Myelodysplastic Syndromes

diagnostics

prognostics

emerging treatment strategies in lower risk disease

Arjan A. van de Loosdrecht Department of Hematology

VU University Medical Center

VU-Institute of Cancer and Immunology (V-ICI)

Cancer Center Amsterdam (CCA)

Amsterdam, The Netherlands

Nederlands Hematologie Congres 2016

Papendal

Vrijdag 22-1-2016

Steensma DP, et al., Blood 2015;126:9-16; Malcovati L, et al., ASH 2015: pp 299-307 (educational)

Cytopenia + mutation – dysplasia = WHAT?

Incidence of MDS in the Netherlands A

SR

/ 1

00,0

00

Year of diagnosis

0,0

1,0

2,0

3,0

0,3 2,0 7,2

20,5

32,1

0,0

10,0

20,0

30,0

40,0

Relative survival of MDS in the Netherlands

RSR: relative survival rate

0%

20%

40%

60%

80%

100%

RS

R

Year Of Diagnosis

1-year RSR

3-year RSR

5-year RSR

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8 9 10

RS

R

Time From Diagnosis (years)

2001-2005

2006-2010

A B

0%

20%

40%

60%

80%

100%

RS

R

Year Of Diagnosis

1-year RSR

3-year RSR

5-year RSR

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8 9 10

RS

R

Time From Diagnosis (years)

2001-2005

2006-2010

A B

Relative survival is the observed patient survival corrected for the

expected survival of comparable group from the general population

Dinmohamed AG et al., Eur J Cancer 2014;50:1004-12

Diagnostic tool Diagnostic value Priority

Peripheral blood

smear

• Evaluation of dysplasia in one or more cell lines

• Enumeration of blasts Mandatory

Bone marrow

aspirate

• Evaluation of dysplasia in one or more

myeloid cell lines

• Enumeration of blasts

• Enumeration of ring sideroblasts

Mandatory

Bone marrow biopsy • Assessment of cellularity, CD34+ cells, and fibrosis Mandatory

Cytogenetic

analysis

• Detection of acquired clonal chromosomal

abnormalities that can allow a conclusive diagnosis

and also prognostic assessment

Mandatory

FISH

• Detection of targeted chromosomal abnormalities

in interphase nuclei following failure of standard G-

banding

Recommended

Flow cytometry

immunophenotype

• Detection of abnormalities in erythroid,

immature myeloid, maturing granulocytes,

monocytes, immature lymphoid compartments

Recommended*

If according to

ELN guidelines

SNP-array

• Detection of chromosomal defects at a high

resolution in combination with metaphase

cytogenetics

Suggested (likely to

become a

diagnostic tool in

the near future)

Mutation analysis of

candidate genes

• Detection of somatic mutations that can allow

a conclusive diagnosis and also reliable

prognostic evaluation

Suggested (likely

to become a

diagnostic tool in

the near future)

Diagnostic approach to MDS 2016 Dutch/EU guidelines

Malcovati L, et al., ELN guidelines. Blood 2013;122:2943-64; Greenberg P et al., J Nat Compr Netw

Canc 2013;11:838-74; *Westers TM, et al., Leukemia 2012;26:1730-41

WHO2016:

reclassifying Myelodysplastic Syndromes

MDS with single lineage dysplasia (MDS-SLD)

MDS with multilineage dysplasia (MDS-MLD)

MDS with single lineage dyplasia and RS (MDS-RS-SLD)

MDS with multilineage dysplasia and RS (MDS-RS-MLD)

MDS with excess blasts-1 (MDS-EB1)

MDS with excess blasts-2 (MDS-EB2)

Arber DA and Hasserjian RP. Hematology 2015;294-298; educational session

WHO2016:

reclassifying MDS: comments

Morphology:

no changes

– dysplasia cut-off levels remains 10% in all lineages

– blast cell counts by cytology [no FCM]

– due to IPSS-R push towards counts of

WHO2016:

reclassifying MDS: comments

Additional new concepts:

Add: SF3B1 mutation and RS 50% erythroid precursors

Add: Familial myeloid neoplasms with germ line mutations

(TERT, GATA2)

Arber DA and Hasserjian RP. Hematology 2015;294-298; educational session

WHO-2016 role of FCM: iMDSflow recommendations Discussion slides regarding clinical needs

