therapeutic options after first line treatment failure · therapeutic options after first line...
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Therapeutic options after first line treatment failure
Orlando ASH 2015
Guillermo Garcia-Manero MDProfessor of MedicineChief Section of MDS
Deputy Chair, Translational ResearchDepartment of Leukemia
MD Anderson Cancer CenterUniversity of Texas
Houston, TX
DISCLOSURE
I have no relevant financial relationships to disclose.
What are the major needs in MDS?(problems that limit significant cure rate)
• Identification of poor prognosis “lower risk” patients– By default sparing patients with no need of therapy
– Concept of early intervention
• Development of new targeted therapies for patients with lower risk MDS
• Development of new therapies for patients with higher risk MDS
• Understanding mechanisms of resistance to epigenetic modulators in MDS
• Understanding mechanisms of transformation to AML
• Incorporation of alloSCT in MDS
• Minimizing risk of relapse post alloSCT in MDS
Natural history of MDS after incorporation of HMAs
Prodrome
LR-MDS HR-MDS
AML
HMA failure?
HMA failureAML-like??
UntreatedHMA?lenalidomide
UntreatedHMA AML-likeSCT
HMA lower risk failure survival: 14-17 monthsHMA higher risk failure survival: 4-6 months
Jabbour. Cancer 2015; Jabbour. Cancer 2010
MDS patient’s BM
CD34+ CD34-
Control BM
CD34+ CD34-
Ch-IP with H3K4-3Me Antibody
Solexa Sequencing of Specific H3K4-3Me Rich Chromatin Fragments
Bio-info analysis
MDS specific biomarkers (Potential Specific Epigenetic Change in MDS)
H3K4me3 Chip-seq Strategy in MDS
Wei. Leukemia 2013.
C5AR1
FPR1 & FPR2
AQP9
MDS
control
MDS
control
MDS
control
MDS
control
PTAFR
control
MDS
TYROBP
criteria for MDS specific H3K4me3 “peak” selection• +/- 2kb to TSS of a known gene•MDS vs control > 3 fold•p value < 10 -6
H3K4m3 CHIP-Seq: Data Analysis & Validation
N=94 N=8C5AR1
rela
tiv
e le
ve
l o
f R
NA
MDS control
0
200
400
600
FPR1
MDS control0
200
400
600
800
1000 N=65 N=4
FPR2
MDS control
0
100
200
300
400
500N=89 N=8
rela
tive
leve
l of
RN
Are
lati
ve le
vel o
f R
NA
PTAFR
rela
tive level o
f R
NA
MDS control
0
200
400
600
800
N=100 N=9
N=87 N=4
AQP9
re
lati
ve
le
ve
l o
f R
NA
MDS control0
500
1000
1500
2000
TYROBP
MDS control
0
50
100
150
200
250
N=100 N=9
rela
tive
leve
l of
RN
A
promoter H3K4me3 enrichment
RNA expressionpromoter H3K4me3
enrichmentRNA expression
Wei. Leukemia 2013.
