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Chronic myeloid leukaemia

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Presentation on theme: "Chronic myeloid leukaemia"— Presentation transcript:

1 Chronic myeloid leukaemia
David Marin, Imperial College London

2 Survival of 246 patients who received Interferon therapy within the UK Medical Research Council's CML-III trial ( ) Survival of 224 patients who received first line imatinib therapy therapy in Hammersmith Hospital ( )

3 28 May 2001 2001

4 1998 (C30H35N7SO4) Imatinib mesylate (STI571 - Glivec)
(From Novartis Pharma)

5 Mechanism of action of imatinib
Bcr-Abl Bcr-Abl Substrate Substrate P P P Y ATP Imatinib P Y = Tyrosine P = Phosphate

6 Bosutinib (SK-606) Ponatinib

7 Selectivity of Tyrosine Kinase Inhibitors
Target kinases for the 4 TKIs Selectivity of Tyrosine Kinase Inhibitors Imatinib (Phos. IC50) PDGFR 72 nM > Kit 99 nM BcrAbl 221 nM Src >1000 nM Nilotinib 20 nM 75 nM 209 nM Dasatinib 0.1 nM 1.8 nM 2.9 nM 18 nM Bosutinib 3 nM 85 nM >3000 >10000 nM 1. Manley PW, et al. Proc Am Assoc Cancer Res 2007;48:772. 2. Weisberg E, et al. Cancer Cell 2005;7:1129. 3. Remsing Rix LL, et al. Leukemia 2009;23:477.

8 Comparison of Kinase Inhibitors: Toxicity
Imatinib (STI571) Gleevec* Nilotinib (AMN 107) Tasigna* Dasatinib (BMS354825) Sprycel* Bosutinib (SK606) Hematologic ++ + Pleural Effusions - +++ Hepatic Pancreatitis GI Bleeding Platelet Function ? Immune Diarrhea Q-Tc +? 8

9 Licensed First Line Second Line Imatinib Nilotinib Dasatinib Bosutinib
1st and 2nd line Gold standard No published experience Nilotinib Early data suggest small advantage over Imatinib 40-50% CCyR Dasatinib Bosutinib No (1st line soon) Not yet clear, maybe slightly better than imatinib Ponatinib No (2nd line soon?) No yet tried 10-30% of responses in 3rd line (T315I active)

10 ¿Darling, Should not you check whether the patient is responding?
Darling, this morning I saw a new patient with CML and I prescribed him a TKI. I have done my duty! ¿Darling, Should not you check whether the patient is responding?

11 Patients who fail to achieve CCyR progress to advance phase (n=204)
Probability of PFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Months from starting imatinib therapy 60 54 48 42 36 30 24 18 12 6 0.1 0.0 p<0.0001 Marin, Blood 2008

12 Patients who achieve CCyR do well and patients who fail to achieve CCyR do badly (IRIS data)
Estimated rate (95% CI) at 42 months: n= % (89%, 96%) n= % (66%, 92%)

13 TKI therapy only prolongs live on those patients who achieve CCyR
2G-TKI responders, n=67, aRR=0.05, p=0.003 Time from diagnosis (years) 7 6 5 4 3 2 1 Provability of OS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Imatinib responders, n= 179, aRR= 0.18, p<0.0001 Interferon controls, n =246, aRR=1 TKI non responders, n= 37 aRR= 0.76, p=0.65 Ibrahim, Haematologica 2011

14 Patients must achieve CCyR
How we know that the patient has achieved CCyR? When the patient has to achieve CCyR? How we make sure that the patient remains in CCyR?

15 Patients must achieve CCyR
How we know that the patient has achieved CCyR? When the patient has to achieve CCyR? How we make sure that the patient remains in CCyR?

16 Patients must achieve CCyR
How we know that the patient has achieved CCyR? When the patient has to achieve CCyR? How we make sure that the patient remains in CCyR?

