7/12/2016
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Myelodysplastic Syndromes:
What’s on the Horizon?
Vu H. Duong, MD, MS
Assistant Professor of Medicine
University of Maryland
July 16, 2016
Overview
• Refining Risk models
• Specific Therapeutic Areas of Need
• New agents in lower-risk disease
• Optimizing hypomethylating agents in
higher-risk disease
• Treatment options after failure/progression
on hypomethylating agents
Refining Risk Models
Molecular Mutations in MDS
Bejar R, NEJM 2011
• 5 mutations independently associated with
poor prognosis:
TP53
EZH2
ETV6
RUNX1
ASXL1
Incorporating Mutational Data
• None of the 4 major risk models
incorporate molecular data/mutations
• No consensus on how to combine clinical
data with molecular data to risk-stratify
patients
Incorporating Mutational Data
• 508 patients evaluated at the Cleveland
Clinic 2000-2012 retrospectively analyzed
• In multivariate analysis: age, IPSS-R
score, EZH2, SF3B1 and TP53 mutations
were significantly associated with survival
Nazha A, Leukemia 2016
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Incorporating Mutational Data
Characteristic
Total
(n=508)
Training Cohort
(n=333)
Validation
Cohort
(n=175)
Median Age (y) 63 68 69
Males 62% 62% 63%
WBC, 109/L (median) 4 3.8 5
ANC, 109/L (median) 1.9 1.6 2.6
Hemoglobin, g/dL (median) 9.7 9.7 9.8
Platelets, 109/L (median) 94 90 103
IPSS-R Category (%)
Very Low
Low
Intermediate
High
Very High
15
39
20
15
11
2
58
17
11
12
4
65
21
6
4
MDS diagnosis (%)
De novo MDS
Secondary MDS
81
19
87
13
87
13
Nazha A, Leukemia 2016
Incorporating Mutational Data
Training Cohort
C-Index: 0.67
Validation Cohort
C-Index: 0.57
IPSS-R
Incorporating Mutational Data
Training Cohort
C-Index: 0.73
Validation Cohort
C-Index: 0.65
New Molecular Risk Model
Therapeutic Areas of Need
• All currently available therapies have their flaws
• Lower-risk disease:
– Anemia after failure of erythropoiesis-stimulating
agents
– Severe thrombocytopenia
• Higher-risk disease:
– Improving upon the standard of care: hypomethylating
agents
– Options after progression on hypomethylating agents
Lower-Risk Disease
Outcomes after ESA failure3-yr incidence of AML
(%)
Median Overall
Survival (months)
No response/relapse
within 6 months17 36.7
Relapse after 6 months 9 54.3
Kelaidi C, Leukemia 2013
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Lenalidomide• Phase II trial with 214 patients
– Low or int-1 risk by IPSS
– Transfusion-dependent anemia
– No del(5q)
Raza A et al, Blood 2008;111:86-93
• Overall response rate 43%
– 26% achieved RBC transfusion-independence
– 17% with ≥ 50% reduction in transfusions
– Few cytogenetic responses
Lenalidomide
• Randomized Phase III Trial
– 239 patients with MDS
– Low or int-1 risk by IPSS, no del(5q)
– Transfusion-dependent anemia
– Ineligible for or refractory to ESAs
• Randomly assigned (2:1) to treatment with lenalidomide or placebo
Santini V, JCO 2016
Lenalidomide
Santini V, JCO 2016
Lenalidomide
• Transfusion independence ≥ 8 weeks achieved
in 26.9% on lenalidomide vs. 2.5% on placebo
• 90% of patients who achieved RBC-TI
responded within 16 weeks
Santini V, JCO 2016
Epoetin with Lenalidomide
Toma A, Leukemia 2016
Epoetin with Lenalidomide
Len (n=65) Len + Epo (n=66) P
Hem Improvement
Transf Independent
23.1%
13.8%
39.4%
24.2%
0.044
0.13
Response Duration 18.1 mo 15.1 mo 0.47
Venous Thrombosis 3 1 ---
Toma A, Leukemia 2016
• Predictors of response:
– Baseline EPO <100 IU/L
– Presence of G polymorphism of CRBN
