Arizona, USA
Myeloproliferative Neoplasms
Hematology Highlights
Las Vegas, NV, USA – February 27, 2014, 2014
Ruben A. Mesa, MD
Professor & Chairman, Division of Hematology & Medical Oncology
Deputy Director, Mayo Clinic Cancer Center
Mayo Clinic – Arizona, USA
©2011 MFMER | 3133089-1
Myeloproliferative Neoplasms
Hematology Highlights 2014
• Burden and Biology of MPNs
• JAK2 Inhibition in 2014
• JAK2 Inhibition and beyond
The Natural History of MPNs
Diagnosis
WHO 2008
Essential
Thrombocythemia
Polycythemia
Vera
Early/ Pre-fibrotic
Primary
Myelofibrosis
Classic Primary MF
Post ET/PV MF
MPN Blast Phase
©2011 MFMER | 3133089-4
Calreticulin (CALR)
Within ER
- chaperone ensuring quality control of glycoprotein folding
- calcium homeostasis
Outside ER
- found in cytoplasmic, cell surface and extracellular compartments
- roles in: proliferation
apoptosis
phagocytosis
immunogenic cell death
CALR mutations in JAK2 negative ET and MF
Burden of ET/PV
Macrovascular
Risk
Et & PV
Associated
Symptoms
Microvascular
Symptoms
MF
MPN
Associated
Associate
Symptoms
d
Splenomegaly
Symptom
s
Anemia/
Cytopenis
Burden of Myelofibrosis
Myelofibrosis and Cytopenias (N=364)
Tx Dep
24%
Hb <10g/dLTx Dep
18%
N.B.
• Varying times
• NL Hg
• Men 13.5 g/dL
• Women 12 g/dL
Hb Normal
25%
Hb 10g/dL Normal
33%
WBC <
Normal
10%
WBC ≥
Normal
90%
PLT < 50
9%
PLT =
50-99
11%
PLT = 100-149
10%
PLT > 150
70%
Emanuel et. al. JCO 2012
©2011 MFMER | 3133089-8
Myelofibrosis and Splenomegaly
11%
Splenomegaly
Not Enlarged
89%
Cervantes et. al.
Blood 2009
(N=1054 PMF)
Splenomegaly
36%
Not Enlarged
64%
Emanuel et. al.
JCO 2012
(N=329 MF)
Why does Splenomegaly
Matter in MF?
• Mechanical discomfort
• Pain
• Possible splenic
infarction
• Early satiety adding to
cachexia
• Splenic sequestration
and exacerbation of
cytopenias
• May delay engraftment
in setting of allogeneic
stem cell transplant
©2011 MFMER | 3133089-9
MPN Symptom Burden by Quartiles
1858 MPN-SAF Respondents
Q1
TSS <8
Q2
TSS 8 -17
Parameter
Age
Q3
TSS 18 - 31
P value of Comparison
0.24
Gender F>M
<0.001
MPN Diagnosis
<0.001
Subtype of MF
0.86
IPSET (ET Risk)
0.18
PV Risk (PV)
0.30
DIPSS (MF Risk)
Quartile 1 (Q1): 0-24%
Quartile 3 (Q3): 50-74%
100%
Q4
TSS >32
<0.001
Quartile 2 (Q2): 25-49%
Quartile 4 (Q4): 75-
ET (N=775)
Q1 – 30%
Q2 – 26%
Q3 – 24%
Q4 – 20%
PV (N=654)
Q1 – 25%
Q2 – 23%
Q3 – 26%
Q4 – 26%
MF (N=423)
Q1 – 17%
Q2 – 21%
Q3 – 26%
Q4 – 36%
New Response Criteria for MPNs
ET2
PV2
MF1
Complete response



Partial response



Clinical improvement

Stable disease

No response



