Prof. Dr. Aristoteles Giagounidis

Klinik für Onkologie, Hämatologie und

Palliativmedizin

Marien Hospital Düsseldorf

Rochusstr. 2, D – 40479 Düsseldorf

aristoteles.giagounidis@vkkd-kliniken.de

Myelodysplastic Syndromes

Faculty Disclosure

Company Name Honoraria/

Expenses

Consulting/

Advisory Board

Funded

Research

Royalties/

Patent

Stock

Options

Ownership/

Equity

Position

Employee Other

(please specify)

Celgene Corporation x X

Novartis x

No, nothing to disclose

X Yes, please specify:

March 30 - April 2, 2014

Sheraton Sonoma County

Petaluma, California

Off-Label Product Use

Will you be presenting or referencing off-label or investigational use of a therapeutic product?

No

X Yes, please specify: Luspatercept in RARS, TPO-RA in MDS, Lenalidomide in non-

del(5q)

Jaiswal S et al. N Engl J Med 2014;371:2488-2498

Clonal hematopoiesis in healthy adults

Clonal hematopoiesis of indeterminate potential

Steensma et al. Blood 2015

Somatic Mutations in MDS

Papaemmanuil, E et al. Blood 2013;122:3616-3627; Haferlach, T et al. Leukemia 2014;28:241-247

Division by Blast Proportion (<5%)

Bejar R, et al. Presentation at ASH 2016 and MDSF 2017

Impact of genetic abnormalities by

blast proportion (<5% blasts)

Impact of genetic abnormalities by

blast proportion (5-30%)

Bejar R, et al. Presentation at ASH 2016 and MDSF 2017

Randomized, double-blind, placebo-controlled, multicenter study: Epoetin alfa versus placebo in IPSS low and int-1 risk MDS

*If no erythroid response, as defined by IWG 2006 criteria, subject withdrawn. **EOS visit 4 weeks after last dose of study drug (week 28 or 52), or 4 weeks after early withdrawal. Fenaux P, et al. EHA 2016. Abstract P248.

4.4 4.4

31.8

45.9

0

10

20

30

40

50

60

% Hematological Improvement (IWG) Any response in 24 wks

EPOANE 3021 trial

Placebo Epo alfa

Epoetin alfa versus placebo in IPSS low and int-1 risk MDS

Fenaux P, et al. EHA 2016. Abstract P248.

A prognostic model for treatment

of anemia in MDS with Epoetin alpha

Variable Score Score Transfusions 0 U/month 0 ≤4 U/month 1 Serum-Epo <200 U/l 0 ≥200 U/l 1

Giagounidis A, ASH education book 2017, in press

Prediction

Score = 0: 67%

Score 1: 25%

Score 2: 0%

Survival and AML transformation in MDS

patients treated with EPO and G-CSF

Pro

babili

ty o

f

freedom

rom

AM

L

<2 U RBC/month ≥2 U RBC/month

Pro

babili

ty o

f

surv

ival

0

.2

.4

.6

.8

1

0 50 100 150 200

0

.2

.4

.6

.8

1

0 50 100 150 200

months months

0

.2

.4

.6

.8

1

0 50 100 150 200

0

.2

.4

.6

.8

1

0 50 100 150 200

HR

P

0.44

<0.001 HR

P

0.92

0.89

HR

P

0.86

0.64

HR

P

1.04

0.91

Untreated

EPO + G-CSF

Jädersten et al, JCO, 2008

Protocol defined

(≥ 26 weeks)

IWG

(≥ 8 weeks)

*P < 0.001 vs placebo

Bars represent 95% CI

*

41

*

56

8

* 50

*

61

6

Lenalidomide for del(5q) MDS

Fenaux et al. Blood 2011

Assessment of predictive factors

for OS (N = 286) Univariate model Multivariate model

Covariate* P value Hazard ratio [95% CI] (P value)

Age, years < 0.001 1.0450 [1.027–1.064] (< 0.001)

