chronic myeloid leukaemia david marin, imperial college london

Chronic myeloid leukaemia

David Marin,

Imperial College London

Time from diagnosis (years)

20181614121086420

Survival of 246 patients who received Interferon therapy within the UK Medical Research Council's CML-III trial (1986-1994)

Survival of 224 patients who received first line imatinib therapy therapy in Hammersmith Hospital (2000-2008)

28 May 2001

(From Novartis Pharma)

(C(C3030HH3535NN77SOSO44))

Imatinib mesylate (STI571 - Glivec)

Substrate

Imatinib

Bcr-Abl

Y = TyrosineP = Phosphate

Bcr-Abl

Substrate

Mechanism of action of imatinib

Bosutinib(SK-606)

Ponatinib

Imatinib

(Phos. IC50)

72 nM >Kit

99 nM >BcrAbl

221 nM >Src

>1000 nM

Nilotinib

(Phos. IC50)

BcrAbl

20 nM >PDGFR

75 nM >Kit

209 nM >Src

>1000 nM

Dasatinib

(Phos. IC50)

0.1 nM >BcrAbl

1.8 nM >PDGFR

2.9 nM >Kit

Bosutinib

(Phos. IC50)

3 nM >BcrAbl

85 nM >PDGFR

>3000 >Kit

>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.

Target kinases for the 4 TKIs

Comparison of Kinase Inhibitors: Toxicity

Licensed First Line Second Line

Imatinib 1st and 2nd line Gold standard No published experience

Nilotinib 1st and 2nd line Early data suggest small advantage over Imatinib

40-50% CCyR

Dasatinib 1st and 2nd line Early data suggest small advantage over Imatinib

40-50% CCyR

Bosutinib No (1st line soon) Not yet clear, maybe slightly better than imatinib

40-50% CCyR

Ponatinib No (2nd line soon?) No yet tried 10-30% of responses in 3rd line (T315I active)

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?

Marin, Blood 2008

Months from starting imatinib therapy

60544842363024181260

Patients who fail to achieve CCyR

progress to advance phase (n=204)

p<0.0001

CCyRNo CCyR

Months since randomization0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Patients who achieve CCyR do well and patients who fail to achieve CCyR do badly (IRIS data)

p<0.001

Estimated rate (95% CI)at 42 months:

n=363 93% (89%, 96%)n=139 74% (66%, 92%)

Time from diagnosis (years)

76543210

Interferon controls, n =246, aRR=1

TKI non responders, n= 37aRR= 0.76, p=0.65

Imatinib responders, n= 179,aRR= 0.18, p<0.0001

2G-TKI responders, n=67,aRR=0.05, p=0.003

TKI therapy only prolongs live on those patients who achieve CCyR

Ibrahim, Haematologica 2011

• 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?

Patients must achieve CCyR

Total num

ber of leukaemia cells2

0.0001

Leucocytosis

RT-PCR positive

RT-PCR negative

Ph-chromosome pos

(Ph-negative)

Adapted from Lin et al. Genes Chromosomes and Cancer 1995

Total num

ber of leukaemia cells

1013High WBC

Metaphases

Normal WBC

Transcript level at

diagnosis

PFS and probability of CCyR according to the haematological response at 3 months

60544842363024181260

PFS: p=0.002

CCyR: p=0.0003

No CHR, n=8

CHR, n=216

Marin, Blood 2008

Total num

Metaphases

MiCyRPh +

Metaphases

Transcript level at

diagnosis

Total num

Metaphases

MiCyRPh +

Ph -MiCyR

Metaphases

Transcript level at

diagnosis

Total num

MCyRMCyR

CCyRPh -

Metaphases

Ph -MiCyR

Total num

CCyRCCyR

Metaphases

Ph -MiCyR

Total num

MMRMMR

CMRPh -

Metaphases

Ph -MiCyR

605448423630241812600.0

Months from start of imatinib therapy

nse 1-35% Ph+

36-95% Ph+

96-100% Ph+

605448423630241812600.0

nse 1-35% Ph+

36-95% Ph+

96-100% Ph+

A, 3 months B, 6 months

de Lavallade, JCO 2008

Probability of CCyR according to the cytogenetic response at 3 and 6 months (n=204)

p< 0.0001 p< 0.0001

How to monitor the patient and desired responses

0.0001

6 9 15 18 21 24 273

Months from start of imatinib

Level of detection

RQ-PCR

G-Banding•MiCyR?•MCyR?•CCyR?{

•MMR?•Early detection of relapse{

FISH negative

So, what is the best first line

therapy?

