Clinical Update on MDS 2015
Guillermo Garcia-Manero MD
Section of MDS
Department of Leukemia
University of Texas
MD Anderson Cancer Center
Houston, Texas
Natural History of MDS After
Incorporation of HMAs
Prodrome
ICUS, CHIP
LR-MDS HR-MDS
AML
HMA failure
?HMA failure
AML-like?
?
Untreated
HMA?
Lenalidomide
Untreated
HMA
AML-like
SCT
HMA lower-risk failure survival: 14-17 months
HMA higher-risk failure survival: 4-6 months
Jabbour EJ, et al. Cancer. 2015;121(6):876-882. Jabbour EJ, et al. Cancer. 2010;116(19):3830-3834. Steensma DP, et
al. Blood. 2015;126(1):9-16.
Papaemmanuil E, et al. Blood. 2013;122(22):3616-3627.
Genomics of MDS
Somatic Mutations in MDS Are Associated With Clinical
Features and Predict Prognosis Independent of the IPSS-R
Analysis of Combined Datasets From the International
Working Group for MDS-Molecular Prognosis Committee
Rafael Bejar, MD, PhD
Elli Papaemmanuil, PhD
Torsten Haferlach, MD
Seishi Ogawa, MD, PhD
Guillermo Garcia-Manero, MD
Jaroslaw P. Maciejewski, MD, PhD
Mikkael A. Sekeres, MD, MS
Matthew J. Walter, MD
Timothy A. Graubert, MD
Mario Cazzola, MD
Luca Malcovati, MD
Pierre Fenaux, MD, PhD
Eva Hellstrom-Lindberg, MD, PhD
Wolfgang Kern, MD
Jacqueline Boultwood, PhD
Andrea Pellagatti, PhD
David Bowen, MD, PhD
Sudhir Tauro, PhD
Michael J Groves, PhD
Paresh Vyas, MD, PhD
Lynn Quek, MD
Aziz Nazha, MD
Felicitas Thol, MD
Michael Heuser, MD
Lee-Yung Shih, MD
Yasunobu Nagata, MD, PhD
Yusuke Okuno, MD, PhD
Eric Padron, MD
David Sallman, MD
Rami S. Komrokji, MD
Alan F. List, MD
Detlef Haase, MD, PhD
Julie Schanz, MD
Valeria Santini, MD
Michaela Fontenay, MD, PhD
Peter J Campbell, MD, PhD
Heinz Tüchler
Kristen Stevenson, MS
Donna S Neuberg, ScD
Peter Greenberg, MD
Benjamin L Ebert, MD, PhD
On behalf of the IWG for MDS
investigators
Bejar R, et al. Blood. 2015;126: Abstract 907.
Y e a r s
Ov
era
ll S
urv
iva
l (%
)
0 2 4 6 8 1 0 1 2 1 4
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
0 (n = 3 7 7 )
1 (n = 5 9 5 )
2 (n = 4 6 0 )
3 (n = 2 1 0 )
4 (n = 1 2 5 )
5 /6 /7 (n = 2 2 )
S F 3 B 1 o n ly (n = 2 0 7 )
N u m b e r o f M u ta te d G e n e s
Overall Survival by Mutation Number
17 Genes Sequenced in 1996 Patients With OS DataASXL1
CBL
DNMT3A
ETV6
EZH2
IDH1
IDH2
JAK2
KRAS
NPM1
NRAS
RUNX1
SRSF2
TET2
TP53
U2AF1
SF3B1Bejar R, et al. Blood. 2015;126: Abstract 907.
