Update in Myeloproliferative
Neoplasms
January 20, 2012
November 16, 2011
FDA Indications for Ruxolitinib
(Jakafi)
Intermediate or high-risk Myelofibrosis
=80-90% of MF patients
JAK2V617F NOT required
Diagnostic Criteria for myelofibrosis
PMF
Must meet all 3 major and ≥2
minor criteria
Post PV or ET MF
Must meet both major and
≥2 minor criteria
JAK2V617F mutation:
Not just for MPN anymore
95-97% PV
>50% ET
50-60% MF
3-13% CMML
3-5% MDS (RARS & thrombocytosis)
<5% AML
Dynamic International Prognostic Scoring
System in MF
DIPSS
Obtained at any time during follow-up
0 = Low
1-2 = Intermediate-1
3-4 = Intermediate-2
5-6 = High
Passamonti et al, Blood 2010
DIPSS-plus
3 additional factors
**Constitutional symptoms constitute weight loss > 10% of baseline value in the year preceding
diagnosis, unexplained fever, or excessive sweats persisting for > 1 month
***Unfavorable karyotype constitutes complex karyotype or sole or 2 abnormalities that include
+8, −7/7q−, i(17q), inv(3), −5/5q− 12p−, or 11q23 rearrangement
Tefferi, Blood 2011
COMFORT-I
Primary endpoint
* Patients randomized to placebo will be eligible to
cross over to ruxolitinib
• Proportion of subjects achieving >35% reduction in spleen volume from
baseline to Week 24 as measured by MRI(or CTscan in applicable subjects)
Secondary endpoints
• Duration of maintenance of a >35% reduction from baseline in spleen volume
among subjects initially randomized to receive INCB018424
• Proportion of subjects with >50% reduction in total symptom score from
baseline to Week 24 as measured by the modified MFSAF v2.0 diary
Percent Change From Baseline in Spleen
Volume in Individual Patients at Week 24
Verstovsek, S. Presented at ASCO 2011
Primary Endpoint: % of Patients with
≥35% Decrease in Spleen Volume at
Week 24 (ITT)
Verstovsek, S. Presented at ASCO 2011
Symptomatic Burden in MF
Night Sweats
Weight Loss
Fever
62%
Constitutional
Symptoms
48%
29%
Early Satiety
Abdominal Discomfort
Cough
75%
72%
Splenomegaly
55%
Bone Pain
Itching
55%
54%
Fatigue
Inactivity
insomnia
Myeloproliferation
99%
76%
Functioning
74%
0%
20%
40%
60%
80%
100%
Percentage of patients reporting symptoms
Scherber et al, Blood 2011
Percent of Patients with ≥50% Decrease in
Total Symptom Score at Week 24 (ITT)
Verstovsek, S. Presented at ASCO 2011
Proportion of Patients with ≥50% Reduction
in Total Symptom Score Over Time
Verstovsek, S. Presented at ASCO 2011
Percent Change From Baseline in Total Symptom
Score in Individual Patients at Week 24
Verstovsek, S. Presented at ASCO 2011
Mean Percent Change in Individual
Symptoms
Verstovsek, S. Presented at ASCO 2011
Symptoms Return without drug
Increased serum cytokines in MPN
MPN patients
Mouse Model
CD40
IL-2R
IL-2
IL-9
MIP-1α
MIP-1β
IL-7
TNF
KC
MMP-2
ICAM-1
MMP-10
IL-8
IL-13 IL-15
IL-18
VEGF
IL-6
(Tyner et al, 2010)
IFN-α
IL-11
VCAM-1
IL-16
IL-1α,ß
TIMP-1
G-CSF
IL-12
IL-10
IFN-γ
Lower in MPN
(Verstovsek et al, 2010 Slezak et al, 2009,
Boissinot et al, 2010, Tefferi et al 2011)
TNF is elevated in MPN and correlates
with JAK2V617F allele burden
Fleischman et al, Blood 2011
Elevated IL-8 and IL-2R associated
with decreased survival in PMF
Intermediate-1
All patients
Intermediate-2
Tefferi et al, JCO 2011
Consequences of Increased Inflammation
HSC
exhaustion
Stress
hematopoiesis
Constitutional Symptoms
-weight loss
-fatigue
-fever
Impact of Ruxolitinib on inflammatory cytokines
Verstovsek et al, NEJM 2010
Ruxolitinib decreases inflammatory
cytokines
Verstovsek et al, NEJM 2010
JAK inhibitors: not just for MPN
Hematology Laboratory Values
*Patients are included at their worst on study grade regardless of whether this represents a
change from their baseline
-Grade 3 and 4 anemia and thrombocytopenia were more common in those with
higher baseline grade
-Discontinuation of treatment because of anemia and thrombocytopenia was rare
(1 patient in each treatment group for each event
Verstovsek, S. Presented at ASCO 2011
Non-hematologic Adverse Events
Observed in at Least 10% of
Ruxolitinib-Treated Patients
Verstovsek, S. Presented at ASCO 2011
Mean hemoglobin and Red Blood Cell
Products Over Time
Verstovsek, S. Presented at ASCO 2011
Red Blood Cell Transfusions
Verstovsek, S. Presented at ASCO 2011
JAK2V617F allele burden
Percentage of JAK2V617F mutant allele can
be quantitatively measured (available at
OHSU), but clinical relevance is unknown
Low JAK2V617F allele burden in PMF
has negative impact
Low V617Fallele burden associated
with shorter survival in PMF
Guglielmelli et al, Blood 2009
Causes of Death in PMF
31%
Leukemia
19%
Progression without leukemia
14%
Thrombosis
10%
Infection
5%
Bleeding
Portal Hypertension
4%
Secondary Neoplasm
4%
13%
Other
0%
5% 10% 15% 20% 25% 30% 35%
Cervantes et al, Blood 2009.