Gender (male vs female) < 0.001

IPSS risk (High, Int-2, Int-1 vs Low) NS

FAB classification (RAEB, CMML vs RA, RARS) 0.011 1.4771 [1.003–2.176] (0.0485)

Time since diagnosis, years NS

Transfusion burden, units/8 weeks < 0.001 1.0663 [1.014–1.120] (0.0116)

Bone marrow blasts (≥ 5% vs < 5%) 0.049

No. of cytopenias (2 or 3 vs 1) NS

Platelet count, per 100 × 109/L < 0.001 0.869 [0.772–0.979] (0.0213)

Absolute neutrophil count, per 1 × 109/L NS

Haemoglobin level, g/dL NS

del(5q) (+ 1 abn. vs isolated) NS 0.902 [0.563–1.447] (0.6698)

del(5q) (+ ≥ 2 abn. vs isolated) < 0.001 1.907 [1.103–3.298] (0.0208)

WPSS risk (High, Very high vs Low, Int) 0.032

RBC-TI ≥ 26 weeks (yes vs no) < 0.001 0.374 [0.256–0.547] (< 0.001)

*Variables are continuous except when specified; variables are baseline except for RBC-TI ≥ 26 weeks.

Lenalidomide discontinuation

Comparison of pts achieving CCyR vs. PCyR

p=0,090

months

Complete cytogenetic remission, n=16

Partial cytogenetic remission, n=11

Tra

nsfu

sio

n in

de

pen

de

nt p

atie

nts

(%

)

75% tranfusion independent

45% tranfusion independent

Giagounidis et al. , Leukemia 2012

AML progression in del(5q) lower-risk MDS

Pro

babili

ty o

f

freedom

of A

ML

0 1 2 3 4 5 6 7 8 9 10 11 12 0.0

0

0.2

5

0.5

0

0.7

5

1.0

0

p=0.045

0 1 2 3 4 5 6 7 8 9 10 11 12 0.0

0

0.2

5

0.5

0

0.7

5

1.0

0

p=0.012

0.0

0

0.2

5

0.5

0

0.7

5

1.0

0

0 1 2 3 4 5 6 7 8 9 10 11 12

p=0.064 0

.00

0

.25

0

.50

0

.75

1

.00

0 1 2 3 4 5 6 7 8 9 10 11 12

p=0.001

By TP53 mutation By 2% p53

Years Years

Years

Pro

babili

ty o

f

freedom

of

pro

gre

ssio

n

Jädersten & Saft, JCO 2011

TP53 not mutated

TP53 mutated

p53++ <2%

p53++ ≥2%

Resistance to lenalidomide in del(5q) MDS

Jädersten & Karsan., Haematologica, 2011:96: 177-180

0

5

10

15

20

25

30

RBC-TI ≥ 8 weeks RBC-TI ≥ 24 weeks

Pati

en

ts (

%)

Placebo (n = 79)

LEN (n = 160)

Lenalidomide for non-del(5q) MDS

Santini et al. ASH 2014

17.5%

0%

26.9%

2.5%

RBC-TI ≥ 24 weeks with LEN was achieved in 17.5% of patients

Lenalidomid in non-del(5q) MDS

CI, confidence interval.

The median duration of response was 32.9 weeks (95% CI

20.7–71.1) among RBC-TI ≥ 8 weeks responders with LEN

Log-rank P = 0.6389

+ Censored

1.0

0.8

0.6

0.4

0.2

0

0 12 24 36 48 60 72 84 96 108 120

Duration of response (weeks)

Placebo

LEN

41

1

34

1

23

0

18 13 11 6 3 3 1 1 LEN

Placebo

No. of RBC-TI patients

Pro

po

rtio

n o

f p

ati

ents

wit

h

RB

C-T

I ≥

8 w

eek

s

Santini et al. ASH 2014

Drug-related adverse events in patients

given lenalidomide

Adverse event

All grades (%)

5q-1 non-5q-2

≥Grade 3 (%)