• Diagnostics:

– Non-conclusive cases by morphology/cytogenetics

– Unilineage versus multilineage dysplasia (vs WHO criteria)

– IDUS/ICUS/CHIP/CCUS

– MDS-U vs RA vs RARS

– CMML and monocytic leukemias

– PB blast count/aberrancies in MDS +/- sF

– Diagnostic scores i.e. Ogata score vs complex score vs ABC score

– Integrated diagnostics

Cremers EMP, et al., Eur J Cancer 2015;54:49-56

Westers TM, et al., Leukemia 2012;26:1730-41; Porwit A, et al., Leukemia 2014:28:1793-98

Validation of the integrated flowcytometric (iFC)

diagnostic algorithm in a prospective clinical trial (HOVON89)

Diagnostic score

Specificity: 95%

Sensitivity: 80%

By FCM dysplasia

in myeloid / erythroid lineage

Cremers EMP et al., 2015 (submitted);

Loosdrecht AA van de, Westers TM. J Nat Compr Cancer Netw 2013;11:892-902;

Westers TM, et al., Leukemia 2012;26:1730-41; Porwit A, et al., Leukemia 2014:28:1793-98

Validation of FCM acc. to integrated Flow Score within

a prospective clinial trial: HOVON 89 (n=174)

Integrated Flow Score:

inconclusive by cytomorphology/Cytogenetics

Cremers EMP et al., Eur J Cancer 2015;54:49-56

iFS VUmc

sensitivity MDS-CM: 61%

specificity (PaCo): 95%

MDS in follow-up by CM

2.6% (3/114) (based on DysM by CM)

25% (2/8) (reactive/fe-def/drug-induced)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

??

CM? CG-FC+

CM ? CG-FC-/+

CM? CG-FC-

n= 379 total: cytopenia

n = 218 diagnosis MDS/non-MDS)

n = 161 CM/CG inconclusive

7%

t=0 FC-analyse

Ogata score

+ myelomonocytoid

FU 122/161

C

B

A

Prognostic

variable

0 0.5 1 1.5 2 3 4

Cytogenetics Very Good Good Int Poor Very Poor

BM Blast % ≤2% >2-10

%

Hemoglobin

g/dl; mmol/l

≥10

≥6.2

8-

Revised International Prognostic Scoring System (IPSS-Revised)

for MDS: clinical heterogeneity

Greenberg P, et al., Blood 2012;120:2454-65; Van

Spronsen M.F., et al., Eur J Cancer 2014;50:3198-3205

very good

n=81

(2.8%)

single:

del(11q)

-Y

OS

60.8 months

HR

0.5 (0.3-0.7)

good

n=1809

(65.7%)

single:

normal

del(5q)

del(12p)

del(20q)

two:

del(5q)

and others

OS

48.6 months

HR

1.0 (0.9-1.1)

intermediate

n=529

(19.2%)

single:

del(7q)

+8

i(17q)

+19

other unrel

clones

two:

w/o

del(5q)/

del(7q)

OS

26 months

HR

1.6 (1.4-1.8)

poor

n=148

(5.4%)

single:

inv(3)/t(3q)/

del(3q)

-7

two:

del(7q)

and others

complex:

3

OS

15.8 months

HR

2.6 (2.1-3.2)

very poor

n=187

(6.8%)

complex:

>3

OS

5.9 months

HR

4.2 (3.4-5.2)

Cytogenetic Score within the IPSS-R

Schanz J, et al., J Clin Oncol. 2012 Mar 10;30(8):820-9. Greenberg PL, et al., Blood 2012:120;2454-2465

Prognostic classification of rare abnormailties

into the IPSS-R: n = 7245

del(3p)

-13/13q-

very good

-X

-21

good

any balanced translocation

+1/+1q/dup1q intermediate

der(1;7)

