SFH SK kurs MDS 28-30 september 2015 Sjukdomsmekanismer Framtidens diagnostik och behandling Eva Hellström Lindberg, MD PhD Karolinska Institutet Hematologiskt

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


therapy

Age <60 years, BM blasts <5%, normal

cytogenetics,transfusion-dependency

(hypocellular bone marrow)




sEpo ≥500 mU/mL and RBC units

≥2/month


≥2/month

rHuEpo+/- G-CSFrHuEpo

+/- G-CSF

Immunosuppressive therapy with ATG



+/- G-CSF

Lenalidomide(within prospective

registry)


registry)

Asymptomatic cytopenia


Symptomatic anemia

Symptomatic anemia

sEpo <500 mU/mLand/or RBC units

<2/month


<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)


therapy


therapy








≥2/month


≥2/month


+/- G-CSF




+/- G-CSF


registry)


registry)



Symptomatic anemia

Symptomatic anemia


<2/month


<2/month


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)


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

Documents

SFH SK kurs MDS 28-30 september 2015 Sjukdomsmekanismer Framtidens diagnostik och behandling Eva Hellström Lindberg, MD PhD Karolinska Institutet Hematologiskt