GS / SAA 2014 / EBMT Educational

Gérard SOCIE, MD, PhD

Long term outcome following IST for AA

Joint educational meeting of the EBMT Aplastic Anemia and Infectious diseases Working Parties

29th September - 1st October 2014, Naples, Italy

Acknowledgment; Austin G Kulasekararaj; Jaroslaw P. Maciejewski

GS / SAA 2014 / EBMT Educational

Locasciulli et al Haematologica; 2007;92:11-18.

GS / SAA 2014 / EBMT Educational

IST

Blood. 2011

0,000

0,250

0,500

0,750

1,000

0,0 1000,0 2000,0 3000,0 4000,0

DD_FUP

surv

ival

ATG yes =786

ATG no= 1213

82%

76%

HSCT

EBMT . unpublished

GS / SAA 2014 / EBMT Educational

Studies Period NAge

(median)Resp Relapse

ClonalEvolution Survival

Germany1986-1989 84 32 65% 19% 8%

58% à 11 ans

NIH1991-1998 122 35 61% 35% 11%

55%à 7 ans

EGMBT 1991-1998 100 16 77% 12% 11%87%

à 5 ans

Japan 1992-1997 119 9 68% 22% 6%88%

à 3 ans

Germany/Australia 1993-1997 114 9 77% 12% 6%87%

à 4 ans

Japan 1996-2000 101 54 74% 42% 8%88%

à 4 ans

NIH 1999-2003 104 30 62% 37% 9%80%

à 4 ans

NIH 2003-2005 77 26 57% 26% 10%93%

à 3 ans

IST

Young et al. Blood 2006

GS / SAA 2014 / EBMT Educational

Immunosuppressive therapy;

long term issues

- CsA dependence

- Relapse

- Clonal evolution

GS / SAA 2014 / EBMT Educational Saracco et al BJH 2007

CsA taper mg/kg/month relapse

Very slow 0.3 8%

Slow 0.4-0.7 8%

Fast > 0.8 60%

GS / SAA 2014 / EBMT Educational

Bacigalupo A, Blood 2000; (95). 1931-1934

CsA dependence

42% at 10

years

Saracco et al, BJH 2008

CsA dependence: ~ 40%

GS / SAA 2014 / EBMT Educational

Immunosuppressive therapy;

long term issues

- CsA dependence

- Relapse

- Clonal evolution

GS / SAA 2014 / EBMT Educational

Relapse: ~ 35%

Am. J. Hematol. 89:571–574, 2014.

GS / SAA 2014 / EBMT Educational

Immunosuppressive therapy;

long term issues

- CsA dependence

- Relapse

- Clonal evolution

GS / SAA 2014 / EBMT Educational

� De Planque M. Br.J. Haematol. 1989; (70). 55-61.

� Tichelli A. Br. J. Haematol. 1988; (69). 413-418.

� Socié G., et al. N. Engl. J. Med. 1993; (329). 1152-1157

GS / SAA 2014 / EBMT Educational

3%

IST: 26%

MDS/LAM Cancers

IST: 18%

� Socié G., et al. N. Engl. J. Med. 1993; (329). 1152-1157

GS / SAA 2014 / EBMT Educational

GS / SAA 2014 / EBMT Educational Am. J. Hematol. 89:571–574, 2014.

Clonal evolution (morphology): ~ 15%

GS / SAA 2014 / EBMT Educational

G-CSF / MDS-AML ?

Kojima; Blood 2002

GS / SAA 2014 / EBMT Educational

G-CSF / MDS-AML ?

occur more frequently in non responders

Blood 2000; 95, 1931-934

n= 3/13 n= 3/29 n= 2/48

GS / SAA 2014 / EBMT Educational

Risk factors HR p

MDS Age > 45yr 2.9 0.01

AML Age > 45yr

G-CSF

4.1

2.5

0.002

0.003

MDS/AML Age > 45yr

G-CSF

2.9

1.9

0.001

0.04

G Socié et al.

Blood 2007; 107:2794

G-CSF / MDS-AML ?

GS / SAA 2014 / EBMT Educational

Table 2. Agreement among seven pathologists in diagnosingbiopsies of 33 patients with severe aplastic anemia (SAA)and 67 patients with refractory cytopenia of childhood (RCC)

Agreement 7 ⁄ 7 6 ⁄ 7 5 ⁄ 7 4 ⁄ 7

All (N = 100), no. (%) 76 (76) 13 (13) 8 (8) 3 (3)

RCC (N = 67), no. (%) 48 (72) 9 (13) 8 (12) 2 (3)

SAA, (N = 33), no. (%) 28 (85) 4 (12) 0 (0) 1 (3)

Histopathology 2012, 61, 10–17.