H3K4me3 Associated Gene Activation in CD34+ Cells of MDS
CFD SLC11A1
MDS BM CD34+
MDS BM CD34-
36 genes 156 genes
Wei. Leukemia. 2013
H3K4me3-associated Gene Activation in MDS CD34+ Cells targets an Innate Immunity Like Pathway
Ingenuity Pathway Analysispredicted NFkB-centered signal activation
= with reported involvement ininnate immune signaling activation
Wei. Leukemia. 2013
Overexpression of Other Innate Immunity Like Signaling Components in MDS BM CD34+
(non-CHIP-Seq identified)
expression level in primary MDS BM CD34+ cells
135
140
0
5
10
TLR1 TLR2 TLR6 MYD88 IL-8
185
190
Genes examined in MDS BM CD34+ cellsTLR1, 2, 3, 4, 6, 7, 8, 9, MYD88, IL-8
6.4 fold 5.5 fold
188 fold
2 fold
138 fold
Genes showing potential prognostic valueTLR1 and MYD88 expression levels negatively associate with overall survival (OS) in MDS patients
p50 p65
I-kBNF-kB
IL8 receptor
Toll like receptors (TLR)
IL8
IL8
“CHIP-Seq” gene products
MYD88
TLR2/ TLR1 TLR2/ TLR6
MDS bone marrow CD34+
Wei. Leukemia. 2013
TLR2 Stimulation Activates Histone
Demethylase JMJD3
De Santa F et al Cell 2007
JMJD3 is Overexpressed in MDS CD34+ Cells
Wei. Leukemia. 2013
Innate Immunity Genes & Patient Response to Epigenetic Targeting Drugs
Yang H et al
0
50
100
150
200
D0 D5 D21 D28
Rela
tiv
e E
xp
ressio
n
Resistance Sensitive
TLR6
N=11 N=7
SAHA/ AZA
0
1
2
3
4
5
6
D0 D5 D21 D28
Resistance Sensitive
C5AR1
0
2
4
6
8
10
12
14
D0 D5 D21 D28
Resistance Sensitive
FPR1
0
5
10
15
20
25
30
35
40
D0 D5 D21 D28
Resistance Sensitive
FPR2
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
D0 D5 D21 D28
Resistance Sensitive
TYROBP
Tumor Immune Evasion Mechanisms:
1. Inhibitory B7 expression by tumor,
APC and stroma cells.
2. APC
3. Treg.
Cellular Immune Dyregulation in MDS
MDS
ImmunosuppressionCTL ↓
Th17 ↓Tregs ↑
DC ↓Macrophage ↓
Adaptive Immune Responses B Cells ↓NK ↓
Selective Leukemic
Clone Growth
What about cellular immunity?Aberrant up-regulation of PD-L1, PD-L2, PD-1 and CTLA4 in CD34+ cells
from MDS, CMML and AML.
Yang et al Leukemia 2014
0
5
10
15
20
0 2 3 5 6 8 10 11 15 17 21 22 24 28 31
Rel
ativ
eex
pre
ssio
n
Days on Therapy
20
40
60
0 2 3 5 6 8 10 11 15 17 21 22 24 28 31
PD-L2
0
2
4
6
8
10
12
14
0 2 3 5 6 8 10 11 15 17 21 22 24 28 31
Re
lati
ve e
xpre
ssio
n
Days on Therapy
PD-L1
0
20
40
60
80
100
0 2 3 5 6 8 10 11 15 17 21 22 24 28 31
Re
lati
ve E
xpre
ssio
n
Days on Therapy
CTLA4
0
1 0
2 0
3 0
4 0
5 0
6 0
0 2 3 5 6 8 1 0 1 1 1 5 1 7 2 1 2 2 2 4 2 8 3 1
Relat
iveExp
ressio
n
D a y s o n T h e r a p y
6 0
8 0
1 0 0
1 2 0
1 4 0
1 6 0
1 8 0
2 0 0
0 2 3 5 6 8 1 0 1 1 1 5 1 7 2 1 2 2 2 4 2 8 3 1
P D - 1
Dynamics of PD-L1, PD-L2, PD-1 and CTLA4 expression in
patients treated with different forms of epigenetic therapy.
Yang et al Leukemia 2014
Epitargeting of immune pathways in MDS
1. Molecular Mechanisms: Interaction
between innate immune signal and
other genetic lesions in MDS
pathogenesis
2. Molecular Mechanisms:
Searching endogenous PAMP/
DAMP that activates innate
immune signaling and
involves in MDS pathogenesis
3. Evaluate Therapeutic
Potential of targeting innate
immune signaling in MDSGomez-Ganan. Leukemia 2015.
