Treatment of High Risk Myelofibrosis. Dr. Steve Kornblau

1. STEVEN M KORNBLAU, MD
Houston, USA
• Professor of Medicine, UT MD Anderson Cancer
Center
• He was a fellow in Hematology and Oncology at the
MD Anderson Cancer Center from 1988 through 1991
and also completed six months of training at the Royal
Free Hospital in London, after which he joined the
faculty at MD Anderson in 1991 and became a full
professor in 2007. He holds a dual position in the
department of leukemia and the department of stem
cell transplantation and cellular therapy. Dr. Kornblau’s
laboratory research focuses on protein expression
patterns in hematological malignancies. Additionally,
he runs the Leukemia Sample Bank at MDACC, one of
the largest leukemia and myeloma tissue repositories
in the world..

2. Therapy of High Risk
Myelofibrosis in 2015
Steven M. Kornblau, M.D.
Departments of Leukemia &
Stem Cell Transplantation and Cellular Therapy
UT MD Anderson Cancer Center
Houston, Texas
Slides courtesy of Drs. Srdan Verstovsek and Naveen Pemmeraju

3. Diagnosis of myelofibrosis
Diagnosis requires meeting all 3 major criteria
and at least two minor criteria.
Blood analysisBone marrow biopsy
Palpable splenomegaly
Does not meet criteria for
other myeloid disorder
Fibrotic or hypercellular
bone marrow
Clonal marker or absence
of reactive fibrosis
Major WHO diagnostic criteria3
Minor WHO diagnostic criteria3
Anemia
Leukoerythroblastosis
Increased serum lactate
dehydrogenase (LDH)
1. Barbui T, et al. J Clin Oncol. 2011; 29: 761-770;
2. Chou JM, et al. Leuk Res. 2003; 27: 499-504;
3. 2008 WHO Diagnostic Criteria for PMF (Vardiman JW, et al. Blood. 2009; 114: 937-951).
Physical exam

4. Myelofibrosis

5. Cervantes et al., Blood 2009;113:2895-2901
Prognostic factors
• Age > 65 years
• Constitutional symptoms
• Hb < 10 g/dL
• Leukocytes > 25 x 109/L
• Blood blasts > 1%
0
.1
.2
.3
.4
.5
.6
.7
.8
.9
1
Probability
0 24 48 72 96 120 144 168 192 216 240 264 288
Months
95% CI 95% CI 95% CI 95% CI
PMF-PS = 0 PMF-PS = 1 PMF-PS = 2 PMF-PS = 3
Survival by PMF-PS
International Prognostic Scoring System (IPSS):
Risk classification of PMF at Presentation
Risk groups #factors
• Low 0
• Intermediate-1 1
• Intermediate-2 2
• High > 3

6. Main Clinical Problems in MF

7. Scherber R et al. Blood 201;118:401-8
«Constitutional
Symptoms»
Splenomegaly
Myeloproliferation
Role /
Functioning
Symptomatic Burden in MF
Symptoms related to:

8. Activation of the JAK/STAT pathway plays a central
role in MPN pathogenesis
Survival
Differentiation
Proliferation
Oncogenesis
Vannucchi AM et al., CA Cancer J Clin. 2009; 59:171-91

9. 2014: Phenotypic Driver Mutations in MPNs
Gene/hotspot PV ET PMF
JAK2 V617F 93-95% 53-64% 58-65%
JAK2 exon12 2-4% 0 0
MPL W515 0 3-5% 4-8%
CALR 0 16-33% 21-25%
“Triple negative” ----- 12-16% 9-11%
Vainchenker W, et al. Blood. 2011; 118:1723-35; Nangalia J, et al. N Engl J Med. 2013; 369:2391-405; Klampfl T et al. N Engl J Med. 2013;
369:2379 - 90; Rotunno G, et al. Blood. 2014; 123:1552-5; Rumi E, et al. Blood. 2014; 123:1544-51; Tefferi A, et al. Am J Hematol. 2014; epub;
Tefferi A, Leukemia. 2014;epub; Gangat N, et al. Eur J Haemtol 2014; epub; Chen CC, et al. Ann Hematol 2014; epub; Andrikovics H, et al.
Haematologica. 2014; 99:1184 -1190; Qiao C, et al. Haematologica. 2014; epub.
The percentages in this table represent a range of two extremes that have been derived from several studies
cited below

