Jak2 inhibitors Martinelli Giovanni, MD Dipartimento di Ematologia L. e A. Seragnoli Università degli Studi di Bologna
Chronic Myeloproliferative Neoplasms BCR-ABL1 CML Classical CNL CEL-NOS Mastocytosis MPN-u JAK2 ex12 Polycythemia Vera >95% MPL W515L/K Essential Thrombocythemia 3-8% Primary Myelofibrosis 70% 60% JAK2 V617F Reviewed in Vannucchi et al. CA Cancer J Clin. 2009; 59(3):171-91
JAK2 functional domains James et al. Nature 2005; 434: 1144 ; Baxter et al. Lancet 2005; 365: 9464; Levine et al. Cancer Cell 2005; 7:387; Kralovics et al. NEJM. 2005: 352:1779; Scott et al. NEJM. 2007; 356:.459.
V617F Burden and Thrombosis in ET HR (95%CI) WT 1 Hetero 1.49 (0.9-2.5) 3.97 Homo * (1.3-11.7) P 0.13 0.013 adjusted for age, sex, previous thrombosis and leukocytosis Vannucchi AM et al, Blood 2007
Prognostic relevance of a low JAK2 V617F burden in PMF 1 st <25% 2 nd 26 50% 3 rd 51 75% 4 th 76 100% WT V617F + 2 nd 3 rd 4 th 1 st P=0.73 P=0.0001 Guglielmelli P. Blood 2009;114:1477 83
Leukemic transformation in MPNs Leukemia occurs in 4% to 8% of PV or ET pts within 18 yrs from diagnosis, and in 8% to 23% of MF pts in the 10 yrs after diagnosis A variable proportion (from 9% to 53%) of saml from JAK2 V617F pos MPN are JAK2 WT However, JAK2 V617F pos saml was invariably preceded by PMF or myelofibrotic transformation of ET/PV Campbell PA, Blood 2006,108:3548; Theocarides A, Blood 2007,110:375; Beer PA, Blood 2010
Two routes to leukemic transformation in JAK2 mut MPNs (i) Normal HSC Pre-JAK2 mutation Founder clone JAK2 mutation MPN Other mutation(s) AML Normal HSC 1 JAK2 mutation MPN (ii) Normal HSC 2 Other mutation(s) AML
Genetic analysis of leukemic transformation in MPNs All four possible mutational combinations were observed Abdel-Wahab O, Cancer Research 2010; online
IRON (The Interlaboratory RObustness of NGS) Study Prof. Haferlach, Münchner Leukämie Labor, München Dr. Timmermann, Max Planck InsXtute for Molecular GeneXcs, Berlin Germany Germany Italy Dr. te Kronnie, Università degli studi di Padova, Padova Prof. Young, St. Bartholomews, London GB USA Dr. Simen, 454 Life Sciences, Branford Dr. Gabriel, Blood Bank, Linz Austria Austria Belgium Prof. Vandenberghe, UZ Leuven, Belgium Prof. MarCnelli, University of Bologna Italy Netherlands Switzerland Italy Brazil Spain Dr. Garicochea, PonXYcia Universidade Católica do Rio Grande do Sul, Porto Alegre Dr. JH Jansen, Radboud University Medical Centre, Nijmegen Leukemia 2011 in press
TET2 and Jak2 SNPs in JMML paxents Modified from Nibourel et al. Blood 2010
We investigated chromosomal aberrations in 408 MPN samples using highresolution SNP. 37.5% had a wild type karyotype and 62.5% harbored at least one chromosomal aberration. We identified 25 recurrent aberrations that were found in three or more samples. An increased number of chromosomal lesions were significantly associated with patient age as well as with disease progression and leukemic transformation but no association was observed with MPN subtypes, JAK2 mutational status and disease duration. Aberrations of chromosomes 1q and 9p positively associated w
The selective JAK inhibitor, INCB018424, shows efficacy in a phase I/II trial in patients with PMF and POST-PV / ET MF Verstovsek S, et Al. Fase I/II, dose-escalation, PO 32 pts, 47% PMF, 38% post-pv, 15% post-et MF 87% JAK2V617F mutati MTD =25 mg bid, DLT= 50 mg bid per piastrinopenia; 21 pts trattati alla MTD Risposta clinica per splenomegalia (CI in accordo al IWG-MRT) Miglioramento del ECOG performance status Marcata down-regolazione di citochine pro-infiammatorie Modesta riduzione a +6m del burden allelico JAK2V617
Last Minutes ASCO
Bologna s experience
MK-0457 (VX-680) MK-0457 (VX-680, Vertex Pharmaceuticals,, Cambridge, MA) è una piccola molecola in grado di inibire le Aurora-chinasi (AK) A, B e C e Jak2 inhibitor. In vitro è attiva contro le cellule che esprimono BCR-ABL sia wild-type che mutato, inclusa la T315I Tre pazienti con la T315I (2 CML e 1 LAL Ph+) hanno ottenuto una risposta clinica con la somministrazione di MK-0457 (i.v( i.v.).) (Giles F,, et al. Blood. 2007) Grave tossicità cardiaca, bloccato lo studio di fase II Nuovo studio di fase I: combinazione di MK-0457 con Dasatinib basato sull ipotesi che l utilizzo l insieme possa bloccare l insorgere l di cloni resistenti (es. T315I); 3 pazienti (LMCr( e LAL Ph+) trattati con buona tollerabilità ematologica e senza importanti effetti collaterali (Martinelli G et al. Hematology Reviews.. 2009)
INCB-18424
AS703569 Aurora Kinase Inhibitor AS703569 (Merck Serono) Phase 1 first in men" 2pts MF enrolled 18 and 22 mths ago Both in complete and parcal response Martinelli G. et Al. In press
SAR302503 Protocollo ARD12042 con il farmaco SAR302503 (JAK2 inibitore), in pazienx affei da policitemia vera (PV) o trombocitemia essenziale (ET), che sono resistenx o intolleranx a idrossiurea. Phase II
LY2784544
RINGRAZIAMENTI BOLOGNA: Gianantonio Rosti Ilaria Iacobucci Simona Soverini Francesca Palandri Fauso Castagnetti Michela Rondoni Nicoletta Testoni Nicola Vianelli Michele Baccarani NAPOLI: Fabrizio Pane TORINO: Daniela Cilloni
AZ960
TG- 101348
CP- 690,550
AT- 9283