Relapse
Other responses
Molecular Molecular
Cytogenetic and
molecular
1. Tefferi A et al. Blood. 2013;122:1395-1398. 2. Barosi G et al. Blood. 2013;121:4778-4781.
New Response Criteria for MF: Complete Response1
Required criteria: for all response categories, benefit must last for ≥12 wks
to qualify as a response
Bone marrow:
Age-adjusted normocellularity;
<5% blasts;
≤Grade 1 MF; and
Peripheral blood:
Hemoglobin ≥ 100 g/L and <UNL;
Neutrophils ≥ 1 x 109/L and <UNL;
Platelets ≥ 100 x 109/L and <UNL;
<2% immature myeloid cells; and
Clinical:
Resolution of disease symptoms
Spleen and liver not palpable
No evidence of EMH
EMH: extramedullary hematopoiesis
1. Tefferi A et al. Blood. 2013;122:1395-1398.
New Response Criteria for MF: Other Categories1
Clinical
improvement
Anemia
response
Achievement of anemia, spleen, or symptoms response
without progressive disease or increase in severity of
anemia, thrombocytopenia, or neutropenia
Transfusion-independent pts: a ≥20 g/L increase in Hb level
Transfusion-dependent pts: becoming transfusion
independent
Baseline splenomegaly that is palpable at 5-10 cm, below
the LCM, becomes not palpable, OR
Spleen
response
Baseline splenomegaly that is palpable at >10 cm, below
the LCM, decreases by ≥50%
Baseline splenomegaly that is palpable at <5 cm, below the
LCM, is not eligible for spleen response
Symptoms
response
A ≥50% reduction in the MPN-SAF TSS
CI: clinical improvement; LCM: left costal margin.
1. Tefferi A et al. Blood. 2013;122:1395-1398.
Myeloproliferative Neoplasms
Hematology Highlights 2014
• Burden and Biology of MPNs
• JAK2 Inhibition in 2014
• JAK2 Inhibition and beyond
JAK Inhibitors and Status of Development
Myelofibrosis as lead indications
Ruxolitinib (FDA Approved)
*
Pacritinib (SB1518)
Momelotinib (CYT387)
*
LY2784544
*
BMS-911543
NS-018
INCB039110 (JAK1)
Fedratininb (SAR302503)
*
No Longer in Development
For MPNs
CEP 701
XL019
* Now Testing
in PV
AZD1280
0
1
2
3
4
©2011 MFMER | 3133089-16
Patient Disposition – 3 Year FU Comfort I
Placebo
Ruxolitinib
(n = 155)
Placebo
(n = 151)
Placebo
Ruxolitinib
(n=111)
Median exposure, weeks
145
37
105
Still on treatment, n (%)
77 (49.7)
0
57 (51.4)
Crossed over, n (%)
Discontinued, n (%)
111 (73.5)
78 (50.3)
40 (26.5)
54 (48.6)
Death
15 (19.2)
7 (17.5)
11 (20.4)
Adverse event
15 (19.2)
9 (22.5)
8 (14.8)
Consent withdrawn
12 (15.4)
7 (17.5)
11 (20.4)
Disease progression
18 (23.1)
13 (32.5)
15 (27.8)
Primary reasons for discontinuation, n (%)*
• All patients originally randomized to placebo crossed over or discontinued within 3
months of the primary analysis
• Median time to crossover: 41.1 weeks
ASH 2013
* Percentages are calculated based on the number of patients who discontinued within the respective treatment group.
17
ASH 2013
Mean Daily Dose (mg, BID) ± SEM
Mean Daily Dose of Ruxolitinib Over Time
25
20 mg BID starting dose
15 mg BID starting dose
20
15
10
5
0
0
8
16
24
32
40
48
56
64
72
80
88
96 104 112 120 128 136 144
Weeks
Number of patients
20 mg BID
100
15 mg BID
55
98
49
93
35
77
33
73
30
69
26
62
20
• Approximately 70% of patients had dose adjustments during the first 12 weeks
of therapy
• By week 24, patients originally randomized to RUX 15 mg BID and 20 mg BID were
titrated to a mean dose of ~10 mg BID and 15-20 mg BID, respectively
18
ASH 2013
Percentage Change in Spleen Size
• Mean reductions in spleen volume and palpable spleen length with
ruxolitinib were stable over time
Spleen Volume
Ruxolitinib
Spleen Length
Placebo
Ruxolitinib
10
0
n = 148 139 120 107 100 84
73
132 107 35
-10
-20
-30
-40
-50
-60
Mean Percentage Change from Baseline
10
Mean Percentage Change from Baseline
Placebo
0
n = 153 152 150 141 130 110 102 90 79
147 141 136 109 47
-10
-20
-30
-40
-50
-60
12 24 48 72
96 120 144
Weeks
12
24
48
4
8
12 24 48 72 96 120 144
Weeks
4
8
12 24
48
19
ASH 2013
Improvements in EORTC QLQ-C30 Over Time
20
15
10
5
0
-5
-10
-15
0
12
24
36
48
60
72
84
24
36
48
60
72
84
Weeks
0
-5
-10
-15
-20