10. Phenotype driver mutations have a strong prognostic
impact in PMF
Rumi E, et al. Blood. 2014; Epub
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 5 10 15 20 25 30
Time, years
Cumulativeprobabilityofsurvival
Overall survival
CALR mutant (median OS 17.7 yr)
JAK2 mutant (median OS 9.2 yr)
MPL mutant (median OS 9.1 yr)
Triple negative (median OS 3.2 yr)
• CALR mutated patients have long anemia-free, thrombocytopenia-free and
marked-leukocytosis-free survival compared with JAK2V617F mutated

11. Risk categories/score
Very LR 0
LR 1
Int 2, 3
HR 4, 5
Very HR >5
Risk factors:
• Age > 65 years (2 point)
• Hb < 10 g/dL (1 points)
• WBC > 25 x109/L (2 point)
• PB Blasts ≥ 1% (1 point)
• Constitutional symptoms (1 point)
• JAK2-mut (1 point)
• MPL-mut (2 points)
• JAK2/MPL/CALR-triple negative (2 points)
Integrated clinical-molecular prognostic model
Rumi et al., Blood 2014

12. Mutations & MPN...the story
continues beyond driver mutations
Genes Chr Mutations Possible pathogenetic mechanisms
TET2 4q24 Across the gene Epigenetic dysregulation
CBL 11q23.3 Exon 8/9 E3 ubiquitin ligase
ASXL1 20q11.1 Exon12 (mainly) Transcriptional repression
LNK 12q24.12 Exon 2 Negative regulator of JAK2 signaling
EZH2 7q36.1 Across the gene Part of histone methyltransferase
(PRC2)
IDH1
IDH2
2q33.3
15q26.1
R132
R172 / R140
Production of an oncometabolite (?)
IKZF1 7p12 Mostly deletion Putative tumor suppressor

13. Mutational profile of MF patients
(483 EU, 396 Mayo)
• 382 (79.1%) had > 1 mut
• 154 pts (32.5%) had >2 mut
• 31 pts (6.4%) had >3 mut
Vannucchi AM et al, Leukemia 2013;27(9):1861-9

14. • A HMR status is associated with reduced OS and increased risk of blast
transformation in PMF patients independent of IPSS/DIPPS-plus
Vannucchi AM et al, Leukemia 2013;27:1861-9
High Molecular Risk Prognostic Category in MF
harboring >1 mutation in any one of ASXL1, EZH2, SRSF2, IDH1/2
Overall Survival Blast Transformation

15. HMR: How many MF patients would be reclassified?
IPSS Risk
Categories
ASXL1
N. (%)
EZH2
N. (%)
SRSF2
N.(%)
IDHs
N. (%)
N (%) Of
HMR
patients
LOW 24/162
(14.8%)
6/165
(3.6%)
7/151
(4.6%)
2/157
(1.3%)
35/166
(21.1%)
INT- 1 28/142
(19.7%)
6/143
(4.2%)
6/136
(4.4%)
6/142
(4.2%)
34 /146
(23.4%)
INT- 2 23/100
(23.0%)
4/99
(4.0%)
9/97
(9.3%)
2/96
(2.1%)
31 /104
(29.8%)
HIGH 27/65
(41.5%)
8/66
(12.1%)
16/63
(25.4%)
1/60
(1.7%)
39/68
(57.3%)

16. Traditional Therapeutic Options for MF
Medicines for
Anemia
•Prednisone
•Androgens
•EPO
•Thalidomide
+/- prednisone
(NOT
Pomalidomide)
Medicines for
Anemia &
Spleen
•Lenalidomide
+/- prednisone
Medicines for
Spleen
•Hydroxyurea
•Busulfan
•2-CDA
•Splenectomy
•Splenic Radiation
“BAT”
Best
Available
Therapy
Medicines for
Symptoms
•Ruxolitinib
•Prednisone

17. • Not selective for mutated JAK2V617F
enzyme (ATP binding inhibitors)
• Lowering of platelets and red blood cells is
expected side effect due to inhibition of
normal JAK2
• However: may benefit patient with and
without JAK2V617F mutation
• JAK-STAT pathway dysregulation, regardless
of JAK2 mutational status, is a key
pathologic feature of MPNs
JAK2 Inhibitors

18. 3-Year Update From COMFORT-I:
Patient Disposition
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
* Percentages are calculated based on the number of patients who discontinued within the respective treatment group.
Verstovsek S, et al. Blood. 2013;122: Abstract 396.

