arizona, usa ©2011 mfmer | 3133089-1 ruben a. mesa, md professor & chairman, division of...
TRANSCRIPT
Arizona, USA
©2011 MFMER | 3133089-1
Ruben A. Mesa, MDProfessor & Chairman, Division of Hematology & Medical Oncology
Deputy Director, Mayo Clinic Cancer CenterMayo Clinic – Arizona, USA
Myeloproliferative NeoplasmsHematology Highlights
Las Vegas, NV, USA – February 27, 2014, 2014
Myeloproliferative NeoplasmsHematology Highlights 2014
•Burden and Biology of MPNs
•JAK2 Inhibition in 2014
•JAK2 Inhibition and beyond
The Natural History of MPNs
Polycythemia Vera
Early/ Pre-fibrotic Primary
Myelofibrosis
Classic Primary MFPost ET/PV MF
MPN Blast Phase
WHO 2008Essential
Thrombocythemia
Diagnosis
©2011 MFMER | 3133089-4
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
Calreticulin (CALR)
CALR mutations in JAK2 negative ET and MF
Burden of ET/PV
MicrovascularSymptoms
MacrovascularRisk
MPN Associate
dSymptom
s
Burden of Myelofibrosis
Anemia/Cytopenis
Splenomegaly
MF AssociatedSymptoms
Et & PV AssociatedSymptoms
Myelofibrosis and Cytopenias (N=364)
©2011 MFMER | 3133089-8
Emanuel et. al. JCO 2012
PLT > 15070%
PLT = 100-14910%
PLT = 50-9911%
PLT < 509%
N.B.• Varying times• NL Hg
• Men 13.5 g/dL• Women 12 g/dL
Hb - Normal25%
Hb 10g/dL - Normal
33%Hb <10g/dL-Tx Dep18%
Tx Dep24%
WBC ≥ Normal90%
WBC < Normal10%
Myelofibrosis and Splenomegaly
©2011 MFMER | 3133089-9
89%
11%Splenomegaly
Not Enlarged
64%
36%Splenomegaly
Not Enlarged
Cervantes et. al.Blood 2009(N=1054 PMF)
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
Quartile 1 (Q1): 0-24% Quartile 2 (Q2): 25-49%Quartile 3 (Q3): 50-74% Quartile 4 (Q4): 75-100% Percentile MPN-SAF TSS
Q1TSS <8
Q2TSS 8 -17
Q3TSS 18 - 31
Q4TSS >32
Parameter P value of Comparison
Age 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) <0.001
MPN Symptom Burden by Quartiles1858 MPN-SAF Respondents
ET (N=775)
PV (N=654)
MF (N=423)
Q1 – 30% Q2 – 26% Q3 – 24% Q4 – 20%
Q1 – 17% Q2 – 21% Q3 – 26% Q4 – 36%
Q1 – 25% Q2 – 23% Q3 – 26% Q4 – 26%
New Response Criteria for MPNs
ET2 PV2 MF1
Complete response Partial response Clinical improvement Stable disease No response Relapse
Other responses Molecular Molecular Cytogenetic andmolecular
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
EMH: extramedullary hematopoiesis1. Tefferi A et al. Blood. 2013;122:1395-1398.
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
Required criteria: for all response categories, benefit must last for ≥12 wks to qualify as a response
New Response Criteria for MF: Other Categories1
1. Tefferi A et al. Blood. 2013;122:1395-1398.
Clinical improvement
Achievement of anemia, spleen, or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia
Anemia response
Transfusion-independent pts: a ≥20 g/L increase in Hb level
Transfusion-dependent pts: becoming transfusion independent
Spleen response
Baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable, OR
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.
Myeloproliferative NeoplasmsHematology Highlights 2014
•Burden and Biology of MPNs
•JAK2 Inhibition in 2014
•JAK2 Inhibition and beyond
JAK Inhibitors and Status of DevelopmentMyelofibrosis as lead indications
AZD1280
XL019
CEP 701
Fedratininb (SAR302503)
INCB039110 (JAK1)
NS-018
BMS-911543
LY2784544
Momelotinib (CYT387)
Pacritinib (SB1518)
Ruxolitinib (FDA Approved)
0 1 2 3 4©2011 MFMER | 3133089-16
No Longer in DevelopmentFor MPNs
* Now Testing in PV
*
*
*
*
Patient Disposition – 3 Year FU Comfort I
Ruxolitinib (n = 155)
Placebo
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 (%) 111 (73.5)
Discontinued, n (%) 78 (50.3) 40 (26.5) 54 (48.6)
Primary reasons for discontinuation, n (%)*
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)
• All patients originally randomized to placebo crossed over or discontinued within 3 months of the primary analysis
• Median time to crossover: 41.1 weeks
17* Percentages are calculated based on the number of patients who discontinued within the respective treatment group.
