Highlights from EHA 2014Myelodysplastic syndromes

Valeria Santini, M.D.Dept of Hematology AOU Careggi, University of FlorenceFlorence, Italy

-Sessione educativa

-2 sessioni simultanee

( 10 comunicazioni cliniche e

1 late breaking abs;

5 comunicazioni biologiche)

-3 sessioni poster

( 32 clinici e

19 biologici)

Scenario

1. Ciò su cui è importante essere aggiornati

(educativa)

2. Nuovi farmaci per MDS/AML refrattarie

3. Correlazione tra markers molecolari e

clinica

Punto 1

Sessione educativa: cosa dobbiamo sapere

su MDS nel 2014

The molecular basis of MDS

B. Ebert

Prognostic biomarkers in MDS

M. Cazzola

Clinical management of MDS

U. Platzbecker

PROGNOSTIC BIOMARKERS IN MYELODYSPLASTIC

SYNDROMES

MARIO CAZZOLA

Department of Molecular Medicine, University of Pavia, Pavia, Italy;

Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy;

OUTLINE

• Importance of morphology in diagnosis and

prognostication of MDS

• Contribution of cytogenetics in diagnosis and

prognostication of MDS

• Current prognostic scoring systems based on

morphology and cytogenetics

• Emerging evidence that detection of somatic gene

mutations can improve both our understanding of MDS

and clinical decision making

Representative examples of morphologic abnormalities of myelodysplasia.

Cazzola M et al. Blood 2013;122:4021-4034

©2013 by American Society of Hematology

WHO 2008: Classificazione delleneoplasie mieloidi e leucemie acute

Sindromi mielodisplastiche WHO 2008

Citopenia refrattaria con displasia unilineare

- anemia refrattaria

- neutropenia refrattaria

- trombocitopenia refrattaria

Anemia refrattaria con sideroblasti ad anello

Citopenia refrattaria con displasia multilineare

Anemia refrattaria con eccesso di blasti

Sindrome mielodisplastica con isolata del(5q)

Sindrome mielodisplastica inclassificabile

Sindrome mielodisplastica dell’infanzia

Provisional entity: citopenia refrattaria dell’infanzia

Survival according to WPSS-R

at diagnosis

IPSS-R variables and weighted scores

* Regression analysis for survival and AML evolution.

ANC, absolute neutrophil count; BM bone marrow. Greenberg PL, et al. Blood. 2012;120:2454-65.

Cytogenetics

Score

Very good

0

Good

1

Intermediate

2

Poor

3

Very poor

4

BM blasts, %

Score

≤ 2

0

> 2–< 5

1

5–10

2

> 10

3

Hb, g/dL

Score

≥ 10

0

8–9.9

1

< 8

1.5

ANC, x 109/L

Score

≥ 0.8

0

< 0.8

0.5

Platelets, x 109/L

Score

≥ 100

0

50–99

0.5

< 50

1

Overall survival and leukemia-free survival of 1110 patients with MDS

Cazzola M et al. Blood 2013;122:4021-4034©2013 by American Society of Hematology

Della Porta M G et al. Blood 2014;123:2333-2342©2014 by American Society of Hematology

Patient-based and disease status–based risk stratification of outcome among MDS patients receiving allo HSCT.

Frequence of somatic mutations in MDS

Papaemmanuil et al, 2013 ; 122:3616

Frequence of somatic mutations in MDSNagata et al, Leukemia 2014

Nagata et al. Leukemia 2014

Survival and risk of leukemic evolution of patients with MDS classified according to the clusters resulting from the unsupervised analysis including WHO classification criteria and

mutation patterns.

Malcovati L et al. Blood 2014;124:1513-1521©2014 by American Society of Hematology

Authors’ Conclusions

• Clonal marker in 90% of patients (vs 505 of cytogenetic

abnormalities)

• Already established genotype/phenotype relationships

SF3B1 mutant MDS

TET2/SRSF2 comutant MDS/MPN (CMML)

• Prognostic relevance of somatic mutations of RNA

splicing and DNA methylation

SF3B1 mutation vs other mutation of the spliceosome (

SRSF2 and U2AF1)

Favorable outcome of pts without somatic muations of RNA

splicing and DNA methylation

Punto 2

Molti pazienti sia con alto che con basso

rischio MDS, dopo una prima risposta alla

terapia, “ricadono”.

Alcune opzioni terapeutiche di seconda linea

sono disponibili , ma c’è comunque

bisogno di identificare nuovi agenti

Abstract number: LB2434 Slides available on EHA website

IDH1/2 mutations in MDS

Present in ~4-12% of patients with MDS

Missense mutations: heterozygous; target highly conserved

Arginine residues

IDH1: R132H mutations

IDH2: R172K or R140Q mutations

All variants produce 2-hydroxyglutarate (2-HG)

Mutations in IDH1/2 are associated with increased 5-

methylcytosine

Initial reports: Unfavorable prognosis for IDH-mut MDS

Authors’ Conclusions

• Treatment with AG-221 leads to a

profound differentiation effect and is

associated with durable complete

remissions in patients who are extremely

ill and have limited treatment options

ACE-536 Increases HemoglobinLevels in Patients with Low or Int-1 Risk MDS:Preliminary Results From A Phase 2 Study