17 Total number of leukaemia cells
13 Leucocytosis 10 100 12 10 10 Ph-chromosome pos 11 10 1 10 10 0.1 RT-PCR positive 9 10 BCR-ABL/ABL ratio (%) (Ph-negative) 0.01 8 10 0.001 7 Total number of leukaemia cells 10 0.0001 6 10 5 10 4 10 RT-PCR negative 3 10 2 10 10 Adapted from Lin et al. Genes Chromosomes and Cancer 1995

18 Total number of leukaemia cells
Metaphases Transcript level at diagnosis 10 1 0.1 0.01 0.001 100 BCR/ABL/ABL ratio (%) Total number of leukaemia cells 1011 1010 109 108 107 1012 1013 High WBC Metaphases Normal WBC CHR

19 Cumulate incidence of CCyR
PFS and probability of CCyR according to the haematological response at 3 months 60 54 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 CHR, n=216 Cumulate incidence of CCyR Probability of PFS No CHR, n=8 PFS: p=0.002 CCyR: p=0.0003 Months from starting imatinib therapy Marin, Blood 2008

20 Total number of leukaemia cells
Transcript level at diagnosis 10 1 0.1 0.01 0.001 100 BCR/ABL/ABL ratio (%) Total number of leukaemia cells 1011 1010 109 108 107 1012 1013 Metaphases CHR Metaphases MiCyR

21 Total number of leukaemia cells
Transcript level at diagnosis 10 1 0.1 0.01 0.001 100 BCR/ABL/ABL ratio (%) Total number of leukaemia cells 1011 1010 109 108 107 1012 1013 Metaphases CHR MiCyR MiCyR Metaphases MCyR

22 Total number of leukaemia cells
10 1 0.1 0.01 0.001 100 BCR/ABL/ABL ratio (%) Total number of leukaemia cells 1011 1010 109 108 107 1012 1013 Metaphases CHR MiCyR MCyR MCyR Metaphases CCyR

23 Total number of leukaemia cells
10 1 0.1 0.01 0.001 100 BCR/ABL/ABL ratio (%) Total number of leukaemia cells 1011 1010 109 108 107 1012 1013 Metaphases CHR MiCyR MCyR CCyR CCyR Metaphases MMR

24 Total number of leukaemia cells
10 1 0.1 0.01 0.001 100 BCR/ABL/ABL ratio (%) Total number of leukaemia cells 1011 1010 109 108 107 1012 1013 Metaphases CHR MiCyR MCyR CCyR MMR MMR Metaphases CMR

25 Patients must achieve CCyR
How we know that the patient has achieved CCyR? When the patient has to achieve CCyR? How we make sure that the patient remains in CCyR?

26 Probability of CCyR according
to the cytogenetic response at 3 and 6 months (n=204) 60 54 48 42 36 30 24 18 12 6 0.0 Months from start of imatinib therapy 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Cumulative incidence of response 1-35% Ph+ 36-95% Ph+ 96-100% Ph+ A, 3 months B, 6 months p< p< de Lavallade, JCO 2008

27 Patients must achieve CCyR
How we know that the patient has achieved CCyR? When the patient has to achieve CCyR? How we make sure that the patient remains in CCyR?

28 Months from start of imatinib
How to monitor the patient and desired responses MiCyR? MCyR? CCyR? { G-Banding { MMR? Early detection of relapse RQ-PCR 100 10 CCyR 1 3 log BCR/ABL/ABL ratio (%) 0.1 FISH negative 0.01 0.001 Level of detection 0.0001 3 6 9 12 15 18 21 24 27 Months from start of imatinib

29 So, what is the best first line therapy?

30 Study Design and Endpoints
R A N D O M I Z ED * Nilotinib 300 mg BID (n = 282) N = 846 217 centers 35 countries Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Follow-up 5 years Primary endpoint: MMR at 12 months Key secondary endpoint: Durable MMR at 24 months Other endpoints: CCyR by 12 months, time to MMR and CCyR, EFS, PFS, time to AP/BC on study treatment, OS including follow-up *Stratification by Sokal risk score 30 30

31 Dasatinib Versus Imatinib Study In Treatment-naïve CML: DASISION (CA180-056). Design
Imatinib 400 mg QD (n=260) Dasatinib 100 mg QD (n=259) N=519 108 centers 26 countries Follow-up 5 years Randomized* *Stratified by Hasford risk score Primary endpoint: Confirmed CCyR by 12 months Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival

32 CCyR Rates* by 12 Months and Overall
P < .001 P < .0001 P = .017 P < .001 % CCyR n = n = n = 283 n = n = n = 283 Among patients who had a cytogenetic assessment at 18 months (n = 442/846), the rates of CCyR were: 99%, 99%, and 89% for nilotinib 300 mg BID, 400 mg BID, and imatinib Data cut-off: 2Jan2010 *ITT population 32

