1. KRÓNIKUS MYELOPROLIFERATIV
BETEGSÉGEK,
NÉHÁNY AKTUALITÁS
Udvardy Miklós
DEOEC Haematologia Tanszék
VEAB 2012

3. 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

4. Molekuláris alapok: Uj krónikus myeloproliferativ definitio
szükségessége, 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…

5. Krónikus myeloproliferativ
betegségek, 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

7. 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

8. Chemical series
Status of
Company and/or lead Target Indication
compounds/project
compounds
Tofacitinib
Pfizer 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 I
YM Biosciences CYT387 JAK1/JAK2 MPN Phase II
LY3009104
Incyte/Lilly JAK1/JAK2 RA Phase II
(INCB28050)
Advanced myeloid
Onyx ONX0803 (SB1518) JAK2 and lymphoid Phase I/II
malignancies
TargeGen TG101348 Pan JAK Myelofibrosis MPN Phase II Phase I
Myelofibrosis
SB1518 SB1578 myeloid and
S*Bio JAK1/JAK2 Phase I Phase II
SB1317 lymphoid
malignancies
Ambit Biosciences AC-430 JAK2 Cancer Phase I
AEgera AEG41174 JAK2/Bcr-Abl Cancer Phase I
Eli Lilly & Co LY 2784544 JAK2 MPN Phase I
BMS BMS-911543 JAK2 Myelofibrosis Phase I/II
Exelixis XL-019 JAK2 Myelofribrosis Phase I

9. © 2011 Wagner, J Carcinog. 2011; 10: 32.
Figure 1
Interaction 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

10. Fig. 1. Involvement of JAK/STAT signaling in
multiple pathways of carcinogenesis and
cancer metastasis. Model highlights and
summarizes the various roles JAK/STAT
signaling pathways play in the hallmarks of
cancer including tumor cell survival,
metastasis, drug resistance and most
importantly the TME response prompted by
tumor-driven inflammation, also inflammation
that can lead to tumorigenesis

11. Fig. 2. Therapeutic rationale for
targeting 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 are
shows the various controlled by JAK kinases, more specifically
immunopathological components of a JAK2 kinase, making this target important in
SLE providing a few examples of the fight against SLE progression
common disease manifestations to
the far right.

12. Jak(2)/Stat út módositás
potenciális 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

13. 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)

14. 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 of
arterial, 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 therapy
dramatically 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 thrombotic
event (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 with
microcirculatory events (P=0.01). Some of the factors (age, hypertension, diabetes, and smoking) powerfully predicted rather arterial
events, whereas others (f.V "Leiden" mutation, protein C deficiency, elevated f.VIII levels, presence of antiphospholipid antibodies) were connected
preferentially 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 any
significance 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 conspicuous
in microcirculatory events. Thrombotic events during follow-up were also associated with lack of ASA therapy: only 6/16 (37.5%) patients at the time
of 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 event
received 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 of
venous events is extraordinarily low. The predictors of the thrombotic events are similar as previously published by others. Above that, we have
proven the usefulness of detection of the so-called thrombophilic states. However, in contrast with the prevailing current opinion, we have shown
that higher platelet counts (and not WBC counts) are important at the time of thrombosis, albeit at diagnosis the Plt counts may inversely and WBC
counts positively correlate with the thrombotic risk. This discrepancy may result from treatment: patients with higher Plt counts at diagnosis may
receive more cytoreducing and/or antiaggregation therapy .