19. Spleen Volume Response: Ruxolitinib vs. BAT
Ruxolitinib BAT
↓ Spleen volume 132 (97%) 35 (56%)
↑ Spleen volume 4 (3%) 28 (44%)

20. Splenomegaly in MF Patient Pre-Therapy

21. Splenomegaly after 2 Months of Therapy

22. Total Symptom Score
Mean%ChangeFrom
Baseline±SEM
70
30
-10
-50
-70
50
10
-30
n = 99
n = 20
P = .0004
n = 46
P<.0001
n = 60
P<.0001
All Placebo
Ruxolitinib
Spleen Volume Reduction
<10% 10 to <35% ≥35%
ImprovementWorsening
Reduction in MF-Related Symptoms by
Spleen Volume Reduction at Week 24
P value vs all placebo.
Mesa et J Clin Oncol. 2013 Apr 1;31(10):1285-92.

23. Durability of Spleen Volume Reduction
• 90/155 (58%) had a 35% reduction at any time point during the study
• 64% maintained a ≥35% reduction for at least 2 years
≥10% reduction
(n = 90)
≥35% reduction
1.0
0.8
0.6
0.4
0.2
0
0 8 16 24 32 40 48 72 80 88 104 112
Probability
Weeks From Onset
9656 64
84 75 72 63 57 52 47 41 35 4
No. at risk
90 4 443
Verstovsek S, et al. ASH 2013, New Orleans, USA, Abstr. 396

24. Improvement in Symptoms
Worsening Improvement
Overall Adjusted Mean Change From Baseline Score
*
*
*
*
*
*
Fatigue
Dyspnea
Financial impact
Appetite loss
Insomnia
Pain
Diarrhea
Constipation
Nausea/vomiting
Ruxolitinib
BAT

25. Fatigue
BL 12 24 36 48 60 72 84 96
10
0
-10
-15
-20
-25
5
-5
Weeks
Duration of Symptom Improvement
Ruxolitinib Placebo
Global Health Status/QoL
MeanChangeFromBaseline
BL 12 24 36 48 60 72 84 96
Weeks
20
10
0
-5
-10
-15
15
5
Physical Functioning
10
-10
15
-5
0
5
BL 12 24 36 48 60 72 9684
Weeks
Arrows indicate improvement.
Role Functioning
15
MeanChangeFromBaseline
10
-10
0
-20
BL 12 24 36 48 60 72 9684
Weeks
5
-5
-15
Verstovsek S, et al. Blood 2013 122:396

26. Improved Exercise Capacity and Body Weight
 6-minute walk test (6MWT) is well established measure of exercise capacity
 MF patients walk 60-90 meters less than age-matched healthy volunteers
Ruxolitinib phase I/II
1 Month 3 Months 6 Months
0
10
20
30
40
50
60
70
80
N=27
N=26
N=21
34 Meters
57 meters
71 meters
Changein6MWTPerformance(meters)
Time on Study
28 56 84 112 140 168
-9.5
-7.5
-5.5
-3.5
-1.5
0.5
2.5
4.5
6.5
8.5
10.5
12.5
Mean Lowest Quartile
Days on Study
ChangeinBodyWeight,kg

27. Incidence of New Onset Grade 3 or 4
Anemia and Thrombocytopenia Over Time
29.0
4.1 4.8 5.3
0
11.5
3.4
1.9
0 0
0
5
10
15
20
25
30
35
40
45
50
0–<6 6–<12 12–<18 18–<24 ≥24
PercentageofPatients
Months
8.7
1.6 1.9
0 0
3.4
1.6 0.9
0 0
0
5
10
15
20
25
30
35
40
45
50
0–<6 6–<12 12–<18 18–<24 ≥24
PercentageofPatients
Months
Anemia Thrombocytopenia
• Discontinuation of treatment because of anemia and thrombocytopenia
was rare (1 patient in each treatment group for each event)
Ruxolitinib Grade 4Ruxolitinib Grade 3
Placebo Grade 3 Placebo Grade 4
9.9
2.9
0.7 0
Verstovsek S, et al. Blood. 2012;120: Abstract 800.

