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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