33 DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. CCyR rates (ITT)
Dasatinib 100mg QD Imatinib 400mg QD P=0.0011 CCyR (%) Mo 3 Mo 6 Mo 9 Mo 12 By analysis of time to CCyR, likelihood of achieving CCyR at any time ~50% higher with dasatinib than with imatinib (stratified log-rank P<0.0001; HR=1.53)

34 Patient Disposition Nilotinib 300 mg BID n = 282 Nilotinib 400 mg BID
Imatinib 400 mg QD n = 283 Still on treatment 80% 81% 75% Discontinued, % 20 19 25 Disease progression* <1 <1 4 Suboptimal response/ treatment failure*# 6 2 8 Adverse events 5 10 8 Abnormal lab. values 2 2 1 Overall, 80% and 81% of patients remained on study in the nilotinib 300 mg BID and 400 mg BID arms, while 75% of patients remained on the imatinib arm Thus, more patients discontinued imatinib (25%) compared with nilotinib 300 mg BID (20%) or 400 mg BID (19%) Importantly, more patients discontinued imatinib due to disease progression to AP/BC, and suboptimal response or treatment failure as defined by the ELN Discontinuation due to adverse events or laboratory abnormalities was lowest for nilotinib 300 mg BID Death 1 Protocol violation 2 2 1 Other reason 4 3 3 *Investigator assessment of criteria #Patients were required to discontinue nilotinib 300 mg BID for suboptimal response but could remain on nilotinib 400 mg BID Data cut-off: 2Jan2010 34

35 DASISION: First-Line Dasatinib vs. Imatinib in CML-CP
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Treatment Discontinuations % Patients Dasatinib 100 mg QD n=258 Imatinib 400 mg QD n=258 Still on treatment 84.5 81.4 Discontinued 15.5 18.6 Treatment failure including progression 5.0 8.9 Study drug toxicity 4.3 Adverse event unrelated 1.2 0.4 Other reason* 4.2 *Includes consent withdrawal, pregnancy, lost to follow-up and death

36 Outcome in 282 patients treated with imatinib
first line in Hammersmith Hospital 94% 6% death non CML 10% death because the CML 84% 77% 7% alive but not in CCyR 29% in CCyR but not on imatinib 48% 48% in CCyR on imatinib

37 Outcome in 135 patients treated with second line
dasatinib or nilotinib in Hammersmith Hospital Probability Time (years) from the onset of second line therapy OS, 82% C-CCyRS, 54% EFS, 35%

38 Outcome in 135 patients treated with second line dasatinib or nilotinib according to the cytogenetic response achieved at 12 months Time (years) from the onset of second line therapy Probability of cCCyR-S p=0.008 CCyR at 12 months, n=48 no CCyR at 12 months, n=51

39 Outcome in 135 patients treated with second line dasatinib or nilotinib according to the cytogenetic response achieved at 12 months Time (years) from the onset of second line therapy Probability CCyR at 12 months, n=48 no CCyR at 12 months, n=51

40 It is far from certain which is going to be the best line therapy as the log term benefit of a modest improvement in the CCyR rate induced by a given drug may be easily overcome by a higher therapy discontinuation rate on that drug

41 the molecular response achieved at 3 months
Cumulative incidence of CCyR in patients treated with dasatinib first line therapy in the SPIRIT-II trial according to the molecular response achieved at 3 months Cumulative incidence of CCyR Time from diagnosis (months) 3 months BCR-ABL/ABL <10% 3 months BCR-ABL/ABL >10% p=0.02

42 Cumulative incidence of CCyR in the SPIRIT-II trial according to the treatment arm and the molecular response achieved at 3 months Time from diagnosis (months) Cumulative incidence of CCyR 3 months BCR-ABL/ABL <10% 3 months BCR-ABL/ABL >10% Dasatinib Imatinib

43 The key principles of therapy are:
Promptly identification of the high risk patients Change of therapy according to tolerance and response

