Questions restant a résoudre dans le traitement de la LMC - 2010

Questions restant a résoudre dans le traitement de la LMC

- 2010

Hammamet, Tunisie, 29 October 2010

John Goldman, Imperial College London

Traitement de la LMC – Quelques considérations d’ actualité pour

2010

1. Quels sont les véritables résultats de l’imatinib dans la LMC-PC ?

2. A quelle dose faut-il débuter l’imatinib ?

3. Quel est le suivi d’un patient sous ITK ?

4. Comment définir la réponse et l’échec a l’imatinib ?

5. Faut-il toujours cibler les cellules souches chez les répondeurs ?

6. Peut-on chez certains patients arrêter le traitement sans risques ?

7. Quelles sont les options pour les patients en échec sous imatinib ?

8. Quelles sont les places du dasatinib et du nilotinib en première ligne ?

9. Quelle prise en charge pour une jeune femme désirant une grossesse ?

Traitement de la LMC – Quelques considérations d’ actualité pour

2010





5. Faut-il toujours cibler les cellules souches chez les répondeurs ?




9. Quelle prise en charge pour une jeune femme désirant une grossesse ?

Qu‘est ce que c'est passe chez le patients apres 7 ans dans l‘etude ‘IRIS‘?

All randomized to imatinibn = 553 (100%)

Discontinued study imatinib* n = 221 (40%)

Still receiving study imatinib n = 332 (60%)

In CCR n = 317 (57%)

No CCR n = 15 (3%) Intolerance

n = 43 (8%)

Inefficacy n = 82 (15%)

Other n = 96 (17%)

Aliven = 17 (40%)

Deadn = 26 (60%)

Aliven = 52 (63%)

Deadn = 30 (37%)

Aliven = 81 (84%)

Deadn = 15 (16%)

*Some patients may have continued imatinib off study. IRIS 7 year update

3.3

7.5

4.8

1.7

0.80.3

2.01.31.5

2.8

1.60.9

0.50

0.4 0.4

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7 8

Years from starting imatinib

Per

cen

t w

ith

eve

nt

EventsLoss of CHR,Loss of MCyR,AP/BC,Death during treatment

AP/BC

• Estimated EFS at 8 years = 81%• One progression to AP/BC and 2 non-CML related deaths occurred in year 8• Estimated rate of freedom from progression to AP/BC at 8 years = 92%

**

* Total events (n = 5) including loss of MCyR (n = 3) and deaths (n = 2), one of which was coded as progression to AP/BC in a patient in CMR 6 months prior to death)* Total events (n = 5) including loss of MCyR (n = 3) and deaths (n = 2), one of which was coded as progression to AP/BC in a patient in CMR 6 months prior to death)

Annual event rates: imatinib arm of the IRIS study

(Deininger et al, presented at ASH 2009)

‘Intention to treat’ analyse des resultats pour 204 patients avec LMC

EFS = alive at 5 yr in stable CCyR and still on imatinib

de Lavallade, Marin et al, JCO 2008; 25:3358-3363

83.3%

82.7%

81.0%

62.7%

16.0%

5 years

EFS

Loss of MCyR

Comparaison de la survie pour 246 patients qui ont recu IFN- dans le RU (MRC etude CML-III 1986-

1994)

Time from diagnosis (years)

20181614121086420

Su

rviv

al

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

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

Survival for 246 patients treated with IFNa (1986-1994)







7. Quel est le rôle de la greffe allogénique de cellules souches hématopoïétiques en 2010 ?


9. Quelle prise en charge pour une jeune femme désirant une grossesse

Traitement de la LMC – Quelques considérations d’actualité pour

2010

Is 400 mg/d the best initial dose of imatinib for new patients with CML in

ECP? 400 mg/d was selected for the IRIS study though the MTD

was never actually established

In a single arm study patients who started treatment with 800 mg/d achieved HRC, RCC, and RMC more rapidly than those who started with 400 mg/d (MD Anderson, Houston)

…..but prospective studies (namely TOPS) comparing 400 and 800 mg/d suggest that by 18 months outcomes are no different

One might speculate that the best starting dose for individual patients not entered into a prospective study might possibly be 600 mg/d