-25
-30
-35
0
Mean Change From Baseline
25
20
15
10
5
0
-5
-10
-15
-20
-25
12
5
12
24
96
108 120 132 144
36
48
60
72
84
96 108 120 132 144
Weeks
RUX
PBO
Arrows indicate improvement
Role Functioning
0
10
96 108 120 132 144
Weeks
Mean Change From Baseline
Fatigue
Mean Change From Baseline
Mean Change From Baseline
Global Health Status/QoL
Physical Functioning
15
10
5
0
-5
-10
0
12
24
36
48
60
72
84
Weeks
96
108 120 132 144
20
ASH 2013
Overall Survival
• Overall survival favored patients originally randomized to ruxolitinib compared with
patients originally randomized to placebo
1.0
Randomized to Ruxolitinib
0.8
Probability
*
Randomized to Placebo  Ruxolitinib
0.6
HR=0.69 (95% CI: 0.46, 1.03); P=0.067
0.4
No. of deaths: Ruxolitinib=42; Placebo=54
Median follow-up: 149 weeks
0.2
Percent of at-risk placebo who crossed over or discontinued
4
13
22
35
54
73
88
97
99 100 100 100 100 100 100 100 100 100 100 100 100 100
8
16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176
0
0
Number of patients at risk
Weeks
Ruxolitinib
155 155 153 148 145 143 137 131 125 124 122 115 112 111 111 108 106 101 84
45
19
1
0
Placebo
154 153 149 144 134 129 119 114 107 105 100 100 95
38
28
8
0
92
88
85
82
79
68
*By week 80, all patients originally randomized to placebo discontinued or crossed over to ruxolitinib therapy
21
Overall Survival: Rank-Preserving Structural
Failure Time (RPSFT) Analysis
ASH 2013
1.0
Probability
0.8
Ruxolitinib
0.6
Placebo  Ruxolitinib
0.4
Placebo-RPSFT
0.2
HR=0.36 (95% CI: 0.204, 1.035)
0
0
8
16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176
Weeks
• RPSFT is a recognized method to estimate HR after adjusting for crossover1-5
• Hazard ratio of 0.36 is consistent with the hypothesis that ITT analysis underestimates
the survival benefit of ruxolitinib relative to “true placebo”
(1) Robins J, Tsiatis A. Commun Stat Theory Methods. 1991;20:2609-31; (2) Demetri GD, et al. Clin Cancer Res. 2012;18:3170-79; (3) National Institute for Health and
Care Excellence (NICE). NICE technology appraisal guidance 179. http://guidance.nice.org.uk/TA179. Issued September 23, 2009; (4) Sternberg CN, et al. Eur J
Cancer. 2013;49:1287-96; (5) National Institute for Health and Care Excellence (NICE). NICE technology appraisal guidance 215.
http://guidance.nice.org.uk/TA215/Guidance/pdf/English. Issued February 2011.
22
Mean Platelet Count and Hemoglobin Level
Over Time
ASH 2013
Platelet Count
Ruxolitinib
115
Placebo
Mean Hemoglobin (g/L)
Mean Platelets (x109/L)
370
Hemoglobin
320
270
220
170
120
0
12
24
36
48
60
72
84
96 108 120 132 144
Ruxolitinib
110
105
100
95
90
85
0
12
24
36
48
Weeks
60
72
84
96 108 120 132 144
Weeks
Number of patients
Number of patients
RUX 155 144 143 136 124 112 110 107 104 100
PBO 151 128 112
Placebo
82
37
94
88
79
155 145 143 136 124 113 110 107 104 100
151 132 113
83
94
88
79
37
23
Incidence of New Onset All Grade Non-hematologic
Adverse Events Regardless of Causality
ASH 2013
Incidence (%)
Fatigue
Diarrhea
Ecchymosis
Peripheral edema
Dyspnea
Dizziness
Pain in extremity
Headache
Nausea
Constipation
Abdominal pain
Insomnia
Vomiting
Pyrexia
Cough
Arthralgia
Upper respiratory tract
infection
0–<12 months
(n=155)
29.0
27.8
21.2
21.3
19.2
18.1
18.0
16.6
16.6
14.5
13.8
13.8
13.7
13.5
13.1
11.8
7.7
Ruxolitinib
12–<24 months
24–<36 months
(n=130)
(n=103)
15.2
15.3
6.7
10.8
10.4
5.7
8.4
12.6
10.2
2.9
10.4
3.0
6.2
4.2
5.1
2.7
6.8
5.1
8.6
10.1
5.7
3.6
5.7
3.7
2.8
2.4
7.3
8.5
13.3
4.0
5.8
6.6
11.1
4.0
≥36 months
(n=82)
7.7
3.9
0
0
3.3
3.5
3.3
0
5.9
9.0
0
0
5.5
2.9
6.0
6.3
3.2
• There was no change in the rate, distribution, or severity of nonhematologic adverse events in the
ruxolitinib group with longer-term treatment; most nonhematologic adverse events were grade 1 or 2
Percentage of patients for each event was based on the effective sample size of the time interval (number of patients at risk at the
beginning of the interval minus half of the censored patients during the time interval).