44 What is the best why to detect who is not doing well?

45 Probability of CCyR according
to the cytogenetic response at 3 and 6 months (n=204) 60 54 48 42 36 30 24 18 12 6 0.0 Months from start of imatinib therapy 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Cumulative incidence of response 1-35% Ph+ 36-95% Ph+ 96-100% Ph+ A, 3 months B, 6 months p< p< de Lavallade, JCO 2008

46 We can do better than that!

47 We can identify what is the 3 months transcript level that predicts for overall survival with the maximal sensitivity and specify

48 Survival in 282 patients treated with imatinib first line in Hammersmith Hospital according to the molecular response achieved at 3 months BCR-ABL/ABL<10% OS= 93.3% Probability of survival BCR-ABL/ABL>10% OS= 54% p<0.0001 Time from onset of imatinib therapy (years)

49 Outcome in 282 patients treated with imatinib first line in Hammersmith Hospital according to the molecular response achieved at 3 months BCR-ABL/ABL<10%, c-CCyRS= 91% Probability of c-CCyRS BCR-ABL/ABL>10% c-CCyRS= 48% p =0.0002 Time from onset of imatinib therapy (years)

50 Evolution of the transcript level in 282 patients treated
with imatinib first line therapy Off Imatinib CMR BCR-ABL1/ABL1 (log) high transcript level at 3 month low transcript level at 3 month

51 8-year cumulative incidence of CMR on imatinib therapy according
to the BCR-ABL1 transcript level at 3 months. Cumulative incidence of CMR Time from onset of therapy (years) 3-month transcript ratio ≤0.61% (n=57), 8-year CI of CMR of 84.7%, p<0.0001 3-month transcript ratio >0.61% (n=222), 8-years CI of CMR of 1.5%

52 It is important to achieve MMR?

53 Months from start of imatinib
Molecular responses 10 1 0.1 0.01 0.001 100 0.0001 BCR/ABL/ABL ratio (%) CCyR 6 9 15 18 21 24 27 3 Months from start of imatinib 12 Level of detection 3 log FISH negative

54 PFS is similar in patients with CCyR regardless of the depth of molecular response
60 54 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 with no MMR, n=91 CCyR with MMR, n= 41 p= 0.4 18 months Marin et al, Blood 2008

55 PFS similar in patients with CCyR regardless of depth of molecular response
Druker BJ, et al. NEJM, 2006;355(25):

56 PFS is similar in patients with CCyR regardless of depth of molecular response
Kantarjian HM, et al. Blood. 2006;108:

57 Probability of loss of CCyR according to the level of molecular response
Marin et al, Blood 2008

58 The definition of MMR is wrong
Do not be silly!

59 Problems with MMR The depth of the molecular response in a given patient is basically driven by the patient’s adherence to therapy The definition of MMR is arbitrary

60 Problems with MMR The depth of the molecular response in a given patient is basically driven by the patient’s adherence to therapy The definition of MMR is arbitrary

61 There is a great variability in the response to imatinib. I wonder why
10 1 0.1 0.01 0.001 100 BCR-ABL/ABL ratio (%) CCyR 3 log 0.0001 Time from start of imatinib

62 Time from start of imatinib
Study design 10 1 0.1 0.01 0.001 100 BCR/ABL/ABL ratio (%) MEMS Imatinib plasma level TKD mutations Time from start of imatinib hOCT1 level MDR-1 polymorphisms BCR-ABL transcript type BCR-ABL transcript level Sokal score Hb WBC Sex Age We correlated all these variables with the molecular response achieved by the patient 62

63 Microelectronic Monitoring System (MEMS 6 Trackcap)
Records the time of opening the container Most reliable method of measuring adherence Our patients: not told about the chip The over adherence was studied in patients taking tamoxifen in the Waterhouse paper 63

64 64 64

65 Long term adherence to imatinib
90 80 70 60 Proportion of patients (%) 50 40.2% 40 30 25.3% 20 13.8% 12.6% 8% 10 <80% 80–90% 90–95% 95–99% ≥100% Percentage of intended dose Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.

66 Lack of adherence is underestimated by conventional methods
Percentage of intended dose ≥100% 95–99% 90–95% 80–90% <80% Proportion of patients (%) 100 90 80 70 60 50 40 30 20 10 Self reporting Pill count MEMS Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.

