MDS A Hematopoietic Disorder of the Elderly - bhs.be · Secondary MDS Prior chemo- or radiation...

MDS – A Hematopoietic Disorder of the Elderly

Myelodysplastic Syndrome and Juvenile Myelomonocytic Leukemia

in Children and Adolescents

Charlotte M. Niemeyer MD

Professor of Pediatrics

Department of Pediatrics

University Medical Center

Freiburg im Breisgau

Germany

• Infections

• Nutritional deficiencies

• Metabolic disorders

• Mitochondrial deletion

(Pearson syndrome)

• Inherited bone marrow

failure disorders

Myelodysplasia in Childhood

Most commonly seen in:

Annamaria Cseh

Alexandra Fischer

Wilfried Truckenmüller

Peter Nöllke

Irith Baumann,

Stephan Schwarz-Furlan

Gitte Kerndrup

Jan van der Tweed

Pascale de Paepe

Vit Campr

Ingrid Simonitsch-Klupp

Rita Devito

Michael Mc Dermott

Jean Philippe

Susanna Fenu

Valerie de Haas

Charlotte Niemeyer

Austria

Belgium

Czech Republic

Germany

Italy

Nordic Countries

Switzerland

The Netherlands

Ireland

Michael Dworzak

Barbara de Moerloose

Jan Starý

Charlotte Niemeyer

Marco Zecca

Henrik Hasle

Markus Schmugge

Marry v.d. Heuvel-Eibrink

Owen Smith

Brigitte Schlegelberger

Kyra Michalova

Gitte Kerndrup

Berna Beverloo

David Betts

Oskar Haas

Laura Sainati

Natalie van Roy

Regional Coordinators

Oncogenetics

Histopathology, Morphology

Coordinating Study Center

Childhood

Myelodysplastic Syndrome

I. Baumann

C.M. Niemeyer

J.M. Bennett

K. Shannon

Pediatric Aspects of the WHO Classification

Myelodysplastic Syndrome PB blasts (%) BM blasts (%)

Refractory Cytopenia (RC) < 2 < 5

Refractory anemia with excess blasts (RAEB) 2 - 19 5 - 19

RAEB in transformation (RAEB-T) 20 - 29 20 - 29

Secondary MDS Prior chemo- or radiation therapy

Prior acquired aplastic anemia

In inherited bone marrow failure disorder

Primary MDS All others

RCC 60%

RAEB 31%

RAEB-T 9%

All Patients

Morphological Subtypes of Primary MDS (EWOG-MDS 98 and EWOG-MDS 2006 interim)

de novo AML

100 %

20 %

Separation of MDS from de novo AML

RAEB

MDS after exclusion of

• AML specific translocations

• Clinically leukemic presentation

• Rapid progression of disease

30 % RAEB-T

Bla

st

(%)

Time (months)

Threshold

(20 % or 30 %)

de novo AML

MDS

Modified from Head, Curr Opin Oncol 2002, 14:19

Karyotype in Advanced MDS

Monosomy 7 31 26

Trisomy 8 5 0

Complex 3 26

Other abnormalities 17 9

Normal karyotype 43 39

Primary advanced MDS

(%)

(N=93)

Secondary MDS after

chemo-/radiation therapy (%)

(N=41)

Complex karyotype: ≥ 3 abnormalites including a structural abnormality,

excluding clonal evolution from monosomy 7

1. Can chemotherapy alone cure the patient ?

• Two Questions for Therapy of Advanced MDS

1. Can chemotherapy alone cure the patient ?

2. Can cytoreductive therapy prior to HSCT

improve EFS ?

