MDS Studien in Deutschland

Uwe PlatzbeckerUniversitätsklinikum “Carl Gustav Carus“ Dresden

D·MDS Deutsche MDS-Studiengruppe

Mutationen bei MDS1+x = schlecht

Papaemmanuil E et al. Blood 2013;122:3616-3627

Mutationen , jetzt wird’s komplex

>10%

5-10%<5%

NPM

1FL

T3

MLL

-PTD

CEB

PAR

UN

X1

IDH

1/ID

H2

NR

AS

TET2

EZH

2

ASX

L1

DN

MT3

AC

BL

SETB

P1

SRSF

2

SF3B

1TP

53JA

K2

AMLMDSCMMLMPN

- +/-0 - - + -

Gesund und mutiert

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

Initialer molekularer Algorithmus(bei Fehlen weiterer prognoselimit. Komorbiditäten)

Platzbecker, persönliche Mitteilung

5q

TP53

andere

ASXL1, RUNX1DNMT3A

KMP + Zytogenetik

46XX/XY aberrant

Weitere prognostische

Marker nützlich?

TP53 bei komplexem K.

Initialer molekularer Algorithmus(bei Fehlen weiterer prognoselimit. Komorbiditäten)

Platzbecker, persönliche Mitteilung

5q

TP53

andere

ASXL1, RUNX1DNMT3A

KlonaleErkrankung?

ASXL1 RUNX1 DNMT3A

TET2

DD MPN/CMML?

JAK-2, MPL Calreticulin

ASXL1 RUNX1 SRSF2 TET-2

KMP + Zytogenetik

46XX/XY aberrant

Ringsidero-blasten?

SF3B1

Weitere prognostische

Marker nützlich?

TP53 bei komplexem K.

Niedrigrisiko Hochrisiko

Risikostratifikation nach IPSS

Aktuelle Optionen bei MDSZulassung

LEN (5q)

A multicenter, single‐arm, open‐label phase II study of the safety of lenalidomide monotherapy and markers for disease progression in patients with IPSS low‐ or

intermediate‐1 risk MDS associated with an isolated deletion 5q

MDS‐LE‐MON‐5

• IPSS LOW/INT-1 + single del(5q)

• <5% Blasten

• Eks erhalten

PI: Germing

Fe-Chelation

Niedrigrisiko Hochrisiko

Risikostratifikation nach IPSS

Aktuelle Optionen bei MDSZulassung

Studien

LEN (5q)

Wirksam aber nicht für

MDS zugelassen

EPO

ARCADE Studie LR-MDS

Amgen

R

• IPSS low/int-1• EPO<500• <4 Eks/8 W.

ESA Versagen

PANOBINOSTAT

RR: 0%

AZA STUDIE

IST

Platzbecker et al. Leukemia 2014

ESA Versagen

LENRR: 26%

AZA STUDIE

IST

Raza et al. Blood 2008

Efficacy and Safety of Lenalidomide Versus Placebo in RBC Transfusion-Dependent Patients With IPSS Low or Intermediate-

1-Risk Myelodysplastic Syndromes Without del(5q) and Unresponsive or Refractory to Erythropoiesis-Stimulating Agents:

Results From a Randomized Phase 3 Study (CC-5013-MDS-005)

Valeria Santini1, Antonio Almeida2, Aristoteles Giagounidis3, Stefanie Gröpper3, Anna Jonasova4, Norbert Vey5, Ghulam J. Mufti6, Rena Buckstein7, Moshe Mittelman8, Uwe

Platzbecker9, Ofer Shpilberg10, Ron Ram8, Consuelo del Canizo11, Norbert Gattermann12, Keiya Ozawa13, Alberto Risueno14, Kyle J. MacBeth15, Jim Zhong16, Francis Séguy17, Albert

Hoenekopp17, C.L. Beach16, Pierre Fenaux18

1AOU Careggi, University of Florence, Firenze, Italy; 2Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; 3Marien Hospital Düsseldorf, Düsseldorf, Germany; 4Charles University General Hospital 1st Department of Medicine, Prague, Czech Republic; 5Institut

