In partnership with The Impact of Thalidomide Maintenance Therapy Varies According to Biological Risk Grouping Annamaria Brioli Fiona M Ross 3, Martin

in partnership with

The Impact of Thalidomide Maintenance Therapy The Impact of Thalidomide Maintenance Therapy Varies According to Biological Risk GroupingVaries According to Biological Risk Grouping

Annamaria BrioliAnnamaria Brioli

Fiona M Ross3, Martin Kaiser1, Charlotte Pawlyn1, Ping Wu1, Walter M Gregory4, Roger Owen5, Graham H Jackson6, Michele Cavo2, Faith E Davies1, Gareth J Morgan1

Abstract presented at the 54th ASHAbstract presented at the 54th ASH®® Annual Meeting and Exposition Annual Meeting and ExpositionAtlanta, December 8-11 2012Atlanta, December 8-11 2012

1Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, UK; 2Seràgnoli Institute of Hematology, Bologna University School of Medicine, Italy; 3Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, UK; 4Clinical Trials

Research Unit, University of Leeds, Leeds, UK; 5St James's University Hospital, Leeds, UK; 6Haematology Department, University of Newcastle, Newcastle-upon-Tyne, UK

UKMF Spring Day UKMF Spring Day 1313thth March 2013 March 2013

Study BackgroundMaintenance therapy can modify residual disease behaviour

delaying or preventing relapsesdecreasing post relapse survival

109

108

107

106

105

104

103

102

10

PresentationPRVGPRCR

sCR

Cure

Tu

mo

ur

bu

lk

Relapse

Time to progression

Induction Maintenance

Clonal extinction and cure

Relapse

Relapse

Relapse

Time

Time to progression

The impact of maintenance may vary according to the underlying biology of the disease

Genetic alterations, such as t(4;14), del(17p) and +1q, can be used to define different biological behaviours1, 2

The presence of co-segregating adverse FISH lesion defines a group of patients with more aggressive disease3

1. Avet-Loiseau H, et al. J Clin Oncol. 2012;30(16):1949-52.

2. Fonseca R, et al. Leukemia 2009;23(12):2210-21

3. Boyd K, et al. Leukemia 2012;26(2):349-55

PFS OS

Study Background

Study BackgroundThalidomide maintenance

Studies have shown conflicting results: improvement of tumor response1-3 vs no improvement4

improvement of progression-free survival (PFS)1-2,5-6 vs no change3

survival benefit1,6-7 vs no advantage3,5

higher benefit in lower2,4 vs higher risk biological groups9

impaired quality of life10

6. Barlogie B, et al. N Engl J Med. 2006;354:1021-30

7. Brinker BT, et al. Cancer. 2006;106:2171-80

8. Barlogie B, et al. J Clin Oncol. 2010;28:1209-14

9. Barlogie B,et al. Blood 2008; 112:3115-3121

10. Hicks LK, et al. Cancer Treat Rev. 2008;34:442-52.

1. Spencer A, et al. J Clin Oncol. 2009;27:1788-93.

2. Attal M, et al. Blood. 2006;108:3289-94

3. Sahebi F, et al. Bone Marrow Transplant. 2006;37:825-9

4. Morgan GJ, et al. Blood 2012: 119:7-15

5. Lockhorst HM, et al. Blood. 2010;115:1113-20

Evaluate the impact of thalidomide maintenance on biological risk groups defined by co-segregating FISH lesion

Study Design

MP

CTDa

NoMaintenance

Thalidomide Maintenance

Ran

do

miz

atio

n

Induction1-3

Older, less fit

• Thalidomide maintenance = 50 mg/day × 4 weeks, increasing thereafter to

100 mg/day if well tolerated, until disease progression

CVAD

CTD

Younger, fitter

HDM200 mg/m2

1. Morgan GJ, et al. Lancet. 2010;376:1989-99.2. Morgan GJ, et al. Haematologica. 2012: 97(3):442-50.

3. Morgan GJ, et al. Blood. 2011;118:1231-8.4. Morgan GJ, et al. Blood. 2012: 119:7-15.

CTD, cyclophosphamide, thalidomide and dexamethasone; CTDa, CTD attenuated (low-intensity); CVAD, vincristine, doxorubicin, dexamethasone and cyclophosphamide; HDM, high-dose melphalan; MP, melphalan and prednisone.

