..Cytogentic & Molecular Risk Cytogentic & Molecular Risk Stratification based management Stratification based management

of Pediatric AML in 2015of Pediatric AML in 2015

Brijesh Arora,Brijesh Arora,

Professor, Division of Pediatric Oncology, Professor, Division of Pediatric Oncology, Tata Memorial Hospital, MumbaiTata Memorial Hospital, Mumbai

SynopsisSynopsis

.Molecular Pathogenesis.Molecular Pathogenesis Genomic abnormalities in Pediatric AMLGenomic abnormalities in Pediatric AML Role of MRDRole of MRD Current risk stratification & Current risk stratification &

recommendationsrecommendations Approach to TreatmentApproach to Treatment

COG

Genomic subtypes in Genomic subtypes in Pediatric AMLPediatric AML

Integrative analysis( Type I & Integrative analysis( Type I & II abnormalities)II abnormalities)

Genetics in Pediatric AML: Proven factorsGenetics in Pediatric AML: Proven factors

Pediatric AML: Probable Pediatric AML: Probable factorsfactors

Pediatric AML: Unproven factorsPediatric AML: Unproven factors

Cytogentic & Molecular factors Cytogentic & Molecular factors used to classify good riskused to classify good risk

Factor St Jude 08 MRC 15/17 COG 1031 BFM2012

t(8;21), inv(16)

YES Yes YES YES

t(1;11) No No No YES

NPM/ BICEBPA

No Yes Yes YES

Cytogentic & Molecular factors Cytogentic & Molecular factors for defining high riskfor defining high risk

Factor St Jude 08 MRC 15/17 COG 1031 BFM2012

FAB M0, M6 & M7without t(1:12)

YES No No No

Secondary AML YES Yes Yes Yes

-5, -7, del (5q), complex ktype

YES Yes Yes Yes

t(4;11),t(5;11) t(6;11),t(10;11),t(9;22)

No Yes No Yest(7;12),12p

t(6;9), t(8;16),t(16;21)

Yes No No Yes

abn (3q),inv3,t(3:3), -17,Abn 17p

No Yes No No

FLT3-ITD YES ( MRD+) Yes Yes YES

FLT3-ITD:Allelic Ratio (AR)FLT3-ITD:Allelic Ratio (AR)

AML outcome: leukemia, Host AML outcome: leukemia, Host & Treatment& Treatment

MRD

Author Trial Group N MRD level %

Hazard ratio

95 % CI

P value

Multivariate

Sievers 2003 CCG 2941

& 2961

252 > 0.5 4.8 2.8-8.4 p <0.0001

independent

Langebrake 2006 AML BFM 98 150 > 0.1 2.0 1.0-4.39

p=0.05

not independent

Coustan-Smith 2003

Saint Judes

AML 02

46 > 0.1 3.79 p 0.037

independent

Results of MRD Studies in Paediatric AML

Impact OF MRD- COG studiesImpact OF MRD- COG studies

Probability of Relapse-free and Probability of Relapse-free and Overall Survival According to MRDOverall Survival According to MRD

94 children treated on MRC AML 12/DCOG ANLL 97 Independent of age, WCC, FLT3/ITD

V.H.J. van Velden et al, 2010

Risk Stratification in 2015Risk Stratification in 2015

COG 1031 risk stratificationCOG 1031 risk stratification

Low-Risk:Low-Risk: Inv(16), t(8;21), nucleophosmin (NPM)

mutations, or CEBPA mutations with any MRD status.

Standard-risk cytogenetics (defined by the absence of either low-risk or high-risk cytogenetic characteristics) with negative MRD at end of Induction I.

COG 1031 risk stratificationCOG 1031 risk stratification

High Risk:High Risk: High allelic ratio FLT3-ITD-positive with

any MRD status. Monosomy 7 with any MRD status. del(5q) with any MRD status. Standard-risk cytogenetics with positive

MRD at end of Induction I.

AML-BFM 2012AML-BFM 2012

St Jude AML-08 Risk groupsSt Jude AML-08 Risk groups

St Jude AML-08 Risk groupsSt Jude AML-08 Risk groups

Conventional Cytogentics & FISHConventional Cytogentics & FISH

CytogenticsCytogentics

Molecular Cytogentics:Molecular Cytogentics:

Impact on treatmentImpact on treatment

Induction Treatment ApproachInduction Treatment Approach

CR & death rates in various CR & death rates in various Pediatric trialsPediatric trials