-9/9q-/9p-

-18/18q- poor

+21

very poor

Haase D and Schanz J, ASH2015;

presented with permission for Dutch

Educational program 2015-16

78

22

74

26

52

48

36

64

83

17

65

35

59

41

42

58

0

20

40

60

80

100

18-5

9 ye

ars

60-6

9 ye

ars

70-7

9 ye

ars

80 yea

rs

18-5

9 ye

ars

60-6

9 ye

ars

70-7

9 ye

ars

80 yea

rs

Age at diagnosis Age at diagnosis

MDS CMML

No cytogenetics performed Cytogenetics performed

% o

f p

atie

nts

78

22

74

26

52

48

36

64

83

17

65

35

59

41

42

58

0

20

40

60

80

100

18-5

9 ye

ars

60-6

9 ye

ars

70-7

9 ye

ars

80 yea

rs

18-5

9 ye

ars

60-6

9 ye

ars

70-7

9 ye

ars

80 yea

rs

Age at diagnosis Age at diagnosis

MDS CMML

No cytogenetics performed Cytogenetics performed

78

22

74

26

52

48

36

64

83

17

65

35

59

41

42

58

0

20

40

60

80

100

18-5

9 ye

ars

60-6

9 ye

ars

70-7

9 ye

ars

80 yea

rs

18-5

9 ye

ars

60-6

9 ye

ars

70-7

9 ye

ars

80 yea

rs

Age at diagnosis Age at diagnosis

MDS CMML

No cytogenetics performed Cytogenetics performed

0% 25% 50% 75% 100%

Very low

Low

Intermediate

High

Very high

Percent of patients

Low Int-1 Int-2 High

IPSS

IPS

S-R

Prognostication of MDS in daily practice Results from the Dutch PHAROS MDS registry

Dinmohamed AG, et al., 2016 (submitted)

Dinmohamed AG et al. Leukemia. 29: 2449-2451 (2015)

Alhan C, et al., Leukemia 2015; Oct 27. doi: 10.1038/leu.2015.295. [Epub ahead of print]

Haferlach T, et al., Leukemia 2014;28:241-7

Emerging prognostic models in MDS:

FCM and molecular abnormalities

IPSS-R low

Outcomes After An MDS Diagnosis: kindly provided by DP Steensma (Leuk Lymphoma 2016:57;17-22)

If the ~32,000/yr MDS patients diagnosed in the U.S. were represented as 100 people…

6 will undergo allogeneic transplant: 2 will be cured, 3 will relapse and die, 1 will die of complications

7 will die of anemia-related complications (CVA, MI etc)

27 will progress to AML and die

26 will die of unrelated causes (e.g., geriatric conditions)

2 die of iron overload 12 will die of hemorrhage

20 will die of infection

What are the major needs in MDS

• Optimizing geriatric assessment in (EU/ELN MDS-Right

HORIZON2020)

• Optimizing supportive care (infection/bleeding/iron)

• Development of new targeted therapies in mds

– ESA refractory lower risk MDS (HOVON/HOVON-associated

studies)

• Identification of the poor prognostic lower risk patients (HOVON and

(EU/ELN MDS-Right HORIZON2020)

• Understanding mechanisms of resistance to ESA/IMiDs and

epigenetic therapies

• Understanding mechanisms of transformation to AML

• Incorporation of alloTx in MDS

– Minimizing risk of TRM/relapse post alloTx in MDS

MDS-F symposium 2015; ASH2015 educational session; oral and poster ASH2015

What are the current and emerging new clinical trial

options in low/high risk MDS?

Lower risk

• IMiDs (lenalidomide) (HOVON89)

• IRAK-1 inhibition (Pacritinib) (HOVON)

• Toll-like receptor inhibition (OPN-301)

• Oral Azacitidine (MDS-003) (NL)

• Luspatercept (NL)

• Telomerase Inhibition (Imetelstat) (NL)

Higher risk

• Genomic annotations: IDH1, IDH2, RAS, FLT3

• Anti-PD1/PDL1 combinations +/- HMA (NL)

• Rigosertib (PI3k/PLK1 inhibitor) (under evaluation in NL)

• (oral) second generation hypomethylating agents

• Decitabine +/- ibrutinib (HOVON135)

MDS-F sympoisum 2015; ASH2015 educational session; oral and poster ASH2015

Therapeutic options for lower IPSS risk MDS:

ELN/Dutch guidelines (update 2016 expected)

Low IPSS risk

Symptomatic anaemia asymptomatic cytopenia

Immunosuppressive therapy with ATG

Watchful-waiting RBC transfusion and ICT

Age < 60 years, BM blasts

KM plot of the time to first post-ESA transfusion for ESA-treated patients that did not have any

transfusions prior to ESA treatment stratified by whether the patient was defined as a responder or not.

