Colt 2014 - Sue Branford - Mechanisms of resistance to TKI 13.8.14

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Slide1:

Mechanisms of Resistance to TKI therapy A/Prof Susan Branford, PhD Centre for Cancer Biology & Universities of Adelaide and South Australia

Slide2:

Defining resistance in CML is impossible without first defining response 2013 European LeukemiaNet (ELN) recommendations 2014 NCCN (USA) Clinical Practice Guidelines: CML 2013 European LeukemiaNet (ELN) recommendations Time dependent milestone response CHR MCyR/10% BCR-ABL1 CCyR/1% BCR-ABL1 MMR – 0.1%

Slide3:

Defining resistance in CML is impossible without first defining response 2013 European LeukemiaNet (ELN) recommendations 2014 NCCN (USA) Clinical Practice Guidelines: CML 2013 European LeukemiaNet (ELN) recommendations Resistance is failure to achieve CHR MCyR/10% BCR-ABL1 CCyR/1% BCR-ABL1 loss of response/AP/BC Ph Chr abnormalities BCR-ABL1 mutations

Slide4:

Mutations arise in a leukaemic stem or progenitor cell Kinase domain Point mutation of the DNA sequence within the kinase domain Mutated resistant clone reactivation of leukaemia proliferating leukaemic stem/progenitor cell

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Tyrosine kinase inhibitors (TKI) are not mutagenic Mutations arise independently of TKI therapy Selected in the presence of TKIs because the mutant BCR-ABL1 confers a survival advantage mutations have been detected in imatinib naive patients with CML using sensitive techniques BCR-ABL1 expressing cells have increased levels of DNA damaging reactive oxygen species DNA repair mechanisms are defective Why do the mutations arise?

When to test for BCR-ABL1 mutations:

failure to reach haematologic, cytogenetic or molecular response milestones When to test for BCR-ABL1 mutations loss of any response progression to advanced phase additional chromosomal abnormalities in Ph-positive clone significant BCR-ABL1 rise

Slide7:

CML ABL BCR 0.01 0.1 1.0 10 100 Months since starting imatinib Diagnosis 6 12 36 24 BCR-ABL1 % IS optimal loss of response Most BCR-ABL1 mutations are detected in patients with a rise in BCR-ABL1 / loss of response, rather than in patients without any response

Slide8:

A rapid rise may indicate complete non-adherence to therapy Noens et al. Blood. 2009;113:5401 Darkow et al. Pharmacoec. 2007;25:481 Approximately one-third of patients are considered to be non-adherent Since it is associated with poorer response, it should be assessed routinely Poor adherence is the main reason for loss of CCyR and imatinib failure, Ibrahim et al, Blood 2011:117;3733

Slide9:

Loss of MCyR within 2 months 0.10 1 Patient tested in Adelaide 22 year old male commenced first-line imatinib July 2000 - IRIS trial 1.0 0.01 10 Years since commencing imatinib PB BCR-ABL1% IS 2 3 4 5 6 7 10 0 CCR MMR } optimal response 100 36-fold rise The patient confessed to stopping his medication for over 6 weeks 8 9 A rise should be confirmed and adherence investigated before any therapeutic intervention When imatinib is stopped, the rise is rapid and exponential – BCR-ABL1 doubles  every 9 days (BCR-ABL1 doubling time) Branford et al, Blood 2012:119;4264 Long-term molecular monitoring of responding patients is important to monitor adherence

Slide10:

Haematologica , 2014;99:437 reviewed 19 manuscripts Lack of supportive evidence demonstrating a difference in adherence across BCR-ABL inhibitors Drug related AEs and forgetfulness were the most common reasons for intentional and unintentional non adherence, respectively Confirmed that non adherence is common and associated with critical outcomes

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Haematologica , 2014;99:437 reviewed 19 manuscripts Explored the non-adherence margin without clinically significant impact on outcome follow on from the ADAGIO trial suggests that imatinib is ‘ unforgiving ’ even minor deviations from the prescribed regimen appear to be associated with poorer clinical outcomes Maintaining an average daily dose of 600 mg imatinib leads to higher rates of MMR by 12 months versus <600 mg; 55% vs 32%, P = .037 Hughes et al, Blood. 2008;112:3965

