Bone Marrow Failure in MDS: Role of Abnormal Telomere Dynamics

59 Pages·2013·5.04 MB·English

by  Faith M. Williams

CURENT MANAGEMENT APPROACHES FOR
MYELODYSPLASTIC SYNDROMES (MDS)

Bone Marrow Failure in MDS:
Role of Abnormal Telomere Dynamics

Neal S. Young, M.D.
Chief, Hematology Branch, NHLBI
Direction, Trans-NIH Center for Human
Immunology, Autoimmunity, and Inflammation
American Society of Hematology, Atlanta, December 7, 2012
THE CHROMOSOME THEORY OF CANCER
Theodor Boveri
Concerning the Origin of Malignant Tumors, 1914
“For unknown reasons, a ‘weakness’ may occur in specific chromosomes with respect to control of
mitosis that at first remains latent and thus is transmitted to a large number for daughter cells. . . .
[W]ith the beginning of senescence, perhaps this latent weakness becomes manifest in the failure of
mitotic control in such a way that when cell division occurs, there is a possibility of generating
daughter cells with recurrent abnormalities.”
AA AND MDS

Clonal evolution in practice (AA, FA, SBDS, DKC)

Diagnostic confusion by pathology

Shared pathophysiologies and responses to treatment

CL ONAL EVOLUTION AND TELOMERE ATTRITION
Telomere biology

Human telomeropathy and organ failure

Telomere attrition and cancer

Therapeutic opprotunities
CANCER RISK IN DKC
literature survey
NCI cohort
Alter BP et al 2009;
113:6549
A RANDOMIZED TRIAL OF H-ATG VS. R-ATG IN SAA
HEMATOLOGIC RESPONSES AT 3 AND 6 MONTHS
Horse ATG Rabbit ATG P-value

3 months 37/60 (62%) 20/60 (33%) 0.003

6 months 41/60 (68%) 22/60 (37%) < 0.001
2002-2008
1.0 1996-2002
5-yr survival = 94%
5-yr survival = 92%
y 0.8 1989-1996
t
i
il 5-yr survival = 91%
b
a
b 0.6
o
r
p

l
a
v 0.4
vi
r
u
S N = 246 responders
0.2
Scheinberg P et al NEJM 2011; 365:430
0.0
Valdez JM et al, Clin Inf Dis 2011; 52:726 0 2 4 6 8 10
Time (years)
CLONAL EVOLUTION IN SEVERE APLASTIC ANEMIA
>300 pts treated since 2000 AT NIH Clinical Center on horse ATG regimens
Median time to evolution = 613 day ( IQR 208-977; range 171-2725)
100
80

n
o
i
t
u
60
l
o
v
e

t
n
e 40
c
r
e
P
20
0
0 1000 2000 3000 4000
Time (days)
Scheinberg P and Young NS, Blood 2012; 120:1185
AA or MDS?
CLINICAL ASSOCIATIONS BETWEEN
MDS AND AUTOIMMUNE DISEASE
Hamblin TJ 2002, in Bennett JM, The
Myelodysplastic Syndromes (Marcel
Fozza C, Longinotti M, Eur J Haematol
Dekker, New York, page 65)
2012; 88:380
SPONTANEOUS PRODUCTION OF TNF
BY MARROW MONONUCLEAR CELLS
60
50
40
30
20
10
0
MDS AA Normal
OLIGOCLONAL T CELL EXPANSION IN TRISOMY 8 MDS
Vβ-Subfamily Analysis by Flow Cytometry
30 30 30
25 normal 25 25
20 20 20
15 15 15
10 10 10
70
5 5 5
0 0 0
normal
25
30 trisomy 8 patient
40
30 30 30
25 trisomy 8 25 25
20 2250 20 20
15 15 15
tt
nn10 10 10
ee5 20 5 5
cc 15
rr0 0 0
ee
PP
15 100 70
30 30 30
10
25 25 25
20 10 20 20
15 15 15
10 5 10 10
5 5 5 5
0 0 0
0
70
0
30 30 30
25 25 25
20 20 Vβ-subfamily 20
15 15 Vβ-subfamily 15
10 10 10
5 5 5
0 0 0