1 / 21

Alessandro M. Vannucchi Section of Hematology , University of Florence, Italy

Benefits of JAK2 I nhibitor T herapy : W hy Do T hey Work in P atients With and W ithout JAK2 M utation. Alessandro M. Vannucchi Section of Hematology , University of Florence, Italy. JAK2 V617F is the Commonest Mutation Causing Abnormal JAK/STAT Signaling in MPN. Survival

red
Download Presentation

Alessandro M. Vannucchi Section of Hematology , University of Florence, Italy

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Benefits of JAK2 InhibitorTherapy: Why Do They Work in Patients With and WithoutJAK2Mutation Alessandro M. Vannucchi Section of Hematology, University of Florence, Italy

  2. JAK2 V617F is the CommonestMutationCausingAbnormal JAK/STAT Signaling in MPN Survival Differentiation Proliferation Oncogenesis Vannucchi et al., CA Cancer J Clin. 2009; 59:171-91

  3. A MyeloproliferativeDisorderisInduced by JAK2V617F in Mice PV MF Zaleska, PlosOne2006;e18

  4. JAK2 inhibitors are notspecificfor the JAK2 V617F mutation Binding to receptors Chaperoning Stabilising at membrane ATP site Signaling through P transfer Inhibits basal activity Kinasesite FERM SH2 PseudoKinase Kinase JH5 JH3 JH7 JH6 JH4 JH2 JH1 Activationloop V617F • JAK inhibitorstarget the ATP binding site of JAK2 at the tyrosinekinase • domain and not the pseudokinase domain • Therefore, bothmutated and wild-type JAK2 are inhibitedby JAK2 • inhibitors V617 James et al. Nature 2005; 434: 1144-8 ; Baxter et al. Lancet 2005; 365: 1054-61; Levine et al. Cancer Cell 2005; 7:387-97; Kralovics et al. NEJM. 2005: 352:1779-90

  5. Inhibition of PV Progenitor ErythroidDifferentiation by the JAK2 Inhibitor TG101348 Geron I et al, Cancer Cell, 13; 2008 321 - 330

  6. Effects of Treatment with Ruxolitinib in a JAK2 V617F-Driven Murine Model Quintás-Cardama et al., Blood 2010;115:3109-3117.

  7. JAK1 and JAK2, or JAK2 Only, Inhibitors Verstovsek et al. N Engl J Med. 2010; 363:1117-27. Pardanani et al. JCO. 2011; online Jan 10.Pardanani et al. ASH Abstract 2010; Blood 2010; 116:460. Santos et al. Blood. 2010; 115:1131-6.La Fave LM, Trends Pharm Sciences 2012; 33:564-582.

  8. Do they work? • If yes, Why?

  9. Do they work? • If yes, Why?

  10. The Effects of Ruxolitinib on Spleen Size is Independent of JAK2 V617F Mutation JAK mutation POSITIVE; N = 33 JAK mutation NEGATIVE; N = 6 0 56 112 168 224 280 336 22.5 20.0 17.5 15.0 12.5 10.0 Spleen length, cm 7.5 5.0 2.5 0 • In the Phase I/II study with TG101348/SAR302503, 8 of 59 ptswere JAK2 wild-type • 3 of 4 ptswhocompletedsixcycleshad >50% reduction of splenomegaly (CI per IWG-MRT) Time on Therapy (days) Verstovsek S et al. NEJM 2010; 363:1117-1127; Pardanani A et al, JCO 2011; 29:789-796

  11. Effect of JAK2 V617F Mutation on the Proportion of Patients Obtaining a >35% Spleen reduction* • No significant difference in response rates was observed between patients with the JAK2V617F mutation compared with those without the mutation, although the trend was towards a greater response rate in JAK2 V617F mutated * By MRI Harrison C et al, ASH 2011; 279

  12. The Effects of Ruxolitinib on Symptomatic Control Is Independent of JAK2 V617F Mutation Kiladjian JJ et al, ASCO 2012: 451A

  13. The Impact of Ruxolitinib on SurvivalIsIndependent of JAK2 V617F Mutation Verstovsek S et al. ASH 2011, 378A

  14. Do they work? • If yes, Why?

  15. SimilarlyActivatedSignalingPathways in JAK2 V617F Mutated and Wild-type MPN Cells Anand S et al. Blood 2011;118:1610-1621

  16. Similar Inhibition of Signaling in JAK2 V617F and Wild-type patients with a Selective JAK2 inhibitor Anand S et al. Blood 2011;118:1610-1621

  17. A Cytokine Storm in PMF Patients • JAK2 V617F • correlated        Fold-increased over controls Tefferi A et al, JCO 2011;29:1356-1363

  18. The Significance of JAK1 and JAK2 Inhibition Vannucchi AM, N Engl J Med. 2010; 363:1180-2.

  19. Ruxolitinib-Induced Normalisation of Inflammatory Cytokines in Phase I/II Trial Baseline, Patients with Myelofibrosis vs. Healthy Controls Patients with Myelofibrosis, Day 28 vs. Baseline • This effect was observed regardless of JAK2 mutational status or MF subtype Verstovsek et al. N Engl J Med. 2010; 363:1117-27.

  20. BAT Ruxolitinib Placebo Predicted Effects of JAK1 and JAK2 inhibition JAK2 inhibitors are notspecific for mutatedprotein THUS they are effectiveregardlessof the JAK2V617F mutated status JAK2wt (± JAK1) inhibitionaffects a variety of cytokinesignalingpathways Concurrent Inhibition of JAK2wt might result in anemia and thrombocytopenia 19.2 Anemia 43.2 1.3 Thr’penia 12.9 31 Anemia 42 7 • A markedreduction of pro-inflammatorycytokineswascoincident with improvement in constitutionalsymptoms Thr’penia 8 % ofpatients Verstovsek S et al. N Engl J Med. 2010; 363:1117-27; Verstovsek S et al. NEJM 2012; 366:799-807; Harrison C et al. NEJM 2012; 366:787-98

  21. Conclusions • Abnormal JAK/STAT signalingis a common pathogeneticmechanism in MPN cellsindependent of the JAK2 mutational status • Current JAK2 inhibitors are notspecific for the mutatedprotein, and target the wild-type JAK2 aswell • JAK2 inhibitors are similarlyeffective in JAK2 mutated and wild-typepatients • Inhibitionof wild-type JAK1 signalingcontributes to the clinicalefficacy of JAK1/JAK2 inhibitors

More Related