Benefits of JAK2 Inhibitor Therapy: Why Do They Work in

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Benefits of JAK2 Inhibitor Therapy:
Why Do They Work in Patients With
and Without JAK2 Mutation
Alessandro M. Vannucchi
Section of Hematology,
University of Florence, Italy
JAK2 V617F is the Commonest Mutation Causing
Abnormal JAK/STAT Signaling in MPN
Survival
Differentiation
Proliferation
Oncogenesis
Vannucchi et al., CA Cancer J Clin. 2009; 59:171-91
A Myeloproliferative Disorder is Induced by
JAK2 V617F in Mice
PV
MF
Zaleska, Plos One 2006;e18
JAK2 inhibitors are not specific for the JAK2
V617F mutation
Binding to receptors
Chaperoning
Stabilising at
membrane
FERM
SH2
JH5
JH7
JH6
Inhibits basal
activity
Signaling
through P
transfer
PseudoKinase
Kinase
ATP site
Kinase
site
JH3
JH4
JH2
JH1
Activation
loop
V617F
•JAK inhibitors target the ATP binding site of JAK2 at the tyrosine kinase
V617
domain and not the pseudokinase domain
• Therefore, both mutated and wild-type JAK2 are inhibited by JAK2
inhibitors
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 Erythroid
Differentiation 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
Drug
Ruxolitinib/INC424
TG101348/SAR302503
JAK1
Other targets

none known

FLT3, Ret
CYT387
JNK1, CDK2
CEP-701
FLT3, TrkA
AZD1480
SB1518
LY2784544

Aurora A, TrkA, FGFr1
FLT3
na
BMS911543
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?
Spleen length, cm
The Effects of Ruxolitinib on Spleen Size is
Independent of JAK2 V617F Mutation
JAK mutation POSITIVE; N = 33
22.5
20.0
17.5
15.0
12.5
10.0
7.5
5.0
2.5
0
0
JAK mutation NEGATIVE; N = 6
56
112
168
224
280
336
Time on Therapy (days)
• 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
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 Survival Is
Independent of JAK2 V617F Mutation
Verstovsek S et al. ASH 2011, 378A
•Do they work?
•If yes, Why?
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
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.
Predicted Effects of JAK1 and JAK2 inhibition
JAK2 inhibitors are not specific for mutated protein
THUS they are effective regardless of the JAK2V617F mutated status
JAK2wt (± JAK1) inhibition affects a variety of
cytokine signaling pathways
Concurrent Inhibition of JAK2wt might result in
anemia and thrombocytopenia
BAT
Placebo
19.2
Anemia
Thr’penia
Ruxolitinib
43.2
1.3
12.9
31
Anemia
• A marked reduction of pro-inflammatory
cytokines was coincident with improvement
in constitutional symptoms
Thr’penia
42
7
8
% of patients
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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