Mutated Genes and Clinical Phenotypes
Mutation
Frequency
26%
0.5%
<.0001
P value
adverse
<.0001
P value
favorable
.01
.01
Gene%
MutFAB WHO
IPSS-
R
Blast
% Plts Sex Age ANC Hgb OS
TP53 8.9
ASXL1 21
SRSF2 15
U2AF1 8.9
NRAS 3.6
RUNX1 10
STAG2 5.6
IDH2 3.4
KRAS 2.3
NPM1 1.5
BCOR 4.7
TET2 26
ZRSR2 6.4
EZH2 5.9
CBL 4.4
RAD21 1.3
PTPN11 1.5
GATA2 1.3
NF1 4.5
ETV6 2.6
PRPF8 2.4
FLT3 0.9
IDH1 2.3
PHF6 2.9
GNAS 0.9
WT1 1.2
ATRX 2.1
U2AF2 1
SMC3 1.3
KIT 1.1
MPL 1.8
DNMT3A 12
JAK2 3.6
SF3B1 22
Bejar R, et al. Blood. 2015;126: Abstract 907.
Final Multivariable Survival Model
HR P value
IPSS-R Risk Groups (vs Very
Low)
Low 1.08 .542
Intermediate 1.97 <.0001
High 2.56 <.0001
Very High 4.36 <.0001
Mutated Genes (vs
Unmutated)
TP53 2.35 <.0001
RUNX1 1.51 .0002
EZH2 1.58 .0006
NRAS 1.44 .019
SF3B1 0.82 .041
CBL 1.35 .056
U2AF1 1.22 .069
ASXL1 1.17 .090
TET2 0.88 .104
IDH2 1.31 .111
KRAS 1.22 .362
NPM1 1.2 .546
Hazard Ratio (95% CI)
Bejar R, et al. Blood. 2015;126: Abstract 907.
Clinical Implications of Genomics in MDS• Whole-exome sequencing of 114 untreated MDS patients
• Independent prognostic value of TP53 mutations
• Four or more driver mutations independently prognostic in MDS.
Takahashi H, et al. Blood. 2015;126: Abstract 3940. Takahashi H, et al. Oncotarget. [In Press].
Somatic Mutations in “Normal” Individuals
Jaiswal S, et al. N Engl J Med. 2014;371(26):2488-2498.
Can We Predict Development of
Therapy-Related MDS?
Wong TN, et al. Nature. 2015;518(7540):552-555.
4 years
Small cell lung ca
Limited stage t-MDS
XRT+ 4 cycles of cisplatin + etoposide
BMPB
0
20
40
60
80
SCLCt-MDS
VA
F (
%)
4 years
SCLC t-MDS
TP53 p. H193R 24 73
UID36491
Takahashi E, et al. Blood. 2015;126: Abstract 1663.
6 years
Rectal adenocarcinoma
T2N0M0 t-MDS
XRT+ capecitabine
BMPB
0
10
20
30
40
50
Rectal Cancert-MDS
VA
F (
%)
6 years
Rectal Cancer t-MDS
TET2 p.L1212* 6 45
UID4473
Takahashi E, et al. Blood. 2015;126: Abstract 1663.
3 years
Small cell lung cancer
Limited stage t-AML
XRT+ 4 cycles of carboplatin + etoposide
BMPB
0
10
20
30
40
50
SCLCt-AML
VA
F (
%)
3 years
SCLC t-AML
IDH2 p.R140Q 14 46
UID6982
Takahashi E, et al. Blood. 2015;126: Abstract 1663.
Adult Murine Hematopoiesis
LYMPHOID
PROGENITOR
COMPARTMENT
= KLMYELOID
PROGENITOR
COMPARTMENT
ERYTHROCYTES
ST-HSC
MP
P
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+CD16/3
2+
Lin-ckit+sca1+CD34+CD135bright
Iwasaki H, et al. Immunity. 2007;26(6):726-740.
= KSLHSC
COMPARTMENT
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
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 9 6
3 9 8 4
****
****
**
Colla S, et al. Cancer Cell. 2015;27(5):644-657. Gañán-Gómez I, et al. Blood. 2015;126: Abstract 2852.
