EVI-1 oncogene expression predicts survival in chronic phase CML patients resistant to imatinib

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1 EVI-1 oncogene expression predicts survival in chronic phase CML patients resistant to imatinib Mustafa Daghistani Department of Haematology, Imperial College London at Hammersmith Hospital, Du Cane Road, London, UK

2 CML an overview A clonal myeloproliferative disorder of the pluripotent hematopoietic stem cell t(9;22)(q34;q11) 1 to 2 cases per 100,000 15% of all adult leukaemias Triphasic - indolent chronic phase, accelerated and terminal acute stage q der9 22 Ph q11.2 Philadelphia chromosome pathognomic marker BCR-ABL fusion - deregulated tyrosine kinase activity: rational target for therapy

3 Cum Survival CML therapy: conventional v s tyrosine kinase inhibitor (TKI) Imatinib (STI571, Glivec) Interferon (CML 3 MRC) (survival time from diagnosis) 20-30% patients imatinib resistant/intolerant KD mutations best-characterised resistance mechanism (30-50%) Other mechanisms unknown

4 Second-Generation (2G) TKIs Dasatinib Nilotinib CCR or MCR in up to 60% of imatinib resistant patients Dasatinib active against all mutations except T315I Resistance still a clinical challenge

5 Established and proposed mechanisms of TKI resistance Gastrointestinal absorption/first pass metabolism Plasma protein binding Cellular drug influx and efflux Enzymatic inactivation Increase in BCR-ABL expression BCR-ABL mutations Activation of BCR-ABL independent pathways

6 3q26 rearrangements in haematological malignancy EVI1 (EVI1/MDS1) gene Oncogene, PR-domain protein EVI-1 translocations are the primary events in aggressive myeloid malignancy inv(3), t(3;21)(q26;q22) etc inv(3)(q21q26) inv(3) 3 De Melo et al. Leukemia, 2007 Over expression in absence of 3q26 rearrangement 3 common der(3) in AML, CML: >60% AP/BC, 10% CP (Ogawa et al, 1996) der(21) We previously observed high frequency of 3q26 abnormality in BC patients resistant to 2G-TKI (AR at UKCCG 2008) Questions: 1) Can EVI1 expression be found in CP patients with imatinib resistance 2) What is the correlation with response to 2G-TKI.

7 Methods and patient materials 75 consecutive patients with Philadelphia (Ph) chromosome-positive CML in CP resistant to imatinib who were treated with dasatinib (n=61) or nilotinib (n=14) No patient harbored a 3q26 rearrangement in the Ph-positive clone The median follow up from starting 2G-TKI was 30 months; 95% of the patients were followed for at least one year. EVI-1 expression was measured using a multiplex TaqMan assay Granulocytes from 30 normal individuals showed no evidence of EVI1 expression by this method

8 Results EVI-1 expression was detected by real-time PCR in 8 (10.7%) of the 75 patients No association between EVI1 expression and any clinical/lab characteristics or characteristics commonly associated with progression to advanced phase none of the EVI1+ patients harboured a T315I mutation Retrospective analysis revealed that EVI-1 expression was not present in diagnostic samples of the 8 patients who were later found to express the protein or in a further 23 CML patients who were negative throughout disease

9 Probability of OS Probability of EFS EVI1 expression predicts for shorter survival in imatinib resistant CP patients Patients with positive EVI-1 expression at the onset of 2G-TKI therapy had a significantly lower 30 month EFS (43.7 vs 90.6%, p=0.0001), PFS (43.7 vs 93.8%, p<0.0001), OS (47.5 vs 95.2%, p=0.0003) and cumulative incidence of CCyR (12.0% vs 59.7%, p=0.05) p= p= IM resistant, EVI-1-negative, n=67 IM resistant, EVI-1-positive, n= Months from start of 2G-TKI Months from start of 2G-TKI 30 EVI1 expression remained an independent predictors for OS, EFS and PFS on multivariate analysis (along with achievement of at least a minor cytogenetic response (MiCyR) during the prior imatinib therapy)

10 Probability of OS After 3 months p=0.003 p=0.01 MiCyR, n=42 No CyR, no EVI-1 expression, n=27 No CyR, EVI-1 expression, n= p= Months from start of 2G-TKI

11 Summary EVI1 expression is detectable in approximately 10% of imatinib-resistant patients without 3q26 rearrangement Expression appears to be acquired over the course of the disease Detection of expression of the EVI-1 oncogene in imatinib-resistant CP CML patients at the start of 2G-TKI therapy is a strong predictor for disease progression and shorter survival. EVI1 expression may therefore be a marker of impending disease acceleration In patients who fail to achieve MiCyR after 3 months of 2G-TKI therapy, EVI-1 expression status may help to distinguish those patients with poor disease outcome from those who have a significantly higher chance of long-term progression-free survival. Measurement of EVI-1 expression at the point of imatinib failure may therefore identify patients who would fare badly on a 2G-TKI regimen and might be better served by early referral for transplant.

12 Acknowledgements Alistair Reid Jamshid Sorouri-Khorashad Valeria Melo Philippa May Letizia Foroni Gareth Gerrard Dragana Milojkovic David Marin John Goldman Jane Apperley Supported by Hammersmith Hospitals Trustees Research Committee

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