Therapy of early-stage
MF: Are JAK inhibitors
for everyone?
Srdan (Serge) Verstovsek
M.D., Ph.D.
Professor of Medicine
Department of Leukemia
University of Texas
MD Anderson Cancer Center
Houston, Texas, USA
Main Clinical Problems in MF
Clinical need
36%
Anemia (Hb <10 g/dL)
10%
Leukocytosis (>25x109/L)
16%
Thrombocytopenia (<100x109/L)
83%
Splenomegaly
65%
Hepatomegaly
Extramedullary hematopoiesis
Thrombosis
1-3%
7.2 %
27%
Constitutional symptoms
Leukemia transformation
13%
Passamonti F et al. Blood 2010;115:1703-8;
Barbui T et al. Blood 2010; 115;778-82; Passamonti F et al. Blood 2010; 116:2857-8
Symptomatic Burden in MF
Symptoms related to:

Role /
Functioning
 Myeloproliferation


Splenomegaly
«Constitutional
Symptoms»
Scherber R et al. Blood 201;118:401-8
Efficacy of ruxolitinib in patients with MF without
clinically significant splenomegaly
Patient disposition
Patients with MF
n=6
Effects of ruxolitinib
Patients with MF
n=6
Previously
treated
5
Fatigue
improved
6
Post
splenectomy
3
Resolution of
night sweats
2
Transfusion
dependent
3
Itching
2
JAK2 V617F
4
Weight gain
(up to 17%)
5
• All pts were symptomatic
• Ruxolitinib was
administered at the dose of
25mg BID
• Improved performance status
• Reduction of liver size 50-68%
• No improvement in marrow
fibrosis
Benjamini et. al., Blood 2012; 120:2768-2769
• The approved indication is: “Ruxolitinib is
indicated for the treatment of disease-related
splenomegaly or symptoms in adult patients with
primary myelofibrosis (also known as chronic
idiopathic myelofibrosis), post polycythaemia
vera myelofibrosis or post essential
thrombocythaemia myelofibrosis.”
U.S. Food and Drug Administration
• On November 16, 2011, the Food and Drug
Administration (FDA) approved ruxolitinib
phosphate for the treatment of intermediate and
high risk myelofibrosis, including primary
myelofibrosis, post-polycythemia vera
myelofibrosis, and post-essential
thrombocythemia myelofibrosis.
• No contraindications
International Prognostic Scoring
System (IPSS): Risk classification
of PMF at presentation
Prognostic factors
Survival by PMF-PS
1
• Age > 65 years
.9
.8
• Hb < 10 g/dL
.7
Probability
• Constitutional symptoms
• Leukocytes > 25 x 109/L
• Blood blasts > 1%
.6
.5
.4
.3
.2
Risk groups
• Low
0
• Intermediate-1
1
• Intermediate-2
2
• High
.1
0
0
24
48
72
96
120 144 168 192 216 240 264 288
Months
95% CI
95% CI
95% CI
PMF-PS = 0
PMF-PS = 1
PMF-PS = 2
95% CI
PMF-PS = 3
>3
Cervantes et al., Blood 2009;113:2895-2901
International Prognostic Scoring
System to predict survival (IPSS)
135 months
22%
95 months
29%
48 months
28%
27 months
21%
Cervantes et al, Blood 2008
Overall Survival: ruxolitinib vs. placebo
(int-2/high risk MF)
1.0
Survival Probability
0.8
Ruxolitinib
Placebo
0.6
0.4
0.2
Median follow-up: 102 weeks.
Most patient on placebo (n=111) were given ruxolitinib (after average of 41 weeks)
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
No. of deaths: Ruxolitinib = 27; Placebo = 41; HR = 0.58 (95% CI: 0.36, 0.95); P = .028
Overall Survival: MDACC Phase 1-2 Study
Cohort vs. Historical Control
by IPSS Risk Category
Survival Probability
Intermediate-2
Survival Probability
High Risk
63
Number of Patients at Risk—MDACC Study 251
61
57
46
Number of Patients at Risk—Historical Control
160
134
114
90
45
67
Months
Hazard ratio=0.50
95% CI: 0.31–0.81
p-value=0.006
27
50
7
35
Number of Patients at Risk—MDACC Study 251
34
33
29
27
18
6
Number of Patients at Risk—Historical Control
140
123
112
90
79
68
58
34
Months
Hazard ratio=0.85
95% CI: 0.43–1.71
p-value=0.71
Overall Survival in MDACC Phase 1-2 Study
Cohort: Intermediate-2 vs. High Risk
Hazard ratio=1.36*
95% CI: 0.64–2.89
p-value=0.43
Number of Patients at Risk—Intermediate-2 Risk
34
34
34
33
29
Number of Patients at Risk—High Risk
63
62
61
57
48
*Hazard ratio >1 favors intermediate-2 risk group.
28
27
24
14
6
46
45
35
22
7
Ruxolitinib: Compassionate
Use Program
n = 1556*
PMF, Post-ET/PV MF
• Irrespective of JAK2 mutation status
• High risk OR INT-1/INT-2
with an enlarged spleen
• PBC < 10%
• Adequate organ function
• ECOG 0, 1, or 2
Korea: 43 patients
Taiwan: 35 patients
Baseline platelet count >200,000/µL
will begin dosing at 20 mg BID
Baseline platelet count of 100,000/µL to
200,000/µL will begin dosing at 15 mg BID
INC424.CU@novartis.com
Participating Countries:
Australia, HK, India, Israel, Korea, Kuwait, Lebanon, Philippines, KSA, Singapore, Taiwan, Thailand, Turkey, UAE
FPFV = Feb 2011
* Approved Patients by 19 November 2012
Expanded Access Program
N = 1600
PMF, Post-ET/PV MF
• Irrespective of JAK2 mutation.
• High risk OR INT-1/INT-2
with an enlarged spleen
• PBC < 10%
• Adequate organ function
• ECOG 0, 1, or 2
Baseline platelet count > 200,000/µL will begin
dosing at 20 mg BID
Baseline platelet count of 100,000/µL to
200,000/µL will begin dosing at 15 mg BID
Baseline platelet count of 75,000/µL to
99,000/µL will begin dosing at 5 mg BID
Endpoints: Collect additional safety of INC424 in
patients with PMF/PPVMF/PET-MF; QoL; MRU
FPFV = 16/08/2011
Participating Countries:
Algeria, Egypt, Israel, Kuwait, Russia, Saudi Arabia, South Africa, Thailand, Tunisia, UAE, Morocco
Therapy of early-stage MF: Are JAK
inhibitors for everyone?
• If defined as patients without splenomegaly or without
disease related symptoms
• If defined as low-risk patients
MY ANSWER:
It deserves to be studied whether intervention in these
patients, to prevent the development of clinically relevant
disease related signs and symptoms, results in meaningful
outcome (to be defined)
THANK YOU
sverstov@mdanderson.org