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?

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).

I have to admit defeat before starting

IS MUTATION ANALYSIS OF BCR-ABL a VERY IMPORTANT TOOL IN THE CLINICAL MANAGEMENT OF CML PATIENTS? IS MUTATION ANALYSIS OF BCR-ABL OF ANY VALUE IN 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?

ASH 2008

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

PCyR CCyR

%

100 mg

• nce

daily (n=49)

55

41 14 70 mg BID (n=50)

54

46 8 140 mg

• nce

daily (n=50)

56

34 22 50 mg BID (n=63)

48

37 11 100 mg

• nce

daily (n=98)

66

54 12 70 mg BID (n=96)

67

58 8 140 mg

• nce

daily (n=89)

70

58 11 50 mg BID (n=86)

67

57 10

20 40 60 80 Any BCR-ABL mutation No BCR-ABL mutation

10 1 0.1 0.01 0.001 100 0.0001 BCR/ABL/ABL ratio (%) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time since the onset of imatinib therapy (months) Imatinib: 400 1000 800 600 100 75 50 25 P e r c e n t a g e

• f

m u t a n t t r a n s c r i p t s Interval from diagnosis to start of imatinib: 4 months

M244V

Group A, High transcript levels- mutant clone predominates

Khorashad, Leukemia 2006

10 1 0.1 0.01 0.001 100 0.0001 BCR/ABL/ABL ratio (%) 3 6 9 12 15 18 21 24 27 30 33 35 36 39 42 45 Time since the onset of imatinib therapy (months) 100 75 50 25 P e r c e n t a g e

• f

m u t a n t t r a n s c r i p t s Imatinib: 400 600 400

Group B, Low transcript levels- mutant clone predominates

S438C

Interval from diagnosis to start of imatinib: 2 months

Khorashad, Leukemia 2006

10 1 0.1 0.01 0.001 100 0.0001 BCR/ABL/ABL ratio (%) 3 6 9 12 15 18 21 24 27 30 33 35 36 39 42 45 Time since the onset of imatinib therapy (months) Imatinib: 400 100 75 50 25 P e r c e n t a g e

• f

m u t a n t t r a n s c r i p t s Interval from diagnosis to start of imatinib: 36 months

Group C, Variable transcript levels- mutant clone is rare

G250E

Khorashad, Leukemia 2006

What is the biological significance

• f 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

18 m 12 m Mutation=M244V, 55%

undetectable 5%

Mutation=0

20%

Mutation screening

Khorashad et al, JCO, 2008

13.9%

Cumulative Incidence of KD Mutations

Cumulative incidence of KD mutations

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 60 54 48 42 36 30 24 18 12 6

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

• f 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

84% 35% 90% 66%

84 78 72 66 60 52 48 42 36 30 24 18 12 6 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Probability of PFS Months from starting imatinib therapy

• - CCyR (n=143)
• - no CCyR (n=107)

P< 0.0001

84 78 72 66 60 52 48 42 36 30 24 18 12 6 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Probability of PFS Months from starting imatinib therapy

P= 0.0001

• -’no mutation’ group (n=225)
• -’mutation’ group (n=25)

CCyR vs no CCyR Mutation vs. no mutation

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

BCR-ABL mutation status before starting dasatinib.

EHA 2009

Frequency of baseline BCR-ABL mutations by in vitro IC50 to dasatinib (N=1043)

IC50 ≤3 nM (n=254) M244V, G250E, Y253F/H/K, F311L, M351T, E355G, F359C/I/V, V379I, L387M, H396P/R Unknown IC50 to dasatinib (n=83) 43 different BCR-ABL mutations

No BCR-ABL mutation (n=641) 61%

IC50 >3 nM (n=44) 4% 2% T315I (n=21) IC50 >200 nM 1% Q252H (n=6) 1% F317L (n=14) <1% V299L (n=1) 2% E255K/V (n=25)

24% 8%

Müller M, et al. ASH 2008: Abstract 449.

2G-TKD mutations

• Dasatinib: T315I, T315A, V299L F317V, F317L
• Nilotinib: T315I, Y253F, Y253H, E255V, E255K

10 1 0.1 0.01 0.001 0.0001 BCR/ABL/ABL ratio (%) 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?

The important is thing that they are resistant, not whether a mutation is present or not!!!!!

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

David Marin

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