Adverse event is included if the incidence was >10% at any yearly interval.
24
Incidence of New Onset Grade 3 or 4 Non-hematologic
Adverse Events Regardless of Causality
ASH 2013
Ruxolitinib
Incidence (%)
0–<12 months
(n=155)
12–<24 months
(n=130)
24–<36 months
(n=103)
≥36 months
(n=82)
Fatigue
6.2
0.9
3.3
0
Pneumonia
5.6
3.6
3.5
0
Abdominal pain
4.2
0
3.2
0
Arthralgia
2.1
0
0
0
Diarrhea
2.1
0
0
0
Dyspnea
2.1
0.9
2.2
2.5
Pain in extremity
2.1
0
1.1
0
Hyperuricemia
1.4
0.9
0
2.5
Fall
1.4
0.9
0
0
GI hemorrhage
1.4
0.9
0
0
Septic shock
1.4
0
0
0
Muscular weakness
1.4
0
1.1
0
Hypoxia
1.4
0
2.2
0
Sepsis
0.7
1.7
2.2
0
Epistaxis
0.7
1.7
0
0
Renal failure acute
0.7
0.9
2.2
2.4
Abdominal pain upper
0.7
0
2.2
0
Myocardial infarction
0
0.9
0
4.8
Percentage of patients for each event was based on the effective sample size of the time interval (number of patients at risk at the
beginning of the interval minus half of the censored patients during the time interval).
Adverse event is included if the incidence was ≥2 patients at any yearly interval.
25
BM Morphology in a Ruxolitinib-Treated Patient: A Case Demonstrating
Improvement on Ruxolitinib
ASH 2013
Baseline Biopsy
Grade 3
Kvasnicka HM, et al. ASCO. 2013 (abstr 7030).
24 Mo
Post Ruxolitinib
Grade 2
48 Mo
Post Ruxolitinib
Grade 0
Permission to use images from Kvasnicka, HM
26
Dynamics of BM Changes Following
Ruxolitinib Treatment at 48 Mo
ASH 2013
Kvasnicka, et al. ASH 2013. Abstract 4055.
27
JAK1 & 2 Inhibitors in MPNs –
Efficacy Summary – As of ASH 2013
Myelofibrosis
Yes
No
Occasional
Not
Reported
Yet
Polycythemia
Vera
Ongoing
Trials
Essential
Thrombocythemia
Spleen
Const.
Sympt.
Anemia
Survival

Counts
Const.
Sympt.
Vasc
Events

Counts
Const.
Sympt.
Vasc
Events
Ruxolitinib - Approved
P III
P III
P III
P III
P II
P II
P II
P II
P II
P II
SAR302503 –
PH III JAKARTA (HOLD)
P III
P III
P II
P III
PacritinibPIII Ongoing (Persist MF)
P II
P II
P II
CYT387
P II
P II
P II
LY2784544
PI
PI
BMS-911543
PH II
PH II
INCB039110
(JAK1 Alone)
PI
PI
CEP701
P II
P II
P II
P II
NS-018
PI
P II
P II
©2011 MFMER | 3133089-28
JAK1 & 2 Inhibitors in MPN – Toxicity ASH 2013
Hematological
Toxicities
Anemia

ANC
Gastrointestinal/ Renal
Toxicities

PLT
Nausea
Diarrhea

LFTs
Or CR
Ruxolitinib Approved
23%
7%
11%
SAR302503 –
PIII Ongoing (MF)
41%
6%
11%
0%
5%
1%
PacritinibPIII Ongoing (MF)
6%
0%
18%
6%
CYT387
PII Ongoing (MF)
10%
INCB039110
(JAK1) – PI/II MF
28%
BMS 911543
3%
LY2784544
3%
10%

Lipase
Neurological
Toxicities
Headache
2%
Dizzy
NeuroP/
Parathia
0.6%
W. E.
%?