5q-1 non-5q-2

Thrombocytopenia 58 26 44 20

Neutropenia 57 28 55 25

Pruritus 32 21 3 1

Rash 28 22 6 4

Diarrhoea 24 15 3 1

Fatigue 12 15 3 4

1. List A, et al. New Engl J Med 2006;355:1456–65

2. Raza A, et al. Blood 2008;111:86–93

Randomized study of ATG/CSA in patients

with MDS: efficacy

Parameter ATG

(n=45)

BSC

(n=43) p-value

Haematological response

CR + PR (%)

median duration (months)

29

16.4

9 0.016

2-year survival (%) 49 63 0.83

2-year transformation-free

survival (%) 46 55 0.73

Passweg JR, Giagounidis A, et al. JCO 2011

Ineffective Erythropoiesis in MDS

Anemia, a hallmark of MDS, is a significant clinical challenge to treat,

particularly after failure of ESAs1

Defects in maturation of erythroid precursors (ineffective erythropoiesis)

lead to erythroid hyperplasia and anemia

Ineffective erythropoiesis is driven by excessive Smad2/3 signaling2

EPO drives proliferation

Excessive GDF-induced Smad2/3 signaling inhibits RBC maturation

Retic Baso E BFU-E CFU-E Pro E RBC Poly E Ortho E

1. Fenaux P, et al. Blood.

2013;121:4280

2. Zhou L, et al. Blood

ESA: erythropoiesis stimulating agent; EPO: erythropoietin;

GDF: growth and differentiating factor; RBC: red blood cell

Luspatercept (ACE-536) Activity in MDS

Modified activin receptor type IIB (ActRIIB) fusion protein,

ligand trap for GDF11 and other TGF-β family ligands

suppresses Smad2/3 activation;

increased Hb in healthy volunteers1

In a murine model of MDS, murine analog RAP-536 corrected ineffective

erythropoiesis, reduced erythroid hyperplasia and increased Hb2

1. Attie, K et al. Am J Hematol

2014;89:766

2. Suragani R et al., Nat Med

2014;20:408

Modified Extracellular Domain of ActRIIB receptor

Fc domain of human IgG1 antibody

Luspatercept

GDF: growth and differentiating factor; TGF: transforming growth factor

Hb: hemoglobin

HI-E response rates to luspatercept

by baseline EPO level and RS status Patients Treated at Doses ≥ 0.75 mg/kg

Platzbecker U, et al. Poster presentation at ASH 2016. Abstract 3168

Baseline EPO (U/L) RS Status ORR in phase 2

(3 mo. treatment)

N=64

All All 29/64 (45%)

EPO ≤ 500

All 25/48 (52%)

RS+ 23/40 (58%)

RS- 2/8 (25%)

EPO > 500

All 4/16 (25%)

RS+ 3/7 (43%)

RS- 1/7 (14%)

TPO-Receptor-Agonists

• Romiplostim: Peptibody

• Eltrombopag: small molecule

• Romiplostim: 36% response rate in thrombocytopenic

MDS patients; No increase of AML;

Eltrombopag: In high risk MDS: Trend toward OS improvement

No increase in AML development

• International study actively enrolling in lower risk MDS

Giagounidis et al; Cancer, 2014 Oliva et. al. Blood; 2013

Romiplostim: Clinical Benefits Based on Baseline Platelet

Count at Study Entry (Platelet <20 or 20-50x109/L)

Placebo (N = 43)

Romiplostim (N = 87)

Placebo (N = 40)

Romiplostim (N = 80)

CSBE (rate/100 pt-yr) 501.2 514.9 226.4 79.5

RR = 1.03, p = 0.83 RR = 0.35, p<0.0001

PTE (rate/100 pt-yr) 1778.6 1250.5 179.8 251.8

RR = 0.71, p<0.0001 RR = 1.38, p = 0.15

<20x109/L 20-50 x109/L

• For patients with a baseline platelet count <20K there

was a significant decrease in platelet transfusion

events.

