CLL Support Associa/on up date. What, if you need treatment. Anna Schuh Consultant Haematologist Oxford University Hospitals

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1 CLL Support Associa/on up date What, if you need treatment. Anna Schuh Consultant Haematologist Oxford University Hospitals

2 Establishing the Diagnosis Blood film: small mature lymphocytes and smear cells Flowcytometry: CD19+ and CD5+ B-cells

3 Fluorescent-in-situ hybridization (FISH): deletion of chromosome17p! normal chrom17! del chrom17p!

4 Targeted muta/on analysis in clinical diagnos/cs TP53 Cosmic database CN-LOH detected by SNP array High resolution melting curve Sanger sequencing of TP53 Next generation sequencing CLL071

5 Standard NHS Care CLL diagnosis W&W Symptoms bulky lymphadenopathy and/or splenomegaly Bone marrow failure rapid disease progression NO GO SLOW GO GO GO 1 st line SupporAve care NO del17p/tp53 mut: Clb or BendamusAne Del17p/TP53 mut: Clinical trial NO del17p/tp53 mut: FCR Del17p/TP53 mut: Alemtuzumab +/ Steroids 2 nd line Clinical Trial PFS: >/=2 years FC(R) PFS: <2 years Clinical Trial BMT from R Clifford, A Schuh. Clinical Medicine Insights Oncology

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7 Total of 400 CLL samples Blood, bone marrow, lymph nodes

8 Clinical Trials Pre clinical mouse, Assue culture Phase I first into man, dose finding, side effects paaents Phase IIa/IIb side effects, efficacy paaents Phase III randomizaaon, 1:1, 1:2, blinding, up to 1000 paaents Phase IV observaaonal post licensing Commercial/invesAgator led/mula centre/single centre SelecAon bias

9 The Trial Team Trial Co ordinator: Set up, cosangs, data publicaaon Research nurses Data analysis PI PaAent Data entry clerks Independent Trial Steering Commiaee Clinical trial office: Co ordinaaon, Supervision, audit etc Safety reporang

10 Thames Valley Clinical Research Network SelecAve therapy for paaents with BRCAness MKFT GWH Ricky Sharma ORH 4th November 2009 Ricky Sharma 4th November 2009 RBFT BHT HWPFT

11 Total pa/ent recruitment to clinical trials (cancer & pre malignant) by LRN 2009/ North London Yorkshire Greater Manchester & Cheshire South West London West Anglia North Trent South East London North of England North Pan Birmingham Peninsula Avon,Somerset,Wiltshire Central South Coast West London Thames Valley Merseyside & Cheshire Greater Midlands Leicestershire, Northamptonshire & North East London Mid Trent Kent & Medway Mount Vernon Humber and Yorkshire Coast Three CounAes Arden Derby/Burton Sussex North of England South Surrey, West Sussex & Hampshire Lancashire and South Cumbria Norfolk and Waveney Dorset Essex (Ipswich Hospitals NHS Trust)

12 Percentage of UK paaents with cancer and premalignant condiaons treated in clinical trials

13 Indication Name IMP Phase Recruitment end of recruitment relapsed/refractory B-cell malignancy HGS 1029 IAP inhibitor Phase I First into man 3 1-Dec st line GO-GO patients ARCTIC/NIHR 7136 FCR vs FCM minir Phase IIb 14 1-Dec-2011 DLBCL RICHTER's transformation CURRENT CLL TRIALS in OXFORD CHOP-OR CHOP-Ofatumumab followed by O maintenance Phase IIa 10 1-Dec st line SLOW-GO patients OMB Chlorambucil+/- Phase III 4 closed Ofatumumab 1st and 2nd line SLOW-GO patients Mable CR vs BR Phase III 22 1-Jun-2012 Lenalidomide vs maintenance after 2nd line treatment SLOW-GO/GO-GO Continuum Phase III 6 1-Dec-2012 Placebo 2:1 Ofatumumab single fludarabine-refractory bulky B-CLL SLOW-GO NCRN042/NIHR 5079 agent Phase IIb 2 1-Dec-2014 fludarabine-refractory/tp53 deleted B-CLL GO-GO NIHR 210 Camp + Dex + Lenalidomide followed by Lenalidomide maintenance or RIC BMT Phase II Due to open in Spring Dec-2014

