second generation jak inhibitors: targeting the jak-stat ...splenomegaly and fatigue. –main side...
TRANSCRIPT
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Rami S. Komrokji, MD Clinical Director, Associate Professor Malignant Hematology Department
H. Lee Moffitt Cancer Center Tampa, Florida
Second-generation JAK inhibitors: Targeting the JAK-STAT pathway
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Disclosures for Rami S. Komrokji, MD Royalty N/A
Receipt of intellectual property/ Patent holder
N/A
Consulting fee Incyte
Speakers bureau Incyte
Fees for non-CME services N/A
Contracted research Incyte
Ownership interest (stocks, stock options)
N/A
Other N/A
N/A = Not Applicable (no conflicts listed) Presentation includes discussion of investigational JAK inhibitors that are not yet FDA approved
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Case presentation
69 year old Caucasian male with past medical history of hypertension: • 1986: Diagnosed with polycythemia rubra vera and treated
with periodic phlebotomy until 2008 when his counts stabilized.
• 2012: He developed progressive splenomegaly, leukocytosis, anemia, and thrombocytopenia (WBC 17 K, Hgb 10.2 g/dL, platelets 150). – A bone marrow was consistent with post PV-myelofibrosis (post
PV-MF). Normal male karyotype – PCR was positive for JAK2V617F mutation
• No suitable donor could be identified for consideration of allogeneic stem cell transplantation.
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Case presentation
69 year old Caucasian male with past medical history of hypertension diagnosed with post PV-MF: • July 2012: He was started on ruxolitinib 15 mg po BID
with excellent clinical response in terms of splenomegaly and fatigue. – Main side effect was anemia with Hgb decreased to the
range of 8-9 g/dL when procrit was administered by local oncologist maintaining Hgb between 9-10 g/dL with no transfusion.
• May 2014: Progressive splenomegaly, ruxolitinib dose increased up to 25 mg po BID but with worsening of his anemia requiring red blood cell transfusion and only modest further clinical response.
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Case presentation questions
• Could a 2nd generation JAK inhibitor offer an advantage over ruxolitinib as first-line therapy in patients with cytopenia?
• Can we consider treatment with a 2nd generation JAK inhibitor after ruxolitinib failure?
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Outline
• Overview of JAK inhibitors highlighting the targets, differences, and stage of development.
• What can a 2nd generation JAK2 inhibitor offer beyond ruxolitinib as an upfront treatment? – Pacritinib – Momelotinib
• Is there a role for a 2nd JAK2 inhibitor after ruxolitinib failure? – Fedratinib data as 2nd line
• Novel approaches targeting JAK/Stat pathway
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JAK2 inhibitors Drug Other target Phase Status
Ruxolitinib JAK-1 III Approved
Pacritinib FLT-3 III ongoing
Momelotinib JAK1, JNK1, TYK2, CDK2, RICJ2 III ongoing
Fedratinib FLT-3, RET III withdrawn
AZD1480 JAK1, JAK3, FLT4, FGFR1, TRKA II
Gandotinib (LY2784544)
I withdrawn
NS-018 SRC, FLT3, ABL I/II
XL019 I withdrawn
BMS-911543 I/II withdrawn
Cervantes F. How I treat myelofibrosis. Blood. 2014;124(17):2635-2642.
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What can a 2nd generation JAK2 inhibitor offer beyond ruxolitinib as
an upfront treatment?
