Benefits of JAK2
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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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Benefits of JAK2 InhibitorTherapy: Why Do They Work in Patients With and WithoutJAK2Mutation

Alessandro M. Vannucchi

Section of Hematology,

University of Florence, Italy


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


A MyeloproliferativeDisorderisInduced by JAK2V617F in Mice

PV

MF

Zaleska, PlosOne2006;e18


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


Inhibition of PV Progenitor ErythroidDifferentiation by the JAK2 Inhibitor TG101348

Geron I et al, Cancer Cell, 13; 2008 321 - 330


Effects of Treatment with Ruxolitinib in a

JAK2 V617F-Driven Murine Model

Quintás-Cardama et al., Blood 2010;115:3109-3117.


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.


  • Do they work?

  • If yes, Why?


  • Do they work?

  • If yes, Why?


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


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


The Effects of Ruxolitinib on Symptomatic Control Is Independent of JAK2 V617F Mutation

Kiladjian JJ et al, ASCO 2012: 451A


The Impact of Ruxolitinib on SurvivalIsIndependent of JAK2 V617F Mutation

Verstovsek S et al. ASH 2011, 378A


  • Do they work?

  • If yes, Why?


SimilarlyActivatedSignalingPathways in

JAK2 V617F Mutated and Wild-type MPN Cells

Anand S et al. Blood 2011;118:1610-1621


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


A Cytokine Storm in PMF Patients

  • JAK2 V617F

  • correlated

Fold-increased over controls

Tefferi A et al, JCO 2011;29:1356-1363


The Significance of JAK1 and JAK2 Inhibition

Vannucchi AM, N Engl J Med. 2010; 363:1180-2.


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.


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


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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