MDS
Low risk
(IPSS low, INT-1)
(BM blasts < 10%)
High risk
(IPSS INT-2, high)
(BM blasts > 10%)
• Iron chelation
• Growth factors
(Epo + G-CSF)
• MTI (5-AZA/decitabine)
• Lenalidomide (5q-)
• Immunomodulation
• Clinical trial
Age <60
• Intensive chemotherapy
• MTI (5-AZA/decitabine)
• Clinical trial
Age ≥60
• MTI (5-AZA/decitabine)
• Clinical trial
• Intensive chemotherapy1
1Consider in younger patients
with diploid cytogenetics2 Consider earlier in younger
patients
Failure/
Progression
Allo SCT
Proposed Treatment Algorithm for
Patients With MDS
Any age
Atallah E, et al. Cancer Invest. 2008;26(2):208-216.
Giagounidis A, Platzbecker U, Germing U, Götze K, Kiewe P, Mayer KT, Ottmann O,
Radsak M, Wolff T, Haase D, Hankin M, Wilson D, Zhang X, Laadem A, Sherman
ML, Attie KM
D·MDS Deutsche MDS-Studiengruppe
Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients With Low or
Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results From the Phase 2
PACE-MDS Extension Study
Giagounidis A, et al. Blood. 2015;126: Abstract 92.
Abstract 92
Luspatercept in MDS: Background
Erythropoiesis
TGF-β Superfamily
Ligands: GDF11, etc.
Smad2/3
Suragani RN, et al. Nat Med. 2014;20(4):408-414. Zhou L, et al. Blood. 2008;122(2):308-319.
Luspatercept
Fusion protein containing
modified activin receptor
type IIB (ActRIIB)
Activin Receptor
Domain
Human IgG Fc
Domain
• Mechanism is distinct from
erythropoietin
• Acts on late-stage
erythropoiesis to increase
mature RBCs in the
circulation
Efficacy Summary: HI-E Response Rate
Patient Subgroup
0.125-0.5 mg/kg
(N = 9)
n (%)
0.75-1.75 mg/kg
(N = 17)
n (%)
LTB patients (N = 7) 0/2 (0%) 2/5 (40%)
HTB patients (N =
19)2/7 (29%) 5/12 (42%)
All patients (N = 26) 2/9 (22%) 7/17 (41%)
HI-E (IWG):
LTB: Hemoglobin increase ≥1.5 g/dL for ≥8 weeks
HTB: Reduction of ≥4 units RBCs transfused over 8 weeks
HI-E, hematologic improvement-erythroid
IWG, International Working Group
LTB, low transfusion burden; HTB, high transfusion burden
Data as of 03 Oct 2014
Giagounidis A, et al. Blood. 2015;126: Abstract 92.
Low-Dose Hypomethylating Agents Are
Effective in Patients With Low- or
Intermediate-1-Risk Myelodysplastic
Syndrome: A Report on Behalf of the MDS
Clinical Research Consortium
Short N, Garcia-Manero G, Montalban Bravo G, Sasaki K, Sekeres M,
Komrokji R, Steensma D, DeZern A, Roboz G, Kadia T, Borthakur G,
DiNardo C, Miller D, Estrov Z, Pemmaraju N, Daver N, Verstovsek S,
Kantarjian H, Jabbour E
Short N, et al. Blood. 2015;126: Abstract 94.
Abstract 94
Response N (%)
CR 33 (36)
mCR 8 (9)
HI 13 (14)
ORR 54 (59)
SD 31 (34)
PD 6 (7)
Low-Dose HMAs in LR-MDS:
Response
• Median time to best response: 2 months (range: 1-20)
• Median number of cycles received: 9 (range: 2-32)
Short N, et al. Blood. 2015;126: Abstract 94.
Transfusion Dependence
at BaselineN
Transfusion Independence
N (%)
RBCs 34 10 (29)
Platelets 5 3 (60)
RBCs + platelets 5 1 (20)
Total 44 14 (32)
Low-Dose HMAs in LR-MDS:
Transfusion Response
Short N, et al. Blood. 2015;126: Abstract 94.
Low-Dose HMAs in LR-MDS:
Cytogenetic Response (N = 38)
Cytogenetic Response N (%)
CCyR 8 (21)
PCyR 11 (29)
NR 19 (50)
Short N, et al. Blood. 2015;126: Abstract 94.