Adult murine hematopoiesis
LYMPHOIDPROGENITOR
COMPARTMENT
= KLMYELOID
PROGENITORCOMPARTMENT
ERYTHROCYTES
ST-HSC
MPP
LMPP
CLP
LT-HSC
CMP
GMPMEP
PRO T-CELL PRO B-CELLPLATELETS MONOCYTESGRANULOCYTES
Lin-ckit+sca1+CD34-CD135-
Lin-ckit+sca1+CD34+CD135-
Lin-ckit+sca1+CD34+CD135+
Lin-ckit+sca1-
CD34+CD16/32-
Lin-ckit+sca1-
CD34-CD16/32-Lin-ckit+sca1-
CD34+CD16/32+
Lin-ckit+sca1+CD34+CD135bright
Modified from Iwasaki H et al. Immunity 2007
= KSLHSCCOMPARTMENT
0 .0
0 .5
1 .0
1 .5
E ffe c t o f 7 -d a y A Z A tr e a tm e n t o n n e u tr o p h il c o u n ts
in T E R T -E R m ic e
Ce
ll c
ou
nts
(1
03
/m
m3
)
B a s e lin e
1 w e e k** ****
G 0
V e h ic leA Z A
G 5
A Z AV e h ic le
Short-term in TERT-ER mice: effect Aza on CBC
N=2
0
5
1 0
1 5
E ffe c t o f 7 -d a y A Z A tr e a tm e n t o n W B C c o u n ts
in T E R T -E R m ic e
Ce
ll c
ou
nts
(1
03
/m
m3
)
B a s e lin e
1 w e e k
****
G 0
V e h ic leA Z A
G 5
A Z AV e h ic le
*
0
5
1 0
1 5
2 0
E ffe c t o f A Z A t re a tm e n t o n h e m o g lo b in
le v e ls in T E R T -E R m ic e
[Hg
b]
(g
/d
L)
B a s e lin e
1 w e e k*** **
G 0
V e h ic leA Z A
G 5
A Z AV e h ic le
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
E f fe c t o f 7 -d a y A Z A tr e a tm e n t o n p la te le t c o u n ts
in T E R T -E R m ic e
Ce
ll c
ou
nts
(1
03
/m
m3
)
B a s e lin e
1 w e e k**** ***
G 0
V e h ic leA Z A
G 5
A Z AV e h ic le
Colla. Cancer Cell 2015; Gomez-Ganan poster 2852 Sunday
N=2
Short-term in TERT-ER mice: effect Aza on HSPC
0
5 0
1 0 0
1 5 0
2 0 0
L T -H S C
Ce
ll n
um
be
r (
we
igh
t-n
orm
ali
ze
d
an
d r
ela
tiv
e t
o C
on
tro
l G
0)
G 0
V e h ic leA Z A
G 5
A Z AV e h ic le
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
S T -H S C
Ce
ll n
um
be
r (
we
igh
-no
rm
ali
ze
d
an
d r
ela
tiv
e t
o C
on
tro
l G
0)
4 1 8 0
G 0
V e h ic leA Z A
G 5
A Z AV e h ic le
*
0
5 0
1 0 0
1 5 0
C M P
Ce
ll n
um
be
r (
we
igh
t-n
orm
ali
ze
d
an
d r
ela
tiv
e t
o C
on
tro
l G
0)
G 0
V e h ic leA Z A
G 5
A Z AV e h ic le
3 9 8 4****
**
****
0
5 0
1 0 0
1 5 0
2 0 0
G M P
Ce
ll n
um
be
r (
we
igh
t-n
orm
ali
ze
d
an
d r
ela
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G 0
V e h ic leA Z A
G 5
A Z AV e h ic le
3 9 9 6
3 9 8 4
****
****
**
Colla. Cancer Cell 2015; Gomez-Ganan poster 2852 Sunday
Papaemmanuil et al Blood 2013;122:3616-27
Genomics of MDS
Clonal Progression from Myelodysplastic Syndrome (MDS) to Secondary Acute Myeloid Leukemia (sAML).
Walter MJ et al. N Engl J Med 2012;366:1090-1098.