Log-rank test p=0.0011

Time to first post-ESA transfusion: Transfusion Naive

patients; all ESA treated

EU-MDS registry 2015 (submitted; presented with permission)

HOVON89: Epo refr/TD non-del(5q) low risk MDS:

preliminary conclusions/perspectives

• HOVON89:

– closed august 12, 2015

– Target number of patients n=200 is reached

– No safety/no efficacy issues in interim analysis (n=100/FU 10

month)

– DB closed April 1, 2016:

• ASH2016 1st clinical data to be presented

• Add-on studies:

– Molecular profile follows expected mutations in lower risk MDS

– Validations of FCM: specificity 95%; sensitivity 85%

– Association studies between FCM and Mol. Mutations ongoing

– MDS/Niche studies ongoing

A phase II, multicentre, randomised, open-label comparative study evaluating the efficacy

of LEN with or without EPO in patients with RBC-TD lower-risk MDS without chromosome

5 abnormalities who are resistant to ESAs (NCT01718379*)/GFM-len-epo-08)

Key eligibility criteria

•Patients with de novo MDS or IPSS low- or int-1-risk MDS

•RBC-TD anaemia

•Resistance or loss of response to a previous treatment with epoetin alpha/beta

(60,000 IU/week) or darbepoetin (>250µg/week), administered for ≥12 weeks

•ECOG performance status ≤2

N=132

Randomisation

Arm A 4 cycles of lenalidomide 10mg p.o.

once daily d1–21/28-day cycle

Arm B 4 cycles of lenalidomide

10mg p.o. once daily on d1–21/28-day

cycle

EPO 60,000 IU/week

Continue treatment until disease

progression

Responders

(IMG 2006 criteria)

Responders

(IMG 2006 criteria)

Toma A, et al., Leukemia 2015; Oct 26 [epub ahead of print]

Primary endpoint: erythroid response rate after 4 courses (IMG 2006 criteria)

HI-E and RBC-TI in patients who received at least 4 cycles (n= 99)

LEN + EPO

N = 50

LEN

N = 49

HI-E 52% 30.6% RR = 1.7, p= 0.03

RBC-TI 32% 18.4% RR = 1.7, p= 0.12

HI-E and RBC-TI in the ITT population (n=129)

LEN + EPO

N = 65

LEN

N = 64

HI-E 40 % 23.4 % RR1.7; p= 0.043

RBC-TI 24.6 % 14.1 % RR1.7; p= 0.13

Toma A, et al., Leukemia 2015; Oct 26 [epub ahead of print]

A phase II, multicentre, randomised, open-label comparative study evaluating the efficacy

of LEN with or without EPO in patients with RBC-TD lower-risk MDS without chromosome

5 abnormalities who are resistant to ESAs (NCT01718379*)/GFM-len-epo-08)

MDS-005: phase III trial of LEN vs placebo in patients

with lower-risk RBC-TD MDS without del(5q)

*≥2 units packed RBCs/28 days in the 112 days prior to randomisation; †≥40,000 units/week

rhEPO for 8 weeks, equivalent dose of darbopoetin, or serum EPO >500mU/mL; ‡5mg for

patients with creatinine clearance 40–60mL/min; §≥5 years from randomisation

ESA = erythropoietin-stimulating agent; QD = daily; SPM = second primary malignancy

Santini V, et al. Oral presentation at

ASH 2014. Abstract 409

Phase III, randomised, multicentre, placebo-controlled study assessing the efficacy and safety of LEN

in patients with lower-risk RBC-TD MDS without del(5q) who are unresponsive/refractory to ESAs

Inclusion criteria

•IPSS low-/

int-1-risk

•Non-del(5q)

•RBC-TD*

•Unresponsive/

refractory to

ESAs†

Long-term

follow-up§

•OS

•AML progression

•Subsequent MDS

treatment

•SPMs 2:1

random

isation

Day 1

68 a

ssessm

ent

Discontinue

treatment

Continue treatment

until erythroid relapse

or disease

progression

LEN 10mg

orally QD‡

(n=160)

Placebo

(n=79)