28. Efficacy of ruxolitinib in patients with MF
without clinically significant splenomegaly
• All pts were symptomatic
• Ruxolitinib was
administered at the dose of
25mg BID
Patients with MF n=6
Fatigue
improved
6
Resolution of
night sweats
2
Itching 2
Weight gain
(up to 17%)
5
Improved
performance
status
6
Reduction of
liver size 50-68%
3 of 3
Benjamini et. al., Blood 2012; 120:2768-2769

29. Mean Platelet Count and
Hemoglobin Level Over Time
Platelet count Hemoglobin
85
90
95
100
105
110
115
0 12 24 36 48 60 72 84 96 108 120 132 144
Weeks
Meanhemoglobin(g/L)
120
170
220
270
320
0 12 24 36 48 60 72 84 96 108 120 132 144
Weeks
Meanplatelets(x109/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
370
Ruxolitinib Placebo Ruxolitinib Placebo

30. Verstovsek S, et al. Oral presentation at ASCO Annual Meeting; June 3-7, 2011. Abstract 6500.
Development of Anemia Does not Affect
Response to Ruxolitinib Treatment

31. Mean Daily Dose of Ruxolitinib Over Time
• 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
MeanDailyDose(mg,BID)±SEM
0 8 16 24 32 72 104 136 14448 88 1206456 96 12840 80 112
Weeks
20 mg BID starting dose
15 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
Verstovsek S, et al. Blood 2013 122:396

32. Optimizing Dose Titration of Ruxolitinib:
The COMFORT-I Experience
• Baseline platelet count of less than 150 × 109/L
was highly predictive of titration to a dosage of
≤10 mg BID within the first 8 weeks of ruxolitinib
therapy
• Baseline hemoglobin value of less than 10 g/dL
was highly predictive of an anemia event
(developed grade ≥3 anemia or required RBC
transfusion) within the first 12 weeks of
ruxolitinib therapy
• Dose titration is a key!!!
• Avoid interruptions!!!
Ruben A, et al. Blood. 2013;122: Abstract 4062.

33. Efficacy by Titrated Dose
Titrated dose is defined as the average dose patients received in the last 4 weeks before assessment.
n=101
n=24 n=26 n=23 n=39 n=21
Spleen Volume
n=103
n=22 n=26 n=23 n=38 n=20
Total Symptom Score
n=35
n=28 n=20 n=31 n=17n=24
Week
24
Week
48

34. What happens if therapy with ruxolitinib
is interrupted?
Days Around Dose Change
Number of patients:
34 33 33 34 34 33 33 33 36 37 39 40 40 40 34 29 26 23 24 24 22 22 22 20 21 20 18 17 15
• Return of the symptoms within 7 days:
AVOID INTERRUPTIONS!!!

35. Recent publications of interest
35
Ruxolitinib leads to improvement of pulmonary
hypertension in patients with myelofibrosis.
Tabarroki A, et al. Leukemia. 2014 Jan 10. [Epub ahead
of print]
Restoration of response to ruxolitinib upon brief
withdrawal in two patients with myelofibrosis.
Gisslinger H, et al. Am J Hematol. 2013 Nov 25. [Epub
ahead of print]

36. COMFORT-I: Incidence of new onset nonhematologic
adverse events over time regardless of causality
Percent of patients
0–<6
months
6–<12
months
12–<18
months
18–<24
months
≥24
months
RUX Placebo RUX RUX RUX RUX
Fatigue 25.7 31.9 5.8 7.9 8.4 5.4
Diarrhea 23.2 22.9 5.7 5.7 3.4 10.3
Ecchymosis 18.1 9.2 5.5 4.3 1.6 0
Dyspnea 16.8 16.1 4.5 6.4 4.8 4.9
Peripheral edema 16.7 23.2 5.3 6.3 4.8 5.1
Headache 15.5 5.0 0.9 2.1 1.5 0
Dizziness 14.2 6.5 5.3 6.5 3.2 4.5
Nausea 12.8 17.0 5.2 3.0 0 8.0
Constipation 12.0 12.1 4.2 5.9 4.3 8.7
Vomiting 12.0 10.8 2.5 1.0 0 4.0
Pain in extremity 11.4 10.7 8.5 4.3 1.6 0
Pyrexia 11.3 6.4 2.4 3.7 6.7 8.2
Insomnia 10.7 10.7 4.2 2.0 2.8 4.1
Abdominal pain 10.1 40.7 5.0 4.9 0 8.2
Arthralgia 10.1 7.9 2.5 5.0 0 4.4
Verstovsek S, et al. Blood 2013 122:396

