YES & YES! YES & YES! David Grimwade Dept. of Medical - - PowerPoint PPT Presentation

“ “Can novel prognostic Can novel prognostic markers predict for success markers predict for success and guide therapy in AML and guide therapy in AML? ?” ”

YES & YES! YES & YES!

David Grimwade

• Dept. of Medical & Molecular Genetics,

King’s College London School of Medicine

The need for novel prognostic markers: The need for novel prognostic markers:

Widely accepted pre Widely accepted pre-

• treatment risk factors used to determine AML

treatment risk factors used to determine AML therapy cannot reliably distinguish patients who will/will not r therapy cannot reliably distinguish patients who will/will not relapse elapse

Grimwade et al, Blood 1998; 92: 2322-2333

Favourable Intermediate Adverse

MRC MRC SWOG/ECOG SWOG/ECOG CALGB CALGB GIMEMA/AML10 GIMEMA/AML10 GERMAN GERMAN AMLCG AMLCG

t(15;17) t(8;21) inv(16)/t(16;16) t(15;17) t(8;21) (lacking del(9q), complex i.e. 3 unrel abn) inv(16)/t(16;16)/ del(16q) t(15;17) t(8;21) inv(16)/t(16;16) t(15;17) t(8;21) inv(16)/t(16;16) t(15;17) t(8;21) inv(16)/t(16;16) Normal Other non-complex Normal +6, +8, -Y, del(12p) Normal Other non- complex Normal

• Y

Normal Other non- complex abn(3q) [exclud t(3;5)] inv(3)/t(3;3), add(5q)/del(5q), -5, add(7q)/del(7q), -7 t(6;11), t(10;11), Other t(11q23) [exclud t(9;11) & t(11;19)] t(9;22), -17/abn(17p), complex (>4 unrel abn) (excluding those with favourable changes) abn(3q), (9q), (11q), (21q), abn(17p)

• 5/del(5q)
• 7/del(7q)

t(6;9) t(9;22) complex (3 unrel abn) inv(3)/t(3;3)

• 7

t(6;9) t(6;11) t(11;19) +8 complex (3 unrel abn) (excluding those with favourable changes) Other inv(3)/t(3;3)

• 5/del(5q)
• 7/del(7q)

abn(11q23) del(12p) abn(17p) complex (3 unrel abn)

SWOG/ECOG SWOG/ECOG CALGB CALGB GIMEMA/AML10 GIMEMA/AML10 GERMAN AMLCG GERMAN AMLCG MRC MRC

Trial groups can Trial groups can’ ’t even agree about t even agree about standard risk factors! standard risk factors!

Limitations to using diagnostic Limitations to using diagnostic karyotype karyotype for treatment stratification for treatment stratification

• Conflicting data regarding prognostic significance of some

primary cytogenetic aberrations

– Influences of sample size & treatment variation

• Incorrect risk group assignment

– Unsuccessful cytogenetic analysis – Cryptic rearrangements

• Normal karyotype (~40% AML) molecularly heterogeneous

45% 38% 17%

Molecular advances over last decade have substantially Molecular advances over last decade have substantially improved outcome prediction & risk stratification improved outcome prediction & risk stratification

2000

• Favourable 24%: t(15;17)/PML-RARA, t(8;21)/AML1-ETO, inv(16)/CBFB-MYH11
• Intermediate 61%: Normal karyotype, other cytogenetic abonormalities
• Adverse 15%: -5/del(5q), -7, abn(3q), complex

2010

Integration of cytogenetic and molecular markers Integration of cytogenetic and molecular markers to predict outcome in AML to predict outcome in AML

t(15;17) t(8;21) inv(16) CEBPA biallelic Other intermediate FLT3-ITD/ NPM wt Other adverse NPM mut/ ITD neg

