Transcript Molecular Pathogenesis of Myeloproliferative Neoplasms (MPNs)

ASH 2012: New JAK
Inhibitors for
Myelofibrosis
Srdan (Serge) Verstovsek
M.D., Ph.D.
Professor of Medicine
Department of Leukemia
University of Texas
MD Anderson Cancer Center
Houston, Texas, USA
Long-Term Outcome of Ruxolitinib
Treatment in Patients With
Myelofibrosis: Durable Reductions in
Spleen Volume, Improvements in
Quality of Life, and Overall Survival
Advantage in COMFORT-I
Abstract 800
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V,
DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT,
Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO,
Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S,
Sun W, Sandor V, Kantarjian HM
COMFORT-I
Background
•Placebo-controlled, randomized, double-blind, phase III study
•Ruxolitinib starting doses:
– Baseline platelet count 100-200×109/L: 15 mg BID
– Baseline platelet count >200×109/L: 20 mg BID
•Doses individually titrated based on safety and efficacy
•Ruxolitinib treatment significantly reduced spleen size and improved
myelofibrosis (MF_-related symptoms and QoL and was also
associated with a survival advantage relative to placebo1
Objective
•To describe long-term efficacy and safety of ruxolitinib with 1 year of
additional follow-up beyond previously published data (median
follow-up ~24 months)
Data cutoff for current analysis: March 1, 2012.
1. Verstovsek S, et al. N Engl J Med. 2012;366(9):799-807.
3
Patient Disposition at Current Analysis
Ruxolitinib
(n = 155)
Placebo
(n = 151)
Placebo
Ruxolitinib
(n=111)
Still on treatment
100 (64.5)
0
73 (65.8)
Discontinued
55 (35.5)
40 (26.5)
38 (34.2)
Patients, n (%)
Crossed over
111 (73.5)
Primary reasons for discontinuation
Death
13 (8.4)
10 (6.6)
11 (9.9)
Adverse event
11 (7.1)
9 (6.0)
7 (6.3)
Consent withdrawn
9 (5.8)
6 (4.0)
9 (8.1)
Disease progression
12 (7.7)
12 (7.9)
5 (4.5)
Other
10 (6.5)
3 (2.0)
5 (4.5)
̶
̶
1 (0.9)
Noncompliance with study medication
•
•
All patients receiving placebo at the primary analysis crossed over or discontinued
within 3 months of the primary analysis
Median time to crossover: 41.1 weeks
4
80
Primary Analysis (Week 24)1
Last Available Measurement†
(Median follow-up ~7 months)*
(Median follow-up ~24 months)*
Ruxolitinib (n = 154) Placebo (n = 153)
60
40
20
0
-20
35%
Decrease
-40
-60
-80
Individual Patients
-100
Change From Baseline, %
Change From Baseline, %
Spleen Volume Reduction
80
Ruxolitinib (n = 154) Crossover (n = 111)
60
40
20
0
-20
35%
Decrease
-40
-60
-80
Individual Patients
-100
• Majority of ruxolitinib-treated patients maintained a spleen volume reduction
• Majority of crossover patients experienced spleen volume reduction relative to
original baseline (median follow-up on ruxolitinib: ~14 months)
–
Lesser degree of reduction likely because these patients experienced a period of
spleen growth on placebo before starting ruxolitinib
*Median follow-up for patients originally randomized to ruxolitinib
†Change from baseline to last available spleen volume measurement
1. Verstovsek S, et al. N Engl J Med. 2012;366(9):799-807.
5
Reduction in MF-Related Symptoms by
Spleen Volume Reduction at Week 241
Total Symptom Score
n = 60
P<.0001
n = 99
-30
-50
n = 20
P = .0304
10
-10
n = 44
P = .001
n = 59
P<.0001
Worsening
n = 46
P<.0001
30
n = 96
Improvement
n = 20
P = .0004
10
50
Mean % Change From
Baseline ± SEM
30
Worsening
50
-10
Total Abdominal Symptom Score
70
Improvement
Mean % Change From
Baseline ± SEM
70
-30
-50
-70
-70
All
Placebo
<10%
10 to <35% ≥35%
Ruxolitinib
Spleen Volume Reduction
All
Placebo
<10%
P value vs all placebo.
