JAK inhibitors and
low blood cell
count
Srdan (Serge) Verstovsek
M.D., Ph.D.
Professor of Medicine
Department of Leukemia
University of Texas
MD Anderson Cancer Center
Houston, Texas, USA
JAK inhibitor
Diseases and studies
CEP701
MF: phase II finished and I/II (new formulation)
ongoing
ET/PV: phase II completed
AZD1480
MF: phase I finished, development stopped
XL019
MF: phase I finished, development stopped
NS-018
MF: phase I ongoing
BMS-911543
MF: phase I/II ongoing
LY2784544
ET/PV/MF: phase I finished; MF: phase II ongoing
CYT387
MF: phase I/II QD completed; phase I/II BID
completed; phase III planned
SB1518
MF: phase I/IIx2 completed, phase III ongoing
SAR302503/TG101348
MF: phase I/II completed; phase II completed, phase
III completed; phase II second line ongoing
ET/PV: phase II ongoing; PV: phase III planned
MF: approved; phase II (low platelets) ongoing
INCB018424/Ruxolitinib
ET/PV: phase II completed; PV: phase III completed
JAK2 Inhibitor Side Effects from
Phase II Studies
GI
X
X
Anemia
Platelets
X
X
X
X
X
Neuropathy
X
Ruxolitinib vs. Placebo: 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
Data cutoff for current analysis: March 1, 2012.
1. Verstovsek S, et al. N Engl J Med. 2012;366(9):799-807.
Verstovsek S, et al. Blood. 2012;120: Abstract 800.
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Consent withdrawn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
Verstovsek S, et al. Blood. 2012;120: Abstract 800.
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
0
0
≥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
Verstovsek S, et al. Blood. 2012;120: Abstract 800.
Mean Daily Dose of Ruxolitinib Over Time
• Approximately 70% of patients had dose adjustments during the first
12 weeks of therapy
• Patients achieved a stable dose with longer-term use
Mean Platelet Counts Over Time
• Platelet counts remain stable with longer-term therapy
Mean Percentage Change From
Baseline
10
Ruxolitinib
Placebo
0
-10
-20
-30
-40
-50
-60
BL
12
24
36
48
60
72
84
Weeks
Median platelet count at baseline: Ruxolitinib, 262.0×109/L; Placebo, 238.0×109/L.
96
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
Verstovsek S, et al. Blood. 2012;120: Abstract 800.
Hemoglobin Levels Over Time in Patients
Without Transfusions or Dose Changes
No RBC Transfusions and
No Dose Changes Before Week 36
No RBC Transfusions Before Week 36
5
Mean Percentage Change
From Baseline
Mean Percentage Change
From Baseline
5
0
-5
-10
-15
-20
BL
4
8
12
16
20
24
28
32
36
Weeks
0
-5
-10
-15
-20
BL
4
8
12
16
20
24
28
Weeks
• Recovery in hemoglobin over time was seen regardless of
transfusions and dose modifications
Analyses were conducted in patients who completed Week 36.
32
36
RBC Transfusions Over Time
50
Percentage of Patients
Proportion of patients with RBC transfusion in prior month
40
Ruxolitinib
Placebo
72
96
30
20
10
Weighted mean rate of the placebo group = 24.37%
0
BL
12
24
36
48
60
84
108
Weeks From First Ruxolitinib Dose
• By Week 36, the proportion of ruxolitinib-treated patients receiving RBC transfusions
decreased to the level seen with placebo and remained stable thereafter
Hemoglobin Levels Over Time By
Ruxolitinib Titrated Dose
• 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.
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=26
n=23
n=38
n=20
n=35
n=28
Week 48
n=24
n=20
n=31
n=17
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.
Development of Anemia Does not Affect
Response to Ruxolitinib Treatment
Verstovsek S et al. NEJM 2012; 366:799-807.
What happens if the therapy with JAK2
inhibitor 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
Serious Adverse Events After
Therapy Interruption
Adverse Event
Total with interruption, n
Total SAEs, n (%)
Ruxolitinib
(n = 155)
Placebo
(n = 151)
49
54
3 (6.1)
3 (5.6)
• 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%
Consideration in everyday practice:
addition of an “Anemia Drug” to a JAK2 inhibitor
• Danazol
• Erythropoietin
• Low dose thalidomide
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
100%
10 BID
10 / 15
10 BID
15 BID
10 / 15
15 BID
10 / 15
80%
15 BID
5 / 10
10 BID
60%
5 BID
10 AM/15 PM
10 BID
5 / 10
10 BID
10 BID
5 AM/10 PM
40%
5 BID
5 / 10
5 / 10
20%
5 QD
5 BID
5 BID
5 BID
0
5 BID
5 BID
0%
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
n = 41
n = 36
n = 31
n = 28
n = 25
n = 17
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.
Talpaz M, et al. Blood. 2012;120: Abstract 176.
Reductions in Total Symptom Score
and Spleen Length
Percent Change From Baseline, Mean ±SEM
Total Symptom Score
0
-10
-20
n = 41
n = 38
-30
n =35
n = 39
-40
n = 27
n = 31
n = 32
n = 28
n = 28 n = 18
-50
n = 18
n = 24
-60
Weeks
TDD,
mg
Spleen Length
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.
Talpaz M, et al. Blood. 2012;120: Abstract 176.
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
Talpaz M, et al. Blood. 2012;120: Abstract 176.
THANK YOU
sverstov@mdanderson.org