37. Additional Safety Findings: COMFORT-I
• AML
─ After 3 years of follow up:
 4 cases in patients originally randomized to ruxolitinib
and 4 in patients originally randomized to placebo
─ Rate of leukemic transformation per person year of
ruxolitinib exposure
 Originally randomized to ruxolitinib: 0.0121/person-
year
 Originally randomized to placebo: 0.0233/person-year
 Historical control: 0.038/person-year
─ No evidence of an increased risk of leukemic
transformation

38. COMFORT-I: Reduction of
JAK2V617F Allele Burden on
Ruxolitinib
• Median variation on placebo
• + 3.5% at week 24
• + 6.3% at week 48
• Median variation on ruxolitinib:
• - 10.9% at week 24
• - 21.5% at week 48
Verstovsek et al. N Engl J Med. 2012 Mar 1;366(9):799-807.

39. Change in BM Fibrosis Grade Over Time
HU and Ruxolitinib*
48 mo
* Compilation of data - not a formal comparison
** Logistic regression method
Kvasnicka HM, et al. J Clin Oncol 31, 2013 (suppl; abstr 7030)
0
10
20
30
40
50
60
70
80
Improvement Stabilization Worsening
0
10
20
30
40
50
60
70
80
Improvement Stabilization Worsening
15%
57%
37%
22%
56%
25%
10%
41%
65%
0%
44%
74%
RUX
HU
Odds Ratio [95% CI]** for
worsening BM fibrosis at 24 mo
Odds Ratio [95% CI]** for
worsening BM fibrosis at 48 mo
Rux 0.32 [0.12 – 0.83] Rux 0.12 [0.03 – 0.50]
24 mo

40. Overall Survival: ruxolitinib vs. placebo
(int-2/high risk MF)
*By week 80, all patients originally randomized to placebo discontinued or crossed over
to ruxolitinib therapy
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
0
0 8 24 40 56 72 88 104 120 136 168 176
Probability
Weeks
16 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
Verstovsek S, et al. Blood 2013 122:396

41. Overall Survival: ruxolitinib vs. BAT
(int-2/high risk MF)
52% reduction in risk of death in the ruxolitinib arm compared to
BAT arm (HR = 0.48; 95% CI, 0.28-0.85; log-rank P = .009)
Harrison C, et al. Haematologica 2014; 99(s1) n. P405

42. Kaplan-Meier Analysis of Overall Survival
COMFORT-I and -II Combined
Ruxolitinib vs control (ITT): HR = 0.65; 95% CI, 0.46-0.90; P = .01.
Ruxolitinib vs control (RPSFT-corrected for crossover) HR = 0.29; 95% CI, 0.13-0.63; P = .01.
Ruxolitinib, n =
1.0
144
0.8
0.6
0.4
0.2
0.0
SurvivalProbability
Weeks
24 48 72 96 120
184285 264 241 221 213
99205 170 154 140 122
6199 158 18 13 11Control, n =
Corrected
for Crossover
Control, n =
Ruxolitinib
Control
Control
Corrected
for Crossover
Vannucchi A, et al. Blood 2013 122:2820

43. Impact Of Ruxolitinib On The Natural History
Of Patients With Primary Myelofibrosis
Patients who introduced ruxolitinib at some point during their disease
history (COMFORT-2) had a better survival when compared to those who
continued standard treatments for the whole follow-up (DIPSS).