Prospective multicentre comparison of imatinib 400 mg and imatinib 800 mg in 1:2 randomisation ratio

Achievement of MMR (%)

IM 400 mg IM 800 mg p

(n=157) (n=319)

6 months 17.2 33.5 0.0002

12 months 40.7 46.4 NS

Most recent publication on the TOPS study

Cortes et al, JCO 2010; 28: 424-430

20

38

31

49

23

46

39

57

0

10

20

30

40

50

60

6 months 12 months

Imatinib 400

Imatinib 600

Im Ara-C

Im Peg IFN

Major molecular response rates at 6 and 12 monthsSuperiority of IM plus IFN- (SPIRIT study, France)

P= 0.0008

P=0.0005

% P

atie

nts

in

MM

R

Time of Molecular Assessment

P=0.0024 P=0.0085

Guilhot et al, 2009

Is 400 mg/d the best initial dose of imatinib for new patients with CML in

ECP?

Data from Houston supported the initial use of 600mg/day…..

…..but prospective studies (namely TOPS) comparing 400 and 800 mg/d suggest that by 18 months outcomes are no different

One might speculate that the best starting dose for individual patients not entered into a prospective study might possibly be 600 mg/d but 400 mg/daily is still the recommended starting dose

The value of adding IFN-alfa to imatinib needs to be confirmed











2010

LeukemiaNet recommendations for monitoring CML-ECP on imatinib

(2006)

Cytogenetics Molecular(Ph+ BM metaphases) (RQ-PCR)

- At diagnosis - At diagnosis (uncertain)

- (3-monthly until CCyR) - Every 3 months for ever

- Annually after CCyR (?) - KD screen if rising transcripts

[FISH only at diagnosis]

Baccarani et al, Blood 2006; 108:1809-1820

Decreasing residual

leukaemia

Num

ber of leukaemia cells (log

10 )

0

1

2

3

4

5

6

7

8

9

10

11

12

13

0

0.0001

0.001

0.01

0.1

1

10

100

BC

R-A

BL1

/AB

L1 r

atio

(%

) Leucocytosis

RQ-PCR positive

Ph-chromosome pos

Ph-negative but

BCR-ABL1 transcript measurement is now the standard method of assessing good

responders 1000

RQ-PCR negative

0.010.01

0.100.10

1.01.0

1010

00Months on standard dose imatinibMonths on standard dose imatinib

48482424 36361212

MCyR 3 moMCyR 3 mo

6060 7272

PB

BC

R-A

BL%

ISP

B B

CR

-AB

L% IS

CHR 1 moCHR 1 mo

CMR CMR 66 mo66 mo

CMRCMR

66

…….and actually residual disease can be .and actually residual disease can be monitored just at the molecular levelmonitored just at the molecular level

CCyR 6 moCCyR 6 mo

MMR 15 moMMR 15 mo

100

Decreasing residual

leukaemia

Num

ber of leukaemia cells (log

10 )

0

1

2

3

4

5

6

7

8

9

10

11

12

13

0

0.0001

0.001

0.01

0.1

1

10

100

BC

R-A

BL1

/AB

L1 r

atio

(%

) Leucocytosis

RQ-PCR positive

Ph-chromosome pos

Ph-negative but

….but transcript measurement may not be sensitive enough to assess complete

responders

1000

?Cure ?

DNA-based PCR may be more sensitive than RQ-PCR

Ross et al, Leukemia, prepublished on line 8/2010











2010

Failure and suboptimal response: Operational definition

(ECP CML on IM 400 mg/d, Baccarani et al. Blood 2006)

Time EchecReppnse sous-

optimal Warnings

Diagnosis - -High risk (Sokal)

del9q+ACA in Ph+ cells

3 mo No HR <CHR

6 mo<CHR

No CyR<PCyR

12 mo <PCyR <CCyR <MMR

18 mo <CCyR <MMR

Any time

Loss of CHRLoss of CCyR

KD mutation (if imatinib-

insensitive)

ACA in Ph+ cellsLoss of MMRKD mutation

(if imatinib-sensitive)