Low-Dose HMAs in LR-MDS:
Survival
Median, mos 1-year rate, %
EFS 20 62
OS NR 86
Short N, et al. Blood. 2015;126: Abstract 94.
Phase I Oral Aza Study
Response To Therapy (N = 41)
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
Short N, et al. Blood. 2015;126: Abstract 94.
Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC ,
Faderl S, Griffiths E, Harb WA, Tibes R, O’Connell C, Redkar S, Lowder JN,
Taverna P, Oganesian A, Nawabi R, Azab M, Garcia-Manero G
Results of First in Human (FIH) Phase 1
Pharmacokinetic (PK) Guided Dose-
Escalation Study of ASTX727, a
Combination of the Oral Cytidine Deaminase
Inhibitor (CDAi) E7727 With Oral Decitabine,
in Subjects With Myelodysplastic
Syndromes (MDS)
Savona M, et al. Blood. 2015;126: Abstract 1683.
Abstract 1683
Study DesignASTX727-01: Phase I Dose Escalation Cohorts
Savona M, et al. Blood. 2015;126: Abstract 1683.
Decitabine PK Profile, IV vs Oral,
Without/With CDAi
Savona M, et al. Blood. 2015;126: Abstract 1683.
• ASTX727 cohorts 4 and 5 achieve LINE-1 demethylation
>10%
Pharmacodynamics:ASTX727-01 LINE-1 Demethylation: Overall
Summary for 5 Cohorts
Savona M, et al. Blood. 2015;126: Abstract 1683.
Time on Study and to Response
Savona M, et al. Blood. 2015;126: Abstract 1683.
Early Intervention in MDS
NCT02269280
LR-MDS
Transfusion dependent
Transfusion independent
AZA x 3 days
DAC x 3 days
AZA x 5 days
Observation
Multicenter via Evans MDS Consortium
TP53 Mutation Effect on HMA
Therapy in MDS
Takahashi H, et al. Blood. 2015;126: Abstract 3940. Takahashi H, et al. Oncotarget. [In Press].
Randomized Phase II Study of SGI-110 in MDS/CMML1
Biologically Effective
Dose
60 mg/m2 daily x 5
Highest Well Tolerated
Dose 90 mg/m2 daily x 5
R
A
N
D
O
M
I
Z
A
T
I
O
N
• Primary endpoint: Overall response rate (CR, PR, mCR, HI)
• Secondary endpoints: Transfusion independence, LINE-1 demethylation,
time to AML, overall survival
IWG 2006
MDS
Response
Criteria
Treatment continued until unacceptable toxicity, disease progression
Major Eligibility
Previously Treated
MDS/CMML
or
Treatment-Naïve
MDS/CMML
• IPSS Int-1,2
and HR
• ECOG PS 0-2
• Adequate
hepato-renal
function
1 Data presented with data cutoff end of July 2014
Garcia-Manero G, et al. Blood. 2015;126: Abstract 529.
A Final Report: Phase I/II Study of
Sequential Azacitidine (AZA) and
Lenalidomide (LEN) in Patients With
Higher-Risk MDS and AML
DiNardo CD, Daver N, Jabbour E, Kadia T, Borthakur G,
Konopleva M, Pemmaraju N, Yang H, Wei Y, Pierce S, Wierda W,
Bueso-Ramos C, Patel KP, Cortes JE, Ravandi F, Kantarjian HM,
Garcia-Manero G
MD Anderson Cancer Center
DiNardo CD, et al. Lancet Haematol. 2015;2(1):e12-20.