ENESTnd: Nilotinib vs Imatinib in CML-CP

Larson R. A. et al.JCO 28:7s ASCO 2010 (suppl; abs 6501, Oral)30

Study Design and Endpoints

• 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

Imatinib 400 mg QD (n = 283)

Nilotinib 300 mg BID (n = 282)

RANDOMIZED*

Nilotinib 400 mg BID (n = 281)• N = 846

• 217 centers

• 35 countries

Follow-up 5 years

31 ASCO 2010, Abstract # LBA6500

Dasatinib Versus Imatinib Study In Treatment-naïve CML: DASISION (CA180-056). Design

● 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

Follow-up

5 yearsRandomized*

Imatinib 400 mg QD (n=260)

Dasatinib 100 mg QD (n=259)• N=519

• 108 centers

• 26 countries

*Stratified by Hasford risk score

Larson R. A. et al.JCO 28:7s ASCO 2010 (suppl; abs 6501, Oral)

80%85%

78% 82%

65%74%

Month 12 Overall

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD

CCyR Rates* by 12 Months and Overall

P < .0001

P < .001

32Data cut-off: 2Jan2010

n = 282 n = 281 n = 283

P < .001

P = .017

• 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*ITT population

n = 282 n = 281 n = 283

DASISION: First-Line Dasatinib vs. Imatinib

in CML-CP. CCyR rates (ITT)

Mo 3 Mo 6 Mo 9 Mo 12

P=0.0011Dasatinib 100mg QD Imatinib 400mg QD

CCyR(%)

• 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)

Larson R. A. et al.JCO 28:7s ASCO 2010 (suppl; abs 6501, Oral)

Patient DispositionNilotinib

300 mg BIDn = 282

Nilotinib400 mg BID

n = 281

Imatinib400 mg QDn = 283

Still on treatment 80% 81% 75%Discontinued, % 20 19 25 Disease progression* <1 4

Suboptimal response/ treatment failure*# 6 2 8

Adverse events 5 8

Abnormal lab. values 2 2 1

Death 1 0 0

Protocol violation 2 2 1

Other reason 4 3 3

Data cut-off: 2Jan2010

*Investigator assessment of criteria

#Patients were required to discontinue nilotinib 300 mg BID for suboptimal response but could remain on nilotinib 400 mg BID

DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Treatment Discontinuations

*Includes consent withdrawal, pregnancy, lost to follow-up and death

% Patients

Dasatinib 100 mg QDn=258

Imatinib 400 mg QDn=258

Still on treatment 84.5 81.4

Discontinued 15.5 18.6

Treatment failure including progression

5.0 8.9

Study drug toxicity 5.0 4.3

Adverse event unrelated 1.2 0.4

Other reason* 4.2 5.0

48% in CCyR on imatinib

29% in CCyR but not on imatinib

7% alive but not in CCyR

10% death because the CML

6% death non CML

Outcome in 282 patients treated with imatinib first line in Hammersmith Hospital

Outcome in 135 patients treated with second line dasatinib or nilotinib in Hammersmith Hospital

Time (years) from the onset of second line therapy

OS, 82%

C-CCyRS, 54%

EFS, 35%

p=0.008

CCyR at 12 months, n=48

no CCyR at 12 months, n=51

Outcome in 135 patients treated with second line dasatinib or nilotinib according to the cytogenetic

response achieved at 12 months

CCyR at 12 months, n=48

no CCyR at 12 months, n=51

Outcome in 135 patients treated with second line dasatinib or nilotinib according to the cytogenetic

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

Time from diagnosis (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

3 months BCR-ABL/ABL <10%

3 months BCR-ABL/ABL >10%

p=0.02

Time from diagnosis (months)

Dasatinib

Imatinib

Cumulative incidence of CCyR in the SPIRIT-II trial according to the treatment arm and the molecular

3 months BCR-ABL/ABL <10%

3 months BCR-ABL/ABL >10%

The key principles of therapy are:

1.Promptly identification of the high risk patients

2.Change of therapy according to tolerance and response

What is the best why to detect

who is not doing well?