Paoli-Calmettes Centre Régional de Lutte Contre le Cancer, Marseille, France; 6King’s College Hospital, London, UK; 7Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 8Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 9Medical Clinic and Polyclinic I, University Hospital, Technical

University Dresden, Dresden, Germany; 10Assuta Medical Center, Tel Aviv, Israel; 11Hospital Universitario de Salamanca, Salamanca, Spain; 12Heinrich-Heine-Universität, Düsseldorf, Germany; 13The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; 14Celgene Institute for Translational Research Europe (CITRE), Seville, Spain; 15Celgene Corporation, San Francisco, CA, USA; 16Celgene Corporation, Summit, NJ,

USA; 17Celgene International, Boudry, Switzerland; 18Service d’Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France

MDS-005: Study Design

pRBC, packed red blood cell; SPM, secondary primary malignancy. aLEN 5 mg for patients with creatinine clearance 40–60 mL/min.

Double-blind (DB) treatment

Screening

RBC-TI ≥ 8 weeks or erythroid response

No RBC-TI ≥ 8 weeks or erythroid response

CONTINUE

STOP

Monat 6

Matching placebo

RANDOMIZED

2:1

Key inclusion criteria• Centrally reviewed IPSS Low or Int-1-risk MDS with karyotypes other than del(5q)

• RBC-TD• Unresponsive or refractory to ESAs

LEN 10 mg/da

0

5

10

15

20

25

30

RBC-TI ≥ 8 weeks RBC-TI ≥ 24 weeks

Pat

ient

s (%

)

Placebo (n = 79)LEN (n = 160)

Ek-Unabhängigkeit

17.5%

0%

26.9%

2.5%

The median duration of response was 32.9 weeks

Möchten Sie auch noch mal jung sein ?Spender (GDF-11) gesucht

“Osteohämatologie”

Bulycheva, Rauner, Medyouf, Theurl, Bornhäuser, Hofbauer, Platzbecker. Leukemia 2015

ACE-536: Die “Liganden-Falle”

Suragani et al. Nature Medicine 2014

D·MDS Deutsche MDS-Studiengruppe

Luspatercept (ACE-536) Increases Hemoglobin and Reduces Transfusion

Burden in Patients with Low orIntermediate-1 Risk Myelodysplastic

Syndromes (MDS):Preliminary Results from a Phase 2 Study

Platzbecker et al. ASH 2014

Ansprechen Hb/Eks

Patient Subgroup0.125-0.5 mg/kg

(N=9)n (%)

0.75-1.75 mg/kg(N=17)n (%)

All patients (N=26) 2/9 (22%) 7/17 (41%)

Ansprechen

Baseline StatusResponse Rate

(HI-E)n (%)

All Patients (N=17) 7 (41%)Ring SideroblastsRS ≥15% (N=13) 7 (54%)RS <15% (N=4) 0 (0%)

Response Rate at Higher Dose Levels (0.75-1.75 mg/kg)

* All 9 patients with SF3B1 mutation present had RS ≥15%** Includes all 3 patients who became transfusion independent

SF3B1 MutationSF3B1 Mutation Present (N=9)* 6 (67%)**SF3B1 Mutation Absent (N=8) 1 (13%)

Ansprechen

WeeksHTB, high transfusion burden

Hem

oglo

bin

(g/

dL)

Follow-up Period

2 2

0

2

4

6

8

10

12

5

6

7

8

9

10

11

-3 BL 3 6 9 12 16 20 24

Units Transfused

Hemoglobin

0.75 mg/kg (starting dose)

71 year old femaleRCMD-RSFailed LEN, EPO

Platzbecker et al. ASH 2014

Phase 2/3 Study of Monotherapy LY2157299 Monohydratein Very Low-, Low-, and Intermediate-Risk Patients with

Myelodysplastic Syndromes

“H9H-MC-JBAV”

Type of trial • Phase II multicenter• Open-label

n • N = 40

Inclusion criteria • IPSS-R very low-, low-, or intermediate-risk• Anemia

Study treatment • LY2157299 p.o.