RBC-TI ≥8

weeks or

erythroid

response

No RBC-TI

≥8 weeks or

erythroid

response

• Primary endpoint: RBC-TI ≥8 weeks

• Secondary endpoints: RBC-TI ≥24 weeks, duration of RBC-TI, erythroid response, time to RBC-TI,

AML progression, safety

MDS-005: phase III trial of LEN vs placebo in patients

with lower-risk RBC-TD non-del(5q) MDS

1. Santini V, et al. Poster presentation at MDSF 2015. Abstract 035

2. Santini V, et al. Oral presentation at ASH 2014. Abstract 409

3. Ebert BL, et al. PLoS Med 2008;5:e35

Rate of RBC-TI ≥8 weeks was significantly higher with LEN vs placebo in patients

with lower-risk MDS non-del(5q), with 90% of patients responding within 4 cycles

• Median duration of RBC-TI ≥8 weeks with LEN, weeks (95% CI): 32.9 (20.7–71.1)

• The Ebert signature (a collection of genes whose expression levels have previously appeared

to correlate with response)3 was not predictive of RBC-TI ≥8 weeks in this population

Time to RBC-TI ≥8 weeks in patients

responding to LEN (n=41)1,2

p

New studies in 2016 for low/int-1 risk MDS within

HOVON/SAKK/Belgium and NMDSG

• Pacritinib in Epo/Lenalidomide refractory lower risk MDS

• (phase 2 start q2-2016)/HOVON-associated

• Pacritinib upfront in non-del5q lower risk MDS

• (HOVON 1xx; in preparation)

• MDS with RS/SF3B1: ACE536 [Luspatercept](Pharma)

• Imetelstat (telomerase inhibitor)(Pharma)

• Azacitidine oral formulation: MDS-AZA-003

• risk adapted treatment in low-int-1 risk MDS • (HOVON: concept in development)

• CMML (Ceplene/IL-2); pilot NMDSG • (HOVON associated)

IRAK family signalling network

Rhyasen GW and Starczynoswski DT. BJC 2015;112:232-237

Rhyasen GW and Starczynoswski DT. Br J Cancer 2015;112:232-237;

Rhyasen GW et al., Cancer Cell 2013;24:90-104

IRAK family signalling network in disease

HOVON-associated study: IRAK1 inhibitor in HOVON89

relapse/refractory patients

• Small phase-II study (pilot: n=27)

• Start q1/2 2016 [MetC approval awaiting]

• Pacritinib: Epo/Lenalidomide refractory patients/TD:

– HOVON89: off-study patients

• Primary Endpoints: HI/TI

• Secondary Endpoints: Safety/tolerability

– Time-to-HI/TI

Aristoteles Giagounidis1, Uwe Platzbecker2, Ulrich Germing3, Katharina Götze4, Philipp Kiewe5, Karin Tina Mayer6, Oliver Ottmann7, Markus Radsak8, Thomas Wolff9,

Detlef Haase10, Monty Hankin11, Dawn Wilson11, Xiaosha Zhang11,

Adberrahmane Laadem12, Matthew L. Sherman11, Kenneth M. Attie11

1Marien Hospital Düsseldorf, 2Universitätsklinikum Carl Gustav Carus, Dresden, 3Universitätsklinikum Düsseldorf, 4Technical University of Munich, 5Onkologischer Schwerpunkt am Oskar-Helene-Heim, Berlin, 6University Hospital

Bonn, 7Universitätsklinikum Frankfurt, Goethe Universitaet, Frankfurt/Main, 8Johannes Gutenberg-Universität,

Mainz, 9OncoResearch Lerchenfeld UG, Hamburg, 10Universitätsmedizin Göttingen, Germany; 11Acceleron

Pharma, Cambridge, MA, 12Celgene Corporation, Summit, NJ, USA

Oral presentation:

Dec 5, 2015

12:15 PM

W331, Level 3

Orange County Convention Center

Giagoundis A, et al. Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients with Low or

Intermediate-1 Risk MDS: Preliminary Results from the Phase 2 PACE-MDS Extension Study. Oral presented at: Annual Meeting and Exposition of the

American Society of Hematology 2015; December 5‒8; Orlando, FL. Abstract 92.