2%
20%
0%
27%
10%
10%
0%
0%
0%
0%
3%
8%
Renal
1%
Toxicity Color – Represents All Grades ( Grade ¾ Toxicity - Percentage in Table Above)
<10%
1120%
2130%
3140%
4150%
5160%
6170%
7180%
8190%
91100%
©2011 MFMER | 3133089-29
Myeloproliferative Neoplasms
Hematology Highlights 2014
• Burden and Biology of MPNs
• JAK2 Inhibition in 2014
• JAK2 Inhibition and beyond
Clinical Status
MPNs – Plateau vs. Decline
ET – Possible Plateau
Asymptomatic Thrombocytosis
No Vascular Events
PV – Possible Plateau 2
Symptomatic Erythrocytosis
MF
on Successful
JAK2
– Possible
Plateau
2 Rx
No VascularET
Events
Improving Weight
Symptomatic
Thrombocytosis
Decreased
Sinus VenousSpleen
Thrombosis
Improved Survival
Post PV MF
6 Months worsening Fatigue
10 kg weight loss
Massive spleen
Time
©2011 MFMER | 3133089-31
Clinical Status
MPNs – Cumulative Benefits
Ruxolitinib
Improved Survival
Improved Spleen
Burden
Improved Symptom
Burden
Time
©2011 MFMER | 3133089-32
Clinical Status
MPNs – Cumulative Benefits
Single Agent Trials JAK2 Inhibitors
Compared to Ruxo
? Other Benefit
-Less cytopenias
-Improved activity
STUDY (JAK2/FLT3 Inhibitor)
Pacritinib (SB1518) (PH III vs. BAT)
NCT01773187
Improved Survival
STUDY (JAK2/JAK1 Inhibitor)
Momelotinib (CYT387) (PH III vs. Ruxo)
NCT001969838
Improved Spleen
Burden
STUDY (JAK2/FLT3 Inhibitor)
NS-018 (PH I/II)
NCT01423851
Improved Symptom
Burden
STUDY (JAK2 Inhibitor – Also ET and PV)
LY2784544 (PH I/II)
NCT01520220
Time
©2011 MFMER | 3133089-33
Clinical Status
MPNs – Cumulative Benefits
Ruxolitinib + drug X for Anemia
STUDY COMBINATION (JAK2 PLUS Androgen)
Ruxolitinib Plus Danazol
Mayo Clinic (AZ) and Mt. Sinai Trial: NCT01732445
Improved Anemia Burden
Improved Survival
Improved Spleen
Burden
Improved Symptom
Burden
STUDY COMBINATION(JAK2 PLUS
Hypomethylation)
Ruxolitinib Plus Azacitidine
MDACC Trial: NCT01787487
STUDY COMBINATION (JAK2 PLUS IMID)
Ruxolitinib Plus Lenalidomide
NCT01375140
STUDY COMBINATION (JAK2 PLUS IMID)
Ruxolitinib Plus Pomalidomide
Germany (ULM): NCT01644110
Time
©2011 MFMER | 3133089-34
Clinical Status
MPNs – Cumulative Benefits
Ruxolitinib + drug X for Deeper
Marrow Changes Impact
STUDY COMBINATION
(JAK2 PLUS HDAC Inhibitors)
Ruxolitinib Plus Panobinostat
Mt. Sinai Trial: NCT01693601
UK Trial: NCT01433445
Improved Marrow Dysfunction
Improved Survival
Improved Spleen
Burden
Improved Symptom
Burden
STUDY COMBINATION (JAK2 PLUS LOXL2
Inhibitors)
Ruxolitinib Plus GS-6624
NCT01369498
STUDY COMBINATION (JAK2 PLUS rhPTX-2
(Anti-fibrosing))
Ruxolitinib Plus PRM -151
Opening Soon
STUDY COMBINATION (JAK2 PLUS PI3 Kinase
Inhibitor)
Ruxolitinib Plus BKM120
NCT01730248
STUDY COMBINATION
(JAK2 PLUS Hedgehog Inhibitor)
Ruxolitinib Plus LDE225
NCT01787552
Clinical Status
MPNs – Cumulative Benefits
Single Agent Trials
