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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Alessandro m vannucchi section of hematology university of florence italy

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 commonest mutation causing abnormal jak stat signaling in mpn

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 myeloproliferative disorder is i nduced by jak2 v617f in mice

A MyeloproliferativeDisorderisInduced by JAK2V617F in Mice

PV

MF

Zaleska, PlosOne2006;e18


Jak2 inhibitors are not specific for the jak2 v617f mutation

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


Alessandro m vannucchi section of hematology university of florence italy

Inhibition of PV Progenitor ErythroidDifferentiation by the JAK2 Inhibitor TG101348

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


Alessandro m vannucchi section of hematology university of florence italy

Effects of Treatment with Ruxolitinib in a

JAK2 V617F-Driven Murine Model

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


Alessandro m vannucchi section of hematology university of florence italy

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.


Alessandro m vannucchi section of hematology university of florence italy

  • Do they work?

  • If yes, Why?


Alessandro m vannucchi section of hematology university of florence italy

  • Do they work?

  • If yes, Why?


Alessandro m vannucchi section of hematology university of florence italy

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


Alessandro m vannucchi section of hematology university of florence italy

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


Alessandro m vannucchi section of hematology university of florence italy

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

Kiladjian JJ et al, ASCO 2012: 451A


Alessandro m vannucchi section of hematology university of florence italy

The Impact of Ruxolitinib on SurvivalIsIndependent of JAK2 V617F Mutation

Verstovsek S et al. ASH 2011, 378A


Alessandro m vannucchi section of hematology university of florence italy

  • Do they work?

  • If yes, Why?


Alessandro m vannucchi section of hematology university of florence italy

SimilarlyActivatedSignalingPathways in

JAK2 V617F Mutated and Wild-type MPN Cells

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


Alessandro m vannucchi section of hematology university of florence italy

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


Alessandro m vannucchi section of hematology university of florence italy

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

The Significance of JAK1 and JAK2 Inhibition

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


Alessandro m vannucchi section of hematology university of florence italy

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.


Predicted effects of jak1 and jak2 inhibition

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


Alessandro m vannucchi section of hematology university of florence italy

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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