1. Tips on using ruxolitinib
in everyday practice
Srdan (Serge) Verstovsek
M.D., Ph.D.
Professor of Medicine
Department of Leukemia
University of Texas
MD Anderson Cancer Center
Houston, Texas, USA 1

2. 3-Year Update From COMFORT-I
Ruxolitinib (n = 155)
Placebo
(n = 151)
Placebo Ruxolitinib (n = 111)
Median exposure, weeks
145 37
105
Still on treatment, n (%)
77 (49.7)
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
9 (22.5)
8 (14.8)
Consent withdrawn
12 (15.4)
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.

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

4. Reduction in MF-Related Symptoms by Spleen Volume Reduction at Week 24
Total Symptom Score
Mean % Change From
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%
Improvement
Worsening
P value vs all placebo.

5. Durability of Spleen Volume Reduction
1.0
≥10% reduction (n = 90)
0.8
0.6
Probability
≥35% reduction
0.4
0.2 8 16 24 32 40 48 56 64 72 80 88 96
104
112
No. at risk
Weeks From Onset 90 84 75 72 63 57 52 47 43 41 35 4 4 4
90/155 (58%) had a 35% reduction at any time point during the study
64% maintained a ≥35% reduction for at least 2 years

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

7. Duration of Symptom Improvement
Global Health Status/QoL
Mean Change From Baseline BL 12 24 36 48 60 72 84 96
Weeks 20 10 -5
-10
-15 15 5
Fatigue BL 12 24 36 48 60 72 84 96 10
-10
-15
-20
-25 5 -5
Weeks
Ruxolitinib
Placebo
Role Functioning
Physical Functioning 15 15 10 10 5 5
Mean Change From Baseline -5
-10 -5
-15
-20 BL 12 24 36 48 60 72 96 84
Weeks
-10 BL 12 24 36 48 60 72 96 84
Weeks
Arrows indicate improvement.

8. Improved Exercise Capacity and Body Weight
6-minute walk test (6MWT) is well established measure of exercise capacity
MF patients walk meters less than age-matched healthy volunteers 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
Change in Body Weight, kg
Ruxolitinib phase I/II

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

10. Incidence of New Onset Grade 3 or 4 Anemia and Thrombocytopenia Over Time
Ruxolitinib Grade 4
Ruxolitinib Grade 3
Placebo Grade 3
Placebo Grade 4
Anemia
Thrombocytopenia
9.9
2.9
0.7
All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis; therefore, data for patients receiving placebo is shown for 0–<6 months only

11. Mean Platelet Count and Hemoglobin Level Over Time
370
115
Ruxolitinib
Placebo
Ruxolitinib
Placebo
110
320
105
270
Mean platelets (x109/L)
Mean hemoglobin (g/L)
100
220 95
170 90
120 85 12 24 36 48 60 72 84 96
108
120
132
144 12 24 36 48 60 72 84 96
108
120
132
144
Weeks
Weeks
Number of patients
Number of patients
RUX
155
144
143
136
124
112
110
107
104
100 94 88 79
155
145
143
136
124
113
110
107
104
100 94 88 79
PBO
151
128
112 82 37
151
132
113 83 37

12. Development of Anemia Does not Affect Response to Ruxolitinib Treatment

13. Mean Daily Dose of Ruxolitinib Over Time25
20 mg BID starting dose
15 mg BID starting dose 20 15
Mean Daily Dose (mg, BID) ± SEM 10 5 8 16 24 32 40 48 56 64 72 80 88 96
104
112
120
128
136
144 98 62
20 mg BID 49 20
15 mg BID
Number of patients
100 55 77 69 33 26 73 30 93 35
Weeks
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 mg BID, respectively

14. 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!!!

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

16. Consideration in everyday practice 1
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
Erythropoietin
Low dose thalidomide
2. start with the lower dose (same as for patients with low platelets): 5mg BID or 10mg BID, and increase in monthly increments

17. Ruxolitinib in Patients With
Low Platelet Counts
starting dose of ruxolitinib 5 mg twice daily, with escalations to maximum 15 mg twice daily in patients with MF and platelets 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

18. Modified Dose Escalation of Ruxolitinib: A Feasible Therapeutic Approach
26 patients received dose escalation approach: Starting with 5 mg BID and escalating monthly
16 received standard dose: Starting with 15 or 20 mg BID
“A dose escalation approach for ruxolitinib therapy is better tolerated and with preserved clinical responses compared to the standard dosing regimen in patients with myelofibrosis”
Tabarroki A, et al. Blood. 2013;122: Abstract 1586.

19. 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
PBO
Fatigue
25.7
31.9
5.8
7.9
8.4
5.4
Diarrhea
23.2
22.9
5.7
3.4
10.3
Ecchymosis
18.1
9.2
5.5
4.3
1.6
Dyspnea
16.8
16.1
4.5
6.4
4.8
4.9
Peripheral edema
16.7
5.3
6.3
5.1
Headache
15.5
5.0
0.9
2.1
1.5
Dizziness
14.2
6.5
3.2
Nausea
12.8
17.0
5.2
3.0
8.0
Constipation
12.0
12.1
4.2
5.9
8.7
Vomiting
10.8
2.5
1.0
4.0
Pain in extremity
11.4
10.7
8.5
Pyrexia
11.3
2.4
3.7
6.7
8.2
Insomnia
2.0
2.8
4.1
Abdominal pain
10.1
40.7
Arthralgia
4.4

20. What happens if therapy with ruxolitinib is interrupted?
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
Days Around Dose Change
Return of the symptoms within 7 days:
AVOID INTERRUPTIONS!!!

21. 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: /person- year
Originally randomized to placebo: /person-year
Historical control: 0.038/person-year
No evidence of an increased risk of leukemic transformation

22. 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

23. Effects of Five Years of Ruxolitinib Therapy on Bone Marrow Morphology in Patients With Myelofibrosis and Comparison With Best Available Therapy
Kvasnicka HM, et al. Blood. 2013;122: Abstract 4055.

24. Recent publications of interest
Ruxolitinib leads to improvement of pulmonary hypertension in patients with myelofibrosis.
Tabarroki A, et al. Leukemia 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 Nov 25. [Epub ahead of print]

25. 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, ; log-rank P = .009)

26. 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).

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

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

29. WHAT IS NEXT: combination trials with JAK2 inhibitors
To increase benefits seen with JAK2 inhibitors
(splenomegaly, symptoms) as well as to bring additional benefits (anemia, BM fibrosis, clone elimination)
To reduce unwanted side effects (anemia, thrombocytopenia) but maintain clinical benefits
MOST IMPORTANTLY:
To improve stem cell transplant result

30. THANK YOU