44. Impact Of Ruxolitinib On The Natural History
Of Patients With Primary Myelofibrosis
44

45. 4/2008
4/2014

46. Overall survival of patients by degree
of spleen length reduction

47. Ruxolitinib is JAK1 and JAK2 Inhibitor
Potential mechanism of action:
• Inhibits signaling of cytokine
and growth factor receptors
that use JAK1 and JAK2 for
signaling
• Suppresses the growth (JAK2
inhibition) of malignant cells
•Down-regulates the cytokines
(JAK1 and JAK2 inhibition) that
contribute to hypermetabolic
state
Pro-Inflammatory
Cytokines
RUXO XX

48. • Not selective for JAK2V617F (patients with
and without JAK2 mutation benefit)
• Safety: lowering of blood count (not a cause
for stopping therapy), others
• Efficacy:
• excellent therapy for disease-related
symptomatic splenomegaly or general
constitutional symptoms
• prolongation of life in patients with
advanced disease
JAK2 Inhibitors for Myelofibrosis

49. Consideration in everyday
practice:
1. Addition of an “Anemia Drug” to a JAK2 inhibitor
for patients who are already seriously anemic or
become anemic
• Danazol
• Low dose thalidomide
2. Start with the lower dose (same as for patients
with low platelets): 5 mg BID or 10 mg BID, and
increase in monthly increments

50. Consideration in everyday
practice:
1. Addition of an “Anemia Drug” to a JAK2 inhibitor
for patients who are already seriously anemic or
become anemic
• Danazol
• Low dose thalidomide
2. Start with the lower dose (same as for patients
with low platelets): 5 mg BID or 10 mg BID, and
increase in monthly increments

51. • starting dose of ruxolitinib 5 mg twice daily, with escalations to maximum 15 mg
twice daily in patients with MF and platelets 50- 100 x 109/L
• Pts with IPSS int-1/2 or high risk MF (evaluable N = 41)
• At 24 wks, most pts optimized to ruxolitinib dose 10 mg BID or higher; spleen
volume reduction and TSS reduction consistent with data reported in COMFORT-I
Ruxolitinib in Patients With
Low Platelet Counts

52. OPEN-LABEL, MULTICENTER, EXPANDED-ACCESS
STUDY OF RUXOLITINIB IN PATIENTS WITH
MYELOFIBROSIS (JUMP TRIAL)
• 520 patients, intermediate-1, -2, and –high risk patients with
splenomegaly (>5cm), median follow up 11 months
• 29% discontinued (anemia 1.9%, thrombocytopenia 1.4%)
• 59% required dose modification
• At week 24, 56% had 50% reduction in spleen size

53. Serious Adverse Events After Therapy Interruption:
blinded study ruxolitinib vs. placebo
• no report of “withdrawal syndrome”
•Percent of patients that discontinued ruxolitinib
due to side effects was 11%
•Percent of patient that discontinued placebo
due to side effects was 11%
Adverse Event
Ruxolitinib
(n = 155)
Placebo
(n = 151)
Total with interruption, n 49 54
Total SAEs, n 3 3

54. New (er)
in
Jak2

55. 55
Registrational program
First Phase 3 Trial of Pacritinib in Myelofibrosis
Enrollment: Early Jan 2013
Sites: 81 in Europe, Russia, Australia, New Zealand, and U.S.
Principal Investigators: Claire Harrison, M.D., Guy’s Hospital, London
Ruben Mesa, M.D., Mayo Clinic Cancer Center, Arizona
*Cross-over from BAT allowed after progression or assessment of the primary endpoint.
PERSIST-1
Eligibility Criteria
No exclusion for platelet
levels, stratified for platelet
counts of 100,000/µL and
50,000/µL
No prior treatment with
JAK2 inhibitors
2:1
Randomization*
n = 327
Primary Endpoint
% of patients achieving
35% reduction in
spleen size from baseline
to Week 24
Best Available
Therapy (BAT)
excluding ruxolitinib
Pacritinib
No notable data at ASH
Finished recruiting results for ASCO 2015

56. 56
Status: Reached agreement with FDA on SPA in Oct. 2013; Trial initiation
ongoing
Sites: ~120 in U.S., Canada, Europe, Russia, Australia, and New Zealand
Anticipated Patient Accrual: ~10-12 months (target LPFV June 2015)
Principal Investigator: Srdan (Serge) Verstovsek, M.D.
MD Anderson Cancer Center, Texas
PESIST-2
Eligibility Criteria
Patients with platelet
counts ≤ 100,000/µL,
prior/current JAK2 therapy
allowed
1:1:1
Randomization1
n = 300
Co-Primary
Endpoints
% of patients achieving
≥ 35% reduction in
spleen volume from baseline
to Week 24 (MRI/CT)
% of patients achieving ≥
50% reduction in total
symptom score (TSS) from
baseline to Week 24
Best Available
Therapy (BAT)2
Pacritinib
400 mg QD
1 Cross-over from BAT allowed after progression or assessment of the primary endpoint.
2 BAT may include ruxolitinib at the approved dose per its label.
Pacritinib
200 mg BID
PERSIST-2
Second Phase 3 Trial of Pacritinib in Myelofibrosis
PERSIST-2