AZA + LEN Response
Phase I N = 28 CR CRi ORR Median
OS, wks
Median
Courses
Response
Duration, wks
LEN DOSE
<25 mg 11 0 0 0% 12 3 (1-6) NA
25 mg 3 2 0 67% NR 6 (6-12) 81 (35-127)
>25 mg 14 2 0 14% 16 2.5 (1-12) 81 (78-85)
Phase I PTS 28 4 0 14%
(P = .014)
17 3 (1-12) 81 (35-127)
Phase II N = 60 CR CRi ORR Median
OS, wks
Median
Courses
Response
Duration, wks
LEN DOSE
IIa: 50 mg 20 2 3 25% 21 2 (1-12) 18 (2-98)
IIb: 25 mg 40 9 13 55% 75 4 (1-16) 27 (2-71)
Phase II PTS 60 11 16 45%
(P = .029)
60 3 (1-16) 24 (2-98)
Phase I + II N = 88 15 16 35%* 33 3 (1-16) 29 (2-127)
*13 of 31 responding patients went on to SCT; 10 of 13 continue in sustained CR
DiNardo CD, et al. Lancet Haematol. 2015;2(1):e12-20.
Garcia-Manero G, Berdeja JD, Komrokji RS, Essell J, Lyons RM,
Maris M, DeZern AE, Sekeres MA, Roboz GJ
A Randomized, Placebo-Controlled,
Phase II Study of Pracinostat in
Combination With Azacitidine (AZA) in
Patients With Previously Untreated
Myelodysplastic Syndrome (MDS)
Garcia-Manero G, et al. Blood. 2015;126: Abstract 911. Garcia-Manero G, et al. Blood. 2015;126: Abstract 2861.
Sekeres M, et al. Blood. 2015;126: Abstract 908.
Abstract 911
Aza + Pracinostat in MDS: Overall Survival
Median Follow Up = 15.4 months
One Year Survival: Pracinostat = 57.1%
Placebo = 57.4%
HR = 1.21
Garcia-Manero G, et al. Blood. 2015;126: Abstract 911.
Garcia-Manero G, Atallah E, Medeiros B, Arellano M, Khaled SK,
Patnaik M, Odenike O, Sayar SH, Tummala MK, Patel P, Maness-
Harris L, Stuart R, Traer E, Karamlou K, Yacoub A
Final Results From a Phase II
Study of Pracinostat in
Combination With Azacitidine
in Elderly Patients With Acute
Myeloid Leukemia (AML)
Abstract 453
Aza + Pracinostat in AML: Overall Survival
EFS: 7.7 months (0.9-21.2+); 1-year survival 62%Garcia-Manero G, et al. Blood. 2015;126: Abstract 453.
A Phase II Study of the
Combination of Oral Rigosertib
and Azacitidine in Patients With
Myelodysplastic Syndromes (MDS)
Navada SC, Silverman LR, Hearn K,
Odchimar-Reissig R, Demakos E, Alvarado Y, Daver N, DiNardo C,
Konopleva M, Borthakur G, Fenaux P, Fruchtman S, Azarnia N,
Garcia-Manero G
Navada S, et al. Blood. 2015;126: Abstract 910.
Abstract 910
Combination Trial Design
Sequence Suggested by Preclinical Findings
Treatment Regimen:
Week 1: Oral rigosertib BID
(560 mg AM/280 mg PM)
Week 2: Oral rigosertib +
azacitidine (75 mg/m2/day
SC or IV)
Week 3: Oral rigosertib BID
Week 4: No treatment
Week 1
Oral
Rigosertib
only
Week 4
No Treatment
Week 2
Oral Rigosertib
+
Azacitidine
(SC or IV)
Week 3
Oral
Rigosertib
only
Navada S, et al. Blood. 2015;126: Abstract 910.
Efficacy Results Number of MDS patients treated
Evaluable for response (8 Ph1, 22 Ph2)
37
30
Overall response 23 (77%)
Hematologic
response*
Complete remission
Partial remission
Marrow CR
Stable disease
Progressive disease
6 (20%)
0
16 (53%)
6 (20%)
1 (3%)
Hematologic improvement* 1 (3%)
Not evaluable 3 (10%)
Too early to evaluate 4 (13%)
Median duration of treatment (months) 4 (1-27+)* Per IWG 2006
Navada S, et al. Blood. 2015;126: Abstract 910.