GS / SAA 2014 / EBMT Educational

Predictive factor?: Telomere length at AA diagnosis

Pro

babi

lity

ofA

llC

lona

lEvo

lutio

n

0.0

0.2

0.4

0.6

0.8

1.0

Time in Years

0 2 4 6 8

Log-rank P = 0.0035

Shorter telomeres = 26%

Longer telomeres = 7%

n=183

Scheinberg et al.

JAMA 2010

GS / SAA 2014 / EBMT Educational

Association of Telomere Length of Peripheral Blood Leukocytes With Hematopoietic

Relapse, Malignant Transformation, and Survival in Severe Aplastic Anemia.Scheinberg, Phillip; Cooper, James; Sloand, Elaine; Wu, Colin; Calado, Rodrigo; MD, PhD; Young, Neal

JAMA. 304(12):1358-1364, September 22/29, 2010.

GS / SAA 2014 / EBMT Educational

Austin G Kulasekararaj et al. Blood 2014; in press

GS / SAA 2014 / EBMT Educational

RBDS

VSAASAA

NSAA

PNH

HypocellularMDS

AMLLow Risk

HighRisk

MDS

LGL (clonal or polyclonal)

5q- MDS/MPD

DC

Hypo AML

AA/PNH

FA

AAMDS100

75

50

25

total prevalenceactuarial risk at 5 years

At 10 years

12%15%20%

evol

utio

n (%

)

Time (months)0 50 150100 200

Maciejewski,Blood 2008

GS / SAA 2014 / EBMT Educational Blood. 2011;117(25): 6876-6884

SNP array–based karyotyping: differences and similarities between

aplastic anemia and hypo cellular MDS

AA (N = 93) and hypo cellular MDS (N = 24)

SNP-A identify cryptic clonal genomic aberrationsIn 19% of AA

Jaroslaw P. Maciejewski

GS / SAA 2014 / EBMT Educational

Study flow diagram and frequency of confirmed STAT3-mutated patients.

Jerez A et al. Blood 2013;122:2453-2459

GS / SAA 2014 / EBMT Educational Maciejewski, Blood 2001

•No risk factors

•del7/7q, +8, 11q-, +21, +6, complex

karyotypes most common

Clonal expansion

Immune selection pressure

Immune escape

-Mutations present at presentation

-Trigger immune surveillance

-Subsequent clonal evolution

-True late clonal event

VS.

GS / SAA 2014 / EBMT Educational

Aplastic Anaemia(n=150)

NSAA (n=65)

SAA (n=51)

VSAA (n=23)

Others (n=11)

Evolved to MDS with somatic mutations (N=11)

• Detected pre evolution• -7 associated with

DNMT3A/ASXL1

No evolution to MDS but have mutations (N=18)

• <10% clones in 10 • Longer F/U needed

Evolution to MDS but no mutations (N=6)

• Mutated in other genes• Undetectable low level

clones

Somatic mutations identify a sub-group of aplastic

anemia patients that progress to

myelodysplastic syndrome

Austin G Kulasekararaj et al. Blood 2014; in press

GS / SAA 2014 / EBMT Educational

PIGA sequencing

(n=23)

Clone >10% (n=17)

Clone <10%(n=6)

Single PIGA mutation (n=7)

Double PIGA mutation(n=6)

PIGA with other somatic mutation(n=4)

No PIG-Amutations

PNH clone(n=65)

large (>50%): 15moderate (10-50%): 14subclinical (<10%): 36

UPN GeneMutant allele

burden (%)variant class

protein change

GranulocytePNH clone

6 PIGA 38 nonsense p.Y54X 996 ASXL1 38 nonsense p.Q748X

19 PIGA 30frameshift deletion

p.N307fsX aa21 59

19 IKZF1 14 missense p.H214D21 PIGA 11 missense p.H128R 9921 BCOR 5 nonsense p.Q176X

33 PIGA 70splicing donor

ND95

33 BCOR 68 nonsense p.W1611X

Austin G Kulasekararaj et al.

Blood 2014; in press

GS / SAA 2014 / EBMT Educational

Could AA be considered a pre-pre-leukemic disorder ?

� Eur.J. Haematol. 1996; 60 (Suppl.): 60-63.

HSC (or Common Myeloid Progenitor ?)

HSC abnormal; Quantitatively and/or qualitatively

Clonal hematopoiesis; PNH +++; SAA + or ?

Telomere loss; aging of residual HSC

RBC

MK

PMN

Intrinsic block

CD8

?

Chromosomal abnormality; -7, +8

N-Rasmutation

MDS/Leukemia