Acute Promyelocytic LeukemiaLow/intermediate risk patients

(WBC ≤10 x 109/L)

ATO(No chemo!)

ATRA+

R

Chemotherapy

ATRA+

Acute Promielocytic Leukemia APL 0406 Study

Ove

rall

surv

ival

pro

babi

lity

Months from diagnosis

98.7%

91.1%

p = 0.02ATRA+ATOATRA+Chemo

Overall Survival

Next Generation Sequencing

Next Generation Sequencing and identification of genetic defect and possible target for personalized therapy

CML or Acute Lymphoblastic

LeukemiaTP53NOTCH1FBXW7IKZF1BCR-ABLIL7RCRLF2

Acute Myeloid Leukemia

TP53IDH1/IDH2EZH2DNMT3ACEBPACBLKRASTET2RUNX1BCOR

PML-RAR alpha

MDSEZH2IDH1IDH2TET2SF1SF3A1SF3B1U2AF1ASXL1CBLNPM1

Myeloprolipherative Disease and Ph-

TP53EZH2IDH1IDH2TET2CBLKRAS

CLLLeukemia

TP53NOTCH1 (PEST)SF3B1 (HEAT)FBXW7MYD88XPO1

Multiple MielomaTP53B-RAF

Hairy Cell Leukemia

B-Raf

7

Imatinib Changed the Therapeutic Landscape for Patients With Ph+ CML

Adapted from R. Hehlmann, German CML Study Group.

aCML IV; bCML IIIA; cCML III. IFN-, interferon-alpha; OS, overall survival; SCT, stem cell transplant.

Years After Diagnosis

Surv

ival

Pro

babi

lity

(All

Ph+

CM

L D

isea

se P

hase

s)

0 2 64 8 10 16 18 20 2212 140.0

0.2

0.1

0.5

0.6

0.7

0.8

0.9

1.0

0.3

0.4 1995-2008, IFN- or SCTc

1986-2003, IFN-

1983-1994, Busulfan

1983-1994, Hydroxyurea

1997-2008, IFN- or SCT plus 2nd-line imatinibb

2002-2008, imatiniba

Best available therapy 5-year OSImatiniba 93%IFN- or SCT plus

2nd-line imatinibb 71%IFN- or SCTc 63%IFN- 53%Hydroxyurea 46%Busulfan 38%

1970

2000

1990

1980

1960

2010

Landscape of Somatic Mutations in Lymphoid

Neoplasms

Acute Lymphoblastic Leukemia

BCR-ABL like ALL

Acute MyeloidLeukemia

Novel rearrangements, copy number alterations, and sequence mutations constitutively activating kinase signaling and dysregulating cytokine receptor signaling.

New assessment risk based on genetic alterations

CLL

Rossi et al. Blood 2012

New target for new therapy

FLT3-ITD PKC412 AMLSG 16-10

CBF-AML

MolecularDiagnostics

48h*

NPM1mut

All others such as• CN-AML (triple neg)• various• MDS-related AML

Azacitidine + intensive inductionAllogeneic transplant-strategy Azacitidine maintenance AMLSG 12-09

ATRA +/- GO AMLSG 09-09

APL [t(15;17)] ATO + ATRA APL0406GIMEMA/AMLSG/DSIL

Dasatinib AMLSG 11-08

Courtesy of Lars Bullinger

Clofarabine + ARAC + IdarubicinAMLSG 17-10

Genotype-based specific treatment in AML

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.

Gene and variant Allele Chr. Position Allele Freq.No Toxicity

Allele Freq.Grade I/II Toxicity

Fisher p value OR

CYP2E1 -333 T >A (rs2070673) A 10 135190557 0.23 0.04 0.001 0.13

CYP2E1 10463 T>C, F421F(rs2515641) T 10 135201352 0.17 0.02 0.003 0.09

1 2 3 4 5 6 7 8 9

CYP2E1

-333 T>A (rs2070673)

10q24.3-qter

10 11

10,463 T>C(rs2515641)

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.

reads for each gene

“Avatar” Diagnosis: es. BCR-ABL1 like ALL

diagnosisrelapse

RNA/DNA

Genome Analyzer II (Illumina/Solexa)/Roche 454

Old Classic therapy + ?(ex. Tki, Antibiotic, Vitamin,..)

Individual new therapy Old therapy combined with new (eg.TKI) therapy

1 week work

Individual New Target(s)

Extra Rapid (mins not months) Bioinformatics NGS analysis

( e.g. KNOME analysis)done by a medical doctor

“Back to bed, soon”

1 day work

The personalized “avatar” for each haematological patient to get right target

therapy, in a correct dosage, (possible at home)

CURESimulation or

Computer assisted decision, in vitro identification of new drugs, etc.

Design and apply experimental “individual” and personalized

clinical trial (need regulatory EMEA changes )

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