• Two Questions for Therapy of Advanced MDS

Inclusion Criteria

Diagnosis: Primary advanced MDS < 30% BM blast at diagnosis

Evaluation according to highest WHO-type

Date of diagnosis: 7/1998 – 12/2006

Conditioning: Bu/Cy/Mel

Donor: MSD, MUD

MMUD (1 Ag +/- 1 Al MM or 2 Al MM)

HLA-typ.: HLA A, B, C, DRB1

(without HLA C in 7 patients)

Transplantat: unmanipulated BM, PBSC

HSCT in advanced primary MDS

Patients


Number of patients 97

Sex (M / F) 65 / 32

Age at HSCT (years) 11.1 (1.4 -19)

Time interval between diagnosis -HSCT (mo) 3.9 (1 – 31.2)

Highest WHO type prior to HSCT

RAEB 53 (55%)

RAEB-T 29 (30%)

MDR-AML 15 (15%)


Transplantation

Donor

HLA-identical sibling 39 (40%)

HLA-compatible unrelated donor 58 (60%)

Source of stem cells

Bone marrow 69 (71%)

Peripheral blood 28 (29%)

Conditoning day -8 -7 -6 -5 -4 -3 -2 -1 0

Busulfan (4 mg/kg/d)

Cyclophosphamide (60 mg/kg/d)

Melphalan (140 mg/m2/d)

12 10 8 6 4 2 0

1.0

0.8

0.6

0.4

0.2

0.0

5-yrs.-SURV: 0.63 [0.53-0.73]

5-yrs.-EFS: 0.59 [0.49-0.69]

SURV: N =97, E=33, Follow-Up: 3.7 yrs. (0.1-10.9)

EFS: E=38, Follow-Up: 3.1 yrs. (0.1-10.9)

PR

OB

AB

ILIT

Y

Survival and Event-Free Survival


YEARS AFTER TRANSPLANTATION

Relapse/TRM Incidence

12 10 8 6 4 2 0

1.0

.8

.6

.4

.2

0.0

P

12 10 8 6 4 2 0

1.0

.8

.6

.4

.2

0.0

CU

MU

LA

TIV

E I

NC

IDE

NC

E

Relapse TRM

YEARS AFTER TRANSPLANTATION YEARS AFTER TRANSPLANTATION

N=97, E=18

0.21 [0.14-0.32]


N=97, E=20

0.21 [0.14-0.31]

12 10 8 6 4 2 0

1.0

0.8

0.6

0.4

0.2

0.0

PR

OB

AB

ILIT

Y



Log Rank: p=0.07

Event-free Survival nach MDS Subtyp

RAEB, p=0.63 [0.59-0.77] N=53, E=18

RAEB-T, p=0.64 [0.46-0.82]

N=29, E=10

MDR-AML, p=0.32 [0.08-0.56]

N=15, E=10

12 10 8 6 4 2 0

1.0

0.8

0.6

0.4

0.2

0.0

PR

OB

AB

ILIT

Y



EFS according to Blast Percentage at SCT

Log Rank: p=0.11

>= 20 %, p=0.45 [0.23-0.67]

N=20, 11 events

5-19 %, p=0.65 [0.50-0.80]

N=46, 15 events

< 5 %, p=0.62 [0.41-0.83]

N=22, 8 events

12 10 8 6 4 2 0

1.0

0.8

0.6

0.4

0.2

0.0

PR

OB

AB

ILIT

Y



Log Rank: p=n.s.

Event-free Survival according to Therapy

None or low-dose therapy,

p=0.58 [0.46-0.70]

N=73, 29 events

AML-like chemotherapy,

p=0.62 [0.42-0.82]

N=24, 9 events

Incidence of Relapse

Increased at

- higher WHO subtype of MDS

- complex karyotype ( ≥ 3 aberrations with at least one structural abnormality)

- higher percentage of blast in BM at HSCT (not significant)

Decreased at

- presence of acute or chronic GvHD (not significant)

Independent of

- donor (MSD vs UD)

- application of intensive chemotherapy prior to HSCT


12 10 8 6 4 2 0

1.0

0.8

0.6

0.4

0.2

0.0

PR

OB

AB

ILIT

Y



Log Rank: p=0.11

Event-free Survival according to Age at HSCT

< 12 yrs.: p=0.67 [0.53-0.81]