• For patients with a baseline platelet count 20-50K there

was a significant decrease in clinically significant

bleeding events.

Giagounidis et al; Cancer, 2014

IWG HI-P, HI-E, and HI-N Response

IWG Response

Pro

po

rtio

n

(%)

0

10

20

30

40

50

60

70

80

90

100

Placebo

Romiplostim

n* =

HI-EHI-P HI-N

83 167 41

n*, number of subjects evaluable for various HI responses

77 13 28

IWG Response

Od

ds

Rati

o (

OR

)

HI-P HI-E HI-N0

5

10

15

20

25

30

35

40

45

50

55

60HI-P

HI-E

HI-N

OR(95%CI)

15.6(4.7, 51.8)*

3.0(0.9, 9.7)

4.6(0.9, 25.3)

* P<0.001

Eltrombopag in patients with LR-MDS and low platelet count receiving supportive care: study design

Eltrombopag + supportive care

n=46

Placebo + supportive care

n=24

Adults with Low /

Int-1 risk MDS and

severe

thrombocytopenia

(platelets < 30 x

109/L)

On therapy: 6 months

Responders:

Continuation

Non-responders:

Permanent

discontinuation;

long-term follow-up

Additional bone marrow exams

Initiated at 50 mg/day; 50 mg increases every 2 weeks (up to 300 mg) to target platelet 100 x 109/L

Oliva EN, et al. Blood 2015;126. Abstract 91.

Oliva, E et al. Lancet Haematol 2017

Eltrombopag in patients with LR-MDS and low platelet count receiving supportive care: key results

Characteristic Eltrombopag

n=59

Placebo

n=31 P value

Response rate*† n=28 (47%) n=1 (3%) 0.001

Mean platelet count increase

53.2 x 109/L NS 0.001

Grade 3/4 AEs n=27 (46%) n=5 (16%) 0.005

Most common grade 3/4 AEs

Nausea; hypertrans-

aminasaemia

Bone marrow fibrosis

–

MDS disease progression n=7 (12%) n=5 (16%) NS

*Response: (1) if baseline platelet > 20 x 109/L: absence of bleeding and increase by ≥ 30 x 109/L; (2) if baseline platelet < 20 x 109/L: platelets > 20 x 109/L and increase by ≥ 100%, not due to platelet transfusions.

†Median time to response: 14 days (7–46 days) at a median daily dose of 75 mg/day (range 50–162.5).

Oliva EN, et al. Blood 2015;126. Abstract 91.

Oliva, E et al. Lancet Haematol 2017

100

Azacitidine for MDS: AZA-001: OS

CCR (n=179)

40

Time from randomisation (months)

Patients

surv

ivin

g (

%)

0 5 10 15 20 25 30 35 0

20

40

60

80

24.5 months

15.0 months

Vidaza (n=179)

Fenaux P, et al. Lancet Oncol 2009;10:223–32

Difference: 9.5 months

p=0.0001

CCR: conventional care regimen

OS: overall survival

Prognostic factors for response and OS in

Int-2/High-risk MDS patients treated with AZA

Itzykson R, et al. Blood. 2011;117:403-

11.

GFM ATU compassionate use study

(n = 282)

OS prognostic score

AZA response score

Variable Response rate,

yes/no % p value*

Prior LD ARA-C 24/46 0.009

Normal

karyotype 51/39 0.003

Marrow blasts

> 15% 35/50 0.004

Response duration

Complex

karyotype 4.6 vs 10.3 months 0.0003

Variable Score

Performance status ≥ 2 1

Circulating blasts 1

RBC transfusion

dependence ≥ 4 U/8 wks 1

Intermediate karyotype 1

High-risk karyotype 2

Low: 0

Intermediate: 1–3

High: 4–5

1.0

0.8

0.6

0.4

0.2

0

54 60

Cu

mu

lati

ve

pro

po

rtio

n

su

rviv

ing

Duration, months 0 6 12 18 24 30 36 42 48

p < 0.0001

Low Intermediate High

AZA-001: number of cycles of

Vidaza from first to best response

Time (cycles) 0 3 6 9 12 15

Cum

ula

tive p

robabili

ty o

f

respon

se

0.8

0.6

0.4

0.2

0

1.0

48% of patients improved initial response to a

higher IWG category with continued

treatment with Vidaza

Median number of cycles from first to best

response, n (range): 3 (1–11)