ASH 2013
Mean Daily Dose of Ruxolitinib Over Time
18
• 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
25
20
15
10
5
0
Mea
n D
aily
Do
se
(mg
, B
ID)
± S
EM
0 8 16 24 32 72 104 136 14448 88 1206456 96 12840 80 112Weeks
20 mg BID starting dose15 mg BID starting dose
98 6220 mg BID
49 2015 mg BID
Number of patients
100
55
77 69
33 26
73
30
93
35
ASH 2013
Series1
-60
-50
-40
-30
-20
-10
0
10
Series1
-60
-50
-40
-30
-20
-10
0
10
Percentage Change in Spleen Size
19
• Mean reductions in spleen volume and palpable spleen length with ruxolitinib were stable over time
Ruxolitinib Placebo
Weeks
Mea
n P
erce
nta
ge
Ch
ang
e fr
om
Bas
elin
e
148 139 120 107 100 84 132 107 3573n =
12 24 48 72 96 120 144 12 24 48
Weeks12 24 48 72 96 120 1444 8 12 24 484 8
Ruxolitinib Placebo
153 152 150 141 130 110 102n = 147 141 136 109 4790 79
Mea
n P
erce
nta
ge
Ch
ang
e fr
om
Bas
elin
e
Spleen Volume Spleen Length
ASH 2013
Improvements in EORTC QLQ-C30 Over Time
Arrows indicate improvementRUX PBO
Global Health Status/QoL
Mea
n C
han
ge
Fro
m B
asel
ine
0 12 24 36 48 72 96 120 144Weeks
20
10
0
-5
-15
15
5
-10
60 84 108 132
Fatigue
Mea
n C
han
ge
Fro
m B
asel
ine
0 12 24 36 48 72 96
Weeks
10
0
-10
-15
-25
-35
5
-5
-20
-30
60 84 120 144108 132
Physical Functioning
Mea
n C
han
ge
Fro
m B
asel
ine
Weeks
15
5
-5
-10
10
0
0 12 24 36 48 72 9660 84 120 144108 132
Role Functioning
Mea
n C
han
ge
Fro
m B
asel
ine
Weeks
25
10
0
-5
-15
-25
15
5
-10
-20
20
0 12 24 36 48 72 9660 84 120 144108 13220
ASH 2013
Overall Survival
*By week 80, all patients originally randomized to placebo discontinued or crossed over to ruxolitinib therapy 21
153 144 129 114 105Placebo 154 149 134 119 107 100 92 85 8 0100 95 88 79 3882 68 28
155 148 143 131 124 115 111 108 1 0Ruxolitinib
Number of patients at risk
155 153 145 137 125 122 112 111 101 45106 84 19
Randomized to Placebo Ruxolitinib
Randomized to Ruxolitinib
1.0
0.8
0.6
0.4
0.2
00 8 24 40 56 72 88 104 120 136 168 176
Pro
bab
ilit
y
Weeks16 32 48 64 80 96 112 128 152144 160
4 22 54 88 99 100 100 100 100 10013 35 73 97 100 100 100 100 100100 100 100
HR=0.69 (95% CI: 0.46, 1.03); P=0.067
No. of deaths: Ruxolitinib=42; Placebo=54
Median follow-up: 149 weeks
Percent of at-risk placebo who crossed over or discontinued
*
• Overall survival favored patients originally randomized to ruxolitinib compared with patients originally randomized to placebo
ASH 2013
Overall Survival: Rank-Preserving Structural Failure Time (RPSFT) Analysis
1.0
0.8
0.6
0.4
0.2
00 8 24 40 56 72 88 104 120 136 168 176
Pro
bab
ilit
y
Weeks16 32 48 64 80 96 112 128 152144 160
HR=0.36 (95% CI: 0.204, 1.035)
Placebo Ruxolitinib
Ruxolitinib
Placebo-RPSFT
22
• 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.
