Somatic mutations in diagnosis and prognosis of MDS - Maria Teresa Voso Dipartimento di Biomedicina e Prevenzione Universita' di Roma Tor Vergata ...
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Somatic mutations in diagnosis and prognosis of MDS
Maria Teresa Voso
Dipartimento di Biomedicina e Prevenzione
Universita’ di Roma Tor Vergata
Recurrently mutated genes in MDS
Haferlach T et al, Leukemia 2014
Biological classification
of somatic mutations
in MDS
1. Epigenetic regulators
2. RNA-splicing factors
3. Signal transduction
4. Transcription factors
5. Apoptotic factors
6. Growth factor receptor
Clonal Evolution in MDS/AML Steensma D et al, Blood 2015
Clonal Hematopoiesis of Indetermined Potential (CHIP)
! Above the age of 70, over 10% of individuals have hematopoietic clones
! CHIP is associated to: - probability to develop a hematologic disease (HR:11)
- all-cause mortality (HR 1.4)
- probability of atherosclerosis/myocardial infaction (HR: 3-4)
Jaiswal, Genovese, NEJM 2014
Models of MDS progression
A) Expansion of a pre-existing clone B) Expansion of a by-stander clone
C) Appearance of new clones
Da Silva-Coelho et al , Nature Communications 2017
Clonal evolution in therapy-related myeloid neoplasms
UPN2: TP53Y220C
Fabiani et al , Oncoarget 2017
Order of mutations during MDS progression
MDS/MPN:
RARS-T
CMML
Bejar & Abdel-Wahab, Blood 2013
SF3B1 and MDS-RS Cazzola et al , Blood 2013
SF3B1Mutations
Overall Survival Risk of disease progression
Malcovati el al, Blood 2015Luspatercept in LR-MDS
" Luspatercept (ACE-536) is a novel fusion protein that blocks TGF β superfamily
inhibitors of erythropoiesis
" 58 patients with MDS were enrolled in the 12 week base study at 9 treatment
centres in Germany
" 32 of 51 patients (63%) receiving higher dose luspatercept (0·75–1·75 mg/kg)
achieved HI-E versus 2 of 9 (22%) receiving lower dose (0·125–0·5 mg/kg)
Platzbecker et al, Lancet Oncol 2017Prognostic Factors for Erythroid Response
IWG RBC-TI
HI-E
Transfusion Burden Low (< 4 RBC/8w) 65% 75%
High 62% 29%
Previous use of ESA Yes 62% 38%
No 65% 39%
Previous Lenalidomide Yes 63% 13%
no 63% 44%
Serum EPO 500 IU/L 43% 14%
Ring-sideroblasts Positive (>15%) 69% 42%
Negative 43% 29%
SF3B1 mutation Positive 77% 44%
Negative 40% 39%
Any splicing factor Positive 73% 50%
mutation negative 36% 8%
IPSS-R V. low to low 65% 48% Platzbecker
Intermediate 59% 31% et al, Lancet
High to V. high 67% Oncol 2017IDH mutations in MDS & AML
Mitochondria Nucleus
Mutated gene AML MDS
IDH1 7-14% 3%
IDH2 8–19% ~5%
AG-120
AG-221
Enasidenib
" IDH enzymes catalyze citrate to α-ketoglutarate (α-KG)
" α-KG catalyzes histone demethylases and TET hydroxylation of 5-methylcytosine
" Mutant IDH1/ IDH2 result in an increase of the oncometabolite, 2-hydroxyglutamate (2-HG)
" 2-HG induces a block of cell differentiation by inhibiting the chromatin-modifying enzymes, DNA
and histone demethylases, which results in hypermethylated DNA, blocking cell differentiation
" AML with mutated IDH is associated with extensive hypermethylation
Medeiros et al, Leukemia 2016AG-221 (Enasidenib) promotes cell differentiation
Cycle
Differentiation 1 Day
effect on15
bone marrow
Screening: Evidence of Cycle 3 Day 1
40% differentiation of 4% BM-blasts
BM-blasts cells
" Differentiation effects: BM-blasts reduced from 40% to 4%
" Evidence of differentiation as early as cycle 1