The vertical line on the y-axis represents the 52% of

patients whose first response was their best response Silverman LR, et al. Cancer 2011;117:2697–702

The risk of terminating treatment

prior to disease progression

Clinical outcomes in a series of 13 patients with MDS/CMML treated with

hypomethylating (HMT) agents (Vidaza: n=12) who discontinued treatment

while still in haematological remission

Voso MT, et al. Eur J Haematol 2013;90:345–8

Median OS, months

(range): 6.6 (1.4−27.2) 77% had progressed after

a median follow up of

24.5 months

CMML: chronic myelomonocytic leukaemia

Strong prognostic impact of del(5q)/5q- and

-7/del(7q) among complex karyotypes

No del(5q)/-5 / -7/del(7q)

Del(5q)/-5 / no -7/del(7q)

Del(5q)/-5 / -7/del(7q)

No del(5q)/-5 / no -7/del(7q)

No del(5q)/-5 / no -7/del(7q)

Del(5q)/-5 / no -7/del(7q)

No del(5q)/-5 / -7/del(7q)

Del(5q)/-5 / -7/del(7q)

P = 0.0001

Azacitidine versus allo SCT

Jabbour et al, American J Hematol 2012

Single center matched pair Analyse frontline Allo SCT vs frontline HMA

Mutations and Transplantation

Lindsley RC, et al. NEJM 2017;376(6):536-47

1514 MDS patients in the Center for International Blood and Marrow Transplant Research Repository

between 2005 and 2014

19% with TP53 mutation

Decitabine in TP53 Mutant MDS/AML

Welch JS, et al. NEJM 2017;375(21):2023-2036

Decitabine in TP53 Mutant MDS/AML

Welch JS, et al. NEJM 2017;375(21):2023-2036

Decitabine and azacitidine in MDS/AML

Guillermo Montalban-Bravo, N Engl J Med 2017; 376:796-798

EXON1 EXON2 EXON3

Gene transcription

CpG island CpG non-island

• Generally unmethylated in

normal cells

• Demethylated state allows gene

transcription

• Methylation of CpG islands

associated with gene silencing:

– imprinted genes

– X-chromosome inactivation

• Generally methylated in

normal cells

• Methylation helps prevent

mutations and genomic

instability

• Methylation helps prevent

recombination and activation

of transposable elements

Esteller M. N Engl J Med 2008;358:1148–59

DNA methylation plays an essential role in

the regulation of gene expression

“Viral mimickry”

Chiappinelli KB, et al. Cell. 2015;162:974–86.

Wolf et al. Cell communication and signaling 2017; 15:13

Tumor cell

Nucleus ERV

ssRNA

dsRNA

dsRNA

Recognition by pattern recognition receptors

Upregulation of

CXCL9

MHC-1

PD-L1

CTLA-4

PD-L1

CTLA-4

https://clinicaltrials.gov/ct2/show/NCT02281084?term=NCT02281084&rank=1

Accessed 9 June 2017 Durvalumab is an investigational molecule and is not approved by any Health Authorit

5% incidence in MDS – Thol et al. Haematologica 2010

AG-221, an IDH2 mutation inhibitor promotes

differentiation in advanced hematologic

malignancies: Results of a Phase 1/2 Trial

All

(N=181)

MDS

(N=17)

n (%)

Overall Response (CR,

PR, CRp, CRi, mCR)

74 (41) 10 (59)

CR 30 (17) 1 (9)

mCR 15 (8) 3 (27)

PR 25 (14) 1 (9)

HI 5 (29)

Steyn EM et al., Valencia 2017