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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

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

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  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

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