benefits of jak2 inhibitor therapy: why do they work in patients with and without jak2 mutation...
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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, TrkA
AZD1480 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
19.2
43.2
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
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