Any . BCR-ABL transcript level

OCA in Ph- cells

Failure and suboptimal response: Operational definition

(ECP CML on IM 400 mg/d, Baccarani et al. Blood 2006)

Time EchecReppnse sous-

optimal Warnings

Diagnosis - -High risk (Sokal)

del9q+ACA in Ph+ cells

3 mo No HR <CHR

6 mo<CHR

No CyR<PCyR

12 mo <PCyR <CCyR <MMR

18 mo <CCyR <MMR

Any time

Loss of CHRLoss of CCyR

KD mutation (if imatinib-

insensitive)

ACA in Ph+ cellsLoss of MMRKD mutation

(if imatinib-sensitive)

Any . BCR-ABL transcript level

OCA in Ph- cells

Months from starting imatinib

Probabilities of achieving CCyR and PFS according to non-failure (red) or failure (blue) at 4 time points

(n=224)

60544842363024181260

1.00.90.80.70.60.50.40.30.20.10.0

Pro

ba

bil

ity

of

PF

SC

um

ula

tiv

e i

nc

ide

nc

e

of

CC

yR


3 months

60544842363024181260

1.00.90.80.70.60.50.40.30.20.10.0

Pro

ba

bil

ity

of

PF

SC

um

ula

tiv

e i

nc

ide

nc

e o

f C

Cy

R


60544842363024181260

1.00.90.80.70.60.50.40.30.20.10.0

Pro

ba

bil

ity

of

PF

SC

um

ula

tiv

e i

nc

ide

nc

e o

f C

Cy

R


60544842363024181260

1.00.90.80.70.60.50.40.30.20.10.0

Pro

ba

bil

ity

of

PF

SC

um

ula

tiv

e i

nc

ide

nc

e o

f C

Cy

R 12 months 18 months

6 months

PFS: 85% vs. 56%, p=0.002

CCyR: 80% vs 0% p=0.0003

PFS: 85% vs. 73%, p=0.009

CCyR: 91% vs 19% p=0.0001

PFS: 90% vs. 76%, p=0.002

CCyR: 94% vs 27% p=0.0001

PFS:97% vs.76%, p=0.001

CCyR: 100% vs 32% p=0.0001

Marin et al, Blood 2008; 112: 4437-4444

Optimal response to and failure of IM in ECP-CML(2009)

OPTIMALRESPONSE

FAILURE

BASELINE NA NA

3 months - CHR, and- At least minor CyR (Ph+ 65%)

- Less than CHR

6 months - At least PCyR (Ph+ ≤ 35%)

- No CyR (Ph+ > 95%)

12 months - CCyR - Less than PCyR (Ph+ > 35%)

18 months - MMolR - Less than CCyR

Any Time - Stable or improving …MMolR

- Loss of CHR- Loss of CCyR- Mutations- ACA in Ph+ cells

Baccarani et al, J Clin Oncol, 2009; 27: 6041-6051

Response Description of monitoring

Haematologic At diagnosisEvery 15 days until CHRAt least every 3 months

Cytogenetic At diagnosis3m, 6m then every 6m until CCyR

RQ-PCR Every 3m until MMolR then 6m

Mutational analysis Suboptimal response/failureBefore changing therapy

Baccarani et al, J Clin Oncol, 2009; 27: 6041-6051

LeukemiaNet recommendations for monitoring CML-ECP on imatinib

(2009)





5. Peut-on chez certains patients arrêter le traitement sans risque ?






2010

Number of patients included: 69

Median age (range): 63 years (29–80)

Gender distribution: 27 males, 42 females

Patients with previous IFN treatment: 34

De novo patients: 35

Follow-up after stopping imatinib:

Median (range): 17 months (6-24)

STIM study (reported from France)

Mahon et al, Sept 2009

Le ‘barriere a 6 mois’ apres avoir discontinue l’imatinib chez in 69 patients selectiones qui

etaient en RMC pendant 2 ans

12 months: 45% (CI:33-56%)

Sur

viva

l with

out

mol

ecul

ar r

elap

se

Months after stopping imatinib

Mahon et al, Sept 2009











2010

1. Increase dose of imatinib 2. Switch to another TKI (dasatinib, nilotinib or

bosutinib)3. Allogeneic stem cell transplantation4. Other anti-CML drugs, eg hydroxycarbamide

omacetaxine (HHT), interferon-alfa, busulfan 5. Autografting (?)