Primary endpoint • HI

Lilly

Fe-Chelation

Niedrigrisiko Hochrisiko

Risikostratifikation nach IPSS

Aktuelle Optionen bei MDSZulassung

Studien

LEN (5q)

Wirksam aber nicht für

MDS zugelassen

EPO

TPO-RA

Ansprechen auf Romiplostim und Überleben bei LR-MDS

Giagounidis et al. Cancer 2014, Platzbecker et al. Leukemia 2014

Baseline-TPO:< 500 pg/ml +2≥ 500 pg/ml -3

Platelets units< 6 +1≥ 6 -3

Prediktives Modell für Ansprechen auf Romiplostim

Score +3

Score -1, -2

Score -6

34 %

65 %

17 %

ORR

TPO = Thrombopoeitin

Giagounidis et al. Cancer 2014, Sekeres & Platzbecker BJH 2014,

Europäische Strukturen für MDS Studien

The European MDS Studies Coordination Office

EUROPA Studie

• IPSS LOW/INT-1 und PLT <50

• <5% Blasten

• Stratifikation nach TPO-Spiegel

Azacitidine p.o. (CC-486):Ansprechen

Garcia-Manero et al., JCO 2011

Response untreated

HI-Erythroid (HI-E) 50 %

HI-Platelet (HI-P) 33 %

STUDIE: Rando vs. BSC in IPSS INT-1 + RBC-TD + PLT <75

Niedrigrisiko

Risikostratifikation nach IPSS

Aktuelle Optionen bei MDSZulassung

Fe-Chelation

LEN (5q)

Intensive CTx/allo Tx

Hochrisiko

AZA

Wirksam aber nicht für

MDS zugelassen

EPO

Studien

AZA +

AZA + LEN > AZA ?

Ramsingh et al. Leukemia 2013

Pollyea et al. Hematologica 2012

Sekeres et al. Blood 2012

Scherman et al. Leukemia 2012

Platzbecker al. Leukemia 2013

AZA LEN

SYNERGIE ?

ORR 54-75%

A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat vs. Azacitidine Monotherapy in

Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup

Study SWOG S1117 [LBA – 5]

Mikkael A. Sekeres, MD, MS, Megan Othus, PhD, Alan F. List, MD, Olatoyosi Odenike, MD, Richard M. Stone, MD., Steven D. Gore, MD, Mark R. Litzow, MD, Rena Buckstein, MD, Mario R. Velasco, MD, Rakesh Gaur, MD, MPH,

Ehab Atallah, MD, Eyal C. Attar, MD, Frederick R. Appelbaum, MD, Harry P. Erba, MD, PhD

SWOG Alliance ECOG NCIC

Sekeres et al. ASH 2014: LBA - 5

Relapse-free Survival (II)All Responders on Tx >6 Months

Phase I study of volasertib+AZA in MDS INT-2/HIGH

MTD

Dose finding part

Volasertib day 1 + 15 q28d

+Azacitidine 75 mg/m2/d s.c.

days 1-7q28d

Extension cohort

Title: An open label Phase I dose escalation trial to investigate the maximum tolerated dose, safety, pharmacokinetics and efficacy of intravenous volasertib in combination with subcutaneous azacitidine in patients with previously untreated high-risk myelodysplastic syndrome (MDS) or Chronic

Myelomonocytic Leukemia (CMML) ineligible for high-intensity therapy

DACOTA-Trialby GFM, FISM and DMDS

Proliferative CMML-1/CMML-2

Hydroxyurea Decitabine

Therapeutische Optionenbei MDS

Intensive CTx/allo TxFe-Chelation

AZA

Lower-risk Higher-risk

Stratification according to IPSS-(R)Zulassung

LEN (5q)

VIDAZALLO trial (n=230)

PI/Co-PI: N. Kröger/U. Platzbecker

MDS IPSS INT-2/HIGH55–70 years

6 x AZA

Start donorsearch

Matched donor

Allo HSCT

No matched donor

AZA until PD

SD, CR, PRPD – off study

Preemptive Aza in MRD+ MDS/AMLRELAZA2-trial (n=52)

AML/MDS in CR after conv. therapy or

alloSCT

MRD-Monitoring

MRD +

12 x AZA

MRD +(<80%)