N=51, E=16

≥ 12 yrs.: p=0.50 [0.35-0.65]

N=46, E=22

12 10 8 6 4 2 0

1.0

0.8

0.6

0.4

0.2

0.0



CU

MU

LA

TIV

E IN

CID

EN

CE

TRM Incidence according to Age at HSCT

< 12 yrs.: p=0.10 [0.04-0.23]

N=51, E=5

≥ 12 yrs.: p=0.33 [0.22-0.50]

N=46, E=15

P<0.01

12 10 8 6 4 2 0

1.0

0.8

0.6

0.4

0.2

0.0



CU

MU

LA

TIV

E IN

CID

EN

CE

TRM Incidence according to time

diagnosis of advanced MDS to HSCT

< 4 mths.: p=0.10 [0.04-0.23]

N=49, E=5

≥ 4 mths.: p=0.31 [0.21-0.48]

N=48, E=15

P=0.01

Relapse / TRM Incidence according to Acute GvHD

12 10 8 6 4 2 0

1.0

.8

.6

.4

.2

0.0

P

12 10 8 6 4 2 0

1.0

.8

.6

.4

.2

0.0

CU

MU

LA

TIV

E I

NC

IDE

NC

E

Relapse TRM


P=n.s.

P<0.01 III-IV: 0.10 [0.03-0.36]

0-II: 0.24 [0.16-0.38]

Grade 0-II, 9 events

Grade III-IV, 11 events

III-IV: 0.48 [0.31-0.74]

0-II: 0.12 [0.07-0.23]

Grade 0-II, N=74, 16 events

Grade III-IV, N=23, 2 events


Incidence of transplant associated mortality

increased at

- older patients (≥ 12 years at HSCT)

- longer time interval between diagnosis and HSCT (≥ 4 mo)

- presence of acute or chronic GvHD (not signifikant)


EWOG-MDS Consensus in Pavia 2006:

…it may be indicated to intensify GVHD prophylaxis with the aim of

reducing TRM in patients > 12 years…

MSD ≥ 12 y at HSCT: CSA 3 mg/kg/d + short course MTX

Relapse/ TRM Incidence according to

GvHD Prophylaxis, Sibling Donor only

12 10 8 6 4 2 0

1.0

.8

.6

.4

.2

0.0

P

12 10 8 6 4 2 0

1.0

.8

.6

.4

.2

0.0

CU

MU

LA

TIV

E I

NC

IDE

NC

E

Relapse TRM


P=0.09

P=n.s.

CSA only, 6 events

CSA+MTX, 1 events

CSA only, N=27, 2 events

CSA+MTX, N=12, 3 events


CSA only: 0.22 [0.11-0.45]

CSA+MTX: 0.08 [0.01-0.54] CSA only: 0.08 [0.02-0.32]

CSA+MTX: 0.32 [0.12-0.86]

RCC 60%

RAEB 31%

RAEB-T 9%

Hypocellular 82%

Normo- 9% Hyper-

9%

All Patients RCC

Morphological Subtypes of Primary MDS (EWOG-MDS 98 and EWOG-MDS 2006 interim)

Hb F, prior to Tx, age adjusted: 91% elevated

MCV, prior to Tx, age adjusted: 64% elevated

other

no result

Increased or normal cellularity

(19% of patients, N=67)

Decreased cellularity

(81% of patients, N=288)