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Pacritinib: A Selective JAK2/FLT3 Inhibitor
William AD, et al. J Med Chem 2011; 54:4638 Hart S, et al. Leukemia 2011; 25:1751
Kinase IC50 (nM)
JAK1 1280
JAK2wt 23
JAK2V617F 19
JAK3 520
TYK2 50
FLT3 22
FLT3-D835Y 6
• Pacritinib (SB1518): oral,
selective, dual JAK2/FLT3
inhibitor
• Potent inhibition of JAK2-STAT3
-STAT5 pathway without
myelosuppression in preclinical
studies
• Did not appear to be associated
with clinically significant
treatment-emergent anemia or
thrombocytopenia in early clinical
studies
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Analysis of 2 Phase II Trials of Pacritinib in Patients with Baseline Platelet Counts of ≤100,000/µL
• International phase II studies (001, 003) conducted between 2010-2012 (n=65) – Pacritinib dosed 400 mg oral once daily
– Spleen size assessed by physical exam (PE) and MRI
– Patient-reported outcomes assessed using the Myelofibrosis Symptom Assessment Form (MF-SAF)1
– Standard adverse event (AE) reporting and central laboratory testing
• Databases were integrated to evaluate safety and efficacy in patients with baseline platelet counts of ≤100,000/µL or >100,000/µL
Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
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Demographics
Baseline Platelets
≤100,000/µL
(n=28)*
Baseline Platelets
>100,000/µL
(n=37)*
All
(n=65)
Age, Median (range) 69 (46-85) 68 (44-85) 68 (44-85)
Male, N (%) 19 (68%) 28 (76%) 47 (72%)
MF Diagnosis, N (%)
Primary MF 21 (75%) 19 (51%) 40 (62%)
Post-PV MF 5 (18%) 11 (30%) 16 (25%)
Post-ET MF 2 (7%) 7 (19%) 9 (14%)
DIPSS Risk Category, N (%)**
Intermediate-1 3 (11%) 11 (30%) 14 (22%)
Intermediate-2 11 (39%) 9 (24%) 20 (31%)
High 4 (14%) 10 (27%) 14 (22%)
JAK2V617F positive, N (%) 23 (82%) 29 (78%) 52 (80%)
** DIPSS was calculated post-hoc and was indeterminate on the remainder of the patients: 10 (36%), 7 (19%)
and 17 (26%), respectively Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
* No significant differences were observed between the two groups
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Baseline hematologic parameters
Baseline Platelets
≤100,000/µL
(n=28)*
Baseline Platelets
>100,000/µL
(n=37)*
All
(n=65)
Platelet Count (x103/mL)
Mean (SD) 56 (± 23) 261 (± 147) 173 (± 151)
Median (IQR) 59
(34-70)
227
(163-315)
121
(60-238)
Range 15-97 104-859 15-859
Platelet transfusions
within 180 days prior to
study screening, N (%) 3 (11%) 0 (0%) 3 (5%)
Hemoglobin (g/dL),
Median (range) 8.8 (3.7-14) 10.7 (7.4-14.4) 9.7 (3.7-14.4)
RBC transfusions within
180 days prior to study
screening, N (%) 13 (46%) 13 (35%) 26 (40%)
Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
* No significant differences were observed between the two groups
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Endpoint Time Period
Baseline Platelets
≤100,000/µL
(n=28)*
Baseline Platelets
>100,000/µL
(n=37)*
All
(n=65)
≥ 50%
Reduction in
spleen size by
PE
Up to 24
weeks 12 / 28 (43%) 14 / 34 (41%) 26 / 62 (42%)
Up to last
visit on
treatment
13 / 28 (46%) 14 / 35 (40%) 27 / 63 (43%)
≥ 35%
Reduction in
spleen volume
by MRI
Up to 24
weeks 7 / 23 (30%) 6 / 26 (23%) 13 / 49 (27%)
Up to last
visit on
treatment
10 / 23 (44%) 8 / 26 (31%) 18 / 49 (37%)
Spleen response
* No significant differences were observed between the two groups
Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
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Baseline Platelets
≤100,000/µL
(n=28)**
Baseline Platelets
>100,000/µL
(n=37)**
All
(n=65)
Up to 24
weeks 11 / 28 (39%) 16 / 34 (47%) 27 / 62 (44%)
Up to last
visit on
treatment
13 / 28 (46%) 17 / 34 (50%) 30 / 62 (48%)
≥50% reduction in patient-reported symptom score*
* The symptom score is the sum of the individual scores for worst fatigue, early satiety,
abdominal pain or discomfort, night sweats, itching, and bone pain reported on the MF-
SAF (Mesa RA, Schwager S, Radia D ,et al. The Myelofibrosis Symptom Assessment Form (MFSAF): An evidence-
based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res.
2009; 33(9): 1199-203).
