Benefits of JAK2 Inhibitor Therapy: Why Do They Work in Patients With and Without JAK2 Mutation

Alessandro M. VannucchiSection of Hematology,

University of Florence, Italy

JAK2 V617F is the Commonest Mutation Causing Abnormal JAK/STAT Signaling in MPN

Vannucchi et al., CA Cancer J Clin. 2009; 59:171-91

SurvivalDifferentiationProliferationOncogenesis

A Myeloproliferative Disorder is Induced by JAK2 V617F in Mice

PV MF

Zaleska, Plos One 2006;e18

Binding to receptorsChaperoningStabilising at membrane Inhibits basal

activity

Signaling through P transfer

JH7 JH6 JH4 JH2 JH1

V617F

JH3JH5

FERM SH2 PseudoKinase Kinase

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

Activationloop

V617

ATP site

Kinasesite

•JAK inhibitors target the ATP binding site of JAK2 at the tyrosine kinase

domain and not the pseudokinase domain

• Therefore, both mutated and wild-type JAK2 are inhibited by JAK2

inhibitors

JAK2 inhibitors are not specific for the JAK2 V617F mutation

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

Inhibition of PV Progenitor Erythroid Differentiation by the JAK2 Inhibitor TG101348

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

Drug JAK1 Other targets

Ruxolitinib/INC424 none known

TG101348/SAR302503 FLT3, Ret

CYT387 JNK1, CDK2

CEP-701 FLT3, TrkAAZD1480 Aurora A, TrkA, FGFr1SB1518 FLT3LY2784544 naBMS911543

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?

0 56 112 168 224 280 336

JAK mutation POSITIVE; N = 33

JAK mutation NEGATIVE; N = 6

Time on Therapy (days)

Sple

en le

ngth

, cm

0

5.07.5

10.012.5

15.017.520.022.5

2.5

The Effects of Ruxolitinib on Spleen Size is Independent of JAK2 V617F Mutation

• In the Phase I/II study with TG101348/SAR302503, 8 of 59 pts were JAK2 wild-type

• 3 of 4 pts who completed six cycles had >50% reduction of splenomegaly (CI per IWG-MRT)

Verstovsek S et al. NEJM 2010; 363:1117-1127; Pardanani A et al, JCO 2011; 29:789-796

• 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

Effect of JAK2 V617F Mutation on the Proportion of Patients Obtaining a >35% Spleen reduction*

* 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

Verstovsek S et al. ASH 2011, 378A

The Impact of Ruxolitinib on Survival Is Independent of JAK2 V617F Mutation

•Do they work?•If yes, Why?

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

Similarly Activated Signaling Pathways 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

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

A Cytokine Storm in PMF Patients

Fold-increased over controls

JAK2 V617F correlated

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

The Significance of JAK1 and JAK2 Inhibition

Ruxolitinib-Induced Normalisation of Inflammatory Cytokines in Phase I/II Trial

This effect was observed regardless of JAK2 mutational status or MF subtype

Verstovsek et al. N Engl J Med. 2010; 363:1117-27.

Baseline, Patients with Myelofibrosis vs. Healthy Controls

Patients with Myelofibrosis, Day 28 vs. Baseline

Predicted Effects of JAK1 and JAK2 inhibition

JAK2wt (± JAK1) inhibition affects a variety of cytokine signaling pathways

JAK2 inhibitors are not specific for mutated proteinTHUS they are effective regardless of the JAK2V617F mutated status

Concurrent Inhibition of JAK2wt might result in anemia and thrombocytopenia

% of patients

Placebo BAT Ruxolitinib

Anemia

Anemia

Thr’penia

Thr’penia

19.243.2

1.312.9

3142

7

8• A marked reduction of pro-inflammatory cytokines was coincident with improvement in constitutional symptoms

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 signaling is a common pathogenetic

mechanism in MPN cells independent of the JAK2 mutational

status

• Current JAK2 inhibitors are not specific for the mutated protein,

and target the wild-type JAK2 as well

• JAK2 inhibitors are similarly effective in JAK2 mutated and wild-

type patients

• Inhibition of wild-type JAK1 signaling contributes to the clinical

efficacy of JAK1/JAK2 inhibitors