67% 9%

8%

16%

61% 19%

12%

8%

Karyotype in Primary RCC

(EWOG-MDS 98 and EWOG-MDS 2006 interim)

normal karyotype normal karyotype

- 7

other

no result

-7

EWOG-MDS May 2011

Dysplastic Megakaryocytes

Granulopoiesis

Erythropoiesis

Normocellular Hypocellular

Histopathological Pattern in RCC

chloracetate-esterase staining

Patchy Erythropoietic Pattern in RCC

Histopathology of RCC

chloracetate-esterase staining

Left Shifted Erythroid Hyperplasia in RCC

Giemsa staining

mitosis

proerythroblasts

proerythroblasts

mature erythroblasts

anti-CD61-staining

Micromegakaryocytes on Immunohistochemistry in RCC

micromegakaryocyte

micromegakaryocyte

Histopathology of RCC

Biopsy Diagnostic of RCC

Biopsy in RCC Mimicking Acquired Aplastic Anemia

Histopathology of Acquired Aplastic Anemia

Acquired Severe Aplastic Anemia

Giemsa staining

0 2 4 6 8 10

Years after IST

0 . 0

0 . 2

0 . 4

0 . 6

0 . 8

1 . 0

Cu

mu

lati

ve in

cid

ence

N=123, E=3, 0.03 (0.01-0.08)

Study SAA 94: Clonal evolution in patients

registered following introduction of reference review

12 14

Baumann I. et al. Histopathology in press

Inter observer reliability of 79%

Reproducability of Histopathological Diagnostic Criteria in RCC

Accordance among 7 pathologists

7 of 7 6 of 7 5 of 7 4 of 7

RCC (N=67) 72% 13% 12% 3%

SAA (N=33) 85% 12% 0% 3%

Baumann I. et al. Histopathology in press

7 pathologists from 6 countries

100 cases of RCC or SAA previously reviewed by one of them

BM biopsies (HE, Giemsa, cloracetate-esterase, anti-CD61)

Double blind, same set of slides

Method

Results

Inherited Bone Marrow Failure Disorders

and RCC Show Overlapping Morphological Features

Hematopoietic stem cell

Radio- ulnar synostosis DBA

CAMT

DC

SCN SDS

FA

15% of RCC Yoshimi et al. ASH 2011

7% of BMF Pinto et al, Haematologica 2009

12 10 8 6 4 2 0

1.0

.8

.6

.4

.2

0.0

years

Monosomy 7 = 80% (62-98) (N=32, 15 events)

Normal karyotype = 27% (5-49) (N=22, 4 events)

Trisomy 8 = 30% (0-84) (N=12, 1 event)

log rank: p<0.01

Progression of Primary Refractory Cytopenia

to Advanced MDS

Kardos et al. Blood 2003;102:1997

PR

OB

AB

ILIT

Y (9

5%

CI)

MFD

Transfusion dependent or

ANC < 1000/µL

No transfusion and

ANC >1000/µL

HSCT watch and wait BM aspiration 6-12 mo

HSCT

IST

hypocellular BM + normal karyotype or trisomy 8

MUD

Rational Approach to Therapy for RCC

Karyotype

-7, 7q-, ≥ 3 abnormalities HSCT as soon as possible

all other

years from HSCT

8 6 4 2 0

1.0

0.8

0.6

0.4

0.2

0.0

HSCT in RCC: Standard Myeloablative Regimen with Busulfan, Cyclophosphamide, +/- Melphalan

5-yrs. CI TRM: 0.17 [0.09-0.32]

5-yrs. CI Relapse: 0.03 [0.00-0.15]

Pro

bab

ility

(9

5%

CI)

5-yrs. EFS MFD 0.78 [0.58-0.98], N =19, E=4 MUD 0.76 [0.60-0.92], N =29, E=7

Locatelli et al. Blood 2007; 110: 251

Karyotype - 7/other abnormalities 13/4 Normal / not available 27/4

BM cellularity Reduced/normal/increased 34/8/6

Number of patients 56

Median age at HSCT, years (range) 13.5 (2.8 - 20.1)

Transfusion dependent for RBC / Platelets / ANC < 1000/µl 40 / 51 / 51

Median interval diagnosis - HSCT, days (range) 262 (44 - 9.1 yrs)

Preparative Regimen

Days -8 -7 -6 -5 -4 -3 -2 -1 0

Thiotepa 5 mg/kg/day • • •

Fludarabine 40 mg/m2/day • • • •

Rabbit ATG Fresenius (UD only) • • •

Strahm et al. BMT 2010; 45 Suppl 2:S1-427

Reduced Intensity Preparative Regimen for HSCT in Hypocellular RCC with normal Karyotype

Years from HSCT

0 . 0

0 . 2

0 . 4

0 . 6

0 . 8

1. 0

Log Rank: p=n.s.