Total Abdominal Symptom Score: abdominal pain, pain under left ribs, and early satiety.
1. Mesa R, et al. Blood. 2011;118: Abstract 3842.
10 to <35% ≥35%
Ruxolitinib
Spleen Volume Reduction
Durability of Spleen Volume Reduction
1.0
≥10% reduction
(n = 90)
Probability
0.8
0.6
≥35% reduction
0.4
0.2
0
0
8
16
24
32
48
56
64
72
80
88
96
104
41
35
4
4
4
112
Weeks From Onset
No. at risk
90
40
84
75
72
63
57
52
47
43
• 90/155 (58%) had a 35% reduction at any time point during the study
• 64% maintained a ≥35% reduction for at least 2 years
≥35% reduction: Time from first 35% reduction to <35% reduction and 25% increase from nadir.
≥10% reduction: Time from first 35% reduction to <10% reduction from baseline.
7
EORTC QLQ-C30 Over Time
Mean Change From Baseline
Global Health Status/QoL
Fatigue
20
10
15
5
10
0
5
-5
0
-10
-5
-15
-10
-20
-25
-15
BL
12
24
36
48
60
72
84
BL
96
12
24
36
Ruxolitinib
60
72
84
96
Placebo
Role Functioning
Mean Change From Baseline
48
Weeks
Weeks
Physical Functioning
15
15
10
10
5
5
0
-5
0
-10
-5
-15
-20
-10
BL
12
24
36
48
Weeks
60
72
84
96
BL
12
24
36
48
60
72
84
96
Weeks
Arrows indicate improvement.
8
Overall Survival: ITT Population
1.0
Survival Probability
0.8
Ruxolitinib
Placebo
0.6
HR = 0.58 (95% CI: 0.36, 0.95); P = .028
No. of deaths: Ruxolitinib = 27; Placebo = 41
0.4
Median follow-up: 102 weeks
0.2
Age-adjusted HR* = 0.61 (95% CI: 0.37, 0.99); P = .040
0
0
12
24
36
48
60
72
84
96
108
120
132
Weeks
No. at risk
Ruxolitinib
155
154
148
145
136
125
121
113
96
44
6
Placebo
154
148
142
133
117
111
102
95
74
32
7
Note: For this unplanned analysis, P-values are descriptive and nominally significant.
*Age was the only baseline characteristic that differed significantly between treatment groups as reported in Verstovsek S, et al. N Engl J
Med. 2012;366(9):799-807 (median age: ruxolitinib, 66 years; placebo, 70 years; P<.05).
9
Incidence of New Onset Nonhematologic
Adverse Events Regardless of Causality
0–<6
Months
Percent of Patients
6–<12
Months
12–<18
Months
18–<24
Months
≥24
Months
RUX
PBO
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
• No reports of a specific withdrawal syndrome after discontinuation of ruxolitinib
10
Incidence of New Onset Grade 3 or 4
Anemia and Thrombocytopenia Over Time
Ruxolitinib Grade 4
Placebo Grade 3
Placebo Grade 4
50
Anemia
45
45
40
40
Percentage of Patients
Percentage of Patients
50
Ruxolitinib Grade 3
35
30
29.0
25
20
15
10
5
11.5
9.9
2.9
4.1 3.4
Thrombocytopenia
35
30
25
20
15
10
8.7
5.3
4.8
5
1.9
0
0
0
3.4
0.7
0
0
1.6 1.6
1.9
0.9
0
0–<6
6–<12
12–<18
Months
18–<24
≥24
0–<6
6–<12
12–<18
0
0
18–<24
Months
• 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
0
0
≥24
Mean Hemoglobin Levels Over Time
•
Mean hemoglobin nadirs after 8–12 weeks of therapy and recovers to a
new steady state which remains stable with longer-term therapy
Mean Percentage Change From
Baseline
5
Ruxolitinib
Placebo
0
-5
-10
-15
-20
BL
12
24
36
48
60
72
84
96
Weeks
Median hemoglobin at baseline: Ruxolitinib, 105 g/L; Placebo, 105 g/L
12
Hemoglobin Levels Over Time by
Ruxolitinib Titrated Dose
<10 mg BID
10 mg BID
15 mg BID
≥20 mg BID
BL
• Patients titrated to 10 mg BID after nadir hemoglobin showed faster
and more complete return of hemoglobin to pretreatment levels
Titrated dose is defined as the average dose patients received between Weeks 8 and 56.