57. Phase 3 Studies with Momelotinib 200 mg tablet
QD for Myelofibrosis
JAK inhibitor naïve
• Randomized, Double Blind
• Primary endpoint: Spleen Response
by MRI at week 24
Previous JAK inhibitor exposure
• Randomized, Open Label
• Required ruxolitinib dose
adjustment to < 20mg BID and
concurrent hematologic toxicity
• Primary endpoint: Spleen
Response by MRI at week 24
N = 150
2:1
randomization
Momelotinib
N = 100
Ruxolitinib + placebo
N = 420
1:1
randomization
Momelotinib + placebo
Best Available Therapy
(ruxolitinib and no treatment
allowed)
N = 50
Day 1 Week 24 Year 5
Year 5Day 1 Week 24
Only notable data at ASH was with
regard to 40% risk of grade 1
peripheral neuropathy – A1837

58. Beyond JAK2 inhibition:
Novel therapies and
treatment approaches in
Myelofibrosis
New agents to keep an eye out for

59. Beyond JAK2 inhibitors for patients with
MF
• Aurora kinase inhibitors
• BCL-xL inhibitors
• CD123 inhibitors
• HDAC inhibitors: Givinostat, SAHA, Pracinostat
• Hypomethylators
• IFN
• Immunotherapy: Nivolumab
• MDM2 inhibitors
• PRM-151 (anti-fibrotic agent)
• Smac Mimetics
• Tamoxifen
• Telomerase inhibitors: Imetelstat

60. LCL161-regulated signalling pathways are shown.
Fulda S JCO 2014;32:3190-3191
©2014 by American Society of Clinical Oncology
Small molecule inhibitor that
mimics the N-terminal portion of
second mitochondrial-derived
activator of caspases (Smac)
Endogenous IAP antagonist
released from mitochondria
into the cytoplasm during
apoptosis
Phase 1-2 data from Advanced
solid tumors, multiple myeloma,
pancreatic & breast cancer
Smac mimetics in hematologic
malignancies (Bing
Carter)Birinipant + AZA in MDS
clinical trial (PI: G. Borthakur)
Clinical trial underway at MDACC

61. SET-2, 3-Day (10% FBS)
0
400000
800000
1200000
1600000
2000000
0
0
0.01
0.03
0.1
0.3
1
3
10
30
Compound (uM)
CellTiterGloUnits
ABT-199
A-1113567
ruxolitinib
navitoclax
UKE-1, 3-Day (10% FBS)
0
400000
800000
1200000
1600000
2000000
0
0
0.01
0.03
0.1
0.3
1
3
10
30
Compound (uM)
CellTiterGloUnits
ABT-199
A-1113567
ruxolitinib
navitoclax
UKE-1, 3-Day (10% FBS)
0
000
000
000
000
000
0
0
0.01
0.03
0.1
0.3
1
3
10
30
Compound (uM)
ABT-199
A-1113567
ruxolitinib
navitoclax
HEL, 3-Day (10% FBS)
0
400000
800000
1200000
1600000
0
0
0.01
0.03
0.1
0.3
1
3
10
30
Compound (uM)
CellTiterGloUnits
ABT-199
A-1113567
ruxolitinib
navitoclax
SET-2UKE-1
HEL
• Killing of JAK2 V617F cell lines is driven by BCL-XL inhibition
• Navitoclax is more potent than approved JAK2 inhibitor, ruxolitinib
BCL-2
JAK2
BCL-2 and BCL-XL
BCL-XL
ABT-199
ruxolitinib
navitoclax
A-1113567
ViabilityUnitsViabilityUnits
Concentration (mM)
Concentration (mM)
Concentration (mM)
JAK2 V617F Cell Lines Depend on
BCL-XL for Survival