COMFORT-I Overall Survival*
* COMFORT-I was not designed nor powered to demonstrate a statistically significant difference in overall
survival within the timeframe of the study endpoint. Patients who remain in COMFORT-I continue to be
followed.
Incyte, JP Morgan Healthcare conference Jan 9,2012
Ruxolitinib Dosing
For plts 50-100 X 109/L: OHSU currently
enrolling for clinical trial of ruxolitinib in
thrombocytopenic patients with MF
Jakafi prescribing information packet
Dose adjustment for thrombocytopenia
Hold Drug for platelets <50 X 109/L
Jakafi prescribing information packet
Drug Interactions:
Strong CYP3A4 inhibitors will increase levels of ruxolitinib, with
strong CYP3A4 inhibitors dose reduction is recommended.
Patients should be closely monitored and dose titrated based on
safety and efficacy.
No dose adjustment is recommended when Jakafi is
coadministered with a CYP3A4 inducer.
Patients should be closely monitored and the dose titrated
based on safety and efficacy
Jakafi prescribing insert
How to prescribe Ruxolitinib
http://www.jakafi.com/Files/RUX1066.pdf
Comparing various JAK inhibitors
Drug
Target
Phase Disease
Efficacy
Toxicity
INCB18424
JAK2, JAK1
Approved
III
MF
PV/ET
Splenomegaly,
symptoms
Anemia, thrombocytopenia
TG101348,
(SAR302503)
JAK2, FLT3
II
MF
Splenomegaly,
symptoms
Anemia, thrombocytopenia,
gastrointestinal
SB1518
JAK2, FLT3
II
MF
Splenomegaly,
symptoms
Gastrointestinal
CEP701
JAK2, FLT3
II
MF, PV/ET
Splenomegaly,
symptoms
Gastrointestinal, anemia,
thrombocytopenia
CYT387
JAK1, JAK2
I
MF
Splenomegaly,
symptoms, anemia
First dose effect, cytopenias
LY2784544
JAK2
I
MF, ET/PV
NPR
NPR
AZD1480
JAK2, JAK3
I/II
MF
NPR
NPR
NS018
JAK2
I
MF
NPR
NPR
Clinical trials of non-JAK2 targeted
therapies for MPN
Drug
RAD001
Target Phase
mTOR
Pomalidomide IMiD
PEG-IFNa-2a
LBH589
Disease
Efficacy
Toxicity
II
MF
Splenomegaly,
symptoms
Minimal
III
MF
Biological III
HDAC
II
PV/ET
Anemia
Erythrocytosis,
thrombocytosis,
symptoms
MF
Splenomegaly,
anemia
Minimal
Myelosuppression,
depression
Anemia,
thrombocytopenia,
gastrointestinal
Lenalidomide for MF
• Mayo Clinic - Blood. 2006 Aug 15;108(4):1158-64.
– 68 patients; lenalidomide at 10 mg/d (5 mg/d if baseline platelet
count < 100 x 10(9)/L) for 3 to 4 months with a plan to continue
treatment for either 3 or 24 additional months, in case of
response. Overall response rates were 22% for anemia, 33%
for splenomegaly, and 50% for thrombocytopenia.