605448423630241812600.0

nse 1-35% Ph+

36-95% Ph+

96-100% Ph+

605448423630241812600.0

nse 1-35% Ph+

36-95% Ph+

96-100% Ph+

A, 3 months B, 6 months

de Lavallade, JCO 2008

Probability of CCyR according to the cytogenetic response at 3 and 6 months (n=204)

p< 0.0001 p< 0.0001

We can do better than

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

Time from onset of imatinib therapy (years)

BCR-ABL/ABL<10% OS= 93.3%

BCR-ABL/ABL>10% OS= 54%

p<0.0001

Survival in 282 patients treated with imatinib first line in Hammersmith Hospital according to the molecular response

achieved at 3 months

Time from onset of imatinib therapy (years)

p =0.0002

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%

BCR-ABL/ABL>10% c-CCyRS= 48%

Off Imatinib

)Evolution of the transcript level in 282 patients treated

with imatinib first line therapy

high transcript level at 3 month

low transcript level at 3 month

Time from onset of therapy (years)

8-year cumulative incidence of CMR on imatinib therapy according to the BCR-ABL1 transcript level at 3 months.

3-month transcript ratio ≤0.61% (n=57), 8-year CI of CMR of 84.7%,

3-month transcript ratio >0.61% (n=222), 8-years CI of CMR of 1.5%

p<0.0001

It is important to achieve MMR?

Molecular responses

0.0001

6 9 15 18 21 24 273

Months from start of imatinib

Level of detection

FISH negative

60544842363024181260

CCyR with no MMR, n=91

CCyR with MMR, n= 41

p= 0.4

18 months

Marin et al, Blood 2008

PFS is similar in patients with CCyR regardless of the depth of molecular

response

PFS similar in patients with CCyR regardless of depth of molecular response

Druker BJ, et al. NEJM, 2006;355(25):2408-17.

PFS is similar in patients with CCyR regardless of depth of molecular response

Kantarjian HM, et al. Blood. 2006;108:1835-1840.

Probability of loss of CCyR according Probability of loss of CCyR according to the level of molecular response to the level of molecular response

Marin et al, Blood 2008

60544842363024181260

p= 0.006

18 months

60544842363024181260

60544842363024181260 60544842363024181260

p= 0.006

18 months

60544842363024181260

CCyR with no MMR, n= 92

p= 0.04

12 months

60544842363024181260

60544842363024181260 60544842363024181260

CCyR with no MMR, n= 92

p= 0.04

12 months

The definition of MMR is

Do not be silly!

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

Problems with MMR

Time from start of imatinib

There is a great variability in the response to imatinib. I wonder why

0.0001

Study design

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

Imatinib plasma

TKD mutations

• Records the time of opening the container

• Most reliable method of measuring adherence

• Our patients: not told about the chip

Microelectronic Monitoring System (MEMS 6 Trackcap)

≥100%95–99%90–95%80–90%<80%

Percentage of intended dose

13.8% 12.6%8%

Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.

Long term adherence to imatinib

Percentage of intended dose≥100%95–99%90–95%80–90%<80%

Self reporting

Pill count

Lack of adherence is underestimated by conventional methods

Well, some patients miss a

few doses, so what?

6-year probability of response

Adherence rate n MMR (%) 4-log (%) CMR (%)

100%<99%

p=0.0191.158.6

p=0.0279.938.6

p=0.0246.722.7

>95%<95%

p<0.00194.529.3

p<0.00177.215.0

p=0.00245.28.2

>90%<90%

p<0.00193.713.9

p<0.00176.04.3

p=0.00243.8

>85%<85%

p<0.00185.811.8

p=0.00169.25.6

p=0.00740.8

>80%<80%

p=0.00181.2

p=0.00563.8

p=0.0437.1

Achievement of a molecular response is related to the adherence to imatinib therapy

6-year probability of MMR according to the measured adherence rate

p<0.001

6-year probability of CMR according to the measured adherence rate

p=0.002

Variables n MMR (%) 4-log (%) CMR (%)