ASH 2013
Mean Platelet Count and Hemoglobin Level Over Time
Platelet Count Hemoglobin
23
85
90
95
100
105
110
115
0 12 24 36 48 60 72 84 96 108 120 132 144
WeeksM
ea
n H
em
og
lob
in (
g/L
)120
170
220
270
320
0 12 24 36 48 60 72 84 96 108 120 132 144
Weeks
Me
an
Pla
tele
ts (
x1
09/L
)
128 82PBO
144 136 112 107 100 88RUX
Number of patients
151
155
112 37
143 124 110 104 94 79
132 83
145 136 113 107 100 88
151
155
113 37
143 124 110 104 94 79
Number of patients
370Ruxolitinib Placebo Ruxolitinib Placebo
ASH 2013
Incidence of New Onset All Grade Non-hematologic Adverse Events Regardless of Causality
24
Incidence (%)Ruxolitinib
0–<12 months (n=155)
12–<24 months (n=130)
24–<36 months (n=103)
≥36 months(n=82)
Fatigue 29.0 15.2 15.3 7.7
Diarrhea 27.8 6.7 10.8 3.9
Ecchymosis 21.2 10.4 5.7 0
Peripheral edema 21.3 8.4 12.6 0
Dyspnea 19.2 10.2 2.9 3.3
Dizziness 18.1 10.4 3.0 3.5
Pain in extremity 18.0 6.2 4.2 3.3
Headache 16.6 5.1 2.7 0
Nausea 16.6 6.8 5.1 5.9
Constipation 14.5 8.6 10.1 9.0
Abdominal pain 13.8 5.7 3.6 0
Insomnia 13.8 5.7 3.7 0
Vomiting 13.7 2.8 2.4 5.5
Pyrexia 13.5 7.3 8.5 2.9
Cough 13.1 13.3 4.0 6.0
Arthralgia 11.8 5.8 6.6 6.3
Upper respiratory tract infection
7.7 11.1 4.0 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.
ASH 2013
Incidence of New Onset Grade 3 or 4 Non-hematologic Adverse Events Regardless of Causality
25
Incidence (%)
Ruxolitinib
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.
ASH 2013
BM Morphology in a Ruxolitinib-Treated Patient: A Case Demonstrating Improvement on Ruxolitinib
26
Baseline BiopsyGrade 3
24 MoPost Ruxolitinib
Grade 2
48 MoPost Ruxolitinib
Grade 0
Kvasnicka HM, et al. ASCO. 2013 (abstr 7030). Permission to use images from Kvasnicka, HM
ASH 2013
Dynamics of BM Changes Following Ruxolitinib Treatment at 48 Mo
27
Kvasnicka, et al. ASH 2013. Abstract 4055.ASH 2013
JAK1 & 2 Inhibitors in MPNs – Efficacy Summary – As of ASH 2013
Myelofibrosis PolycythemiaVera
EssentialThrombocythemia
Spleen Const.Sympt.
Anemia Survival Counts
Const.Sympt.
VascEvents
Counts
Const.Sympt.
VascEvents
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
Pacritinib-PIII Ongoing (Persist MF)
P II P II P II
CYT387 P II P II P II
LY2784544 P I P I
NS-018
BMS-911543 PH II PH II
INCB039110 (JAK1 Alone)
P I P I PI
CEP701 P II P II P II P II P II P II©2011 MFMER | 3133089-28
NotReported
Yet
Yes No
Occasional Ongoing Trials
JAK1 & 2 Inhibitors in MPN – Toxicity ASH 2013Hematological
ToxicitiesGastrointestinal/ Renal
ToxicitiesNeurological
Toxicities
Anemia ANC
PLT
Nausea Diarr-hea
LFTsOr CR
Lipase
Head-ache
Dizzy NeuroP/Parathia
Ruxolitinib - Approved
23% 7% 11% 2% 0.6%
SAR302503 – PIII Ongoing (MF)
41% 6% 11% 0% 5% 1% W. E.% ?