MSD 1.00 MFD 0.95 (0.88-1.00)

0 2 4 6 8 10

MSD 0.76 (0.52-1.00)

MFD 0.84 (0.72-0.96)

OS EFS MSD N=15, event=0, event=3

MFD N=41, event=2, event=6

Events: graft failure, platelet non-engraftment, TRM

Strahm et al. BMT 2010; 45 Suppl 2:S1-427

OS

EFS

HSCT: Reduced Intensity Preparative Regimen in Hypocellular RCC with normal Karyotype

Pro

bab

ility

(9

5%

CI)

Patient characteristics (N = 32)

Median age at diagnosis (years) 10 (1.8 - 17.2)

Median ANC at IST (/µl) 600 (0 - 1300)

Transfusion dependent at IST PLT 32/32

RBC 29/32

Karyotype: normal/ abnormal / no result 14/ 1/ 17

Median interval diagnosis – IST (days) 70 (7 - 304)

Immunosuppressive Therapy in RCC Yoshimi et al. Haematologica 2007; 92: 397

Therapy according to study SAA 94 (Führer et al, Blood 2005; 106:2102)

• Horse ATG (Lymphoglobulin): 15 mg/kg/days x 8 days

• CSA: 5 mg/kg/day adjusted by blood levels

• G-CSF: 5 µg/kg/day for patients with ANC < 0.5x10 9 /L

Complete response (CR): Hb: age adjusted normal level, Plt: >150 000/µL, ANC: >1500/µL

Partial response (PR): Transfusion independency, Plt: > 20 000/µL, ANC: > 500/µL

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

6 months last follow up (med. 6.3 years)

Toxic death

Clonal evolution

Relapse

NR

PR

CR

SCT 32%

71%

58%

35%

6%

Immunosuppressive Therapy in RCC Yoshimi et al. Haematologica 2007; 92: 397 Update of Response, November 2011

Overall and Failure Free Survival after IST

Failure : death, no response at 6 months, relapse, clonal evolution, 2nd IST, HSCT

Years from IST

0 2 4 6 8 10 12

1.0

0

5-yrs OS: 86.8%

5-yrs FFS: 47.7%

Median time of follow-up 6.3 years

Pro

bab

ility

(9

5%

CI)

Yoshimi et al. Haematologica 2007; 92: 397 Update of Response, November 2011

0.8

0.6

0.4

0.2

Summary and Conclusion

Refractory cytopenia of childhood (RCC) is characterized by a distinct

morpholocial and histopathological pattern.

RCC can be separated from acquired SAA at diagnosis in a reproducible

and reliable fashion.

Prior to the establishment of a diagnosis of RCC inherited bone marrow failure

disorders need to be excluded. Chromosomal breakage test (FA)and telomere

length measurements (DC) are strongly recommended.

Cross-continental collaboration is required to analyze and classify pediatric

cohorts with bone marrow failure.

Genomic studies will help to eventually unravel the nature of disorders

currently best classified as RCC.

Juvenile Myelomonocytic Leukemia

Courtesy of The JMML Foundation

Splenomegaly 93%

Lymphadenopathy 59%

Skin infiltration 25%

WBC (med.) 33 x 109/l

Monocytes (med.) 5.4 x 109/l

Platelets (med.) 54 x 109/l

Precursors in PB 90 % of patients

Clinical Presentation

Niemeyer et al. Blood 89: 3534, 1997

P. Emanuel, 2003

% m

axim

al C

FU

-GM

co

lony g

row

th

GM-CSF (ng/ml)

0 0.01 0.02 0.04 0.08 0.16 0.32 2

0

10

20

30

40

50

60

70

80

90

100 Normal

JMML (n=186)