Options for the patient who has failed imatinib 400 mg/day

Jabbour et al. Blood 2009;113:2154-2160

Durability of MCyR obtained after imatinib dose increase

BCR-ABL1 inhibitors:Imatinib, nilotinib, dasatinib, bosutinib

Bosutinib(SK-606)

Imatinib(STI571)

Nilotinib(AMN107)

Dasatinib

1. Efficacy: Little to choose between dasatinib (BMS), nilotinib (Novartis) and bosutinib (Pfizer)

2. All three agents are ineffective in patients with a T315I kinase domain mutant subclone

3. Mutations: F317Lnilotinib, Y253H, E255K/V, F359V/Cdasatinib4. Toxicity:

Myelo- Hepatic Pancreatic Pleural Diarrhoea QTc interval

suppression lipase effusions prolongation

Dasatinib +++ - - +/++ - +Nilotinib + ++ + - - +Bosutinib + - - - +/++ ?

Choosing a second generation TKI for patients intolerant of or resistant to

imatinib

The Hammersmith scoring system for predicting CCyR to 2G-TKI in 80

patients resistant to imatinib Performed a multivariate analysis of outcome on 80

patients ..resistant to imatinib as primary treatment for CML-ECP

67 received dasatinib and 13 nilotinib; no discernible ..differences

There were 4 significant factors predicting for CCyR:

1. Sokal score at diagnosis

2. Level of cytogenetic response to prior imatinib

3. Neutropenia on imatinib

4. (Interval between definition of resistance and starting 2G-TKI) Milojkovic et al, Haematologica 2010; 95: 224-231

The Hammersmith scoring system for predicting CCyR to 2G-TKI using only the 3

factors most significant in multivariate analysis

0No

1YesNeutropenia

0.5Int/High

0LowSokal risk score

3≥95% Ph+

11-94% Ph+

0CyR

Best CyR on IM

Score

Milojkovic et al, Haematologica 2010; 95: 224-231

The Hammersmith Score for prediction of CCyR to 2G-TKI

3024181260

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Months from starting 2G-TKI therapy

Cu

mu

lati

ve in

cid

ence

of

CC

yR

Good risk n=20

Intermediate risk n=26

Poor risk n=34

p<0.0001

p=0.001

p<0.0001

3024181260

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.03024181260

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Months from starting 2G-TKI therapy

Cu

mu

lati

ve in

cid

ence

of

CC

yR

Good risk n=20

Intermediate risk n=26

Poor risk n=34

p<0.0001

p=0.001

p<0.0001

21%

100%

58%

Poor2.5 to 4.5

Intermediate≥1.5 <2.5

Good<1.5

RiskScore

Milojkovic et al, Haematologica 2010; 95: 224-231







7. Quel est le rôle de la greffe allogénique de cellules souches .hématopoïétiques en 2010 ?




2010

Transplant for CML-CP in TKI era

Imatinib failure by ELNMutation analysis

T315I

Allo-SCT*

2G-TKITrial 3-6 months

2G-TKI failure2G-TKI responder

? Ponatinib








8. Quel est la place du dasatinib ou du nilotinib en première ligne ?



2010

ENEST study – CML in ECP Design and Endpoints

• Primary endpoint: MMR at 12 months

• Secondary endpoint: CCyR by 12 months

• Other endpoints: time to and duration of MMR and CCyR, EFS, PFS, time to AP/BC, OS

*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

Saglio et al, ASH 2009

ENEST study: CCyR Rates (ITT)

67

80

63

78

45

65

0

20

40

60

80

100

Month 6 Month 12

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

p<0.0001

p=0.0005

% C

CyR


ENEST study: MMR rates over time (ITT)

% M

MR

p<0.0001

p<0.0001


ENEST study: Overall progression to AP/BC (ITT)

nu

mb

er

of

pa

tie

nts

• No patients who achieved MMR progressed to AP/BC

• 3 patients who achieved CCyR on imatinib progressed to AP/BC

p=0.0095* p=0.0037*

0.7% 0.4%

3.9%


TKI in newly diagnosed CML-CP(MD Anderson, Houston)