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Luspatercept
http://www.acceleronpharma.com/wp-content/uploads/2014/12/ASH-536-MDS-Oral-Presentation-FINAL.pdf
Luspatercept
Erythropoietin Luspatercept
Luspatercept• Phase II extension study in IPSS-defined lower
risk MDS with anemia
– Epo > 500 U/L or ESA refractory/intolerant/
unavailable
– No prior hypomethylating agent
Giagounidis A. ASH 2015, #92
Luspatercept
Thrombopoetin Agonists
Kuter DJ. Cancer 2015
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Romiplostim• Randomized phase II study in patients
with low or int-1 risk MDS by IPSS
• Platelets < 20 x 109/L or ≥ 20 x 109/L with a history of bleeding
Giagounidis A et al. ASH Annual Meeting 2011, #117
Romiplostim Placebo P
CS bleeding
events/patient1.47 1.94 0.13
Plt transfusion
units/100 pt-years3120.2 2221.8 <0.001
HI-P 36.5% 3.6% <0.001
Giagounidis A et al, Cancer 2014
Beyond 58 wks Romiplostim Placebo HR
AML 6% 4.9% 1.20
Death 18% 20.5% 0.86
Romiplostim• Trial was stopped in 2011 due to increased
progression to AML
– At interim analysis: romiplostim 6.0%, PBO 2.4%
* Of 14 patients who progressed to AML, 9 had baseline
RAEB-1 or RAEB-2
Eltrombopag
• Oral Agent
• Binds to TPO-R at the
transmembrane domain
• Does NOT compete with
TPO for receptor binding
Eltrombopag• Randomized phase II study in patients
with low or int-1 risk MDS by IPSS
• Platelets < 30 x 109/L
• Naive to TPO-R agonists
Oliva EN. ASH 2015 #91
Eltrombopag
• Doses up to 300mg daily
At 12 weeks: Eltrombopag
n=46
Placebo
n=24
Mean plt increase 53.2 Gi/L NS
Responses 23 (50%) 2 (8%)
Progression 5 (11%) 2 (8%)
• Median Time to Response: 14 days
• Also improved fatigue
Oral Azacitidine (CC-486)
• Phase III study accruing
• Lower-risk by IPSS, RBC transfusion
dependent and/or thrombocytopenic
Parameter 14-day
n=26
21-day
n=27
Total
n=53
ORR 10/26 (38.5%) 8/27 (29.6%) 18/53 (34%)
Any HI
HI-E
HI-P
HI-N
6/26 (23.1%)
4/23 (17.4%)
4/17 (23.5%)
2/10 (20%)
7/27 (25.9%)
6/25 (24%)
2/15 (13.3%)
0/6 (0%)
13/53 (24.5%)
10/48 (20.8%)
6/32 (18.8%)
3/12 (25%)
Marrow CR 0/7 (0%) 3/5 (60%) 3/12 (25%)
Garcia-Manero G, ASH Annual Meeting 2012
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Low-Dose Hypomethylating
Agents
• Low- or intermediate-1-risk MDS, CMML
or MDS/MPN
• Azacitidine 75 mg/m2 daily x 3 days or
Decitabine 20 mg/m2 daily x 3 days every
4 weeks
• 88 patients treated
– 30 patients (36%) received azacitidine
– 53 patients (64%) received decitabine
Short NJ, ASH Annual Meeting 2015, #94
Low-Dose Hypomethylating
Agents• Overall response rate: 61%
– CR: 32 pts (39%)
– CRi: 11 (13%)
– Hematologic Improvement: 8 (10%)
• Median time to best response: 2.2 months
• Median duration of response not reached
with 71% of responders still on study
• Well-tolerated with only 6 pts (7%)
requiring dose reduction
Short NJ, ASH Annual Meeting 2015, #94
Higher-risk Disease
Hypomethylating Agents
The Good
• Response rates are
reasonable
• Well-tolerated
• Can be given as an
outpatient
The Bad
• Treatment is not
curative
• Treatment is indefinite
• No FDA-approved
options after failure,
and patients fare
poorly
• No significant
difference in OS or
duration of response
• Encodes enzyme that converts
5-methylcytosine to 5-
hydroxymethycytosine
• Leads to DNA demethylation
• Mutated in ~15% of MDS and
AML0
,2
,4
,6
,8
1
Probability o
f S
urviv
al
0 10 20 30 40 50 60
Time (months)
Tps de Censure (WT)
Tps de Censure (MUT)
Survie Cum. (WT)
Survie Cum. (MUT)
Kaplan-Meier Graphe de Survie Cum. pour FU