DATDAT

ADEADE

MACEMACE MidACMidAC

Allo BMTAllo BMT

ABMTABMT

MRC AML 10

R1R1

ADEADE

DATDAT DONORDONOR

NO NO DONORDONOR

R2R2

NFTNFT

MRC AML 12

R1

ADE

MAE

V

RISK GROUPASSIGNED

ADE

V MACE

MidAC

CLASP MidAC

MidAC

CLASP MidAC

STANDARD + POOR

Allo BMT

CLASP AlloBMT

MAE

R2

R2

DONOR

NO DONOR

R2

GOOD

Mitoxantrone= Daunorubicin

MRC AML 15

Course 1Course 1+ LP+ LP

Course 2Course 2+ LP+ LP

Course 3Course 3 Course 4Course 4 Course 5Course 5

R

ADE 3+10+5

‘Good’, ‘Standard’ and‘Poor’ risk without a

donor in CR

ADE 3+8+5

FLAG-IDAFLAG-IDA

Risk group assessment

CRR

If no CR go to Relapse Protocol

‘Poor’ risk, but with aMatched donor and CR

Ara-C 3 g/m2

MACE

Ara-C 3 g/m2

MidAc

E Sibling/UD allogeneic BMT

R

No furthertreatment

Ara-C 1.5 g/m2

R = RandomiseE = Elect

Non-APL Patients (At a later date there may be a further randomisation for Mylotarg at Course 1 and 3)

BFM 2004BFM 2004

St Jude AML02- Dose of AraCSt Jude AML02- Dose of AraC

Antharcycline dose intensityAntharcycline dose intensity

High dose Daunorubicin not tested in view High dose Daunorubicin not tested in view of risk of cardiotoxicityof risk of cardiotoxicity

Current approachCurrent approach

Post Induction regimePost Induction regime

Number of coursesNumber of courses

MRC AML 12

R1

ADE

MAE

V

RISK GROUPASSIGNED

ADE

V MACE

MidAC

CLASP MidAC

MidAC

CLASP MidAC

STANDARD + POOR

Allo BMT

CLASP AlloBMT

MAE

R2

R2

DONOR

NO DONOR

R2

GOOD

4 courses = 5 courses

MRC 15 Consolidation: MACE MRC 15 Consolidation: MACE v Ara-Cv Ara-C

CNS prophylaxisCNS prophylaxis

St Jude AML-02: Impact of TIT.St Jude AML-02: Impact of TIT.

Role of SCT?Role of SCT?

AML-BFM 98Intent-to-treat Analysis

.56, SE=.04

Kein Spender (N=188, 77 events)

.58, SE=.09

HLA-id. Spender (N= 58, 20 events)

years

Log-Rank p = .16

P

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8

No donorHLA-id. donor

.43, SE=.04

Kein Spender (N=188, 104 events)

.47, SE=.07

HLA-id. Spender (N= 58, 32 events)

years

Log-Rank p = .52

P

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8

OS Event-free survival

No donorHLA-id. donor

HR= standard +poor

AML 10 & 12Survival from CR by Risk Group

SCT No SCT 2P Value

All patients 57% 65% 0.3

Standard 46% 61% 0.2

Poor 28% 47% 0.2

Standard Poor100

75

50

25

0 1 2 3 4 5

61 %

46% 47%

28%

0 1 2 3 4 5

100

75

2P = 0.2

4910

49240No Allograft

Allograft

No Allograft

Allograft

Years from CR Years from CR

2P = 0.2

2P = 0.2

50

25

BMT =480 Chemotherapy = 893

Outcome % % P value

Favorable-risk disease

    Relapse 21 21 30 0.06

    Disease-free survival 63 61 0.58

    Overall survival 83 73 71 0.85

Intermediate-risk disease

    Relapse 36 26 54 < 0.001

    Disease-free survival 58 39 < 0.001

    Overall survival 70 62 51 0.006

Poor-risk disease

    Relapse 53 67 56 0.69

    Disease-free survival 33 35 0.82

    Overall survival 39 33 35 0.80

Nonclassifiable

    Relapse 32 44 0.004

    Disease-free survival 52 50 0.14

    Overall survival 60 61 0.49

Risk Stratified Outcomes Comparing Matched Sibling BMT and Chemo Alone

MRC 15% COG 40% with no cytogeneticsHoran J, Journal of Clinical Oncology 2008, Vol 26, Issue 35

Role of MyelotargRole of Myelotarg

Role of TKIsRole of TKIs

Sorafinib- promising in FLT3-ITD mutated Sorafinib- promising in FLT3-ITD mutated AML and some benefit in Non-mutated AML and some benefit in Non-mutated populationpopulation

Heterogeneity within Heterogeneity within cytogenetic classes on GEPcytogenetic classes on GEP

Copy number Heatmap for Copy number Heatmap for Pediatric AML ( N-111)Pediatric AML ( N-111)

Frequency of CNA & MutationsFrequency of CNA & Mutations

Summary of AML PathogenesisSummary of AML Pathogenesis

Less than 2.0 copy number per case ( ALL Less than 2.0 copy number per case ( ALL 7/case)7/case)

Deletion= amplificationDeletion= amplification Recurrent focal lesion are rareRecurrent focal lesion are rare 30% with translocation had no CAN or 30% with translocation had no CAN or

point mutationpoint mutation