* No significant differences were observed between the two groups
Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
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Platelet count change over time
Baseline platelets ≤100,000/µL Baseline platelets >100,000/µL
Baseline platelets >350,000/µL
Me
an
Pe
rce
nt
Ch
an
ge
in
Pla
tele
t C
ou
nt
(± S
EM
)
Me
an
Pe
rce
nt
Ch
an
ge
in
Pla
tele
t C
ou
nt
(± S
EM
)
Me
an
Pe
rce
nt
Ch
an
ge
in
Pla
tele
t C
ou
nt
(± S
EM
)
Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
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Hemoglobin change over time
Baseline platelets ≤100,000/µL Baseline platelets >100,000/µL
Me
an
Pe
rce
nt
Ch
an
ge
in
He
mo
glo
bin
(±
SE
M)
Me
an
Pe
rce
nt
Ch
an
ge
in
He
mo
glo
bin
(±
SE
M)
Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
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Pacritinib: Conclusions
• Demonstrated encouraging spleen size and patient-reported symptom score reduction regardless of baseline platelet counts
• Duration of exposure and daily dose were unaffected by starting platelet counts
• There was no apparent association with clinically significant treatment emergent anemia or thrombocytopenia
• A phase III trial, PERSIST-2, will evaluate pacritinib in MF patients with platelet counts ≤ 100,000/µL vs. BAT, including ruxolitinib
• The PERSIST-1 phase III trial, which compares pacritinib to BAT, not including a JAK2 inhibitor, is currently enrolling, has no upper or lower limit for platelet counts
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Small-molecule, ATP-competitive, JAK1 and JAK2 inhibitor
Has good selectivity over other JAK family kinases (JAK3, TYK2) and excellent selectivity over other tyrosine and serine/threonine kinases
Inhibits STAT phosphorylation downstream of constitutively active JAK2 or cytokine-stimulated JAK1 or JAK2
Orally active
Update on the long-term efficacy and safety of momelotinib, a
JAK1 and JAK2 inhibitor, for the treatment of myelofibrosis
Pardanani A, et al. Blood 2013;122(21): abstr 108
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Dose Groups
100 mg QD (n=3)
150 mg QD* (n=52)
200 mg QD (n=3)
300 mg QD* (n=60)
400 mg QD (n=6)
150 mg BID* (n=42)
Continues long-term dosing of momelotinib
48 subjects remain on study as of Oct, 2013
Data collection and analysis ongoing
Median duration of treatment (days): 627 (range 23 1294)
Core Study CCL09101 (n=166)
Treatment Duration: 9 months
Extension Study CCL09101E
(n=120)
*Dose level targeted for expansion
MTD
Dose-limiting toxicities: Grade 3
hyperlipasemia, Grade 3 headache
Studies CCL09101 and CCL09101E
Pardanani A, et al. Blood 2013;122(21): abstr 108
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Key eligibility criteria for study CCL09101
Diagnosis of PMF or Post-PV/ET MF
IPSS high risk or Int-2 risk, or Int-1 risk with
symptoms and/or unresponsive to available
therapy
AST or ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if due to
extramedullary hematopoiesis
Bilirubin ≤ 2 x ULN or direct bilirubin < 1.0
Creatinine ≤ 2.5 x ULN
ANC ≥ 500/µL, platelet ≥ 50,000/µL
4-weeks wash out for prior radiation
therapy
14-days wash out for prior systemic
therapy
Presence of peripheral neuropathy is not
allowed (amendment 3/2011)
Clinically active hepatitis B or C is not
allowed
Known positive HIV is not allowed
Pardanani A, et al. Blood 2013;122(21): abstr 108
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Baseline characteristics Characteristic Value
Number of subjects 166
Age (years)
Median (range) 68 (34-89)
Sex
Male/Female 58%/42%
Myelofibrosis
Primary 63%
Post-PV 22%
Post-ET 15%
JAK2V617F positive 77%
Prior therapy
JAK inhibitor 13%
Characteristic Value
Splenomegaly > 10 cm 79%
Palpable spleen size (cm)
Mean 18.3
Median 18
RBC transfusion dependent 43%
Median hemoglobin level (g/dL) 9.4
Transfusion independent
(n=93) 10.3
Transfusion dependent
(n=72) 8.7
Median platelet count (109/L) 182
Pardanani A, et al. Blood 2013;122(21): abstr 108