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CML ABL BCR 0.01 0.1 1.0 10 100 Months after starting therapy Diagnosis 6 12 36 24 optimal 0.01 0.1 1.0 10 100 primary res Diagnosis 6 12 36 24 29% of CML patients with imatinib resistance vs 8% of sensitive patients, P =.02 Ng et al Inherited modifiers of response? Common in East Asians 12% allele frequency loss of response BCR-ABL1 mutations and non adherence are the most common known mechanisms of loss of response

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BIM is a pro-apoptotic protein that is a particularly critical mediator of targeted therapy induced apoptosis in blood and solid tumour cancers Combined loss of BIM and BAD abrogates imatinib induced leukaemic cell death Kuroda, PNAS 2006;103:14907 BIM mRNA expression in treatment-naive cancers predicts responsiveness to kinase inhibitors Cancer Discovery . 2011;1:352 “ BIM plus BAD account for most, perhaps all, imatinib-induced killing of Bcr-Abl+ leukemic cells ” Kuroda, PNAS 2006;103:14907

Slide14:

BIM is a pro-apoptotic protein that is a particularly critical mediator of targeted therapy induced apoptosis in blood and solid tumour cancers gefitinib, erlotinib – EGFR kinase activated in epithelial tumours, eg NSCLC sunitinib – FLT-3 kinase carrying activating ITD in AML imatinib and nilotinib – targeting BCR-ABL1 in CML These TKIs initiate apoptosis by inducing transcription of the BIM gene

Slide15:

P = .0027 The BIM deletion polymorphism predicts shorter PFS in individuals with EGFR-mutant NSCLC treated with EGFR TKI therapy Ng et al, Nat Med. 2012;18:521 Strongest known inherited modifier of TKI response

Slide16:

BIM is a member of the BCL2 family of proteins involved in the intrinsic apoptotic process BIM deletion polymorphism leads to an increase in abundance of an alternatively spliced BIM isoform that lacks apoptotic function Resistance was overcome in cell lines with BH3 mimetic drug ABT-737, obatoclax, sabutoclax pro-apoptotic proteins eg BIM anti-apoptotic proteins eg BCL2 cancer cells evade death signals tumour cell survival tumour cell death upregulated by tyrosine kinase inhibitors

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Identified PTGS1 (Cox1, drug metabolism gene) – higher expression in patients with primary resistance (no MCyR at 12 months) J Clin Oncol 2009;27:3642

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Blood. 2010:115:315 75-probe set signature of CD34+ selected cells distinguished imatinib -responders from non-responders MCyR was predicted more accurately by this probe set than by using the Sokal score Aim of these studies was to develop diagnostic tests using a limited panel of genes to determine a risk-based treatment strategy Validation required Gene expression studies using microarrays are now being replaced with new technology – RNA-Seq, use next generation sequencing technologies

Slide19:

CML ABL BCR 0.01 0.1 1.0 10 100 Months since starting imatinib Diagnosis 6 12 36 24 BCR-ABL1 % IS ? primary res blast crisis 1989 TP53 RB NRAS PNAS . 1989;86:6783 Chr abnormalities clonal evolution Leuk . 2011;25:557 Haematologica . 2014;EHA Recurrently mutated genes in BC RUNX1, ASXL1, IKZF1 WT1 >10% of pts UBE2A acquired modifiers of response

Slide20:

Mechanisms of resistance to TKIs are diverse Summary  BCR-ABL1 mutations are the most common known mechanism of resistance  Non adherence may influence the long term outcome  Inherited factors may modify response to TKIs

Slide21:

Australia Timothy Hughes David Yeung Wendy Parker David Ross Linda Fletcher Hamish Scott Junia Melo Deb White Jodi Braley Leuk Unit staff, SA Path International Nick Cross - UK Andreas Hochhaus - Germany Jerry Radich - US Jorge Cortes - US Martin Müller - Germany John Goldman - UK David Marin - UK Simona Soverini - Italy Dong-Wook Kim - Korea Gianantonio Rosti - Italy Michele Baccarani - Italy Guiseppe Saglio - Italy Giovanni Martinelli - Italy Richard Clark - UK John Seymour, Mark Herzberg, Andrew Grigg, ALLG and patients with CML Acknowledgments

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