Alternate Targets
STUDY (Interferons)
Peg Interferon α2b in “Early” MF
Cornell Lead: NCT01758588
? Other Benefit
-Less cytopenias
-Improved activity
Improved Survival
Improved Spleen
Burden
STUDY (Activin - ActRIIA-IgG1Fc)
Sotatercept (ACE 011)
MDACC: NCT01712308
STUDY (Telomerase Inhibitor)
Imetelstat (GRN163L)
Mayo Clinic (Rochester): NCT01731951
Improved Symptom
Burden
STUDY (JAK1 Inhibitor)
INCB039110 (PH II)
NCT01633372
Time
Imetelstat: A Telomerase Inhibitor
Telomerase enzyme:
• Reverse transcriptase comprised of an RNA component (hTR) and a
reverse transcriptase catalytic protein subunit (hTERT)
• Binds to the 3’ strand of DNA and adds TTAGGG nucleotide repeats to
offset the loss of telomeric DNA occurring with each replication cycle
• Not active in somatic cells; transiently upregulated in normal
hematopoietic progenitor cells to support controlled proliferation
imetelstat binds to RNA template
preventing maintenance of telomeres
• Highly upregulated in malignant progenitor cells, enabling continued
and uncontrolled proliferation
Imetelstat:
(hTERT)
(hTR)
• Proprietary: 13-mer thio-phosphoramidate oligonucleotide
complementary to hTR, with covalently-bound lipid tail to increase cell
permeability/tissue distribution
• Long half-life in bone marrow, spleen, liver (estimated human t½ = 41
hr with doses 7.5 – 11.7 mg/kg);
• Potent competitive inhibitor of telomerase: IC50 = 0.5-10 nM (cell-free)
• Target: malignant progenitor cell proliferation
–
Tefferi– 37et.
al. ASH 2013
Preliminary efficacy results from Mayo Clinic
investigator-sponsored trial of imetelstat in myelofibrosis
Geron’s independent efficacy analysis of the first 22 MF patients enrolled in the study
– 10 –al. ASH 2013
Tefferi et.
Preliminary efficacy results from Mayo Clinic
investigator-sponsored trial of imetelstat in myelofibrosis
Geron’s independent efficacy analysis of the first 22 MF patients enrolled in the study
– 10 –al. ASH 2013
Tefferi et.
Change in Spleen Volume at Week 12 by
Dose Cohort
Median % Change in Spleen Volume*
Percentage Change From
Baseline at Week 12
20
5,0
0
n=7
n=38
n=9
-9,9
-14,1
-20
100 mg BID
200 mg BID
*Only patients with baseline and week 12 data were included.
600 mg QD
INCB039910 ASH 2013- Mascarenhas et. al
40
Improvement in TSS at Week 12 by Dose
Cohort
≥50% Reduction in TSS*
Median % Change in TSS†
100 mg BID 200 mg BID 600 mg QD
60
0
50.0
50
40
34,9
30
22,2
20
10
n=9
n=43
Percentage Change From
Baseline at Week 12
Percentage of Patients
n=6
n=34
n=8
-20
-28,5
-40
-45,8
-60
-80
-76,8
n=10
0
-100
100 mg BID 200 mg BID 600 mg QD
*Patients who discontinued prior to the week 12 visit were considered nonresponders; 20%-33% of patients in each
group discontinued prior to week 12.
†Only patients with baseline and week 12 data were included.