GM-CSF Hypersensitivity in JMML

RAS GDP SHC

GRB2

SHP-2 (PTPN11)

growth factor cell membrane

SOS1 NRAS GTP

RAF1

MEK2

ERK1

ERK1/2

nucleus

CBL

KRAS GTP

HRAS GTP

BRAF

MEK1

ERK2

ERK1/2

cytosol

SPRED1

P

P

neurofibromin

NF1

RAS MAPK Pathway

Neurofibromatosis Type I JMML

Desktop anzeigen.scf

Loss of Heterozygosity – Uniparental Disomy

Steinemann et al. Haematologica 2010

Loh, ML et al. Blood 2009;114:1859

SNP Arrays reveal copy neutral 11q isodisomy

Wildtype

Diagnosis

Analysis of the commonly involved region identified CBL

as the candidate gene

CBL encodes c-Cbl, a Protein with Complex Functions

• involved in many signaling pathways, including Ras signaling

• E3 ubiquitin ligase: degrades activated RTKS via ubiquitylation

• also functions as an adaptor protein

Clinical Features of JMML Patients with CBL Mutation

Dysmorphic facial features

Growth < 3rd percentile

Developmental delay

Cryptorchism

Hearing loss

1-2 café au lait spots

juvenile xanthogranuloma

Niemeyer et al. Nat Genet, 2010

ID Optic

atrophy

Hyper-

tension

Cardio-

myopathy

Status/

Age (yrs)

A053 + + + A 18.2

A054 A 17.7

D256 + + A 13.0

D048 + + + D 9.9

D389 + + + A 7.5 D088 D 7.3

Follow-up of JMML Patients with CBL Mutation

no HSCT:

HSCT:

6 patients aged 7-19 years

died of JMML

8 / 11 patients with mixed chimerism,

resolution of JMML

spontaneous

resolution of MPD

Radiographic Evidence of Vasculitis

Aorta Aorta Left subclavian artery

Noonan Syndrome

Dysmorphic syndrome with :

• typical facial features

• short neck with redundancy of skin

• cardiac anomalies (pulmonic stenosis,

ASD/VSD, hyertrophic cardiomyopathy)

• chest deformity

• crytorchism

• short stature

• failure to thrive

• (mild) mental retardation

Noonan syndrome and JMML :

3 of 4 pts have spontaneous resolution

1 pt acquired chromosomal abnorm.

Bader-Meunier et al., J Pediatr, 1997

RAS GDP SHC

GRB2

SHP-2 (PTPN11)


SOS1 NRAS GTP

RAF1

MEK2

ERK1

ERK1/2

nucleus

CBL

KRAS GTP

HRAS GTP

BRAF

MEK1

ERK2

ERK1/2

cytosol

neurofibromin

Noonan

LEOPARD

Costello

SPRED1 Legius

NF1 CFC

P

P

Genetic syndromes of the RAS-MAPK Pathway: “RASopathies”

Modified from Tidyman

Current Opinion in Genetics & Development 2009

Noonan-like

RAS GDP SHC

GRB2

SHP-2 (PTPN11)


SOS1 NRAS GTP

RAF1

MEK2

ERK1

ERK1/2

nucleus

CBL

KRAS GTP

HRAS GTP

BRAF

MEK1

ERK2

ERK1/2

cytosol

neurofibromin

Noonan

Noonan-like

LEOPARD

Costello

SPRED1 Legius

NF1 CFC

P

P

JMML and the “RASopathies”

Modified from Tidyman

Current Opinion in Genetics & Development 2009

RAS GDP SHC

GRB2

SHP-2 (PTPN11)


SOS1 NRAS GTP

RAF1

MEK2

ERK1

ERK1/2

nucleus

CBL

KRAS GTP

BRAF

MEK1

ERK2

neurofibromin SPRED1

P

JAK

STAT

germline somatic

„initial“ mutation (%)

