IS MUTATION ANALYSIS OF BCR-ABL OF ANY VALUE IN CLINICAL MANAGEMENT - PowerPoint PPT Presentation

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

Tell me generals, are we politicians necessary?

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).

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

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

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

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 70 67 66 67 11 8 10 PCyR 60 56 12 55 54 CCyR 48 8 14 22 11 40 % 58 58 57 54 46 20 41 37 34 0 100 mg 70 mg 140 mg 50 mg 100 mg 70 mg 140 mg 50 mg once BID once BID once BID once BID daily daily daily daily (n=49) (n=50) (n=50) (n=63) (n=98) (n=96) (n=89) (n=86) ASH 2008

Group A, High transcript levels- mutant clone predominates P e r 100 100 c e n t a 10 75 g BCR/ABL/ABL ratio (%) e o f 1 50 m u t a n 25 0.1 t t r a n s 0 0.01 c r i 800 Imatinib: 400 600 1000 p t s 0.001 0.0001 M244V 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time since the onset of imatinib therapy (months) Interval from diagnosis to start of imatinib: 4 months Khorashad, Leukemia 2006

Group B, Low transcript levels- mutant clone predominates P e r c e 100 100 n t a g e 10 75 o BCR/ABL/ABL ratio (%) f m u 1 50 t a n t t 25 0.1 r a n s c 0 0.01 r i p Imatinib: 400 600 400 t s 0.001 S438C 0.0001 0 3 6 9 12 15 18 21 24 27 30 33 35 36 39 42 45 Time since the onset of imatinib therapy (months) Interval from diagnosis to start of imatinib: 2 months Khorashad, Leukemia 2006

Group C, Variable transcript levels- mutant clone is rare P e r c e n t 100 100 a g e o 10 75 f BCR/ABL/ABL ratio (%) m u t a 1 50 n t t r a 25 0.1 n s c r i p 0.01 0 t s Imatinib: 400 0.001 0.0001 G250E 0 3 6 9 12 15 18 21 24 27 30 33 35 36 39 42 45 Time since the onset of imatinib therapy (months) Interval from diagnosis to start of imatinib: 36 months Khorashad, Leukemia 2006

What is the biological significance of KD mutations?

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

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

Cumulative Incidence of KD Mutations 1.0 Cumulative incidence of KD mutations 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 13.9% 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 Months from starting imatinib therapy Khorashad et al, JCO, 2008

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

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

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

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

Landmark at 2 Years, PFS CCyR vs no CCyR Mutation vs. no mutation 90% 1.0 84% 1.0 0.9 0.9 0.8 66% 0.8 Probability of PFS Probability of PFS 0.7 0.7 0.6 0.6 35% -- CCyR (n=143) 0.5 0.5 -- no CCyR (n=107) 0.4 0.4 --’no mutation’ group (n=225) 0.3 0.3 --’mutation’ group (n=25) 0.2 0.2 P< 0.0001 P= 0.0001 0.1 0.1 0.0 0.0 0 6 12 18 24 30 36 42 48 52 60 66 72 78 84 0 6 12 18 24 30 36 42 48 52 60 66 72 78 84 Months from starting imatinib therapy Months from starting imatinib therapy Khorashad et al, JCO, 2008

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

How should we use the mutation screening in practice?

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

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

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

10 BCR/ABL/ABL ratio (%) The important is thing 1 that they are resistant, 0.1 not whether a mutation 0.01 is present or not!!!!! 0.001 0.0001 0 3 6 9 12 15 18 21 24 27 30 33 35 36 39 42 45 Time since the onset of imatinib therapy (months) My patient is not responding, Should I do a mutation analysis?

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 3.Mutations are surrogate marker for genomic instability

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