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An overview of the differences of different JAK inhibitors Alessandro M. Vannucchi University of Florence, Italy.

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Presentation on theme: "An overview of the differences of different JAK inhibitors Alessandro M. Vannucchi University of Florence, Italy."— Presentation transcript:

1 An overview of the differences of different JAK inhibitors Alessandro M. Vannucchi University of Florence, Italy

2 JAK2 Signaling Abnormalities in MPN

3 JAKs are Involved in Multiple Cytokine Signaling Vannucchi AM, N Engl J Med. 2010; 363:

4 Verstovsek S et al. NEJM 2010; 363: Dysregulated Cytokine Expression in MF Patients

5 Tefferi A et al. JCO 2011;29: All (n=127) Treatment naive (n=90) Int-1 (n=27) Int-2 (n=70) Abnormally Increased IL-8 and IL2R Plasma Levels Are Prognostically Detrimental

6 Reddy M et al. Exp Opin Ther targets 2012; 16: A portfolio of JAK2 inhibitors

7 Reddy M et al. Exp Opin Ther targets 2012; 16: A portfolio of JAK2 inhibitors JAK1JAK2JAK3TYK2 Ruxolitinib X SAR CYT ? SB Ly VF 2260 wt ?

8 All JAK2 Inhibitors are Type I and are not Mutation Specific

9 Efficacy of JAK2 Inhibitors: Summary Spleen response*Symptoms Ruxolitinib42% COMFORT-I 28.5% COMFORT-II Y Body weight gain SAR % overall 45% MTD cohort 66% pts >6cycles Y No body weight gain CYT38750% overallY *, >35% by MRI (ruxolitinib) or >50% by palpation (SAR & CYT)

10 Response by Dose (Core Study) 150 mg QD (n=52) 300 mg QD (n=60) 150 mg BID (n=42) Total 1 (n=166) Transfusion dependent at baseline (evaluable) Transfusion independence rate (12 wks)63%75%57% 2 68% Minimum 2 g/dL increase in hemoglobin level (8 wks)11%8%14%13% IWG-MRT anemia response rate48%55%36%48% CYT387: Transfusion Independence Response Of the transfusion dependent patients who did not achieve a full transfusion independence response, 23% achieved at least a 50% reduction in transfusion requirement in any 3-month period 1 Includes 100mg QD (n=3), 200mg QD (n=3), and 400mg QD (n=6) doses 2 Not statistically significant vs. 300mg QD 3 Data based on responders * Ongoing as of November 2012 Onset and Durability of Response (Core and Extension Study)MedianMin-Max Time to confirmed response (12 weeks) (Core; days) Duration of transfusion-free period (12 weeks) (Core and Extension; days) 3 Not yet reached85-988* 3 additional subjects achieved 12 week transfusion independence response during the Extension Study Pardanani A et al, ASH 2012

11 CYT387: Effects on Anemia Pardanani A et al, ASH 2012 Percentage of Patients Receiving RBC Transfusions in Prior 4 Weeks

12 Vannucchi AM et al, ASH 2012

13 Effect of TG101348/SAR therapy on JAK2 V617F allele burden Pardanani A et al. JCO 2011;29:

14 Ruxolitinib Induced Inhibition of Inflammatory Cytokines Verstovsek S et al. NEJM 2010; 363:

15 Pardanani A et al, JCO 2011; 29: Inhibition of Inflammatory Cytokines does not Mediate Efficacy of SAR203505

16 CYT387: cytokine changes ……….. Our data suggests a cytokine-mediated effect; a majority of patients had treatment-related decrease in circulating IL-1β and IL-1RA levels, which were the only two cytokines associated with transfusion-independence response. Similarly, spleen response was correlated with treatment-associated decreases in a number of cytokines. Overall, these data implicate down-regulation of circulating inflammatory cytokines, further confirmed by gene expression analysis, as the major mechanism for CYT387s clinical activity in MF. Pardanani A et al, Leukemia 2013

17 Verstovsek S, NEJM 2012; Talpaz M, ASH 2012; Komrojki B, ASH 2012; Pardanani A, Leukemia 2013 Courtesy, R. Mesa 2013 Toxicity of JAK2 Inhibitors: Summary

18 Conclusions A portfolio of different JAK2/(1) inhibitors is available in addition to ruxolitinib There is no clear difference in efficacy against splenomegaly and symptoms Different JAK2 inhibitors may have different activity against inflammatory cytokines CYT387 may have unique effects on anemia Modest activity against JAK2V617F allele burden Overlapping hematologic toxicity


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