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Spleen response
Spleen Response Number of
Subjects (%)
Total enrollment 166 (100%)
Baseline spleen size > 5 cm at baseline 148 (89%)
≥ 50% reduction in splenomegaly that lasts
≥ 8 weeks for splenomegaly ≥ 10 cm at
baseline: A (A/148)
52 (35%)
Resolution of splenomegaly that lasts ≥ 8
weeks for splenomegaly > 5 and < 10 cm:
B (B/148)
6 (4%)
Spleen Response: A + B 58 (39%)
Pardanani A, et al. Blood 2013;122(21): abstr 108
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Anemia response
Anemia Response Number of
Subjects (%)
Transfusion dependent at baseline 72 (43%)
Achieved transfusion independence on study
that lasts ≥ 12 weeks: C (C/72) 49 (68%)
Transfusion independent with Hgb < 10 g/dL at
baseline 39 (24%)
Rise in Hgb ≥ 2 g/dL on study that lasts ≥ 12
weeks: D (D/39) 10 (26%)
Anemia Response: C + D 59 (53%)
Transfusion dependence at baseline is defined as ≥ 2 units of RBC transfusions in the 30 days prior to C1/D1 and/or identified as transfusion dependent in medical history
Pardanani A, et al. Blood 2013;122(21): abstr 108
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Duration of anemia response
Number of events (%): 18 (30.5)
Number of censored (%): 41 (69.5)
Median (days) (95% CI): 1,042 (514, NE)
Event Censored
Duration of anemia response (days)
Pro
ba
bili
ty
0 200 400 600 800 1000
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pardanani A, et al. Blood 2013;122(21): abstr 108
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Treatment-related adverse events (> 10% of subjects)
Total number of subjects enrolled 166
All Grades ≥ Grade 3
Thrombocytopenia 77 (46.4%) 49 (30%)
Neuropathy peripheral 73 (44.0%) 0 (0%)
Diarrhoea 42 (25.3%) 0 (0%)
Dizziness 40 (24.1%) 0 (0%)
Nausea 37 (22.3%) 0 (0%)
Headache 26 (15.7%) 2 (1%)
Alanine aminotransferase increased 25 (15.1%) 4 (2%)
Aspartate aminotransferase increased 20 (12.0%) 2(1%)
Lipase increased 24 (14.5%) 8 (5%)
Hyperamylasaemia 17 (10.2%) 0 (0%)
• Thrombocytopenia includes platelet count decreased, thrombocytopenia
• Neuropathy peripheral includes formication, hypoaesthesia, paraesthesia, peripheral sensory neuropathy, neuropathy
peripheral
• Lipase increased includes hyperlipasaemia, lipase increased
• Hyperamylasaemia includes amylase increased, hyperamylasaemia
• Treatment-relatedness assessed by investigator
Pardanani A, et al. Blood 2013;122(21): abstr 108
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First dose effect of momelotinib
Number (%)
Total subjects enrolled 166
Adverse event of dizziness* on C1/D1 23 (14%)
Related to study drug 16 (10%)
Unrelated to study drug 5 (3%)
Relatedness not reported 2 (1%)
Adverse event of hypotension* on C1/D1 11 (7%)
Related to study drug 8 (5%)
Unrelated to study drug 3 (2%)
• *Dizziness includes dizziness, lightheadedness
• *Hypotension includes low blood pressure, decreased blood pressure, hypotension
• 3 subjects with dizziness also reported hypotension
• Treatment-relatedness assessed by investigator
Pardanani A, et al. Blood 2013;122(21): abstr 108
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Platelet count and momelotinib starting dose
Month
525
150 mg QD
300 mg QD
150 mg BID
Doses at C1D1
Me
an
pla
tele
t co
un
t
1 2 3 4 6 5 7 8
0
25
50
75
25
100
125
150
175
200
225
250
275
300
325
350
375
400
425
450
475
500
Me
an
Pla
tele
ts
0
25
50
75
100
125
150
175
200
225
250
275
300
325
350
375
400
425
450
475
500
525
Time (Months)
1 2 3 4 5 6 7 8
Dose at C1D1: 150 mg QD 300 mg QD 150 mg BID
Pardanani A, et al. Blood 2013;122(21): abstr 108
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N=420
1:1 randomization
Screening (≤ 35 days)
Double-blind Treatment Phase Open-label Phase Long-term Follow-up
Momelotinib + placebo
Ruxolitinib + placebo
Week 24
Momelotinib QD Momelotinib
Momelotinib
Week 192
Year 4 Year 5 Day 1
Within 5 days of randomization
Phase 3 study design (GS-US-352-0101)
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Is there a role for a 2nd JAK2 inhibitor after ruxolitinib failure?