CBL

PTPN11

RAS

NF1

12*

9

35 2

0

0

*

* = + LOH

Germline and Somatic Mutations in JMML

Germline Somatic

Mild effects on

cell growth

Strong effects

on cell growth

Tolerated in the

germline

Not tolerated in

the germline

Noonan JMML

cell

Some develop

JMML

PTPN11

mutation

Tartaglia, Niemeyer et al. Nat Genet 2003

RAS GDP SHC

GRB2

SHP-2 (PTPN11)


SOS1 NRAS GTP

RAF1

MEK2

ERK1

ERK1/2

nucleus

CBL

KRAS GTP

BRAF

MEK1

ERK2

neurofibromin SPRED1

P

JAK

STAT

germline somatic

„initial“ mutation (%)

CBL

PTPN11

RAS

NF1

12*

9

35

25

2

1

0

0

*

* = + LOH

Germline and Somatic Mutations in JMML

(Blood 2008)

(Blood 2007)

(PBC 2008)

A Favorable Outcome In Children with Juvenile Myelomonocytic Leukemia (JMML) with RAS Mutations

Sayoko Doisaki, MD*, Hideki Muramatsu, MD, PhD*, Asahito Hama, MD, PhD*, Akira Shimada, MD, PhD, Yoshiyuki Takahashi, MD, PhD* and Seiji Kojima, MD, PhD*

(ASH 2010)

Spontaneous improvement of JMML with RAS Mutations

Autoimmune lymphoproliferative like disease

with somatic KRAS and NRAS Mutations

• Disorder characterized by :

hepatosplenomegaly, lymphadenopathy, autoimmune cytopenia

and other autoimmune disease

• Disorder does neither fit criteria for ALPS nor JMML

Masatoshi Takagi, et al. Blood 2020

• Clonality? Which cell lines at which progenitor precursor stage involved?

Therapeutic Options for JMML

PTPN11 RAS NF1 CBL

Germline (-/+ LOH)

Somatic HSCT

HSCT w+w

cytoreduction

w+w

cytoreduction

35%

w+w

HSCT

w+w

HSCT?

2%

25%

1% 9% 12%

0% 0%

-- --

Overall survival from diagnosis

24 20 16 12 8 4 0

1.0

0.8

0.6

0.4

0.2

0.0

YEARS FROM Diagnosis

PRO

BABIL

ITY

28

5-year OS: All negative: 0.79 (0.64-0.94)

Clinical NF-1: 0.37 (0.21-0.53)

PTPN11: 0.46 (0.34-0.58)

RAS: 0.58 (0.46-0.70)

Log Rank: p=0.02 ( 5-yrs.)

No mutation: N=31; E= 7 RAS: N=76; E=30 PTPN11: N=90; E=45 NF 1: N=39; E=25

10.11.2011

Overall survival from diagnosis regarding HSCT, stratum mutational group

SCT: n=78

No HSCT: n=12

PTPN11 RAS

NF1 No mutation

PRO

BABIL

ITY

PRO

BABIL

ITY

PRO

BABIL

ITY

PRO

BABIL

ITY

SCT: n=57

No HSCT: n=19

SCT: n=29

No HSCT: n=10

SCT: n=28

No HSCT: n= 3

10.11.2011

CDKN1C

CDKN2B

DAPK1

MGMT

MLH1

RARB

TP73

CALCA

RASSF1

BMP4

PAWR

RECK

PTEN

RASA1

SOCS1

hypermethylation associated with hyperactive RAS

regulatory function in RAS pathway

hypermethylation in other leukemias

Aberrant DNA Methylation

Candiate genes

Quantitative measurements using mass spectrometry (MassARRAY) Olk-Batz et al, Blood 117:4871ff, 2011

Aberrant DNA Methylation is the most important

Risk Faktor for Relapse after HSCT

Overall survival, multivariate analysis

Sex: F vs. M

Age: <3 years vs. >=3 years

Platelets: 33x109/L vs. > 33 x109/L

Mutation vs. no mutation

High methylation vs. no methylation

N.S.