Uwe Platzbecker1, Ulrich Germing2, Aristoteles Giagounidis3, Katharina Götze4,

Philipp Kiewe5, Karin Mayer6, Oliver Ottmann7, Markus Radsak8, Thomas Wolff9,

Monty Hankin10, Dawn Wilson10, Matthew Sherman10, Kenneth Attie10

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

Bonn, Bonn, 7Klinikum der J.W. Goethe-Universität Frankfurt, Frankfurt/Main, 8University Medical Center – Johannes

Gutenberg-Universität, Mainz, 9OncoResearch Lerchenfeld UG, Hamburg, Germany, 10Acceleron Pharma, Cambridge, MA,

United States

Slides kindly provided by U. Platzbecker

Abstract number S1296

Therapeutic Options in MDS

Intensive CTx/allo TxFe-Chelation

Hypomethylating Agents

Registered

Lenalidomide (del 5q)

- 80–90% of MDS patients become dependent on RBC transfusions

- Ineffective erythropoiesis

- Many patients unresponsive/refractory to ESAs/HMT

Lower-risk Higher-risk

Stratification according to IPSS-(R)

ESA

ACE-536: Background

Suragani et al. Nature Medicine 2014

TGF-ß Superfamily

Signaling

ACE-536

Erythropoiesis

GDF11,Others

Modified Extracellular

Domain (ECD) of ActRIIB

Fc domain of human IgG1

Fusion protein containing modified activin receptor IIB (ActRIIB)

Phase 2, multicenter, open-label, dose-finding

IPSS Low/Int-1

Transfusion-dependent (TD), or

Non-transfusion dependent (NTD, Hgb <10 g/dL)

EPO >500 U/L or nonresponsive/refractory to ESAs

No prior azacitidine or decitabine

Schedule: ACE-536 SC every 3 weeks for 3 months (up to 5 doses)

Preliminary data as of 28 April 2014

ACE-536 PACE-MDS Study: Overview

ACE-536Treatment Period

Screening Period

-28 1 22 43 64 85 113 141 1

Follow-up Period

Study Day

Adverse Events in ≥ 10% of Patients Overall

• No drug-related serious adverse events

• Severity Grade 1 (mild) unless noted otherwise

Preferred Term

0.125

mg/kg

(N=3)

n

0.25

mg/kg

(N=3)

n

0.50

mg/kg

(N=3)

n

0.75

mg/kg

(N=6)

n

1.0

mg/kg

(N=3)

n

1.33

mg/kg

(N=3)

n

Overall

(N=21)

n

Diarrhoea - 1 11

Gr 2- 1 4

Bone Pain - -1

Gr 2-

2

Gr 1, Gr 2- 3

Fatigue - - - - - 3 3

Muscle Spasms - -2

Gr 1, Gr 2- 1 - 3

Myalgia - 1 1 - 1 - 3

Nasopharyngitis - 1 -2

Gr 1, Gr 2- - 3

Hemoglobin Responsein 2/5 pts non transfusion dependent

Patient ID

Dose Group (mg/kg)

Prior MDS Therapy

Hgb Increase≥ 1.5 g/dL for ≥

2 wks

Hgb Increase≥ 1.5 g/dL for ≥ 8

wks [IWG]

0103 0.125 No No No

0201 0.25 No No No

0404 0.75 ESA Yes No

0405 0.75 ESA No No

0406 0.75 ESA Yes Yes

NTD, non-transfusion dependent; ESA, erythropoiesis-stimulating agent

Maximum Hemoglobin Increase in NTD Patients

NTD, non-transfusion dependent

0,81,0

1,6

1,9

3,3

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

0.125mg/kg(n=1)

0.25mg/kg(n=1)

0.75mg/kg(n=3)

Ma

x.

Ch

an

ge

in

He

mo

glo

bin

(g

/d

L)

Patient

ID

Dose Group

(mg/kg)

Prior MDS

Therapy

% Change

RBC Units

≥4 Unit Decrease

/ 8 Weeks [IWG]

0101 0.125 LEN 0 No

0102 0.125 ESA -50% (42) No

0202 0.25 ESA -25% No

0203 0.25 -50% (42) No

0301 0.5 LEN -50% (84) Yes

0302 0.5 +25% No

0303 0.5 ESA 0 No

0401 0.75 ESA, LEN -100% (40) Yes

0402 0.75 ESA 0 No

0403 0.75 +50% No

0501 1.00 -33% No

0502 1.00 ESA, LEN -39% (138) Yes

0503 1.00 0 No

0601 1.33 0 No

0602 1.33 ESA 0 No

0603 1.33 -67% (62) Yes

Transfusion ResponseIn 6/16 transfusion dependent pts

TD, transfusion dependent; LEN, lenalidomide; ESA, erythropoiesis-stimulating agent

Authors’ Conclusions

• Treatment with ACE 536 is safe and well

tolerated

• Patients may obtain substantial Hb

increase

• Dosing every 3 weeks

• Required more studies with larger number

of patients

Punto 3

Esiste ormai ampia evidenza che

l’identificazione di mutazioni geniche

somatiche e di markers molecolari può

migliorare la qualità delle nostre decisioni

cliniche, assieme alla migliore

comprensione della patogenesi delle

MDS (M. Cazzola EHA 2014)

Abstract number P299 E-poster online EHA website

Baseline serum

levels of miRNA-21

Levels of miRNA 21 correlate with disease progression

in MDS treated with HMT

Authors’ Conclusions

• Serum microRNA 21 level is significantly

associated with the response to treatment

with azacitidine and decitabine

• miR-21 is a potential biomarker to be

further validated for prediction of response

to the most common agents used in MDS

therapy

Questions?