Maintenance4

Median time on maintenance treatment:

7 months

MRC Myeloma IX trial


Study accrual 2003-2007

N° pts enrolled

N° entered maintenance

N° ® thalidomide

N° ® no maintenance

1960

818

408

410

Cutoff date February 2012

Median follow-up -from beginning of therapy

-from beginning of maintenance

5.9 years

5.4 years

Thalidomide maintenance vs no maintenance

PFS and OS according to maintenance randomization

Thal maintenance

Nomaintenance

Thal maintenance

Nomaintenance

PFS OS

Months from maintenance randomization

surv

ival


surv

ival

p<0.001

Median PFS:23.0 m vs 15.3 m

p=0.397

Median OS:59.1 m vs 57.6 m


Evaluable patients

881 patients entered maintenance

369 patients with complete:IgH@del 17(p13)+1(q32)

182 thalidomide maintenance

187 no maintenance

Median time from initiation of trial to maintenance randomization: 8.3 months

Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

Patients’ characteristics


Response rate pre maintenance randomization

60% of patients in each maintenance arm had received ASCT50% of patients in each maintenance arm had received Zoledronic acid

60% of patients in each maintenance arm had received ASCT50% of patients in each maintenance arm had received Zoledronic acid


Presence of genetic alterations

SRSR HRHR UHRUHR

Each lesion was considered whether present in isolation or plus an additional adverse lesion (+(1)(q21) and del(17)(p13) for IGH translocations, +(1)(q21), del(17)(p13) and t(4;14) for hyperdiploidy).

FISH based risk groups:Standard risk: no adverse FISH lesionHigh risk: presence of one of t(4;14), t(14;16), t(14;20), del17(p13), +1(q32)Ultra high risk: presence of two or more between t(4;14), t(14;16), t(14;20), del17(p13), +1(q32)


FISH based risk groupsPFS

p=0.004


surv

ival

Thal maintenance

Nomaintenance

Standard risk FISH

p=0.475

surv

ival


Thal maintenance

Nomaintenance

p=0.840

surv

ival


Thal maintenance

Nomaintenance

High risk FISH

Ultra-high risk FISH






surv

iva

l

p=0.431Thal

maintenanceNo

maintenance


surv

iva

l

p=0.039

Thal maintenance

Nomaintenance


p=0.975

surv

iva

l

Thal maintenance

Nomaintenance

FISH based risk groupsOS

Standard risk FISH High risk FISH

Ultra-high risk FISH

Median OS:NR in both arms


Median PFS:34.7 m vs NR


Translocation defined risk groupsPFS

No t(4;14) t(4;14) t(4;14)+1

Thal maintenance

Nomaintenance

p=0.069 p=0.280 p=0.813

Thal maintenance

Nomaintenance

Thal maintenance

Nomaintenance

No t(11;14) t(11;14) t(11;14)+1

p=0.163 p=0.455 p=0.362

Thal maintenance

Nomaintenance

Thal maintenance

Nomaintenance

Thal maintenance

Nomaintenance


surv

iva

l

surv

iva

l

surv

iva

l

surv

iva

l

surv

iva

l

surv

iva

l













Translocation defined risk groupsOS

p=0.182

p=0.940

p=0.128

Thal maintenance

No t(11;14) t(11;14) t(11;14)+1Thal

maintenance

Nomaintenance

Thal maintenance

Nomaintenance

No t(4;14) t(4;14) t(4;14)+1Thal

maintenanceThal

maintenance

Nomaintenance

Thal maintenance

Nomaintenance

p=0.106

p=0.762p=0.987


surv

iva

l


surv

iva

l


surv

iva

l


surv

iva

l


surv

iva

l


surv

iva

l

Nomaintenance

Nomaintenance

Median OS:54.6 m vs NR

Median OS:NR vs 36.1 m



Median OS:NR in both arm

Median OS:29..6 m vs NR

Hyperdiploidy defined risk groupsPFS


surv

iva

l

p=0.003

Thal maintenance

Nomaintenance

Hyperdiploidy alone

p=0.417

Thal maintenance

Nomaintenance


surv

iva

l

No Hyperdiploidy


surv

iva

l

Thal maintenance

Nomaintenance

p=0.142

Hyperdiploidy+1





Hyperdiploidy defined risk groupsOS


surv

iva

l

p=0.958

Thal maintenance

Nomaintenance

Hyperdiploidy alone


surv

iva

l

p=0.258

Thal maintenance

Nomaintenance


surv

iva

l

Thal maintenance

Nomaintenance

Hyperdiploidy+1

No Hyperdiploidy

p=0.056


Median OS:NR in both arm



Conclusions

The association of multiple FISH adverse genetic lesions has an additive effect

Maintenance thalidomide: prolongs PFS of both transplant eligible and non eligible patientsprolongs PFS in patients with low biological risk disease (hyperdiploidy and standard risk FISH)