Luspatercept Treatment Leads to Long Term

Increases in Hemoglobin and Reductions in

Transfusion Burden in Patients with Low or

Intermediate-1 Risk MDS: Preliminary Results

from the Phase 2 PACE-MDS Extension Study

Luspatercept in MDS: Results

• Mean (SE) change in Hb for LTB patients

– 9 of 13 (69%) LTB patients achieved IWG HI-E response for mean Hb increase

Giagoundis A, et al. Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients with Low or

Intermediate-1 Risk MDS: Preliminary Results from the Phase 2 PACE-MDS Extension Study. Oral presented at: Annual Meeting and Exposition of the

American Society of Hematology 2015; December 5‒8; Orlando, FL. Abstract 92.

• 13 of 19 (68%) HTB patients achieved IWG HI-E response for transfusions

• 8 of 19 (42%) HTB patients achieved RBC-TI

– 3 of 3 LTB patients with 2U RBC/8 weeks achieved RBC-TI SE, standard error.

Luspatercept: Results

• Most patients in the extension study were RS+

• ≥ 50% patients responding to luspatercept had prior ESA

treatment or baseline EPO of ≤ 500 U/L

Giagoundis A, et al. Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients with Low or

Intermediate-1 Risk MDS: Preliminary Results from the Phase 2 PACE-MDS Extension Study. Oral presented at: Annual Meeting and Exposition of the

American Society of Hematology 2015; December 5‒8; Orlando, FL. Abstract 92.

Baseline feature, n (%) IWG HI-E

N = 32

RBC-TI ≥ 8 Weeksa

N = 22

All Patients 22 of 32 (69) 11 of 22 (50)

RS positive 21 of 29 (72) 10 of 19 (53)

Baseline EPO

< 200 U/L 16 of 20 (80) 7 of 13 (54)

200–500 U/L 5 of 7 (70) 2 of 4 (50)

> 500 U/L 1 of 5 (20) 2 of 5 (40)

Prior ESA Treatment

Yes 12 of 19 (63) 7 of 14 (50)

No 10 of 13 (77) 4 of 8 (50)

EPO, erythropoetin; ESA, erythropoetin stimulating agent; RS, ring sideroblast.

a Includes 19 HTB patients and 3 LTB patients evaluable for RBC-TI (≥ 2 units over 8 weeks).

CONFIDENTIAL 37

Rationale for Targeting Telomerase in MDS

• MDS patients have higher telomerase activity (TA), higher expression level of

hTERT (Telomerase reverse transcriptase) and shorter telomere length (TL)

compared to age-match normal control

• Higher TA & hTERT, shorter TL correlated to IPSS risk score in MDS

• Shortened telomeres in MDS have been associated with the disease progression

and conversion to AML

• High TA & short TL represent poor prognostic features in lower risk MDS

• MDS pts with high TA have shorter survival

• Inhibition of TA should hasten apoptosis of malignant clone

• Preliminary clinical results of imetelstat in int-1 risk MDS showed clinical benefit

(transfusion independence)

A Phase 2/3 Study to Evaluate the Activity of Imetelstat in TD Low

or Intermediate-1 Risk MDS who have Failed ESA Treatment

MDS

Transfusion

Dependent

Failed

ESA

• IPSS Risk: • Low

• Intermediate-1

• RBC 4 units/8w (12w pre-study)

• Pretransfusion Hb ≤9.0 g/dL

• Epo 40K qw* x8w without Hb inc ≥1.5 g/dL or RBC dec ≥4 units/8w

• Relapsed following response

• Poor candidate: sEPO>500mU/mL

38

*or equivalent agent/dose CONFIDENTIAL

Imetelstat (n~115) R

A

N

D

O

M

I

Z

E

2:1

Best Supportive Care (n~55)

RBC transfusions,

hematopoietic growth factors

Stratification factors:

• IPSS risk (low / intermediate-1)

• Prior lenalidomide (yes / no)

39

Imetelstat

7.5 mg/kg IV q4w x2 cycles,

escalate to 9.4 mg/kg IV q4w

based on tolerability

Study Design: Phase 2/3, Open Label, N~200

Phase 2, run-in single arm n up to 30

Phase 3 randomized 2:1, controlled

n~170

CONFIDENTIAL

Conclusions: MDS in 2016

• WHO2016 is coming soon

– SF3B1 is incorporated in defining MDS-RS if RS