Hemoglobin levels within 60 days of transfusion are not included.
13
Efficacy by Titrated Dose
Total Symptom Score
Spleen Volume
n=101
n=24
n=26
n=23
n=39
n=21
Week 24
n=103
n=22
n=35
n=28
n=24
n=20
n=31
n=17
Week 48
Titrated dose is defined as the average dose patients received in the last 4 weeks before assessment.
Verstovsek S, et al. Blood. 2012;120: Abstract 800.
n=26
n=23
n=38
n=20
Long-Term Efficacy, Safety, and
Survival Findings From COMFORT-II,
a Phase 3 Study Comparing Ruxolitinib
With Best Available Therapy for the
Treatment of Myelofibrosis
Abstract 801
Cervantes F, Kiladjian J-J, Niederwieser D, Sirulnik A, Stalbovskaya V,
McQuitty M, Hunter DS, Levy RS, Passamonti F, Barbui T, Barosi G,
Gisslinger H, Vannucchi AM, Knoops L, Harrison CN
Patient Disposition
n (%)
Still on treatment
Discontinued
Crossed over
Primary reasons for discontinuation
Adverse event
Consent withdrawn
Protocol deviation
Disease progression
Noncompliance with study medication
Noncompliance with study procedures
Unsatisfactory therapeutic effect
Other
Ruxolitinib
(n = 146)
BAT
(n = 73)
Ruxolitinib
After Crossover
From BAT
(n = 45)
81 (55.5)
65 (44.5)
--
0
73 (100.0)
45 (61.6)
26 (57.8)
19 (42.2)
--
20 (13.7)
8 (5.5)
2 (1.4)
16 (11.0)
3 (2.1)
0
2 (1.4)
14 (9.6)
5 (6.8)
9 (12.3)
0
4 (5.5)
0
1 (1.4)
0
9 (12.3)
5 (11.1)
0
5 (11.1)
5 (11.1)
1 (2.2)
0
1 (2.2)
2 (4.4)
The majority of patients randomized to ruxolitinib
remained on treatment after more than 2 years on study
Mean % Change From Baseline in
Spleen Volume Over Time
Ruxolitinib, n = 146
136
125
111
98
BAT Excluding patients who crossed over to ruxolitinib
60
n = 73
44
39
34
BAT Including patients who crossed over to ruxolitinib
60
45
40
34
n = 73
78
64
53
42
31
10
24
16
6
2
0
0
24
20
15
8
11
3
BAT patients who crossed over to ruxolitinib
had reductions in spleen volume after crossover
Overall Survival
1.0
Ruxolitinib
BAT
No. of Patients
146
73
Events
20 (13.7%) 16 (21.9%)
Censored
126 (86.3%) 57 (78.1%)
Ruxolitinib
BAT
n=
146
73
Lost to follow-up
(cumulative)
138
61
127
51
117
49
3.4%
13.7%
9.6%
24.7%
11.0%
26.0%
109
45
14.4%
27.4%
30
12
0
0
14.4%
27.4%
Suggests a relative reduction in the risk of death with ruxolitinib compared with
BAT (HR = 0.51; 95% CI, 0.26-0.99; log-rank test P = .041)a
a
P values are provided for descriptive purposes and were not adjusted for multiple comparisons.