Efficacy: MDS Patients With Prior HMA Failure
Number of patients evaluable for
response (3 Ph1, 8 Ph2)
11
(8 AZA, 2 DAC, 1 both)
Number of prior HMA cycles 4-20
Hematologic response per IWG 2006 7 (64%)
CR 1
PR 0
mCR 4
mCR with concurrent HI 2
Stable disease 3
Progressive disease 1
Hematologic improvement (trilineage) 3
HMA-naïve patients (N = 19) response
per IWG16 (84%)
Navada S, et al. Blood. 2015;126: Abstract 910.
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)
Garcia-Manero G, Fenaux P, Al-Kali A, Baer MR, Sekeres M, Roboz G, Gaidano G,
Scott B, Greenberg P, Platzbecker U, Steensma DP, Kambhampati S, Godley L,
Collins R, Atallah E, Wilhelm F, Darnis-Wilhelm I, Azarnia N, Maniar M,
Silverman LR, for the ONTIME Investigators
Garcia-Manero G, et al. Blood. 2014;124: Abstract 163. Garcia-Manero G, et al. Lancet Oncol. [In press].
ONTIME Trial: Median Overall Survival for Pts With
Primary HMA Failure - Blinded, Centralized Assessment
Per Prebet 2011, “Primary HMA Failure” was defined as either no response to or
progression during HMA therapy
Garcia-Manero G, et al. Blood. 2014;124: Abstract 163.
Post-HMA HR-MDS (N = 225)
Key Eligibility Criteria:
- Failed HMA < 9 months DoT
- < 80 years of age
Randomization
2:1
IV rigosertib
+
BSC
N = 150
Overall Survival
- Interim analysis
(86 events)
- Intent-to-treat
analysis
(171 events)
• Stratification at randomization
Very High Risk vs other IPSS-R
US vs Europe vs Asia
• Statistical analysis
– for ITT = 0.0397; for IPSS-R VHR = 0.01
– Trial can succeed in two ways
Physician’s
Choice
+
BSC
N = 75
Follow-up
Design of New Phase III INSPIRE Trial
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
Rela
tiv
e e
xp
ressio
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
Rela
tiv
e E
xp
ressio
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 H, et al. Leukemia. 2014;28(6):1280-1288.
Effect of Mutations on SCT Outcomes
Gene
Adjusted
HR
(95% CI)
P
value
TP53 (n = 14)3.90
(1.85, 8.22)<.001
DNMT3A (n =
14)
3.54
(1.45, 8.64).005
TP53 and DNMT3A Mut Absent (n = 46)
TP53 or DNMT3A Mut Present (n = 26)
P<.001
Overall Survival After Transplant
HR for Overall Survival
Bejar R, et al. J Clin Oncol. 2014;32(25):2691-2698.
Assessing Risk Post SCT in MDS
• Genomic analysis may allow risk SCT assessment in MDS
• German study of N = 308 pts (MDS/AML)
• 54-gene panel
• Median age 58 (19-75)
• 75% of patients active disease at SCT
• Complex cytogenetics, IDH2, NRAS, PTPN11, PHF6 poor risk factors
• P53 negated by complex cytogenetics
• Haploidential SCT and transplant not in response also poor predictors
Heuser M, et al. Blood. 2015;126: Abstract 912. Yoshizato T, et al. Blood. 2015;126: Abstract 711. Bejar R, et al.
J Clin Oncol. 2014;32(25):2691-2698.
In Conclusion
• Increased role of genomic annotation in MDS:
– IDH1, IDH2, RAS, Flt-3, and SCT
• Better understanding of cellular effect of HMAs
• Newer agents: antiCD33, antiCD123, ABT-119, TGF-b inhibitors
• Lower-dose HMAs for lower-risk MDS
• Potent oral forms of HMAs: CC-486, ASTX727
• Second-generation HMAs: SGI-110
• Combinations: + PD1/PDL1 inhibitors??
• Rigorsetib for HMA failures
• 3 ongoing phase III trials: CC-486, Rigosertib, ACE-536