• MD Anderson - J Clin Oncol. 2009 Oct 1;27(28):4760-6.
– 40 patients; lenalidomide 10 mg/d (5 mg/d if baseline platelet
count < 100 x 10(9)/L) on days 1 through 21 of a 28-day cycle
for six cycles with prednisone taper. ORR 30% for anemia and
42% splenomegaly by IWG-MRT criteria.
• ECOG Phase 2 (E4903) - Blood. 2010 Nov 25;116(22):44368.
– 48 patients; lenalidomide 10mg daily + prednisone taper;
anemia improved in 19% and splenomegaly in 10% by IWGMRT criteria.
Pomalidomide +/- prednisone in
treatment of anemia in MF
Tefferi et al, JCO 2009
Phase II trial of pomalidomide alone in MF
• Low dose pomalidomide alone (0.5mg/d) in 58 MF
patients with anemia
• Response limited to JAK2V617F mutated patients
• 24% of V617F+ patients responded in terms of
anemia and 9/10 became transfusion independent
• Response predicted by basophilia in first month of
treatment
• 58% of patients with plts ≤ 100K experienced >50
% increase in plt count
Begna et al, Leukemia 2011
rIFN-α may reverse fibrosis in early
PMF
Silver et al, Blood 2011
Peg-IFN-alpha2a for PV/ET
• Kiladjian et al Blood 2008;112:3065:
– 37 patients; 95% had hematologic CR; only 3 stopped tx at 12
months. Decreased JAK2V617F allele burden in 90%.
Molecular CR in 7 patients. 90-180 mcg weekly.
• Quintas-Cardama et al JCO 2009;27:5418:
– 40 PV/39 ET; one prior cytoreductive treatment; 70%/76%
hematologic CR; 14%/6% molecular CR. Only 10% of patients
discontinued due to toxicity; no grade 4 toxicities; grade 3 were
not frequent but included pain, fatigue, dyspnea, and pruritis.
Tolerability of PEG-IFN-alpha-2a at 90 mcg weekly was
excellent.
• Phase III trials comparing Hydroxyurea vs. Pegasys are underway
(upfront high risk PV or ET; HU-resistant or refractory).
PEG-IFNα induces hematologic
response in PV/ET
Start at 90µg/week, with goal of 135µg/week
Tolerable dosing
Kiladjian et al, Blood 2008
90µg/wk PEG-IFNα-2a induces molecular
response in PV/ET
Quintas-Cardama et al, JCO 2009
Toxicities Associated with PEG-IFNα-2a
-PEG-IFNα-2a 90µg/week
-10% of patients discontinued due to IFN related toxicity
Quintas-Cardama et al, JCO 2009
The curative approach: allogenic SCT
Conditioning
Myeloablative
Reduced-Intensity
N
Study
Donor
551
Retr
42
562
Retr
43
RD=36
URD=20
RD=40
URD=9
1033
Prosp
FluBu+AT
G
55
RD=33
URD=70
66
Prosp
FluMel+/ATG
Obstacles: -Donor availability
-Advanced patient age
-Comorbidities
1Guardiola
Median
Age
55
RD=32
URD=34
TRM
(%)
OS
27
47% (5-y)
58% (3-y)
16
67% (5-y)
RD=16
URD=33
RD=78%
(2-y)
URD=44%
(1y)
-High TRM
-Still ill defined morbidity
-Impact of cGVHD
et al, Blood 1999. 2Deeg et al, Blood 2003. 3Alchalby et at, Blood 2010.
4Rondelli, ASH 2011 Abst 1750.
Treatment Algorithm for myelofibrosis
DIPSS/DIPSS-plus
Int-2/high
Low, Int-1
asymptomatic
symptomatic
Consider SCT
Yes
No
observation
*conventional
drug therapy
*ruxolitinib
refractory
Investigational
drug therapy
MyA 45-50y
RI 45-65
Treatment of Anemia: Conventional
Approach
-Prednisone
-Danazol/Androgens
-Erythropoietin stimulating agents (ESA)
15-20% response,
Short lived
-Thalidomide + Prednisone
≈ 20% response,
neurotoxicity
-Lenalidomide
≈ 20% response, myelosuppression
Best in pts with del(5q31)
-Splenectomy
up to 50-75% response
duration ≈ 1yr
-RBC transfusions
Treatment goals
•
•
•
•
Prevent thrombosis
Prevent hemorrhage
Alleviate constitutional symptoms
Minimize primary and iatrogenic disease
progression
• Improve QOL and survival