14 NHS NICE/CLINICAL TRIAL available treatments* GO GO SLOW GO 1 st line FCR FCRvsFCM mr Chlorambucil BendamusAne Complement: C+/ O Mable: CRvsBR 2nd line FC*??? Chlorambucil FCR (LITE) Mable: CRvsBR Purine analogue refractory/ resistant*** Alemtuzumab sc + pulsed Dex CLL210 SupporAve care NCRN242: Ofatumumab CuraAve/ maintenance BMT CLL210 ConAnuum ConAnuum (if treated with purine analogue) Richter s CHOP R CHOP O *TP53 mutaaon analysis before EVERY treatment ** if FC in 1 st line, then FCR in 2 nd line (NICE) *** No response aper 2 courses or relapse within 2 years

15 B cell Receptor Cell division CLL progression

16 New Therapies in Phase I/II ASH update 1. Small molecule that mimeac Bcl 2 family proteins and induce cell death: iv drugs and oral drugs, different schedules (oblimersen) 2. Blocking BCR signalling: Lyn, Syk, Bruton kinases: oral, conanuous administraaon, lymphocyte redistribuaon phenomenon 3. PI3K delta isoforms: oral, conanuous administraaon, lymphocyte redistribuaon phenomenon

17 PHASE III in Oxford: Randomized, double blind placebo controlled study evaluaang efficacy and Safety of GS 1101 in combinaaon with BR as therapy for paaents with previously treated CLL Prior treatment with >/=1 chemotherapy DocumentaAon of CLL progression <24 months since compleaon of the last prior CLL 1:1 randomizaaon oral bd administraaon, conanuously unal unacceptable toxicity or progressive disease or other reasons

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19 Bone Marrow TransplantaAon BMT outcome: 40% cure 20% death 40% relapse (half aper long Ame)

20 Turmeric and green tea: a recipe for B Chronic Lymphocy/c Leukemia Laura S. Angelo and Razelle Kurzrock

21 Human Genome Project NATURE VOL FEBRUARY HiSeq 2000 MiSeq

22 Human Genome Project and what it means for CLL

23 Targeted Sequencing versus whole genome/exome

24 SF3B1 DNA RNA Spliceosome Protein Abnormal protein Abnormal/too much RNA CANCER??? NEJM 2012

25 New treatments targeang founder mutaaons in RNA processing machinery DNA RNA Spliceosome Protein transcripaon Going back to the bench to test small molecules

26 Moderns Concept of tumour progression Genetic heterogeneity caused by Darwinian evolution and selection!"#$%&'$()%*+$#*)#"%&',-%,."-) Cancer stem cell /'#($+0'0) 1-*#20-) Jacobsen, N Engl J Med 2010;363: Greaves, Nature 2010 Dick, Nature 2011 Genome wide analysis to monitor the molecular sequence of events underlying relapse Personalized Medicine

27 Somatic SNV allele frequency Somatic SNV allele frequency Cell count 109 cells/litre Sequen/al Whole Genome Analysis a b c d Samples e a b c d Samples e

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29 HEALTH ECONOMICS, GENETIC TESTING AND CLL James Buchanan Health Economist Department of Public Health, University of Oxford

30 GENETIC TESTING AT THE MOMENT Currently lots of basic science work going on to develop new geneac tests in lots of disease areas BUT not enough translaaonal research is being done to get these tests from the laboratory to the bedside Health economists can contribute a lot to translaaonal research because: People think these tests are too expensive People are unsure how these tests will benefit paaents

31 WHAT WORK ARE HEALTH ECONOMISTS DOING RIGHT NOW IN GENETICS? Not enough! There are many methodological problems We normally conduct cost effecaveness analyses of new treatments or tests i.e. what effect does a drug have on life expectancy? GeneAc tests might provide valuable informaaon on life expectancy or the natural course of a disease However as these tests do not directly affect life expectancy, we would not capture this effect using our current methods

32 MY PHD How can we overcome these problems and provide beaer health economics data on geneac tesang to decision makers? Using geneac tesang in CLL as a case study One soluaon ask paaents how they value geneac tesang in CLL How? By using a paaent preference survey PaAents asked to make choices between different types of test PaAents given informaaon on test aaributes such as speed of test result, or test accuracy

33 WHAT AM I DOING CURRENTLY AND HOW CAN YOU HELP? Currently designing a paaent preference survey for CLL paaents Will be given to cancer paaents in the haematology department in Oxford What aaributes of tesang do paaents think are important? Quick results? Accurate results? Number of tests required? Where the test takes place? How much informaaon you receive and who gives you the test results? All of your thoughts and opinions would be welcome

34 THANKS FOR LISTENING