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Efficacy and safety of fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) previously treated with
ruxolitinib: A phase II study (JAKARTA-2)
• Patients ≥18 yrs with splenomegaly and platelet count ≥50 ×109/L received fedratinib 400 mg orally, once daily for consecutive 4-wk cycles.
• Eligible patients had received ≥14 d RUX treatment, and had discontinued RUX for ≥14 d prior to starting fedratinib.
• No consensus definition of RUX resistance/intolerance, (investigator assessment) as resistant (lack or loss of response) or intolerant to RUX.
• Primary endpoint : spleen response rate (RR) (≥35% reduction in spleen volume from baseline at Wk 12 [MRI/CT blinded central review]
Harrison CN, et al. Blood. 2013;122(21):abstr 661
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Efficacy and safety of fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) previously treated with
ruxolitinib: A phase II study (JAKARTA-2)
• 27 patients received fedratinib treatment (median RUX exposure 10.7 months [range 1.9–34.4])
• Baseline Characteristics: – The median age was 69 yrs – 56% male – 67% primary MF – 63% high-risk MF – 67% JAK2V617F positive – 41% platelet count <100 × 109/L – median spleen volume 3190 mL [1072–7815].
• Eighteen patients were considered resistant by the treating physician (8 lack of response, 3 disease progression, 7 loss of response) and 9 intolerant (6 hematologic, 3 non-hematologic toxicity)
• Median fedratinib exposure : 4 cycles (range 1–10); 19 patients remain on treatment.
Harrison CN, et al. Blood. 2013;122(21):abstr 661
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Efficacy and safety of fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) previously treated with
ruxolitinib: A phase II study (JAKARTA-2)
RUX resistant (n=18)
RUX intolerant (n=9)
Overall (n=27)
Spleen response at Wk 12a, n/N (%)
6/14 (43)
2/6 (33)
8/20 (40)
Symptom response to Wk 12b, n/N (%
3/18 (17)
2/8 (25)
5/26 (19)
a7 patients not evaluable: no post-baseline MRI/CT scan (n=5); no baseline MRI/CT scan (n=1); MRI/CT scan outside time window for Wk 12 assessment (n=1). b1 patient not evaluable: no baseline and at least one post-baseline assessment of TSS.
Harrison CN, et al. Blood. 2013;122(21):abstr 661
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Momelotinib: Response rates of JAK inhibitor-treated subjects
Number
Previously treated with JAK inhibitor 22
Ruxolitinib 14
TG101348 5
“JAK inhibitor study” 3
Spleen evaluable1 20
Spleen response2: A (A/20) 2 (10%)
Transfusion independence evaluable3 13
Transfusion independence response4: B (B/13) 7 (54%)
(1) Spleen evaluable: baseline palpable splenomegaly > 5 cm and had completed ≥ 8 weeks of treatment
(2) Spleen response: ≥ 50% decrease from baseline in palpable spleen length for baseline splenomegaly ≥
10 cm or resolution of palpable splenomegaly for baseline splenomegaly > 5 and < 10 cm
(3) Transfusion independence evaluable: transfusion dependent at baseline and had completed ≥ 12
weeks of treatment
(4) Transfusion independence response: For those who are transfusion dependent at baseline,
achievement of transfusion independence that lasts ≥ 12 weeks
Pardanani A, et al. Blood 2013;122(21): abstr 108
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Novel approaches targeting JAK/Stat pathway
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Targets of intervention by putative small-molecule inhibitors around the cytokine receptor,
JAK-STAT, MAPK, and PI3K-mTOR pathways.
Constantinescu S N , and Vainchenker W. Hematology Am Soc
Hematol Educ Program 2012;2012:553-560
Copyrighted Figure
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Searching for “mutant”-specific JAK2 inhibitors by targeting a predicted mechanism of
activation of JAK2 kinase domain (JH1) by the V617F pseudokinase (JH2) mutation.
Constantinescu S N , and Vainchenker W. Hematology Am Soc
Hematol Educ Program 2012;2012:553-560
Copyrighted Figure
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Conclusions
• 2nd generation JAK2 inhibitors may offer advantages as first-line therapy in term of efficacy or toxicity based on different 2ndry targets.
• Responses to 2nd generation JAK2 inhibitors may be observed after failure of ruxolitinib and should be further pursued in clinical trials.
• Novel approaches targeting JAK-STAT pathway include search for mutant specific inhibitors, non-competitive inhibitors, and targeting downstream signaling.