N.S.

N.S.

N.S.

N.S.

N.S.

PTPN11

RAS

NF1

CBL N.S.

0.013

p<0.01

Years from diagnosis

40 26 16 7 4 no methylation

29 13 7 3 2 intermediate methylation

18 4 3 0 0 high methylation

Number of patients

Years from HSCT

Number of patients




Pro

ba

bili

ty

121086420

1.0

0.8

0.6

0.4

0.2

0.0

Pro

ba

bili

ty

Years from HSCT

p<0.01

Pro

ba

bili

ty

p<0.01

121086420

1.0

0.8

0.6

0.4

0.2

0.0

Years from HSCT

Cum

ula

tive

incid

ence

p<0.01

121086420

1.0

0.8

0.6

0.4

0.2

0.0

P

Relative risk (95% confidence interval)

1 2 3 4 5 6 7 8

E

Overall survivalA Overall survival after HSCT

Event-free survival after HSCTC Relapse after HSCT

121086420

1.0

0.8

0.6

0.4

0.2

0.0




Number of patients Number of patients




B

D

Overall survival, multivariate analysis

Sex: F vs. M

Age: <3 years vs. >=3 years

Platelets: 33x109/L vs. > 33 x109/L

Mutation vs. no mutation

High methylation vs. no methylation

N.S.

N.S.

N.S.

N.S.

N.S.

N.S.

PTPN11

RAS

NF1

CBL N.S.

0.013

p<0.01

Years from diagnosis




Number of patients

Years from HSCT

Number of patients




Pro

ba

bili

ty

121086420

1.0

0.8

0.6

0.4

0.2

0.0

121086420

1.0

0.8

0.6

0.4

0.2

0.0

Pro

ba

bili

ty

Years from HSCT

p<0.01

Pro

ba

bili

ty

p<0.01

121086420

1.0

0.8

0.6

0.4

0.2

0.0

Years from HSCT

Cum

ula

tive

incid

ence

p<0.01

121086420

1.0

0.8

0.6

0.4

0.2

0.0

P

Relative risk (95% confidence interval)

1 2 3 4 5 6 7 8

E

Overall survivalA Overall survival after HSCT

Event-free survival after HSCTC Relapse after HSCT

121086420

1.0

0.8

0.6

0.4

0.2

0.0

121086420

1.0

0.8

0.6

0.4

0.2

0.0




Number of patients Number of patients




B

D

Sex: F vs M

Age: < 3 years vs. > 3 years

Platelets: < 33x109/L vs > 33x109/L

Mutation vs no Mutation

PTPN11 RAS

NF1 CBL

High methylation vs no methylation

Olk-Batz et al, Blood 117:4871ff, 2011

Olk-Batz et al, Blood 117:4871ff, 2011

diagnosis

Jan 07Nov 07 Dec 07 Jan 08 Feb 08 Mar 08 Apr 08 May 08 Jun 08

Azacitidine 1st cycle2nd

cycle3rd cycle 4th cycle 5th cycle 6th cycle 7th cycle 8th cycle

Liver [cm] 2 2 1 1 normal normal normal normal normal

Spleen [cm] 10 6 3 2 1 normal normal normal normal

Spleen volume

[mL]> 280 178 136 138 115 80 82

% Blasts PB 0 1 0 1 0 0 0 0 0

% Blasts BM 5 7 2 2 1

Platelets [G/L] 18 30 53 68 66 100 151 227 255

Monocytes [/µL] 2260 1270 220 790 270 148 45 130 160

Monosomy 7

(FISH)72% 58% 0% 0%

KRAS Mutation c.38 G>A c.38 G>A c.38 G>Anot

detected

Case: Disease Activity during Azazytinde Therapy

Furlan et al, Blood 2009

MDS A Hematopoietic Disorder of the Elderly - bhs.be · Secondary MDS Prior chemo- or radiation...

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