67 67

68 Well, some patients miss a few doses,
so what?

69 6-year probability of response
Achievement of a molecular response is related to the adherence to imatinib therapy 6-year probability of response Adherence rate n MMR (%) 4-log (%) CMR (%) 100% <99% 36 51 p=0.01 91.1 58.6 p=0.02 79.9 38.6 46.7 22.7 >95% <95% 57 30 p<0.001 94.5 29.3 77.2 15.0 p=0.002 45.2 8.2 >90% <90% 64 23 93.7 13.9 76.0 4.3 43.8 >85% <85% 69 18 85.8 11.8 p=0.001 69.2 5.6 p=0.007 40.8 >80% <80% 75 12 81.2 p=0.005 63.8 p=0.04 37.1 Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.

70 6-year probability of MMR according to the measured adherence rate
Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388. 70

71 6-year probability of CMR according to the measured adherence rate
Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.

72 Other variables are also predictive for the achievement of molecular response
MMR (%) 4-log (%) CMR (%) Hemoglobin ≤115 g/l >115 g/l RR 40 47 p=0.036 59.2 80.7 1.186, p=0.012 p=0.03 39.5 69.1 1.323, p=0.01 p=0.011 14.7 47.6 1.209, p=0.07 Leukocytes ≤140 x 109/l >140 x 109/l 44 43 p=0.012 78.8 63.1 0.996, p=0.008 p=0.022 56.7 37.6 0.996, p=0.015 p=0.17 35.4 28.1 0.996, p=0.11 BCR-ABL1/ABL1 ratio ≤100% >100% p=0.25 71.4 52.6 0.996, p=0.44 p=0.038 53.0 26.6 0.971, p=0.002 p=0.1 32.7 8.4 0.979, p=0.13 hOCT1 transcript level ≤0.16 >0.16 30 p<0.001 55.2 81.4 2.199, p<0.001 p=0.01 42.0 64.8 1.990, p=0.001 p=0.02 16.6 45.3 1.665, p=0.04 Imatinib plasma level ≤1 g/ml >1 g/ml 41 60.1 83.2 2.11, p=0.01 p=0.07 68.0 2.50, p=0.06 p=0.14 23.3 44.4 2.25, p=0.09 Adherence rate >90% ≤90% 64 23 93.7 13.9 1.093, p<0.001 76.0 4.3 1.104, p=0.002 p=0.002 43.8 RR= 1.135, p=0.012 Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.

73 But adherence to therapy is the critical factor for achieving molecular response
MMR adherence to imatinib therapy, RR=11.17 (p=0.001) hOCT1 transcript level, RR=1.79 (p=0.038) CMR adherence to imatinib therapy, RR=19.35 (p=0.004) Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.

74 Imatinib plasma levels are not an independent predictor of molecular response
Adherent patients Total population Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.

75 Who will sustain CCyR?

76 Time from start of imatinib
Study design 10 1 0.1 0.01 0.001 100 BCR/ABL/ABL ratio (%) MEMS Time from start of imatinib hOCT1 level MDR-1 polymorphisms BCR-ABL transcript type BCR-ABL transcript level Sokal score Hb WBC Sex Age We correlated all these variables with the molecular response achieved by the patient 76

77 Poor adherent patients have a higher probability of losing the CCyR and a lower EFS
Ibrahim, Blood 2011

78 On multivariate analysis, the adherence rate and having failed to achieve a major molecular response are the only independent predictors for loss of CCyR and discontinuation of imatinib therapy. Ibrahim, Blood 2011

79 Probability of imatinib failure
Adherence and the achievement of MMR are the only independent predictors for outcome Probability of imatinib failure 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Months from enrolment 0.0 24 18 12 6 p<0.0001 CCyR, no MMR, Adherence Rate ≤85%, n=11 MMR, n=53 CCyR, no MMR, Adherence Rate >85%, n=23 p=0.003 Ibrahim, Blood 2011

80 Problems with MMR The depth of the molecular response in a given patient is basically driven by the patient’s adherence to therapy The definition of MMR is arbitrary

81 Total number of leukaemia cells
10 1 0.1 0.01 0.001 100 BCR/ABL/ABL ratio (%) Total number of leukaemia cells 1011 1010 109 108 107 1012 1013 Metaphases CHR MiCyR MCyR CCyR CCyR Metaphases MMR

82 166 out of 282 patients who received imatinib as first line therapy were in CCyR at 12 months
Transcript level OS (%) EFS >0.1% <0.1% 125 41 p=0.5 94.2 96.3 p=0.08 80.4 93.7