Importance of molecular diagnostics to guide appropriate therapy

• Case History

– 75yr old female – WBC 15 x 109/l – Suspected M3v – Randomised to AIDA in NCRI AML17 trial – Cytogenetics: Normal – FISH: No PML-RARA fusion signal – Diagnosis: RT-PCR: PML-RARA neg Diagnosis: NPM1 mutant AML

• Case History

– 25yr old female – Presented – PE (23.12.09) – FBC: Hb 10g/dl, WBC 0.5, Plt 86 – Marrow – APL? – Cytogenetics: Normal – FISH: No PML-RARA fusion signal – PML antibody test +ve – RT-PCR: PML-RARA +ve (reciprocal RARA-PML neg) – Diagnosis: APL secondary to PML-RARA insertion RT-PCR: PML-RARA +ve (reciprocal RARA-PML neg) Diagnosis: APL secondary to PML-RARA insertion PML antibody test +ve  ATRA + Idarubicin

Is it APL?

Importance of molecular diagnostics to guide therapy

Early detection of MRD provides Early detection of MRD provides independent prognostic information in AML independent prognostic information in AML

MRD post-induction

10 20 30 40 50 60 70

Months from diagnosis

100 75 25 50

% in CR

< 5x10-3 (n=24) ≥ 5x10-3 (n=18) p=0.01

Flow Flow cytometry cytometry RQ RQ-

• PCR

PCR (WT1) (WT1)

p=0.004 for each increasing log reduction in WT1

Cilloni et al, J Clin Oncol 2009 San Miguel et al, Blood 1997 Independent prognostic factor: San Miguel et al, Blood 2001 Kern et al, Blood 2004 Maurillo et al, J Clin Oncol, 2008 Rubnitz et al, Lancet Oncol, 2010 Independent prognostic factor: WT1 log reduction assessed by ELN standardised assay remains significant when adjusting for age, presenting WBC & cytogenetics

Use of sequential MRD monitoring to direct Use of sequential MRD monitoring to direct pre pre-

• emptive therapy to prevent impending relapse

emptive therapy to prevent impending relapse

1010 >1012 106 108

Leukaemic Leukaemic cell burden cell burden

MRD undetectable range

Rapid Rapid responders responders Slow Slow responders responders

Pre Pre-

• emptive therapy

emptive therapy to prevent frank relapse to prevent frank relapse

Sequential MRD monitoring for Sequential MRD monitoring for PML PML-

• RARA

RARA transcripts by standardised transcripts by standardised Europe Against Cancer (EAC) RQ Europe Against Cancer (EAC) RQ-

• PCR assay to predict relapse in APL

PCR assay to predict relapse in APL

0.0001 0.001 0.01 0.1 1

pml rara/abl sensitivity abl

Molecular relapse Relapse

Normalised PML-RARA transcript level (PML-RARA copies/ ABL copies)

Diagnosis

Treatment since diagnosis

S-DAT/ ATRA S-DAT/ MACE/MiDAC ATO Mylotarg Na valproate Theophylline FLAG-ida

Relapse

Serial MRD monitoring by standardised RQ Serial MRD monitoring by standardised RQ-

• PCR assay

PCR assay to guide patient management in to guide patient management in PML PML-

• RARA

RARA+ APL + APL

Case History:

9 month male infant FBC: Hb 8g/dl, WBC 28.6 x 109/l, Plt 12 x 109/l PML-RARA+ APL

Persistent disease Persistent disease AlloSCT

ATO Ongoing Molecular CR

ATRA + Chemo

ATO ATO Maint

Evaluation of MRD monitoring & pre Evaluation of MRD monitoring & pre-

• emptive therapy to reduce

emptive therapy to reduce rates of frank relapse in rates of frank relapse in PML PML-

• RARA

RARA+ APL in MRC AML15 trial + APL in MRC AML15 trial

Grimwade et al, J Clin Oncol 2009; 27: 3650-8.