Pacritinib-PIII Ongoing (MF)
6% 0% 18% 6%
CYT387PII Ongoing (MF)
10% 2% 20% 1%
INCB039110 (JAK1) – PI/II MF
28% 27% 10%
BMS 911543 3% 10% 10% 0% 0% 0% 0%
LY2784544 3% 0% 3% 8% Renal
©2011 MFMER | 3133089-29
<10%11-
20%21-
30%31-
40%41-
50%51-
60%61-
70%71-
80%81-
90%91-
100%
Toxicity Color – Represents All Grades ( Grade ¾ Toxicity - Percentage in Table Above)
Myeloproliferative NeoplasmsHematology Highlights 2014
•Burden and Biology of MPNs
•JAK2 Inhibition in 2014
•JAK2 Inhibition and beyond
MPNs – Plateau vs. Decline
©2011 MFMER | 3133089-31
ET – Possible PlateauAsymptomatic ThrombocytosisNo Vascular Events
ET – Possible Plateau 2Symptomatic ThrombocytosisSinus Venous Thrombosis
Time
Clinical Status
PV – Possible Plateau 2Symptomatic ErythrocytosisNo Vascular Events
Post PV MF6 Months worsening Fatigue10 kg weight lossMassive spleen
MF on Successful JAK2 RxImproving WeightDecreased SpleenImproved Survival
MPNs – Cumulative Benefits
©2011 MFMER | 3133089-32Time
Clinical Status
Improved Symptom Burden
Improved Spleen Burden
Improved SurvivalRuxolitinib
MPNs – Cumulative BenefitsSingle Agent Trials JAK2 InhibitorsCompared to Ruxo
©2011 MFMER | 3133089-33Time
Clinical Status
Improved Symptom Burden
Improved Spleen Burden
Improved Survival
? Other Benefit-Less cytopenias-Improved activity
STUDY (JAK2/FLT3 Inhibitor) NS-018 (PH I/II)NCT01423851
STUDY (JAK2/FLT3 Inhibitor)Pacritinib (SB1518) (PH III vs. BAT)
NCT01773187
STUDY (JAK2 Inhibitor – Also ET and PV) LY2784544 (PH I/II)
NCT01520220
STUDY (JAK2/JAK1 Inhibitor)Momelotinib (CYT387) (PH III vs. Ruxo)
NCT001969838
MPNs – Cumulative BenefitsRuxolitinib + drug X for Anemia
©2011 MFMER | 3133089-34Time
Clinical Status
Improved Symptom Burden
Improved Spleen Burden
Improved Survival
Improved Anemia Burden
STUDY COMBINATION (JAK2 PLUS Androgen)Ruxolitinib Plus Danazol
Mayo Clinic (AZ) and Mt. Sinai Trial: NCT01732445
STUDY COMBINATION(JAK2 PLUS Hypomethylation)
Ruxolitinib Plus AzacitidineMDACC Trial: NCT01787487
STUDY COMBINATION (JAK2 PLUS IMID)Ruxolitinib Plus Lenalidomide
NCT01375140
STUDY COMBINATION (JAK2 PLUS IMID)Ruxolitinib Plus PomalidomideGermany (ULM): NCT01644110
MPNs – Cumulative BenefitsRuxolitinib + drug X for Deeper Marrow Changes Impact
Clinical Status
Improved Symptom Burden
Improved Spleen Burden
Improved Survival
Improved Marrow Dysfunction
STUDY COMBINATION (JAK2 PLUS HDAC Inhibitors)Ruxolitinib Plus Panobinostat
Mt. Sinai Trial: NCT01693601UK Trial: NCT01433445
STUDY COMBINATION (JAK2 PLUS LOXL2 Inhibitors)
Ruxolitinib Plus GS-6624NCT01369498
STUDY COMBINATION (JAK2 PLUS rhPTX-2 (Anti-fibrosing))
Ruxolitinib Plus PRM -151Opening Soon
STUDY COMBINATION (JAK2 PLUS PI3 Kinase Inhibitor)
Ruxolitinib Plus BKM120NCT01730248
STUDY COMBINATION (JAK2 PLUS Hedgehog Inhibitor)
Ruxolitinib Plus LDE225NCT01787552
MPNs – Cumulative BenefitsSingle Agent Trials Alternate Targets
Time
Clinical Status
Improved Symptom Burden
Improved Spleen Burden
Improved Survival
? Other Benefit-Less cytopenias-Improved activity
STUDY (Interferons)Peg Interferon α2b in “Early” MF
Cornell Lead: NCT01758588
STUDY (Activin - ActRIIA-IgG1Fc) Sotatercept (ACE 011)MDACC: NCT01712308
STUDY (Telomerase Inhibitor)Imetelstat (GRN163L)
Mayo Clinic (Rochester): NCT01731951
STUDY (JAK1 Inhibitor) INCB039110 (PH II)
NCT01633372
Imetelstat: A Telomerase Inhibitor
imetelstat binds to RNA template preventing maintenance of telomeres
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
• Highly upregulated in malignant progenitor cells, enabling continued and uncontrolled proliferation
Imetelstat:
• 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
(hTR)
– 37 –
(hTERT)
Tefferi et. al. ASH 2013
Preliminary efficacy results from Mayo Clinic investigator-sponsored trial of imetelstat in myelofibrosis
– 10 –
Geron’s independent efficacy analysis of the first 22 MF patients enrolled in the study
Tefferi et. al. ASH 2013
Preliminary efficacy results from Mayo Clinic investigator-sponsored trial of imetelstat in myelofibrosis
– 10 –
Geron’s independent efficacy analysis of the first 22 MF patients enrolled in the study
Tefferi et. al. ASH 2013
100 mg BID 200 mg BID 600 mg QD-20
0
20
5.0
-14.1
-9.9
Change in Spleen Volume at Week 12 by Dose Cohort
40
Per
cen
tag
e C
han
ge
Fro
m
Bas
elin
e at
Wee
k 12
n=7
n=9
*Only patients with baseline and week 12 data were included.