Efficacy, Hematologic Effects, and
Dose of Ruxolitinib in Myelofibrosis
Patients with Low Starting Platelet
Counts (50–100×109/L)
Abstract 176
Talpaz M, Paquette R, Afrin L, Hamburg S, Jamieson K,
Terebelo H, Ortega G, Lyons RM, Tiu R, Winton E, Natrajan K,
Odenike O, Peng W, O’Neill P, Erickson-Viitanen S, Leopold L,
Sandor V, Levy R, Kantarjian H, Verstovsek S
Distribution of Ruxolitinib Dose
Over Time
• In patients who completed 24 weeks of treatment, most have
optimized their dose of ruxolitinib to 10 mg BID or higher
10 BID
10 / 15
15 BID
10 / 15
10 BID
15 BID
10 / 15
10 BID
5 / 10
10 BID
5 BID
10 BID
5 / 10
5 / 10
5 / 10
5 BID
5 BID
5 BID
5 BID
n values represent patients with available dose information at the time of data analysis.
Data shown for each time point represent the dose that patients were on during the previous 4 weeks.
5 BID
Reductions in Total Symptom Score
and Spleen Length
Total Symptom Score
Spleen Length
n = 41
n = 38
n =35
n = 39
n = 27
n = 31
n = 32
n = 28
n = 28 n = 18
n = 18
n = 24
Weeks
TDD,
mg
Mean
Median
4
8
12
16
20
24
10.0
13.2
15.1
16.8
18.3
19.1
10
15
15
20
20
20
Weeks
TDD,
mg
Mean
Median
4
8
12
16
20
24
10.0
13.2
15.1
16.8
18.3
19.1
10
15
15
20
20
20
Percent change from baseline is not calculated for patients with a “0” TSS or palpable spleen size of “0 cm” at baseline. Mean and median
dose shown for patients with available dosing information.
TDD, total daily dose.
Change From Qualifying Platelet Count to
Nadir and to Week 24 of Individual Patients
Qualifying to Week 24
160
160
140
140
Platelet Count (×109/L)
Platelet Count. ×109/L
Qualifying to Nadir
120
100
80
60
40
120
100
80
60
40
20
20
0
0
Individual Patients
Individual Patients
22
Phase III Study SAR302503 vs. placebo
Multinational, multicenter, randomized, double-blind, placebo-controlled
- Intermediate-2 or
high-risk Primary MF
-Post-Polycythemia
Vera MF
-Post-Essential
Thrombocythemia MF
●No Stratification factors
●Randomization 1/1/1
●1 cycle = 28 days
R
A
N
D
O
M
I
Z
A
T
I
O
N
n=75
Q4 weeks
SAR302503 500mg
Daily oral doses
n=75
Q 4 weeks
SAR302503 400mg
Daily oral doses
n=75
End
of C6
Cross
over
1/1
Q 4 weeks
Placebo
Daily oral doses
● 225 patients at ~128 sites
● Recruitment: 8 months, 25 countries
● Safety data monitored by DMC (~Q6 months)
● Cross over possible
End of C6 or
progressive
disease
Enrollment
Completed
(Sept 2012)
EOT
A Phase II Randomized Dose-Ranging
Study of the JAK2-Selective Inhibitor
SAR302503 in Patients With
Intermediate-2 or High-Risk Primary
Myelofibrosis (MF), Post-Polycythemia
Vera MF, or Post-Essential
Thrombocythemia MF
Abstract 2837
Talpaz M, Jamieson C, Gabrail NY, Lebedinsky C,
Neumann F, Gao G, Liu F, Tefferi A, Pardanani A
ARD11936 Study Design
• Intermediate-2 or high-risk
primary MF (IWG-MRT
criteria)
• Post-polycythemia vera
myelofibrosis according to
the 2008 World Health
Organization (WHO) criteria
Patients who continued to benefit
clinically could remain on study until
the occurrence of disease progression
or unacceptable toxicity
1 cycle = 28 days
Primary endpoint:
R
A
N
D
O
M
I
Z
A
T
I
O
N
SAR302503 300 mg orally once daily
SAR302503 400 mg orally once daily
SAR302503 500 mg orally once daily
• % change in spleen volume at EOC 3 by central review assessed by MRI
Secondary endpoints: • % of patients who achieve ≥35% reduction in spleen volume from baseline
• To measure improvement in baseline MPN-associated symptoms
• Safety (NCI CTCAE v4.03), PK/PD
EOC, end of cycle; MF, myelofibrosis; MPN-SAF, myeloproliferative neoplasm symptom assessment form; MRI, magnetic
resonance imaging; PK/PD, pharmacokinetics/pharmacodynamics
Percent Change in Spleen Volume From Baseline
in Individual Patients at the End of Cycle 3
30 –
Change in Spleen Volume, %
20 –
10 –
0–
-10 –
-20 –
-30 –
35%
-40 –
-50 –
-60 –
-70 –
-80 –
SAR302503
300 mg (n = 8)
SAR302503
400 mg (n = 10)
SAR302503
500 mg (n = 10)
• There was a dose-dependent increase in spleen
response with increasing doses of SAR302503.
