IS MUTATION ANALYSIS OF BCR-ABL OF ANY VALUE IN CLINICAL MANAGEMENT OF CML PATIENTS? David Marin, Imperial College London

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1 IS MUTATION ANALYSIS OF BCR-ABL OF ANY VALUE IN CLINICAL MANAGEMENT OF CML PATIENTS? David Marin, Imperial College London

2 Tell me generals, are we politicians necessary?

3 I have to admit defeat before starting Mutation analysis, like politicians have some uses. However, these uses have been grossly exaggerated and in clinical practice its utility is very limited (although real).

4 IS MUTATION ANALYSIS OF BCR-ABL OF ANY VALUE IN CLINICAL MANAGEMENT OF CML PATIENTS? IS MUTATION ANALYSIS OF BCR-ABL a VERY IMPORTANT TOOL IN THE CLINICAL MANAGEMENT OF CML PATIENTS? no

5 The points I want to make are: The meaning of KD mutations is often misunderstood The uses in clinical practice are very limited

6 Are you sure? Sensitivity studies help us to choose the best antibiotic. Similarly mutation analysis help us to choose the best TKI

7 Dasatinib 100 mg QD in CML-CP: 24-month data (034) Figure 3. MCyR rates in patients with or without a baseline BCR-ABL mutation % 80 Any BCR-ABL mutation No BCR-ABL mutation PCyR CCyR ASH mg once daily (n=49) 70 mg BID (n=50) 140 mg once daily (n=50) 50 mg BID (n=63) 100 mg once daily (n=98) 70 mg BID (n=96) 140 mg once daily (n=89) 50 mg BID (n=86)

8 Percentage of mutant transcripts Group A, High transcript levels- mutant clone predominates BCR/ABL/ABL ratio (%) Imatinib: Time since the onset of imatinib therapy (months) M244V Interval from diagnosis to start of imatinib: 4 months Khorashad, Leukemia 2006

9 Percentage of mutant transcripts Group B, Low transcript levels- mutant clone predominates BCR/ABL/ABL ratio (%) Imatinib: Time since the onset of imatinib therapy (months) S438C Interval from diagnosis to start of imatinib: 2 months Khorashad, Leukemia 2006

10 Percentage of mutant transcripts Group C, Variable transcript levels- mutant clone is rare BCR/ABL/ABL ratio (%) Imatinib: Time since the onset of imatinib therapy (months) G250E Interval from diagnosis to start of imatinib: 36 months Khorashad, Leukemia 2006

11 What is the biological significance of KD mutations?

12 In order to answer this question we systematically screened all our CP (n=319) patients treated with imatinib for mutations regardless of whether or not they shown any sign of resistance

13 Mutation screening Mutation=0 Mutation=M244V, 55% undetectable 5% 20% 12 m 18 m Khorashad et al, JCO, 2008

14 Cumulative Incidence of KD Mutations 1.0 Cumulative incidence of KD mutations % Months from starting imatinib therapy Khorashad et al, JCO, 2008

15 Mutations in Patients who Achieved CCyR 214 CCyR patients: 6 (3%) with mutations All of them lost CCyR T315I, L387M, S417F, E459K, G459K, and M351T Median interval from mutation detection to loss of CCyR: 20.8 months Median interval from mutation detection to any change in the BCR-ABL transcript level: 12 months Khorashad et al, JCO, 2008

16 The Development of Mutation Predicts for the Loss of CCyR KD mutation was the only predictive factor for loss of CCyR in the multivariate analysis: RR=3.8, p=0.005 Khorashad et al, JCO, 2008

17 Prognostic Impact on PFS Among 319 patients, 49 (15%) progressed to advanced phase 17 of 49 (35%) had a mutation detected before progression 14 of 17 had a mutation detected while still in CHR median interval (detection-progression): 16.3 months median interval (detection-loss of CHR): 13.7 months Khorashad et al, JCO, 2008

18 Prognostic Impact on PFS Multivariate analysis in the whole population (m=319), showed that KD mutations and the achievement of CCyR are the only independent predictor for PFS CCyR (RR=0.15, p<0.0001) Mutation detection (RR=2.3, p=0.014) Khorashad et al, JCO, 2008

19 Landmark at 2 Years, PFS CCyR vs no CCyR Mutation vs. no mutation Probability of PFS CCyR (n=143) -- no CCyR (n=107) 6 P< % 66% Months from starting imatinib therapy Probability of PFS no mutation group (n=225) -- mutation group (n=25) 6 P= % 35% Months from starting imatinib therapy 84 Khorashad et al, JCO, 2008

20 Conclusion TKD mutations are mere surrogate markers for genetic instability and in many cases are not the real reason for resistance Khorashad et al, JCO, 2008

21 How should we use the mutation screening in practice?

22 A. Perform a mutation analysis on a regular basis (i.e every 3 months) regardless of any sign of resistance Caveat: it is extremely cost ineffective A. Perform mutation analysis only at the moment of switching therapy

23 BCR-ABL mutation status before starting dasatinib. Frequency of baseline BCR-ABL mutations by in vitro IC 50 to dasatinib (N=1043) EHA 2009 No BCR-ABL mutation (n=641) 61% 8% Unknown IC 50 to dasatinib (n=83) 43 different BCR-ABL mutations 24% IC 50 3 nm (n=254) M244V, G250E, Y253F/H/K, F311L, M351T, E355G, F359C/I/V, V379I, L387M, H396P/R 2% T315I (n=21) IC 50 >200 nm <1% V299L (n=1) 1% Q252H (n=6) 1% F317L (n=14) 2% E255K/V (n=25) IC 50 >3 nm (n=44) 4% Müller M, et al. ASH 2008: Abstract 449.

24 2G-TKD mutations Dasatinib: T315I, T315A, V299L F317V, F317L Nilotinib: T315I, Y253F, Y253H, E255V, E255K

25 BCR/ABL/ABL ratio (%) The important is thing that they are resistant, not whether a mutation is present or not!!!!! Time since the onset of imatinib therapy (months) My patient is not responding, Should I do a mutation analysis?

26 3. Mutations are surrogate marker for genomic instability You agree with me if you think that: 1. What matters is whether the patient is resistant, not if a mutation is present. 2. Mutation analysis may be helpful in choosing a 2G-TKI in 5%-10% of the cases

27 Hugues de Lavallade Jamshid S Khorashad Dragana Milojkovic Letizia Foroni Marco Bua Jane Apperley & John Goldman Acknowledgements Thanks David Marin