INCB039910 ASH 2013- Mascarenhas et. al
41
Mean Hemoglobin Levels Over Time by
Dose Cohort
13,0
12,5
12,0
11,5
11,0
10,5
10,0
9,5
9,0
0
2
4
6
8
10
12
13,0
12,5
12,0
11,5
11,0
10,5
10,0
9,5
9,0
0
2
4
6
8
10
Weeks
Weeks
All Patients
Patients entering the study without
transfusion requirements*
n, patients
100 mg BID 10
200 mg BID 45
600 mg QD 29
600 mg QD
200 mg BID
Mean (±SEM) Hemoglobin (g/dL)
Mean (±SEM) Hemoglobin (g/dL)
100 mg BID
12
n, patients
10
45
21
9
45
10
8
41
9
8
43
10
6
39
9
6
37
9
100 mg BID 7
200 mg BID 24
600 mg QD 19
7
24
15
7
24
6
6
22
6
6
23
6
4
21
5
4
22
6
INCB039910
2013Mascarenhas et. al
*Receipt of 2 or more units of red blood cell product transfusions in the
12 weeks priorASH
to day
1.
42
Clinical Status
MPNs – Cumulative Benefits
Difficult PV-ET
STUDY (ET and PV)
MPD-RC 112 Peg Inf a2a vs. Hydroxyurea (PH III)
NCT01259856
Improved Marrow Dysfunction
Improved Survival
STUDY (ET and PV)
MPD-RC 111 Peg Inf a2a AFTER Hydroxyurea
(PH III)
NCT01259856
STUDY (PV)
AOP Peg Inf a2a vs Hydroxyurea (PH III)
NCT01230775
Improved Spleen Burden
Improved Symptom Burden
Improved Vascular Event Risk
(?PV)
STUDY COMBINATION (PV)
Ruxolitinib Vs. Hydroxyurea (RELIEF)
NCT01632904
FUTURE STUDY COMBINATION
JAK2 Inhibitor Plus PEG INFa 2a/b
Individualizing MPN Pharmacotherapy
Patient Goals & Input
Improving Symptom Burden
/HR QOL
CURE
“Balancing” Spleen/
Cytoses/ Cytopenias
Extending Life
©2011 MFMER | 3133089-44
Acknowledgements
Argentina
Ana Clara Kneese, MD
Federico Sackmann, MD
Australia
David M Ross MBBS, PhD
Cecily Forsyth
John Seymour, MBBS, PhD
Karen Hall, MD
Kate Burbury MD
Tam Constantine, MD
Canada
Lynda Foltz, MD
Vikas Gupta, MD
China
Hsin-An Hou, MD
Huan-Chau Lin,
MD Hung Chang, MD
Ming-Shen Dai, MD
Yuan-Bin Yu, MD
Yung-Chen Su, MD
Zhijian Xiao, MD
Denmark
Christen Lykkegaard Andersen, MD
Hans Hasselbalch, MD
France
Brigitte Dupriez, MD
Jean-Jacques Kiladjian, MD
Jean-Loup Demory MD
Magali Demilly, PhD
Germany
Heike L. Pahl, PhD
Ireland
Mary Francis McMullen, MD
Israel
Martin Ellis, MD
Italy
Alessandro M. Vannucchi, MD
Francesco Passamonti, MD
Giovanni Barosi, MD
Tiziano Barbui, MD
Netherlands
Harry Schouten, MD, PhD
Jan Jacques Michiels, MD
Karin Klauke, MD
Peter te Boekhorst, MD
Sonja Zweegman, MD PhD
Stephanie Slot, MD
Suzan Commandeur, MD
New Zealand
Hilary Blacklock, MD
Panama
Francis Guerra, MD
Singapore
Wee Joo Chng, MB ChB
Spain
Ana Kerguelen Fuentes, MD
Carlos Besses, MD
Francisco Cervantes, MD
Dolores Fernandez-Casados
Sweden
Andreasson Bjorn, MD
Elisabeth Ejerblad, MD
Gunnar Birgegard, MD
Jan Samuelsson, MD
Johanna Ablesson, MD
Peter Johansson, MD
UK
Anthony Green, MD
Claire N. Harrison, MD
Deepti Radia, MD
Uruguay
Pablo Muxi, MD
USA
Alison Moliterno, MD
Brady Stein, MD MHS
Casey O'Connell
Catriona Jamieson
Daniel Rubin, ND
Elizabth Hexner
Hala Simm
Jason Gotlib, MD
Jeff Sloan, PhD
Jessica Altman, MD
Joseph Prchal, MD
Kimberly Hickman
Martin Tallman, MD
Mike Boxer, MD
Olatoyosi Odenike, MD
Robert Silver, MD
Ross Levine, MD
Soo Jin Kim
Srdan Verstovsek, MD
©2011 MFMER |