Post on 03-Jan-2016
SFH SK kurs MDS 28-30 september 2015 SjukdomsmekanismerFramtidens diagnostik och behandling
Eva Hellström Lindberg, MD PhDKarolinska InstitutetHematologiskt CentrumKarolinska UniversitetssjukhusetStockholm
Pathogenesis
Hematopoietic stem cell
CLP
CMP
B cells
T, NK-Tcells
NK cells
Dendritic cells
Pro-B
Pro-T
Pro-NK
GMP
MEP
Granulocytes
Macrophages
Platelets
Red cellsMkP
ErP
Increased proliferation Increased apoptosisImpaired differentiation
Cytopenia
Sjukdomsmekanismer vid MDS
Hematopoietic stem cell
Long term Short term Multipotent progenitor
CLP
CMP
B cells
T, NK-Tcells
NK cells
Dendritic cells
Pro-B
Pro-T
Pro-NK
GMP
MEP
Granulocytes
Macrophages
Platelets
Red cellsMkP
ErPAdapted from Reya et al. Nature (2001)
Bone marrowmicroenvironment
Epigeneticalterations
Genetic alterations
Mutational spectrum in MDS
Papaemmanuil, Blood 2013, Haferlach, Leukemia 2014
738 pts
944 pts
MDS uppstår i benmärgens stamceller
• Recurrent mutations exclusively propagated by HSC compartment
• No mechanism connecting mutations and cellular biology (?)
HSC
GMP MEP
Myeloid Erythroid
Hematopoietic hierarchy
Haferlach et al., Leukemia, 2013Woll et al., Cancer Cell, 2014
Mutational frequencies in MDS
Haferlach, Leukemia 2014
Mutations in the splicing machinery define clinically distinct MDS subgroups
Ring sideroblast Chronic myelomonocytic leukemia (CMML)del(5q)
SF3B1 SRSF2P95H/R/LNon-splicing
Exon
SRSF2
U2AF2
U2A
F1
ZRSR2SF3B1
SF3A1
Pre-mRNA Exon
Frequency of spliceosomal mutations in MDS subroupsGenes
Adapted from Papaemmanuil et al., Blood, 2013 and Haferlach et al., Leukemia, 2014
Low risk Low risk High risk
8
Refractory anemia with ring sideroblasts (RARS)
Malcovati et al. Blood, 2009
Clonal hematopoietic stem cell disorder
Mild-severe transfusion dependency
and low risk of leukemic transformation
Expanded erythropoieis, >15% ring
sideroblasts
Accumulation of aberrant mitochondrial
ferritin
70-90% of patients carry SF3B1
mutations
Tehranchi et al, Blood , 2003
Mutations in the splicing machinery - a new key to MDS?
Papaemmanuil, NEJM, 29 Sept 2011
Yoshida, Nature, 6 Oct 2011
Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasmsMalcovati L*, Papaemmanuil E*BLOOD, on-line, 2011
SF3B1 mutated patients show ”underexpressed” mRNA profiles with emphasis on mitochondrial pathways
Papaemmanuil E (Cambridge), for the CMD group, NEJM 2011
Sorting out the spectrum of MDS and MDS-MPN with ring sideroblastsNumber of patients with ≥1% RS 307
Diagnosis:
Myelodysplastic syndrome 243
RARS 90
RCMD-RS 69
RCUD (RA) 7
RCMD 27
MDS with isolated del(5q) 7
RAEB-1 20
RAEB-2 23
Myelodysplastic/Myeloproliferative neoplasm 50
CMML 9
RARS-T 41
Acute myeloid leukemia 14
Malcovati for KI and Pavia MDS research groups, Blood, 2015
Prognostic value of SF3B1 mutations in patients with MDS and RS
Overall Survival
HR .35, P=.007
CI of Disease Progression
HR .37, P=.045
HR .32, P=.005 HR .26, P=.045
RA
RS
/RC
MD
-R
S
All
WH
O
cate
gori
es
Mutations in DNA methylation genes in SF3B1 mutated MDS is associated with MLD
P=.015
P=ns
Any mutation except for SF3B1 impacts long-term outcome in lower as well as in higher-risk MDS
Karimi et al, Haematologica 2015
Survival Freedom from AML
Epigenetics Definition
Epigentics refers to heritable changes in gene expression that does not involve changes to the DNA sequence
Enables change in phenotype without a change in genotype
Crucial for cellular differentiation in multicellular organisms
Epigenetic regulation
MDS genomet är hypermetylerat
Figueroa M, Blood 2009
438 MDS patients, implication of recurrent mutations
Bejar, NEJM 2011Bejar, NEJM 2011
TP53 mutations are uniformely bad in MDS
Bejar, NEJM 2011Bejar, NEJM 2011
The 5q- syndrome
3-4% of all MDS* Previously considered low-risk Previously not thought to be TP53
mutated (by Sanger sequencing, requiring a clone size of 20%)
Before lenalidomide introduction, less thorough follow-up with regard to disease evolution
Van den Berghe, 1974, *Schanz et al, JCO 2011. Swedish registry 2013
Survival according to TBI response; 004 study
List, EHA Education program 2008Fenaux, et al, BLOOD 2012
• 55 patients–IPSS Low (n=32), Int-1 (n=23)
»MDS associated with isolated del(5q), n=50»RCMD, with del(5q) +1, n=4»RAEB, with isolated del(5q), n=1
–37 treated with lenalidomide
• TP53 mutations–10 of 55 (18%)
»equally common in IPSS Low and Int-1»6 mutations in classical low-risk 5q- syndrome»8 of 10 samples taken within 4 months from diagnosis»median clone size 18% (range 1 - 54)
Jädersten & Saft, JCO 2011;29:1971-79.