Variable censure : censureOS
Facteur : TET2spliceMUT
Critère d’inclusion : evaluables en réponse medullaire de basetet2_MAJ.svd
Mutated
WT
Mutated,
n=13
WT,
n=73
P
Value
OR, incl SD
with HI
11 (85%) 34 (47%) 0.01
OR 9 (69%) 23 (31%) 0.01
CR 5 (38%) 15 (21%) 0.17
Itzykson R et al. Leukemia 2011; 25:1147
Predicting Response Predicting Response
Bejar R et al. Blood 2014
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Azacitidine Combination Studies
Drug Target Identifier
Durvalumab (MEDI4736) PD-L1 NCT02775903
Nivolumab PD-1 NCT02530463
Ibrutinib BTK NCT02553941
Vosaroxin Topoisomerase II NCT01913951
Pevonedistat NEDD8 NCT02610777
Volasertib PLK-1 NCT02721875
Eltrombopag TPO-R NCT02158936
PF-04449913 (Glasdegib) Hedgehog Pathway NCT02367456
Vadastuximab Talirine (SGN-CD33A) CD33 NCT02706899
Rigosertib PLK-1 NCT01926587
Sirolimus mTOR NCT01869114
North American Intergroup Randomized
Phase 2 MDS Study S1117
Aza (n=92) Aza+Len
(n=93)
Aza+Vor
(n=92)
Overall Response
Rate (%)
37 42 (p=0.45) 27 (p=0.16)
CR/PR/HI (%) 24/0/13 21/1/22 17/1/9
ORR Duration –
Median (Range,
months)
9 (1-26) 11 (2-31) 13 (1-32)
CMML ORR (n=52) 29 63 (p=0.04) 12 (p=0.4)
CMML ORR Duration -
Median (Range,
months)
4 (1-26) 14 (2-31) 21 (1-32)
Sekeres M et al. ASH 2015, #908 Sekeres M et al. ASH 2015, #908
North American Intergroup Randomized
Phase 2 MDS Study S1117
Outcomes after HMA Failure
MDS & CMML Patients
1. Jabbour E et al, Cancer 2010; 116:3830
2. Prébet T et al, JCO 2011; 29:3322
3. Duong VH, Clin Lymphoma Myeloma Leuk 2013;13:711
Institution No. of
Patients
Treated
No. of
HMA
failures
AML
Progression
Median
OS
(months)
OS at 12
months
MDACC1 NR 87 25 (29%) 4.3 30%
GFM2 435 NR NR 5.6 29%
Moffitt3 151 59 12 (20.3%) 5.8 17%
Options After HMA Failure?
• NO STANDARD OF CARE - Clinical trial is preferred
Prébet T et al, JCO 2011; 29:3322
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Decitabine after Azacitidine• MDACC prospective trial:
– 28% RR (3/14), median OS 6 months
• Univ. of Maryland experience:
– No responses in 25
patients with MDS
or AML
– Median OS: 5.9 m
Duong VH, Leuk Lymphoma 2014
Borthakur G, Leuk Lymphoma 2008
SGI-110 (Guadecitabine)
• Dinucleotide of
decitabine and
guanosine
• Longer half life
• Longer exposure time
• Protection from
degradation
SGI-110: Randomized Phase II SGI-110: Randomized Phase II
Garcia-Manero G, EHA 2016, Abstract P249
Response Category Prev Treated (n=53)
CR 2 (3.8%)
mCR 15/34 (44%)
HI 11 (20.8%)
Rigosertib
• Binds to the Ras-binding domain of multiple kinases
• Inhibits signaling pathways controlled by PI3K and PLK (often activated in hematologic malignancies)
• Randomized, multicenter phase III trial in patients previously treated with azacitidine or decitabine
Garcia Manero, G. Lancet Oncology 2016
Rigosertib (n=199) BSC (n=100)
Number of deaths 161 (81%) 81 (81%)
Median Survival (months)
95% Confidence Interval
8.2
6.0-10.1
5.9
4.1-9.3
Stratified Hazard Ratio
95% Confidence Interval
0.87
0.67-1.14
P-value 0.33
Rigosertib vs. BSC
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Rigosertib vs. BSC Rigosertib
Acknowledgements
Hematology Group:
Maria Baer, MD
Ashkan Emadi, MD, PhD
Arnob Banerjee, MD, PhD
Jennie Law, MD
Seung Tae Lee, MD
Ronald Gartenhaus, MD
Ann Zimrin, MD
Ashraf Badros, MD
Hakan Kocoglu, MD
And to all of our patients!!!
BMT:
Aaron Rapoport, MD
Nancy Hardy, MD
Jean Yared, MD
Saul Yanovich, MD
Hematopathology:
Zeba Singh, MBBS
Madhurima Koka, MD, PhD
All of our fantastic nurses and staff