Symptom Reduction at the End of Cycle 3 by
the MPN-SAF in Patients With Symptoms
Present at Baselinea
SAR302503
300 mg
n = 10
400 mg
n = 10
500 mg
n = 11
5 (50)
[19 - 81]
5 (50)
[19 - 81]
4 (36)
[11 - 69]
Night sweats
5/5 (100%)
5/6 (83%)
4/4 (100%)
Itching
6/7 (86%)
1/3 (33%)
3/4 (75%)
Abdominal discomfort
4/7 (57%)
3/7 (43%)
3/6 (50%)
Abdominal pain
3/6 (50%)
4/7 (57%)
3/5 (60%)
Bone pain
2/3 (67%)
1/4 (25%)
1/3 (33%)
Early satiety
3/7 (43%)
4/7 (57%)
3/4 (75%)
Inactivity
2/6 (33%)
3/7 (43%)
3/5 (60%)
Proportion of patients with ≥50% reduction in total
MPN-SAF score from baseline n (%) [95% CI]
Symptom Response,a n/N
aA
response was defined as a 2-point improvement in or resolution of the symptom.
MPN-SAF: Myeloproliferative Neoplasm Symptom Assessment Form
Most Common Nonhematologic
Adverse Eventsa
SAR302503
300 mg
n = 10
n (%)
400 mg
n = 10
500 mg
n = 11
All grades
Grade 3/4
All Grades
Grade 3/4
All Grades
Grade 3/4
Fatigue
3 (30)
1 (10)
1 (10)
0
4 (36)
0
Diarrhea
7 (70)
1 (10)
9 (90)
2 (20)
6 (55)
0
Nausea
6 (60)
1 (10)
5 (50)
1 (10)
8 (73)
0
Vomiting
5 (50)
1 (10)
4 (40)
1 (10)
7 (64)
0
Constipation
2 (20)
0
3 (30)
0
1 (9)
0
Pruritis
1 (10)
0
2 (20)
0
1 (9)
0
Edema, peripheral
2 (20)
0
3 (30)
0
1 (9)
0
0
0
1 (10)
1 (10)
3 (27)
1 (9)
Hyperkalemia
2 (20)
1 (10)
1 (10)
0
1 (9)
1 (9)
Paresthesia
1 (10)
0
2 (20)
0
2 (18)
0
Dyspnea
1 (10)
0
3 (30)
0
2 (18)
0
Cough
2 (20)
0
1 (10)
0
2 (18)
0
Infections
aReported
in ≥10% of patients across all dose groups. Safety was assessed in patients who received at least one dose
of study drug.
Laboratory Abnormalities
SAR302503
300 mg
n = 10
400 mg
n = 10
500 mg
n = 11
n (%)
All
grades
Grade
3/4
All
Grades
Grade
3/4
All
Grades
Grade
3/4
Anemia
9 (100)a
3 (33)a
10 (100)
3 (30)
10 (91)
6 (55)
Neutropenia
1 (10)
0
0
0
0
0
Thrombocytopenia
5 (50)
2 (20)
3 (30)
0
6 (55)
1 (9)
aData
available for 9 patients in the 300 mg group
• Anemia was the most common hematologic toxicity.
• Grade 3/4 thrombocytopenia was minimal.
THANK YOU
[email protected]