NPM1, AML1-ETO, CBF-MYH, DEK-CAN CD34+ DC

dkfz.DKTK

Post HSCTPost HSCTPrior to HSCT

-30 0 21 100 360

MRI MRI MRI

• LPI, eLPI, DCI, Hepcidin

• LPI, eLPI, DCI, Hepcidin• Immune modulation

ALLogeneic Iron inVEstigatorsobservational Trial (n=140)

Wermke & Platzbecker

AZA Versagen

Prebet et al. JCO 2011, Jabbour et al. Cancer 2010• Medianes OS: 4.3–5.6 Monate

Temsirolimus in MDSTEMDS-study

Wermke et al. unpublished

prior after

• IPSS LOW/INT-1 und EPO Versagen• IPSS INT-2/HIGH und AZA Versagen• N=40

• Advanced MDS/AML (10-50% blasts)• Relapsed/refractory to standard Tx• Platelet transfusions or PLT <30,000/µL

Eltrombopag6 months

Placebo6 months

Randomized, double-blind, placebo-controlled, phase I/II study on eltrombopag in MDS/AML

Overall SurvivalEs

timat

ed S

urvi

val F

unct

ion

Time Since Randomization (Weeks)

1.0

0.1

0.0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 5 10 15 20 25 30 35 40 45 50 55 60

Median Overall Survival

HR=0.71; P=0.19; 95% CI, 0.40–1.27

Platzbecker et al. EHA

Eltrombopag: 27.0 weeks

Placebo: 15.7 weeks

Overall Survival and Subgroup Analysis from a Randomized Phase III Study of

Intravenous Rigosertib vs Best Supportive Care in Patients with

Higher-risk Myelodysplastic Syndrome After Failure

of Hypomethylating Agents (ONTIME Trial of ON 01910)

G. Garcia-Manero, P. Fenaux, A. Al-Kali, M. R. Baer, M. Sekeres, G. Roboz, G. Gaidano, B. Scott, P. Greenberg, U. Platzbecker, D. P. Steensma, S. Kambhampati, L. Godley,

R. Collins, E. Atallah, F. Wilhelm, I. Darnis-Wilhelm, N. Azarnia, M. Maniar, L. R. Silverman, for the ONTIME Investigators

ONTIME Trial: Primary Efficacy Results – ITT

Blast

TA

INTERAKTION PD-1 – PDL-1 VERHINDERT LYSE

BLOCK PD-L1 ERMÖGLICHT LYSE MDS-BLAST

PD-1

PD-L1

Antikörper

SITUATION MDS STUDIENRATIONALE

Niedrigrisiko

Risikostratifikation nach IPSS

Aktuelle Optionen bei MDSZulassung

Fe-Chelation

LEN (5q)

Intensive CTx/allo Tx

Hochrisiko

AZA

Wirksam aber nicht für

MDS zugelassen

EPO

TPO-RA

Studien

AZA +

TPO-RA LEN

Activin-Inhibitoren Checkpoint-inhibitoren

DAC

AZA + ALLO

Eisen + ALLO

DankeMentors and collaborators:

G. Ehninger/M. Bornhäuser (Dresden)

T. de Witte (Nijmegen)

N. Kröger (Hamburg)

A. Giagounidis/U. Germing (Düsseldorf)

W.K. Hofmann (Mannheim)

D. Haase (Göttingen)

H.J. Deeg (Seattle)

M. Sekeres (Cleveland)

G. Mufti (London)

L. Ades/P. Fenaux (Paris)

Groups:

Dresden MDS team (S. Gloaguen, S. Helas, M. Sauer, C. Kahle, E. Bulycheva, I. Habermann, A. Liebkopf, C. Schönefeldt, M. Wermke)

German MDS Study Group (GMDSSG)

Groupe Francophone Des Myelodysplasies (GFM)

German Cooperative Transplant Group (GCTSG)

Study Alliance Leukemia (SAL)

European MDS study coordinating office (EMSCO)

European Leukemia Net (ELN)

PERFORIN/GRANZYMFAS/FASL

Blast

TA

ERKENNUNG TUMORANTIGEN (TA) AUF MDS-BLAST LYSE MDS-BLAST

INTAKTE TUMORIMMUNSURVEILLANCE