Pro
babi
lity
of
free
dom
of A
ML
0 1 2 3 4 5 6 7 8 9 10 11 120.0
00
.25
0.5
00
.75
1.0
0
p=0.045
0 1 2 3 4 5 6 7 8 9 10 11 120.0
00
.25
0.5
00
.75
1.0
0
p=0.012
0.0
00
.25
0.5
00
.75
1.0
0
0 1 2 3 4 5 6 7 8 9 10 11 12
p=0.0640
.00
0.2
50
.50
0.7
51
.00
0 1 2 3 4 5 6 7 8 9 10 11 12
p=0.001
By TP53 mutation By 2% p53 IHC
TP53 mutations / IHC+ associated with poor outcome55 patients with low and INT-1 risk MDS with del(5q)50 with isolated del(5q)
Years Years
Years
Pro
babi
lity
of
free
dom
of p
rogr
essi
on
Jädersten & Saft, JCO 2011
TP53 not mutated
TP53 mutated
p53++ <2%
p53++ ≥2%
IHC evaluation of the 85 pts in the MDS-004 cohort that had biopsies taken
P53 IHC dark staining
MDS004 substudy n=85
Negative 55 (65%)
≥1%-<2% 14 (16%)
≥2%-<5% 11 (13%)
≥5% 5 (6%)
30/85 (35%)
Saft et al, submitted
0 1 2 3 4 5 6 7
0.0
0.2
0.4
0.6
0.8
1.0 + Censored
Logrank p=0.0175
Time from randomization (years)
Su
rviv
al P
rob
abil
ity
P53 IHC: < 1% ≥1%
Number of patients
5027
4318
3612
317
245
133
10
5530
Group Median Time_____ __________
< 1% 4.3(3.5,6.4)
>=1% 2.4(1.7,3.7)
Strong p53 expression associated with shorter overall survival
Saft, Haematologica 2015
0 1 2 3 4 5 6 7
0.0
0.2
0.4
0.6
0.8
1.0
+ Censored
Logrank p=0.0006
Time from randomization (years)
Pro
bab
ilit
y o
f A
ML
Pro
gre
ssio
n
P53 IHC: 1: < 1% 2: ≥1%
Number of patients5027
4215
3510
297
235
122
5530
Group 2-Year Rate 5-Year Rate_____ __________ ___________ < 1% 3.9(0.0,9.3) 19.6(7.1,32.2) >=1% 31.7(13.2,50.2) 56.3(33.3,79.3)
Strong p53 expression associated with higher risk for transformation to AML in LEN treated del(5q) pts
Saft, Haematologica 2015
35%
65%
Overall survival by mutational status.