" Full neutrophil recovery at cycle 2
" Achieved CR by start of cycle 4
Stein et al, Blood 2017" Daily oral enasidenib 100 mg QD in 28-day cycles in16 MDS patients
Stein et al, ASH Meeting 2016Mutation burden Papaemmanuil et al, Blood 2013
TP53, EZH2, RUNX1, ASLX1, or ETV6 Mutations
Bejar & Steensma, Blood 2014TP53 Mutations
MDS
Mut-TP53 significantly contributes to dismal survival
in MDS and AML with complex karyotype
Bejar et al, Blood 2014, Papaemmanuil et al, NEJM 2016TP53 and HSCT in MDS Yoshizato et al, Blood 2017
Responders
Non-responders
74% of pts with a donor
Falconi G., Fabiani E., unpublished
Ann Oncol 2017Clearance of TP53 Mutations during Hypomethylating
Treatment (DAC, 20 mg/m2/day for 10 days)
TP53-mut, n=21 pts
Welch et al, NEJM 2016PD/NA
7 15 11
27
5
15
3
11 5 3 Risk Risk Risk
No. at Risk
0
0 CR/CRi/mCR 53 44 20 9 4
g Survival According to Risk Karyotype PR/SD D Survival
36 17According
10 to8TP53 Mutation
4
Survival
D Survival According 27
Unfavorable
to Risk Karyotype Intermediate Favorable to TP53 Mutation
Risk Risk Risk PD/NA 15 11 5 3
100 100 100
D Survival According
80 to TP53 Mutation
TP53 mutation C Survival According toKaryotype
Risk Karyotype
80
D Surviva
80
100
100
P = 0.29 P = 0.29
Survival (%)Survival (%)
Survival (%)
Survival (%)
60 60 60
80
80
P = 0.79 P=
40 Unfavorable-risk Unfavorable-risk 40 40 P = 0.29
Survival (%)
60 karyotype karyotype 60
Wild-type Wild
20 P = 0.79 20 20 TP53 TP
Favorable-risk or Favorable-risk or 40 Unfavorable-risk
40
intermediate-risk karyotype
intermediate-risk karyotype karyotype TP53 mutation
TP53 mutation
0 Wild-type 0 0
0 200 20 0 600 200800 400
400 1000 600 800
TP53 1000 020 200 400 0 600200 800400 1000 600 800
Favorable-risk or
Days Daysmutation
TP53 Days
intermediate-risk Days
karyotype
0 0
No. at Risk 0 200 400 600 No. 1000
800 at Risk No. at
0 Risk
200 400 600 800 1000
43 31
Unfavorable risk12 43 6 31 4 12 6 4
TP53 mutation 21
TP53 20
mutation 7 21 4 20 2 7 4 2
71 43
Favorable or 28 71 15 43 6 Days
28 15 6
Wild-type TP53 78 51
Wild-type Days
TP53 31 78 16 51 7 31 16 7
intermediate
No. at Risk risk No. at Risk No. at Ri
TP53 mutation 21 20 7 4 2 Unfavorable risk 43 31 12 6 4 TP53 mu
g Wild-type
to Stem-Cell
TP53 Transplantation
78 51 31 16 F
7 Survival
Survival According to Stem-Cell Transplantation after
Favorable or 71
Stem-Cell 43 28
Transplantation15 6
According to
F Survival after Stem-Cell Transplantation Wild-type
According
HSCTintermediate
TP53 Mutation risk TP53 Mutation TP53 in HSCT
100 100 100
F Survival after Stem-Cell Transplantation According to
E Survival According to Stem-Cell Transplantation F Surviva
TP53 Mutation TP53
80 80 80
100 100 Transplantation Transplan
Transplantation Transplantation and wild-type and wild
Survival (%)
60 TP53
(%) (%)
Survival (%)
60
80 60 TP53
Transplantation 80
SurvivalSurvival
and wild-type Transplantation and Transplantation
TP53 40 Transplantation and
60
40 Survival (%) TP53 mutation
40
60 TP53 mutation
Transplantation and
40 TP53 mutation 20 P = 0.99
20 PAcknowledgements
Francesco Lo Coco Sergio Amadori
William Arcese
Valentina Alfonso
Laura Cicconi Francesco Buccisano
M. Domenica Divona Eleonora De Bellis
Emiliano Fabiani Iliaria Del Principe
Giulia Falconi Luca Maurillo
Licia Iaccarino Adriano Venditti
Serena Lavorgna
Nelida Noguera
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