62. JAK2 Inhibitors Reduce MCL-1, Synergize w Navitoclax
MCL-1
BCL-XL
Actin
JAK i (h):
navitoclax (nM)
%Inhibition
JAK2 V617F Cell Line
UKE-1, 3-Day (10% FBS)
0
400000
800000
1200000
1600000
2000000
0
0
0.01
0.03
0.1
0.3
1
3
10
30
Compound (uM)
CellTiterGloUnits
ABT-199
A-1113567
ruxolitinib
navitoclax
ruxolitinib
navitoclax
AZ JAK inhib
ABT-199 was inactive
HEL, ruxolitinib 3-Day (10% FBS)
0
300000
600000
900000
1200000
1500000
0
0.003
0.01
0.03
0.1
0.3
1
3
10
30
Compound (uM)
AlamarBlueUnits
Abbott
navitoclax
AZ
Cell Viability (3days)
ruxolitinib
Driving lesion
BAK BAX BIM
BCL-XLMCL-1
STAT3 navitoclax
Apoptosis
BCL-2
Significant single agent activity vs. JAK2 V617F cells
JAK2

63. ABT-737 reverses
resistance to JAK2
inhibitors
BCL-XL Inhibition Reverses Resistance
to JAK2 Inhibitors
BCL-XL inhibition
sufficient to reverse
resistance

64. ABT-263 (Navitoclax)
• Inhibitor of BCL-2 related family of proteins (BCL-xL,
BCL-w)
• Phase I trials in CLL, lymphoid malignancies, small cell
lung ca and other solid tumors
• Phase I R/R CLL trial: n=29, daily oral navitoclax x 14
days or 21 days (Roberts et al JCO, 2011)
– Nine patients (35%) of 26 patients who received
≥110mg/d achieved PR and 7 maintained SD >6 mo
– Thrombocytopenia
• Ph II trial ABT-263 single agent in patients with MF
– LOI accepted w abbvie, Investigator-Initiated
– Both as single agent and in combination with Ruxolitinib

65. CD123 is a membrane biomarker and
therapeutic target
• IL-3, IL-5, GM-CSF Receptors
share the common signaling
subunit βc
• Each of these 3 Receptors is a
heterodimer
• IL-3 α = CD123
– Found on pluripotent
progenitor cells
– Induces tyrosine
phosphorylation /promotes
proliferation and
differentiation within
hematopoietic cell lines
IL-3 R
α (CD123)
cytokine-
specific
β(common
subunit)
heterodimer
Estrov Z et al Ann Hematol 1991
Testa U, et al Biomarker Research 2014

66. SL-401
• SL-401 is a recombinant protein consisting of human IL-3
linked to truncated diphtheria toxin payload
SL-401 protein (58 kD)
- Receptor-mediated endocytosis.
-Irreversibly blocks protein synthesis
- Induction of apoptosis (A. Frankel,
D. Hogge) CATALYTIC DOMAIN
TRANSMEMBRANE DOMAIN
IL3
IL3IL-3
CATALYTIC
TRANSLOCATION
IL-3
• Single agent clinical activity: AML, BPDCN
• Pilot study in BPDCN: 7/9 patients (78%) had major responses including 5
CR and 2 PR (Frankel et al Blood July 2014)
• High expression in other myeloid malignancies including MPNs, CML,
MDS and CMML
Konopleva, Frankel, Rowinsky

67. SL-401
• Phase I/II (Company: Stemline) PI: N Pemmaraju, Co-
PI: S Verstovsek
• Evaluate MTD in Ph I portion, overall response rate
in Ph II
• Dose-escalation multicenter study
• Target accrual: Stage 1 dose-escalation: 12-36
patients; Stage 2 expansion: up to 72 additional
patients
• 4 different advanced MPNs:
– MF (DIPSS-plus ≥2)
– CMML R/R hypomethylator
– Advanced SM
– Advanced Primary Eosinophilic Disorder

68. Conclusions
• Many promising non-JAK inhibitor therapeutic
approaches for patients with MF as single agents or
in combination
• We have highlighted 3 of these approaches with
upcoming planned clinical trials:
– LCL-161, Investigator Initiated Ph II: MF
– ABT-263, Investigator Initiated Ph II: MF
– SL-401, Company sponsored, Ph I/II: MF, CMML,
SM, PED

70. Hallmarks of Cancer Cells
Hanahan&Weinberg Cell 2011