Cost effectiveness of MRD monitoring Cost effectiveness of MRD monitoring

Assuming monitoring cost of £3,000/patient & life expectancy of 25y for patients successfully salvaged:

• WBC>10: 10% survival benefit at 5 years - £1,350/ quality adjusted life year (QALY)
• WBC<10: 1% survival benefit at 5 years - £14,300/QALY

0.000001 0.00001 0.0001 0.001 0.01 0.1 1 10 100 1000 2 4 6 8 10 12 14 16 18

Months

NPM1 mut/ ABL CN

15-0349 15-1079 15-1172 15-1468 15-1596 15-1612 15-1631 15-2336

Relapse Relapse 4 mo later 4 mo later Relapse Relapse Relapse Relapse Relapse Relapse Relapse Relapse Relapse Relapse 6 mo later 6 mo later CR CR CCR 12 mo later CCR 12 mo later

PCR positive PCR negative

Months from diagnosis

MRD detection of mutant MRD detection of mutant NPM1 NPM1 by RQ by RQ-

• PCR in MRC AML15

PCR in MRC AML15

Normalised copy number: NPM1 mutant/ABL Semin Oncol 2008;35:388-400.

• Molecular diagnostics identifies disease mutations

conferring important independent prognostic information

• Molecular diagnostics are essential to distinguish a

sizeable group of patients with favourable prognosis who are unlikely to benefit from routine allografting in 1st CR

• MRD detection can identify patients destined to fail

frontline therapy, who may benefit from additional therapy

• Embracing new technologies to refine diagnosis and track

treatment response is critical for the development of more personalized approaches to AML therapy

In favour of the motion: In favour of the motion:

Acknowledgments Acknowledgments

Guy Guy’ ’s Hospital London s Hospital London

Daniela Daniela Diverio Diverio Rajinder Rajinder Flora Flora Elizabeth Nugent Elizabeth Nugent Jelena Jelena Jovanovic Jovanovic Yvonne Morgan Yvonne Morgan Ellen Solomon Ellen Solomon

MRC Trials Tissue Bank/ MRC Trials Tissue Bank/

• Dept. of Haematology, UCL Hospitals
• Dept. of Haematology, UCL Hospitals

Stephen Stephen Langabeer Langabeer Sivatharsini Sivatharsini Srirangan Srirangan Yashma Yashma Patel Patel Helen Walker Helen Walker Rosemary Gale Rosemary Gale David David Linch Linch

MRC/NCRI Trials MRC/NCRI Trials

Alan Burnett Alan Burnett Tony Goldstone Tony Goldstone Nigel Russell Nigel Russell Sylvie Freeman Sylvie Freeman Robert Hills Robert Hills Anthony Moorman Anthony Moorman Christine Harrison Christine Harrison Brenda Gibson Brenda Gibson Keith Wheatley Keith Wheatley

Non Non-

• APL MRD studies

APL MRD studies

Sarah Daly Sarah Daly Anna Barfield Anna Barfield Stuart Green Stuart Green Abida Abida Awan Awan Khalid Khalid Tobal Tobal John Yin John Yin

Regional Banks/labs Regional Banks/labs

Steve Austin/ Paul White/ Mandy Steve Austin/ Paul White/ Mandy Gilkes Gilkes Mike Griffiths/Susanna Mike Griffiths/Susanna Akiki Akiki/ Joanne Mason/ Kerry Wall / Joanne Mason/ Kerry Wall Paul Evans/Mike Short Paul Evans/Mike Short Anthony Bench Anthony Bench Ian Carter Ian Carter Gill Wilson Gill Wilson Anne Anne Sproul Sproul Vincent van Vincent van der der Velden Velden

European European LeukemiaNet LeukemiaNet

Andreas Andreas Hochhaus Hochhaus Giuseppe Giuseppe Saglio Saglio Gisela Gisela Barbany Barbany Peter Peter Hokland Hokland Charlotte Charlotte Guldborg Guldborg Nyvold Nyvold R Rü üdiger diger Hehlmann Hehlmann