Flt3 alterations in MDS
Daver et al. AJH 2013
Time (Months)
Pro
bab
ility
of
Tra
nsfo
rma
tio
n-f
ree
Su
rviv
al
0 20 40 60 80 100 120 140
0.0
0.2
0.4
0.6
0.8
1.0
Non-FLT3/RASFLT3/RAS
Effect of acquisition of Flt3 or Ras mutations in MDS
Takahashi. Leukemia 2014
5AZA + Sorafenib – Outcomes and Survival
46%
Ravandi. Blood 2013
Lower risk non-HMA failure
Results: AML-Free Survival by CyR in Patients With
Isolated del(5q) and del(5q) + 1 Additional Abnormality
For the risk of AML transformation or death, CyR was associated with a 41% reduction
(95% CI 0.38–0.92; P = 0.019) in patients with isolated del(5q) and a 58% reduction (95% CI
0.17–1.02; P = 0.056) in patients with del(5q) + 1 additional abnormality, compared with no CyR
Median AML-free survival,
months (95% CI)
Major + Minor 58.1 (34.8–NR)
Non-responder 30.7 (8.7–63.1)
Sekeres MA, et al. ASH 2013; abstract 390.
Isolated del(5q) (n = 130) del(5q) + 1 additional abnormality (n = 32)
Time to AML or death (months)
Pro
po
rtio
n o
f p
ati
en
ts
0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80
Log-rank P = 0.0259
CyR
Responder
Non-responder
Log-rank P = 0.0042
Median AML-free survival,
months (95% CI)
Major + Minor 59.9 (43.2–NR)
Non-responder 36.7 (17.1–51.2)
Time to AML or death (months)
Pro
po
rtio
n o
f p
ati
en
ts
0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80
CyR
Responder
Non-responder
Low dose DAC in LR MDS:
Transfusion Independence RateArm A
(Daily)
N(%)
Arm B
(Weekly)
N (%)
RBC Transfusion
Independence 20 (62.5) 15 (68.2)
Platelet Transfusion
Independence 22 (68.8) 18 (81.8)
RBC/PLT
Transfusion
Independence
20 (62.5) 13 (59.1)
Garcia-Manero JCO 2013
Phase 1 Oral Aza Study
Response to Therapy (N=41)Garcia-Manero JCO 2011
Disposition
MDS (N=29)N (%)
CMML (N=4) N (%)
AML (N=8)N (%)
Ongoing 8 (28) 2 (50) 2 (25)
Terminated 21 (72) 2 (50) 6 (75)
Median duration of oral therapy,
# of cycles, (range) 6.0 (1–23+) 7.0 (3–17+) 4.5 (1– 14+)
Cycle 7 Response Assessment* 13 (45) 2 (50) 2 (25)
CR / PR / HI 4 (31) 1 (50) 0 (0)
SD 8 (61) 1 (50) 2 (100)†
Progression 1 (8) 0 (0) 0 (0)
* IWG 2003 or 2006†Subjects did not meet criteria for progression or response by IWG 2003
Lower risk HMA failure
• Median follow-up: 16 (1-80) months
• Median TFS and OS: 15 and 17 months
LR MDS post HMA Failure. Outcome
n events mos290 204 15290 201 17
Jabbour et al Cancer 2015
Pleiotropic effectson Progenitors and AML blasts
Dual Inhibition of p38 and Tie2 by ARRY-614
30
Ang-1 Ang-2
• Major regulator of the cellular pathways which sense stress
• Over-activated, leading to inappropriate production of myelosuppressive cytokines
• Dysregulated, may be a survival factor for AML blast
• Increased signaling associated with poor prognosis
p38 MAPK in MDS Tie2 in MDS – Emerging Target
p38
Stress/Inflammatory Stimuli (Cytokines, Hypoxia, FasL)
TNF-α, IL-6, Chemokines
Decreased RBC, WBC, platelets
Apoptosis
Garcia-Manero et al. Clin Cancer Res 2015
ARRY-614 Prior TherapiesN = 71Median prior therapies: 3 (range 0-6; 5 pts with no prior MDS therapies)
‡ATG and/or prednisone†includes cyclosporine, cytarabine, valproic acid, cladribine, mitoxantrone, rituximab, dexamethasone*includes siltuximab, HDAC inhibitors, hedgehog inhibitor, TXA127,
HMA
ESA
Lenalidomide
G/GM-C
SF
Immunosu
ppressi
on‡
Other†
Investigatio
nal*0
20
40
60
80
100
Decitabine Only
Aza and Decitabine
Azacitidine Only
% o
f Pa
tient
s
Garcia-Manero et al. Clin Cancer Res 2015
Epitargeting of immune pathways in MDS
1. Molecular Mechanisms: Interaction
between innate immune signal and
other genetic lesions in MDS
pathogenesis
2. Molecular Mechanisms:
Searching endogenous PAMP/
DAMP that activates innate
immune signaling and
involves in MDS pathogenesis
3. Evaluate Therapeutic
Potential of targeting innate
immune signaling in MDSGomez-Ganan. Leukemia 2015.