Median % Change in Spleen Volume*
n=38
INCB039910 ASH 2013- Mascarenhas et. al
Improvement in TSS at Week 12 by Dose Cohort
100 mg BID 200 mg BID 600 mg QD0
10
20
30
40
50
60
22.2
34.9
50.0
41
Per
cen
tag
e o
f P
atie
nts
Per
cen
tag
e C
han
ge
Fro
m
Bas
elin
e at
Wee
k 12
n=9 n=43
*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.
≥50% Reduction in TSS*100 mg BID 200 mg BID 600 mg QD
-100
-80
-60
-40
-20
0
-28.5
-45.8
-76.8
Median % Change in TSS†
n=10
n=6 n=34 n=8
INCB039910 ASH 2013- Mascarenhas et. al
Mean Hemoglobin Levels Over Time by Dose Cohort
0 2 4 6 8 10 129.0
9.5
10.0
10.5
11.0
11.5
12.0
12.5
13.0
42
0 2 4 6 8 10 129.0
9.5
10.0
10.5
11.0
11.5
12.0
12.5
13.0
Weeks Weeks
Mea
n (
±SE
M)
Hem
og
lob
in (
g/d
L)
Mea
n (
±SE
M)
Hem
og
lob
in (
g/d
L)
10 10 9 8 8 6 6 100 mg BID45 45 45 41 43 39 37 200 mg BID29 21 10 9 10 9 9 600 mg QD
7 7 7 6 6 4 424 24 24 22 23 21 2219 15 6 6 6 5 6
n, patients
Patients entering the study without transfusion requirements*
All Patients
*Receipt of 2 or more units of red blood cell product transfusions in the 12 weeks prior to day 1.
100 mg BID 200 mg BID 600 mg QD
100 mg BID200 mg BID600 mg QD
n, patients
INCB039910 ASH 2013- Mascarenhas et. al
MPNs – Cumulative BenefitsDifficult PV-ET
Clinical Status
Improved Symptom Burden
Improved Spleen Burden
Improved Survival
Improved Marrow Dysfunction
STUDY COMBINATION (PV)Ruxolitinib Vs. Hydroxyurea (RELIEF)
NCT01632904
STUDY (ET and PV) MPD-RC 112 Peg Inf a2a vs. Hydroxyurea (PH III)
NCT01259856
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
FUTURE STUDY COMBINATIONJAK2 Inhibitor Plus PEG INF a 2a/b
Improved Vascular Event Risk (?PV)
Patient Goals & Input
Improving Symptom Burden/HR QOL
“Balancing” Spleen/ Cytoses/ Cytopenias
Extending Life
CURE
©2011 MFMER | 3133089-44
Individualizing MPN Pharmacotherapy
©2011 MFMER | 3133089-46
Acknowledgements Argentina Ana Clara Kneese, MDFederico Sackmann, MD Australia David M Ross MBBS, PhDCecily Forsyth John Seymour, MBBS, PhD Karen Hall, MD Kate Burbury MD Tam Constantine, MD Canada Lynda Foltz, MDVikas Gupta, MD China Hsin-An Hou, MD Huan-Chau Lin, MD Hung Chang, MDMing-Shen Dai, MD Yuan-Bin Yu, MD Yung-Chen Su, MD Zhijian Xiao, MD Denmark Christen Lykkegaard Andersen, MD Hans Hasselbalch, MDFrance Brigitte Dupriez, MD Jean-Jacques Kiladjian, MD Jean-Loup Demory MDMagali Demilly, PhD Germany Heike L. Pahl, PhD
Ireland
Mary Francis McMullen, MDIsraelMartin Ellis, MD Italy Alessandro M. Vannucchi, MD Francesco Passamonti, MD Giovanni Barosi, MD Tiziano Barbui, MD Netherlands Harry Schouten, MD, PhD Jan Jacques Michiels, MDKarin Klauke, MDPeter te Boekhorst, MD Sonja Zweegman, MD PhD Stephanie Slot, MD Suzan Commandeur, MD New Zealand Hilary Blacklock, MD Panama Francis Guerra, MDSingapore 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 USAAlison Moliterno, MD Brady Stein, MD MHS Casey O'ConnellCatriona 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