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