83 166 out of 282 patients who received imatinib as first line therapy were in CCyR at 12 months
Transcript level OS (%) EFS >0.1% <0.1% 125 41 p=0.5 94.2 96.3 p=0.08 80.4 93.7 >0.53 <0.53 20 146 p=0.01 81.5 94.4 p<0.0001 29.5 74.3

84 It can not be a talk about CML without mentioning KD mutations

85 I am going to try to challenge the orthodox view about kinase domain mutations

86

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

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

89 Figure 3. MCyR rates in patients with or without a baseline BCR-ABL mutation
80 Any BCR-ABL mutation No BCR-ABL mutation 70 66 67 67 11 56 8 10 60 55 PCyR 54 12 CCyR 48 8 14 22 11 % 40 58 58 57 54 46 20 41 37 34 100 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)

90 Group A, High transcript levels- mutant clone predominates
10 1 0.1 0.01 0.001 100 0.0001 100 75 Percentage of mutant transcripts 50 BCR/ABL/ABL ratio (%) 25 Imatinib: 600 800 1000 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 M244V Time since the onset of imatinib therapy (months) Interval from diagnosis to start of imatinib: 4 months Khorashad, Leukemia 2006

91 Group B, Low transcript levels- mutant clone predominates
100 100 10 75 Percentage of mutant transcripts 1 50 0.1 25 BCR/ABL/ABL ratio (%) 0.01 Imatinib: 400 600 400 0.001 S438C 0.0001 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

92 Group C, Variable transcript levels- mutant clone is rare
10 1 0.1 0.01 0.001 100 0.0001 100 75 Percentage of mutant transcripts 50 25 BCR/ABL/ABL ratio (%) Imatinib: 400 3 6 9 12 15 18 21 24 27 30 33 35 36 39 42 45 G250E Time since the onset of imatinib therapy (months) Interval from diagnosis to start of imatinib: 36 months Khorashad, Leukemia 2006

93 What is the biological significance of KD mutations?

94 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

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

96 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 Cumulative incidence of KD mutations 13.9% 60 54 48 42 36 30 24 18 12 6 Months from starting imatinib therapy Khorashad et al, JCO, 2008

97 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 97

98 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 98

99 First detection of mutation
Example 1 10 1 0.1 0.01 0.001 100 0.0001 BCR/ABL/ABL ratio (%, blue) Time since the onset of imatinib therapy (months) 100% 75% 50% 25% 0% Percentage of mutant transcripts (%, red) 2 3 4 5 6 7 8 9 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 CCyR Loss of CCyR BP Panel A, patient 34 (E459K) Doubling transcript levels First detection of mutation

100 First detection of mutation
Example 2 10 1 0.1 0.01 0.001 100 0.0001 BCR/ABL/ABL ratio (%, blue) Time since the onset of imatinib therapy (months) 100% 75% 50% 25% 0% Percentage of mutant transcripts (%, red) 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 v CCyR Loss of CCyR Panel B, patient 29 (M351T) Doubling transcript levels First detection of mutation

101 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 101

102 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 102

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

104 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

105 How should we use the mutation screening in practice?

106 Perform mutation analysis only at the moment of switching therapy
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 Perform mutation analysis only at the moment of switching therapy

107 Frequency of baseline BCR-ABL mutations by in vitro IC50 to dasatinib (N=1043)
Unknown IC50 to dasatinib (n=83) 43 different BCR-ABL mutations 8% IC50 ≤3 nM (n=254) M244V, G250E, Y253F/H/K, F311L, M351T, E355G, F359C/I/V, V379I, L387M, H396P/R No BCR-ABL mutation (n=641) 61% 24% <1% V299L (n=1) IC50 >3 nM (n=44) 4% 1% Q252H (n=6) 1% F317L (n=14) 2% E255K/V (n=25) 2% T315I (n=21) IC50 >200 nM Müller M, et al. ASH 2008: Abstract 449.

108 2G-TKD mutations Dasatinib: T315I, T315A, V299L F317V, F317L
Nilotinib: T315I, Y253F, Y253H, E255V, E255K

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

110 Thanks to John Goldman and other friends who are too numerous to be mentioned individually David, Thankfully your patients fare better than your plants


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