. Cytogentic & Molecular Risk Stratification based management of Pediatric AML in 2015 Brijesh Arora, Professor, Division of Pediatric Oncology, Tata Memorial Hospital, Mumbai

Synopsis.Molecular Pathogenesis.Molecular Pathogenesis Genomic abnormalities in Pediatric AML Genomic abnormalities in Pediatric AML Role of MRD Role of MRD Current risk stratification & recommendations Current risk stratification & recommendations Approach to Treatment Approach to Treatment

COG

Genomic subtypes in Pediatric AML

Integrative analysis( Type I & II abnormalities)

Genetics in Pediatric AML: Proven factors

Pediatric AML: Probable factors

Pediatric AML: Unproven factors

Cytogentic & Molecular factors used to classify good risk FactorSt Jude 08MRC 15/17COG 1031BFM2012 t(8;21), inv(16) YESYesYES t(1;11)No YES NPM/ BICEBPA NoYes YES

Cytogentic & Molecular factors for defining high risk FactorSt Jude 08MRC 15/17COG 1031BFM2012 FAB M0, M6 & M7without t(1:12) YESNo Secondary AMLYESYes -5, -7, del (5q), complex ktype YESYes t(4;11),t(5;11) t(6;11),t(10;11), t(9;22) NoYesNoYes t(7;12),12p t(6;9), t(8;16),t(16;21) YesNo Yes abn (3q),inv3,t(3:3), - 17,Abn 17p NoYesNo FLT3-ITD YES ( MRD+) Yes YES

FLT3-ITD:Allelic Ratio (AR)

AML outcome: leukemia, Host & Treatment MRD

AuthorTrial GroupNMRD level % Hazard ratio 95 % CI P value Multivariate Sievers 2003CCG 2941 & > p < independent Langebrake 2006AML BFM 98150> p=0.05 not independent Coustan-Smith 2003 Saint Judes AML 02 46> p independent Results of MRD Studies in Paediatric AML

Impact OF MRD- COG studies

Probability of Relapse-free and Overall 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 2015

COG 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 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 2012

St Jude AML-08 Risk groups

Conventional Cytogentics & FISH Cytogentics Cytogentics

Molecular Cytogentics:

Impact on treatment

Induction Treatment Approach

CR & death rates in various Pediatric trials

DAT ADE MACEMidAC Allo BMT ABMT MRC AML 10 R1 ADE DAT DONOR NODONOR R2 NFT

MRC AML 12 R1 ADE MAE V RISK GROUP ASSIGNED ADE V MACE MidAC CLASPMidAC CLASPMidAC STANDARD + POOR Allo BMT CLASPAlloBMT MAE R2 DONOR NO DONOR R2 GOOD Mitoxantrone= Daunorubicin

MRC AML 15 Course 1 + LP Course 2 + LP Course 3 Course 4 Course 5 R ADE ‘Good’, ‘Standard’ and ‘Poor’ risk without a donor in CR ADE FLAG-IDA Risk group assessment CR R If no CR go to Relapse Protocol ‘Poor’ risk, but with a Matched donor and CR Ara-C 3 g/m 2 MACE Ara-C 3 g/m 2 MidAc E Sibling/UD allogeneic BMT R No further treatment Ara-C 1.5 g/m 2 R = Randomise E = Elect Non-APL Patients (At a later date there may be a further randomisation for Mylotarg at Course 1 and 3)

BFM 2004

St Jude AML02- Dose of AraC

Antharcycline dose intensity High dose Daunorubicin not tested in view of risk of cardiotoxicity High dose Daunorubicin not tested in view of risk of cardiotoxicity

Current approach

Post Induction regime

Number of courses

MRC AML 12 R1 ADE MAE V RISK GROUP ASSIGNED ADE V MACE MidAC CLASPMidAC CLASPMidAC STANDARD + POOR Allo BMT CLASPAlloBMT MAE R2 DONOR NO DONOR R2 GOOD 4 courses = 5 courses

MRC 15 Consolidation: MACE v Ara-C

CNS prophylaxis

St Jude AML-02: Impact of TIT.

Role of SCT?

AML-BFM 98 Intent-to-treat Analysis No donor HLA-id. donor OS Event-free survival No donor HLA-id. donor HR= standard +poor

AML 10 & 12 Survival from CR by Risk Group SCTNo SCT2P Value All patients57%65%0.3 Standard46%61%0.2 Poor28%47%0.2 Standard Poor % 46% 47% 28% P = No Allograft Allograft No Allograft Allograft Years from CR 2P =

BMT =480Chemotherapy = 893 Outcome%P value Favorable-risk disease Relapse Disease-free survival Overall survival Intermediate-risk disease Relapse362654< Disease-free survival5839< Overall survival Poor-risk disease Relapse Disease-free survival Overall survival Nonclassifiable Relapse Disease-free survival Overall survival Risk Stratified Outcomes Comparing Matched Sibling BMT and Chemo Alone MRC 15% COG 40% with no cytogenetics Horan J, Journal of Clinical Oncology 2008, Vol 26, Issue 35

Role of Myelotarg

Role of TKIs Sorafinib- promising in FLT3-ITD mutated AML and some benefit in Non-mutated population Sorafinib- promising in FLT3-ITD mutated AML and some benefit in Non-mutated population

Heterogeneity within cytogenetic classes on GEP

Copy number Heatmap for Pediatric AML ( N-111)

Frequency of CNA & Mutations

Summary of AML Pathogenesis Less than 2.0 copy number per case ( ALL 7/case) Less than 2.0 copy number per case ( ALL 7/case) Deletion= amplification Deletion= amplification Recurrent focal lesion are rare Recurrent focal lesion are rare 30% with translocation had no CAN or point mutation 30% with translocation had no CAN or point mutation