Bejar et al, JCO 2014, 87 patientsMedian age 58 (18-73)24 RA / RCMD42 RAEB5 CMML
Therapeutic Algorithm for Adult Patients with Primary MDS and Low INT-1 IPSS Risk (European LeukemiaNet)
Low IPSS riskLow IPSS risk
Watchful waitingWatchful waitingsEpo <500 mU/mL and/or RBC units
<2/month
sEpo <500 mU/mL and/or RBC units
<2/monthMDS del(5q)MDS del(5q)
RBC transfusion and iron chelation
therapy
RBC transfusion and iron chelation
therapy
Age <60 years, BM blasts <5%, normal
cytogenetics,transfusion-dependency
(hypocellular bone marrow)
Age <60 years, BM blasts <5%, normal
cytogenetics,transfusion-dependency
(hypocellular bone marrow)
sEpo ≥500 mU/mL and RBC units
≥2/month
sEpo ≥500 mU/mL and RBC units
≥2/month
rHuEpo+/- G-CSFrHuEpo
+/- G-CSF
Immunosuppressive therapy with ATG
Immunosuppressive therapy with ATG
rHuEpo+/- G-CSFrHuEpo
+/- G-CSF
Lenalidomide(within prospective
registry)
Lenalidomide(within prospective
registry)
Asymptomatic cytopenia
Asymptomatic cytopenia
Symptomatic anemia
Symptomatic anemia
sEpo <500 mU/mLand/or RBC units
<2/month
sEpo <500 mU/mLand/or RBC units
<2/month
Malcovati, Hellström-Lindberg, et al for the ELN network, Blood 2013
Options for ESA (and LEN) refractory transfusion-dependent lower-risk MDS?Refractoriness usually not associated with progress to higher-risk MDS
Therapeutic Algorithm for Adult Patients with Primary MDS and Low INT-1 IPSS Risk (European LeukemiaNet)
Low IPSS riskLow IPSS risk
Watchful waitingWatchful waitingsEpo <500 mU/mL and/or RBC units
<2/month
sEpo <500 mU/mL and/or RBC units
<2/monthMDS del(5q)MDS del(5q)
RBC transfusion and iron chelation
therapy
RBC transfusion and iron chelation
therapy
Age <60 years, BM blasts <5%, normal
cytogenetics,transfusion-dependency
(hypocellular bone marrow)
Age <60 years, BM blasts <5%, normal
cytogenetics,transfusion-dependency
(hypocellular bone marrow)
sEpo ≥500 mU/mL and RBC units
≥2/month
sEpo ≥500 mU/mL and RBC units
≥2/month
rHuEpo+/- G-CSFrHuEpo
+/- G-CSF
Immunosuppressive therapy with ATG
Immunosuppressive therapy with ATG
rHuEpo+/- G-CSFrHuEpo
+/- G-CSF
Lenalidomide(within prospective
registry)
Lenalidomide(within prospective
registry)
Asymptomatic cytopenia
Asymptomatic cytopenia
Symptomatic anemia
Symptomatic anemia
sEpo <500 mU/mLand/or RBC units
<2/month
sEpo <500 mU/mLand/or RBC units
<2/month
Malcovati, Hellström-Lindberg, et al for the ELN network, Blood 2013
SCT if transplantable??
SCT if transplantable??
Results do not encourage use of aza in ESA resistant lower-risk MDS
6/30 = 20% responseMedian response duration 5 moTwo patients had responses > 6 moSignificant SAEs 2 deaths on treatmentNo association response - mutations
U Platzbecker1, U Germing2, A Giagounidis3, K Goetze4, P Kiewe5, K Mayer6, O Ottman7, M Radsak8,T Wolff9, D Haase10, M Hankin11, D Wilson11, A Laadem12, M Sherman11 and K Attie11
Study supported by Acceleron and Celgene
D ·M D S Deutsche M DS-Studiengruppe
Uwe Platzbecker, MD
LUSPATERCEPT INCREASES HEMOGLOBIN AND REDUCES TRANSFUSION BURDEN IN PATIENTS WITH LOW OR
INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROMES (MDS): PRELIMINARY RESULTS FROM A PHASE 2 STUDY
1Universitätsklinikum Carl Gustav Carus, Dresden; 2Universitätsklinikum Düsseldorf;3Marien Hospital Düsseldorf; 4Technical University of Munich; 5Onkologischer Schwerpunkt
am Oskar-Helene-Heim, Berlin; 6Universitätsklinikum Bonn; 7Klinikum der J.W. Goethe-Universität Frankfurt; 8University Medical Center - Johannes Gutenberg-Universität, Mainz; 9OncoResearch Lerchenfeld UG, Hamburg;
10Department of Hematology and Medical Oncology, University Medicine of Göttingen, Germany;11Acceleron Pharma, Cambridge, MA; 12Celgene Corporation, Summit, NJ, USA
Luspatercept, a modified activin receptor type IIB (ActRIIB) fusion protein,acts as a ligand trap for GDF11 and other ligands of the TGF-β superfamily to suppress Smad2/3 activation; increases Hgb in healthy volunteers1
