways of carcinogenesis andcancer metastasis. Model highlights andsummarizes the various roles JAK/STATsignaling pathways play in the hallmarks ofcancer including tumor cell survival,metastasis, drug resistance and mostimportantly the TME response prompted bytumor-driven inflammation, also inflammationthat can lead to tumorigenesis
  9. 9. Fig. 2. Therapeutic rationale fortargeting JAK2 for the treatment of Cytokines the contribute to SLE include IL-12,systemic lupus erythematosus. Model IL-6, IFNα/β and TNFα, many of which areshows the various controlled by JAK kinases, more specificallyimmunopathological components of a JAK2 kinase, making this target important inSLE providing a few examples of the fight against SLE progressioncommon disease manifestations tothe far right.
  10. 10. Jak(2)/Stat út módositáspotenciális területei Onkologia, haematologia  Nem daganatos betegség MPN, V613F Jak statustól  Mastopathia függetlenül?  IBD, Crohn R683G és I682F mutatio,  Rheumatoid arthritis JH2 domain, prekurzor B  SLE (kb. a proteaszóma ALL gatlással ekvivalens) Emlőfejlődés, prolactin,  Graves emlő alveoláris cc. Adjuváns th.  Sjogren Colitis ulcerosa, cc.  Sclerosis multiplex transformatio  Endothelium, porta- hepatica occlusio
  11. 11. Hazai helyzetkép Sok centrum involvált, motivált, Jak detectio elérhető Ohurea, anagrelide elérhető, interferon nehézkes, pedig szükséges, (P. Fenoux allel burden, terhesség, fiatal kor, etc.) Myeloproliferativ (nem Ph+) munkacsoport és hazai regiszter (l. cseh, szlovák, osztrák, AOP támogatás) Jak2 inhibitor tanulmányok (Jakafi/FDA, Sanofi)
  12. 12. Thrombosis in MPN with Thrombocythemia Is Associated with Higher Platelet 3857 Count At the Time of the Event: Data From the Czech Registry of Patients Treated with Anagrelide Program: Oral and Poster Abstracts Session: 634. Myeloproliferative Syndromes: Poster III Monday, December 12, 2011, 6:00 PM-8:00 PM Hall GH (San Diego Convention Center) Jiri Schwarz, MD, PhD1*, Miroslav Penka, MD, PhD2*, Petra Ovesna, PhD3*, Olga Cerna, MD4*, Yvona Brychtova, MD5* and Petr Dulicek, MD, PhD6*Results: Of 449 thrombotic events reported, 335 occurred in history (i.e. before registry entry) and 114 during follow-up. The numbers ofarterial, venous, and microcirculatory events in history were 147, 124 and 64, respectively. Of the 114 thrombotic events in 88 patients during follow-up (3.79 events/100 patient-years), 45 were classified as major. There were 61 arterial, 16 venous and 37 microcirculatory events. ANG ± ASA therapydramatically decreased the number of venous events (7.8-fold), while arterial and microcirculatory events were reduced 2.4-fold and 1.7-fold, respectively.At diagnosis, the strongest predictors of all thrombotic events jointly were JAK2V617F mutation (P=0.001), hereditary or acquired thrombophilia(P<0.001), hypertension (P=0.006), smoking (P=0.02) and diabetes mellitus (P=0.04). Also previous thrombosis predicted a subsequent thromboticevent (P=0.002). Age >65 yrs was a less powerful predictor (P=0.08). WBC and hematocrit levels positively correlated with the thrombotic risk(P=0.002 and P=0.006, respectively), whereas Plt counts correlated inversely with all thrombotic events (P=0.012) but correlated positively withmicrocirculatory events (P=0.01). Some of the factors (age, hypertension, diabetes, and smoking) powerfully predicted rather arterialevents, whereas others (f.V "Leiden" mutation, protein C deficiency, elevated f.VIII levels, presence of antiphospholipid antibodies) were connectedpreferentially with venous events.However, when full blood cell counts from the time of the thrombotic events were studied and compared to mean levels of all entries during follow-up, we could detect higher platelet counts at the time of the thrombotic event (454 vs 420 G/L, P=0.007), while we could not demonstrate anysignificance of the WBC counts at the time of the event. The correlation of the Plt count was marked in all types of events and was most conspicuousin microcirculatory events. Thrombotic events during follow-up were also associated with lack of ASA therapy: only 6/16 (37.5%) patients at the timeof the venous event, 35/61 (57.4%) patients at the time of the arterial event and 11/37 (29.7%) patients at the time of the microcirculatory eventreceived ASA therapy (whereas ASA administration was reported in 80.0% of follow-up entries).Conclusions: The current study indicates that during ANG ± ASA therapy, the incidence of thrombosis is very low in MPN-t and especially the rate ofvenous events is extraordinarily low. The predictors of the thrombotic events are similar as previously published by others. Above that, we haveproven the usefulness of detection of the so-called thrombophilic states. However, in contrast with the prevailing current opinion, we have shownthat higher platelet counts (and not WBC counts) are important at the time of thrombosis, albeit at diagnosis the Plt counts may inversely and WBCcounts positively correlate with the thrombotic risk. This discrepancy may result from treatment: patients with higher Plt counts at diagnosis mayreceive more cytoreducing and/or antiaggregation therapy .
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