Higher risk HMA failure
Outcome in MDS post hypomethylating failure
Jabbour. Cancer 2010
Overall Survival and Subgroup Analysis from a Randomized Phase III Study of
Intravenous Rigosertib vs Best Supportive Care in Patients with Higher-risk
Myelodysplastic Syndrome After Failure of Hypomethylating Agents (ONTIME Trial of ON 01910)
35
G. Garcia-Manero, P. Fenaux, A. Al-Kali, M. R. Baer, M. Sekeres, G. Roboz, G. Gaidano,
B. Scott, P. Greenberg, U. Platzbecker, D. P. Steensma, S. Kambhampati, L. Godley,
R. Collins, E. Atallah, F. Wilhelm, I. Darnis-Wilhelm, N. Azarnia, M. Maniar,
L. R. Silverman, for the ONTIME Investigators
ASH 2014
ONTIME Trial: Primary Efficacy Results – ITT
36ASH 2014
37
Per Prebet 2011, “Primary HMA Failure” was defined as either no response to or progression during HMA therapy
ONTIME Trial: Median Overall Survival for Pts with Primary HMA Failure - Blinded, Centralized Assessment
ASH 2014
Clofarabine Plus Low-Dose Cytarabine
For The Treatment Of Patients With
higher-Risk Myelodysplastic Syndrome
Who Have Relapsed Or Are Refractory
To Hypomethylating Agent
Jabbour E, Sasaki K, Daver N, Pemmaraju N, Jain N,
Kadia T, DiNardo C, Ravandi F, Miller D, Maduike R,
Borthakur G, Konopleva M, Faderl S, O’Brien S, Cortes
J, Kantarjian H, Garcia-Manero G
Department of Leukemia at MD Anderson Cancer Center
Houston, Texas
ASH 2014
Best Response N (%); Median [range]
Complete response 10 (15)
Marrow CR 9 (14)
CRp 3 (5)
Partial response 1 (2)
Hematologic improvement 4 (6)
Overall response rate 27 (44)
# Cycles to best response 1 [1-7]
Early death 1 (2)
CLO and LDAC in HR MDS post HMA. Response (N=61)
ASH 2014
Multivariate analysis
Response Survival
Parameter OR P HR P
Cyto Complex vs. No 5.4 0.04 2.6 0.04
Plt ≤30 vs. >30 NA NS 3.5 0.001
PS ≥2 vs. <2 NA NS 5.5 <0.001
Response vs. Non-Response NA NS 7.1 <0.001
Prior response to HMA NA NS NA NS
CLO and LDAC in HR MDS post HMA. MVA for Response and Survival
ASH 2014
CLO and LDAC in HR MDS post HMA. Survival by Response Status
ASH 2014
Aberrant up-regulation of PD-L1, PD-L2, PD-1 and CTLA4in CD34+ cells from MDS, CMML and AML.
Yang et al Leukemia 2014
Examples of clinical trial options
• Genomic annotation: IDH1, IDH2, RAS, Flt-3
• PD1/PDL1 combinations
• Toll-like receptor inhibitors (OPN-305)
• Oral azacitidine (CC-486)
• Bortezomib
• Omacetaxine
• FF-501