Hemoglobin ≤115 g/l>115 g/lRR

p=0.03659.280.7

1.186, p=0.012

p=0.0339.569.1

1.323, p=0.01

p=0.01114.747.6

1.209, p=0.07

Leukocytes ≤140 x 109/l>140 x 109/lRR

p=0.01278.863.1

0.996, p=0.008

p=0.02256.737.6

0.996, p=0.015

p=0.1735.428.1

0.996, p=0.11

BCR-ABL1/ABL1 ratio≤100%>100%RR

p=0.2571.452.6

0.996, p=0.44

p=0.03853.026.6

0.971, p=0.002

p=0.132.78.4

0.979, p=0.13

hOCT1 transcript level ≤0.16>0.16RR

p<0.00155.281.4

2.199, p<0.001

p=0.0142.064.8

1.990, p=0.001

p=0.0216.645.3

1.665, p=0.04

Imatinib plasma level ≤1 g/ml>1 g/mlRR

p=0.0260.183.2

2.11, p=0.01

p=0.0753.068.0

2.50, p=0.06

p=0.1423.344.4

2.25, p=0.09

Adherence rate>90%≤90%RR

p<0.00193.713.9

1.093, p<0.001

p<0.00176.04.3

1.104, p=0.002

p=0.00243.8

0RR= 1.135, p=0.012

Other variables are also predictive for the achievement of molecular response

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)

Imatinib plasma levels are not an independent predictor of molecular response

Total population Adherent patients

Who will sustain CCyR?

Study design

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

Months from enrolment0

2418126

p<0.0001

Adherence rate ≤85%, n=18

Adherence rate >85%, n=69

2418126

p<0.0001

2418126

p<0.0001

2418126

p<0.0001

Poor adherent patients have a higher probability of losing the CCyR and a lower EFS

Ibrahim, Blood 2011

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

2418126

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

p<0.0001

2418126

p<0.0001

CCyR, no MMR, Adherence Rate ≤85%, n=11

MMR, n=53

CCyR, no MMR, Adherence Rate >85%, n=23

p=0.0009

p<0.0001

Adherence and the achievement of MMR are the only independent predictors for outcome

Ibrahim, Blood 2011

Problems with MMR

Total num

CCyRCCyR

Metaphases

Ph -MiCyR

166 out of 282 patients who received imatinib as first line therapy were in CCyR at 12 months

Transcript level

p=0.08

166 out of 282 patients who received imatinib as first line therapy were in CCyR at 12 months

Transcript level

p=0.08

p=0.01

p<0.0001

It can not be a talk about CML

without mentioning KD

mutations

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

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

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)

80 Any BCR-ABL mutation No BCR-ABL mutation

0.0001

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)

Imatinib: 400 1000 800 600

Percen

tage o

f mutant transcripts

Interval from diagnosis to start of imatinib: 4 months

Group A, High transcript levels- mutant clone predominates

Khorashad, Leukemia 2006

0.0001

0 3 6 9 12 15 18 21 24 27 30 33 35 36 39 42 45

Percen

tage o

Imatinib: 400 600 400

Group B, Low transcript levels- mutant clone predominates

0.0001

0 3 6 9 12 15 18 21 24 27 30 33 35 36 39 42 45

Imatinib: 400

Percen

tage o

Group C, Variable transcript levels- mutant clone is rare

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

18 m12 m

Mutation=M244V, 55%

undetectable 5%

Mutation=0

Mutation screening

Khorashad et al, JCO, 2008

Cumulative Incidence of KD Mutations

0.060544842363024181260

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

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

0.0001

Percentage of m

utant transcripts (%, red)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

Loss of CCyR

Panel A, patient 34 (E459K)

Doubling transcript levels

First detection of mutation

Example 1

Example 2

0.0001

Percentage of m

utant transcripts (%, red)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63

CCyR Loss of CCyR

Panel B, patient 29 (M351T)

Doubling transcript levels

First detection of mutation

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

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)

Landmark at 2 Years, PFS

8478726660524842363024181260

-- CCyR (n=143)-- no CCyR (n=107)

P< 0.0001

8478726660524842363024181260

P= 0.0001

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

CCyR vs no CCyR Mutation vs. no mutation

Conclusion

TKD mutations are mere surrogate markers for genetic instability and in many cases are not the real reason for resistance

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

B. Perform mutation analysis only at the moment of switching therapy

BCR-ABL mutation status before starting dasatinib.EHA 2009

Frequency of baseline BCR-ABL mutationsby 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-ABLmutation(n=641)

IC50 >3 nM(n=44)

2% T315I (n=21)IC50 >200 nM

1% Q252H (n=6)

1% F317L (n=14)

<1% V299L (n=1)

2% E255K/V (n=25)

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

2G-TKD mutations

• Dasatinib: T315I, T315A, V299L F317V, F317L

• Nilotinib: T315I, Y253F, Y253H, E255V, E255K

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

Thanks to John Goldman and other friends who are too numerous to be

mentioned individually

David, Thankfully your patients fare better than your

plants

chronic myeloid leukaemia david marin, imperial college london

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