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 29 th September - 1 st October 2014, Naples, Italy Acknowledgment; Austin G Kulasekararaj; Jaroslaw P. Maciejewski
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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 unpublished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
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