AknowledgmentsUniversity of Birmingham

MT Drayson

K Walker

A Adkins

N Newnham

Wessex Regional Genetics Laboratory, Salisbury

F Ross

L Chieccio

LTHT, Leeds

G Cook

S Feyler

D Bowen

HMDS, Leeds

RG Owen

AC Rawstron

R de Tute

M Dewar

S Denman

ICR, London

FE Davies

M Jenner

B Walker

D Johnson

D Gonzalez

N Dickens

K Boyd

P Leone

L Brito

A Avridromou

C Pawlyn

M Kaiser

L Melchor

Everyone else from the Morgan and Davies Teams

MRC Leukaemia Trial Steering Committee

MRC Leukaemia Data Monitoring and Ethics Committee

NCRI Haematological Oncology Clinical Studies Group

UK Myeloma Forum Clinical Trials Committee

Myeloma UK

Funding

Medical Research Council

Pharmion

Novartis

Chugai Pharma

Bayer Schering Pharma

OrthoBiotech

Celgene

Kay Kendall Leukaemia Fund

Chief Investigators

JA Child

GJ Morgan

GH Jackson

CTRU, Leeds

K Cocks

W Gregory

A Szubert

S Bell

N Navarro Coy

F Heatley

P Best

J Carder

M Matouk

D Emsell

A Davies

D Phillips

Aknowledgments

Nottingham City Hospital Western General Hospital, Edinburgh Royal Devon and Exeter Hospital Leeds General Infirmary Birmingham Heartlands Hospital Royal Hallamshire Hospital, Sheffield Hull Royal Infirmary Royal Liverpool University Hospital Mid Yorkshire NHS Trust Ninewells Hospital, Dundee University Hospital of Wales, Cardiff Torbay Hospital, Torquay Addenbrooke’s Hospital, Cambridge Aberdeen Royal Infirmary Worcester Royal Infirmary St James's University Hospital, Leeds Russells Hall Hospital, Dudley Derbyshire Royal Infirmary Christie Hospital, Manchester Royal Cornwall Hospital, Truro Southampton General Hospital Blackpool Victoria Hospital James Cook University Hospital Colchester General Hospital Glan Clwyd Hospital Medway Maritime Hospital, Gillingham Norfolk and Norwich University Hospital James Paget Hospital, Great Yarmouth Royal United Hospital, Bath St Helier Hospital, Carshalton The Great Western Hospital, Swindon Gloucestershire Royal Hospital Singleton Hospital, Swansea New Cross Hospital, Wolverhampton Ysbyty Gwynedd, Bangor Monklands General Hospital, Airdrie Eastbourne District General Hospital Sandwell General Hospital Wycombe General Hospital Hillingdon Hospital, Uxbridge Lincoln County Hospital Chesterfield & N Derbyshire Royal Kings Mill Hospital, Sutton-in-Ashfield Queen Elizabeth Hospital, Kings Lynn Kent and Canterbury Hospital University Hospital Aintree, Liverpool St Bartholomew’s Hospital, London Cheltenham General Hospital Western Infirmary, Glasgow Southern General Hospital, Glasgow Hereford County Hospital Glasgow Royal Infirmary Darent Valley Hospital Salisbury District Hospital Stepping Hill Hospital, Stockport Trafford General Hospital, Manchester Bristol Haematology & Oncology Centre Good Hope Hospital, Sutton Coldfield St Richard’s Hospital, Chichester Oldchurch Hospital, Romford Darlington Memorial Hospital Pembury Hospital Taunton and Somerset Hospital Diana Princess of Wales Hospital, Grimsby Warwick Hospital Walsgrave Hospital Bradford Royal Infirmary Southend General Hospital The Royal Bournemouth Hospital Manchester Royal Infirmary Whiston Hospital, Prescot Derriford Hospital Stoke Mandeville Hospital, Aylesbury Queen Elizabeth Hospital, Gateshead Worthing Hospital Scarborough General Hospital Countess of Chester Hospital Royal Victoria Infirmary, Newcastle Hope Hospital, Manchester Victoria Infirmary, Glasgow Rotherham General Hospital Poole Hospital Princess Royal University Hospital Milton Keynes General Hospital Barnsley District Hospital North Devon District Hospital Kingston Hospital Royal Alexandra Hospital, Paisley Borders General Hospital Queen Elizabeth Hospital, Birmingham City Hospital, Birmingham King George Hospital, Ilford Conquest Hospital, St Leonard's on Sea Pilgrim Hospital, Boston Dorset County Hospital Southmead Hospital, Bristol Royal Surrey County Hospital University Hospital of North Tees George Eliot Hospital Southport and Formby District General Hospital North Tyneside General Hospital Epsom General Hospital Grantham and District Hospital Harrogate District Hospital Basildon Hospital Doncaster Royal Infirmary Royal Marsden Hospital, Sutton Nevill Hall Hospital, Abergavenny Queen Mary's Hospital, Sidcup Prince Charles Hospital, Merthyr Tydfil Prince Philip Hospital Royal Bolton Hospital Central Middlesex Hospital Northwick Park Hospital, Harrow Arrowe Park Hospital Ipswich Hospital South Tyneside District Hospital Mid Staffordshire General Hospital Mayday Hospital Forth Valley West Suffolk Hospitals NHS Trust

Patients and staff from 121 participating institutions in the UK

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In partnership with The Impact of Thalidomide Maintenance Therapy Varies According to Biological Risk Grouping Annamaria Brioli Fiona M Ross 3, Martin