In a murine model of MDS, RAP-536 (murine ortholog of luspatercept) corrects ineffective erythropoiesis, reduces erythroid hyperplasia and increases hemoglobin2
1. Attie, K et al. Am J Hematol 2014;89:766
2. Suragani R et al., Nat Med 2014;20:40833
High EPO levels drive proliferation
Excessive GDF-induced Smad2/3 signaling inhibits RBC maturation
ReticBaso EBFU-E CFU-E Pro E RBCPoly E Ortho E
Baseline Characteristics (2 of 2)
Patient Subgroup N = 44n (%)
IPSSLow 22 (50%)Int-1 20 (46%)Int-2 2 (4%)IPSS-RVery Low 2 (4%)Low 25 (57%)Intermediate 14 (32%)High 3 (7%)Ring Sideroblast (RS) N=43RS positive (≥15% of cells) 35 (81%)RS negative (<15% of cells) 8 (19%)Splicing Mutation SF3B1 N=43SF3B1 mutation present 25 (58%)SF3B1 mutation absent 18 (42%)
Data as of 23 Feb 201534
Erythroid Response in RS+, mSF3B1 PatientsHigher Dose Groups (0.75-1.75 mg/kg)
Patient Population IWG HI-E
All Patients (n=35) 19 (54%)
RS positive (n=30) 19 (63%)
RS negative (n=4) 0 (0%)
SF3B1 mutation present (n=22) 16 (73%)
SF3B1 mutation absent (n=13) 3 (23%)
Data as of 23 Feb 2015
• 39% (9/23) of RS positive patients achieved transfusion independence (TI)
• ACE-536 will betaken forward in a prospective randomized phase III trial
IWG HI-E: For LTB patients: Hemoglobin increase ≥ 1.5 g/dL for ≥ 8 weeks
For HTB patients: ≥ 4 Unit reduction in transfusions over 8 weeks
Unmet medical needs for patients with higher-risk MDS
Intermediate-2 or high IPSS risk
Intermediate-2 or high IPSS risk
Supportive careSupportive care
AzacitidineAzacitidine No suitable stem cell donor
No suitable stem cell donor
Poor risk cytogenetics
Poor risk cytogenetics ≥10% BM blasts≥10% BM blasts
Age ≥65-70 years orpoor performance
status
Age ≥65-70 years orpoor performance
status
Age <65-70 years andgood performance
status
Age <65-70 years andgood performance
status
≥10% BM blasts, no poor risk
cytogenetics
≥10% BM blasts, no poor risk
cytogenetics
Available stem celldonor
Available stem celldonor
<10% BM blasts<10% BM blasts
AzacitidineAzacitidine Allo-SCTAllo-SCTAML-like CT
ORAzacitidine
AML-like CTOR
AzacitidineAllo-SCTAllo-SCT
AML-like CT or Azacitidine
(within clinical trial orprospective registry)
AML-like CT or Azacitidine
(within clinical trial orprospective registry)
Malcovati, Hellström-Lindberg, et al for the ELN network, Blood 2013
Improve primary efficacy of Aza
Treat aza failures
Improve outcome of allo SCT
Aza decision according to-mutational profile?-expression profile?-methylation profile?
Mut i chromatin-modifierande gener associerade med bättre överlevnad vid aza behandling av högrisk MDS
Tobiasson et al, Submitted
ASXL1EZH2MLL
How can azacytidine treatment be improved?
0 5 10 15 20 25 30 35 40
Time (months) from RandomizationTime (months) from Randomization
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
po
rtio
n S
urv
ivin
gP
rop
ort
ion
Su
rviv
ing
CCRCCRAZAAZA
Fenaux et al, Lancet Oncology 2009
• + HIDAC inhibitors• + lenalidomide• + eltrombopag• + small molecules
North American Intergroup Randomized Phase 2 MDS Study S1117: 03/12 – 06/14
AZA (IV/SC)N=92
AZA (IV/SC) + LEN (PO)N=93
AZA (IV/SC) + Vorin (PO)N=91
Higher-risk MDS or CMML
(IPSS >1.5 and/or blasts >5%)
Groups: SWOG, ECOG,Alliance, NCIC
Total Sample Size: 276
Primary Objective: 20%improvement of ORR (CR/PR/HI) based on 2006 IWG Criteria
Secondary Objectives: OS,RFS, LFS
Power 81%, alpha 0.05 for each combo arm vs. AZA
Sekeres et al. ASH 2014: LBA - 5
Sekeres et al. ASH 2014: LBA - 5
Response rates and relapse-free and survival all responders
Response ratesAza 37%Aza + LEN 39%Aza + VOR 24%
ONTIME Trial: Median Overall Survival for Pts with Primary HMA FailureRigorsertib vs BSC
Investigator Assessment Blinded, Centralized Assessment
Better relative efficacy in pts with high-risk genetics (TP53, ASXL1)Rigorsertib ill be taken forward in randomized phase III trial
MDS Registry – National biobank project2013-2017 Sweden and the Nordic countries
Targeted sequencingHaloplex, 74 genes