Transcript amsterdam ecco 2013 martinelli g 2 - NGS

Acute Promielocytic Leukemia
APL 0406 Study
Acute Promyelocytic Leukemia
Low/intermediate risk patients
(WBC ≤10 x 109/L)
R
ATRA
+
ATO
(No chemo!)
ATRA
+
Chemotherapy
Overall Survival
98.7%
Overall survival probability
91.1%
ATRA+ATO
ATRA+Chemo
p = 0.02
Months from diagnosis
Next Generation Sequencing and identification of genetic
defect and possible target for personalized therapy
CLL
Leukemia
Multiple Mieloma
TP53
NOTCH1 (PEST)
SF3B1 (HEAT)
FBXW7
MYD88
Hairy
XPO1
TP53
B-RAF
Cell
Leukemia
Next
Generation
Sequencing
MDS
EZH2
IDH1
IDH2
TET2
SF1
SF3A1
SF3B1
U2AF1
ASXL1
CBL
NPM1
B-Raf
Myeloprolipherative
Disease and PhTP53
EZH2
IDH1
IDH2
TET2
CBL
KRAS
Acute Myeloid
Leukemia
CML or Acute
Lymphoblastic
Leukemia
TP53
NOTCH1
FBXW7
IKZF1
BCR-ABL
IL7R
CRLF2
TP53
IDH1/IDH2
EZH2
DNMT3A
CEBPA
CBL
KRAS
TET2
RUNX1
BCOR
PML-RAR alpha
Imatinib Changed the Therapeutic
Landscape for Patients With Ph+ CML
Best available therapy
Imatiniba
IFN- or SCT plus
2nd-line imatinibb
IFN- or SCTc
IFN-
Hydroxyurea
Busulfan
(All Ph+ CML Disease Phases)
Survival Probability
1.0
0.9
2002-2008, imatiniba
0.8
0.7
5-year OS
2010
93%
71%
63%
53%
46%
38%
2000
1997-2008, IFN- or SCT
plus 2nd-line imatinibb
0.6
1990
0.5
1995-2008, IFN- or SCTc
0.4
1980
0.3
1986-2003, IFN-
0.2
1983-1994, Hydroxyurea
0.1
1970
1983-1994, Busulfan
0.0
0
2
4
6
8
10
12
14
Years After Diagnosis
16
18
20
22
1960
aCML
IV; bCML IIIA; cCML III.
IFN-, interferon-alpha; OS, overall survival; SCT, stem cell transplant.
Adapted from R. Hehlmann, German CML Study Group.
7
Landscape of Somatic
Mutations in Lymphoid
Neoplasms
Acute Lymphoblastic
Leukemia
Acute Myeloid
Leukemia
CLL
BCR-ABL like ALL
Rossi et al. Blood 2012
Novel rearrangements, copy number alterations,
and sequence mutations constitutively activating
kinase signaling and dysregulating cytokine receptor
signaling.
New assessment risk based on genetic
alterations
New target for new
therapy
Genotype-based specific treatment in AML
APL [t(15;17)]
ATO + ATRA APL0406
GIMEMA/AMLSG/DSIL
CBF-AML
Dasatinib AMLSG 11-08
FLT3-ITD
PKC412 AMLSG 16-10
NPM1mut
ATRA +/- GO AMLSG 09-09
Molecular
Diagnostics
48h*
All others such as
• CN-AML (triple neg)
• various
• MDS-related AML
Courtesy of Lars Bullinger
Azacitidine + intensive induction
Allogeneic transplant-strategy
Azacitidine maintenance
AMLSG 12-09
Clofarabine + ARAC + Idarubicin
AMLSG 17-10
Personalized Therapy:
a new horizon to get the right target gene(s)
for the right therapy, for right patient
“at the right dosage”
Modified from Modern Pathology (2013) 26, S97–S110, Iacobucci I et al. Curr Cancer Drug Targets. 2013
Association among SNPs and liver toxicity
The genotyping profile of 63 patients without liver toxicity (70%) was
compared to that of 28 patients (30%) with grade I/II liver toxicity.
10,463 T>C
(rs2515641)
-333 T>A
(rs2070673)
CYP2E1
2
1
3
4
5 6 7 8
9
10
11
10q24.3-qter
Gene and variant
Allele Freq.
Allele Freq.
No Toxicity Grade I/II Toxicity
Allele
Chr.
Position
CYP2E1 -333 T >A
(rs2070673)
A
10
135190557
0.23
CYP2E1 10463 T>C, F421F
(rs2515641)
T
10
135201352
0.17
Fisher
p value
OR
0.04
0.001
0.13
0.02
0.003
0.09
Suggestions for
discussion
• As EHA Association we strongly belive that hematological diseases are probably the best
suitable model for diffuse patients oriented personalized therapy.
• My short presentation of “state of the art” and NGS-PTL project and especially of the new
frontiers in blood cancer research strongly suggests that EHA and European
haematologists researcher are proud to have increased so much in the last years a “real”
applied personalized therapy, to have improved the diagnostic tools for better
stratification of leukemic groups, and to have extensively use of target therapy.
• Haematology and their research are “fit” with the H2020 and with EAPM aims to
improve patients survival with targeted and personalized (individualized) therapy but
need for more research funding, more easier access to academic sponsored innovative
clinical trials, more regulatory support for conducing “patients oriented” therapy.
• We need research funding for blood cancers: it looks like Horizon 2020 gives better
opportunities, but these must be translated into call texts.
The personalized “avatar”
“Avatar”
Diagnosis: es. BCR-ABL1 like ALL
for each haematological patient to get right target
therapy, in a correct dosage, (possible at home)
1 week work
Genome Analyzer II (Illumina/Solexa)/Roche 454
reads for each
gene
CURE
diagnosis
relapse
RNA/DNA
Simulation or
Extra Rapid (mins not months)
Computer assisted decision,
Bioinformatics NGS analysis
in vitro identification of new drugs, etc.
( e.g. KNOME analysis)
Design and apply experimental “individual”
done by a medical doctor
and personalized
“Back to bed, soon”
clinical trial
(need regulatory EMEA changes ) 1 day work
Individual new therapy
Old therapy combined
with new (eg.TKI) therapy
Old Classic therapy +
?
(ex. Tki, Antibiotic, Vitamin,..)
Individual New Target(s)
Conclusions
The identification of novel diagnostic and prognostic biomarkers,
identified through the genomic and transcriptomic signatures, is
expected to guide tailored approaches to hema/leukemia and to
improve unified deep analysis of He,matological disease complexity as
well as the anti-leukemia therapeutic success, guaranteeing the
sustainability and efficiency of the healthcare system.
unique footprints
common path to cure