ParameterPercent response

IM400N=50

IM800N=205

DasatinibN=45

NilotinibN=47

CCyR

3 mo 37 62 78 97

6 mo 54 82 94 100

12 mo 65 86 97 95

MMR (12mo) 24 47 36 48

Cortes et al. ASCO 2008; abst# 7013 & 7016

SPIRIT 2 (RU): design for ECP-LMC

(Target 425 patients in each arm)

Imatinib 400

R

Dasatinib 100

Chronic phase CML within 3

months of diagnosis







7. Quel est le rôle de la greffe allogénique de cellules souches .hématopoïétiques en 2010 ?

8. Quel est la places du dasatinib ou du nilotinib en première ligne ?

9. Quelle prise en charge pour une jeune femme désirant une .grossesse ?


2010

How do you approach the female CML patient who wants

a child? Women taking imatinib at the time of conception have a ……slightly increased risk of various fetal abnormalities

Women of child-bearing age should therefore be advised ……to use contraception

For the woman who conceives while taking imatinib, ……termination of pregnancy might be considered

For the woman already on imatinib who wants to ……conceive, consideration should be given to a ‘drug ……holiday’

Therapy - Today

1. Imatinib is an excellent drug for 2/3 of patients who present with CML in early chronic phase; there is no convincing reason not to start at a dose of 400mg/day

2. The European LeukemiaNet has produced useful definitions of failure for patients who start treatment with imatinib, which are recently updated.

3. Occasional patients in CMR appear not to relapse, even when imatinib is discontinued for some while.

4. There are various options for managing the patient who is deemed to have failed imatinib, including second generation TKIs and stem cell transplantation

Therapy - Tomorrow

1. Initial treatment with second generation TKIs

2. Third generation TKIs – active against the T315I subclonePonatinib (Ariad), DCC2036 (Deciphera)

3. TKI used in alternating periods

4. TKIs used in conjunction with IFN-alfa or cytarabine

5. Other agents in the pipeline Farnesyl transferase inhibitors

Homoharringtonine, arsenicals, etc.PP2A activation by FTY720 (Neviani et al, 2007)PKF-115 to target activated -catenin

6. Immunotherapy Peptide vaccination – eg BCR-ABL1, K562, PR3, WT1, PRAME,

IL1 receptor accessory protein (IL1RAP) Expanded or engineered CTLs

Therapy - Tomorrow

1. Initial treatment with second generation TKIs

2. Third generation TKIs – active against the T315I subclonePonatinib (Ariad), DCC2036 (Deciphera)

3. TKI used in alternating periods

4. TKIs used in conjunction with IFN-alfa or cytarabine

5. Other agents in the pipeline Farnesyl transferase inhibitors

Homoharringtonine, arsenicals, etc.PP2A activation by FTY720 (Neviani et al, 2007)PKF-115 to target activated -catenin

6. Immunotherapy Peptide vaccination – eg BCR-ABL1, K562, PR3, WT1, PRAME,

IL1 receptor accessory protein (IL1RAP) Expanded or engineered CTLs

Interleukin receptor accessory protein

1) Upregulated in cord cells transfected with BCR-ABL1

2) Upregulated also in DC34+ CML cells

3) May be the first example of a surface antigen specific

for BCR-ABL1-positive cells

Jaras, Fioretos et al, PNAS; August 10, 2010

Gene expression analysis identifies IL1RAP as upregulated in CML CD34+

CML cells

CML 34+ cells

+/- RV BCR-ABL1


Kinase activity of p210BCR-ABL1

upregulates IL1RAP on cell surface


Left panels: Cord blood cell transfected with BCR-ABL1 (blue); Right panel: With imatinib (yellow) and without imatinib (gray). MIG= murine stem cell virus/IRES/green fluorescent protein

Remerciements a

Jane Apperley

Junia Melo (now in Adelaide)

Jaspal Kaeda

Jamshid Khorashad

David Marin

Katy Rezvani

Richard Szydlo …and many others!

Susan Branford (Adelaide)

Nick Cross (Southampton)

Tim Hughes (Adelaide)

Michael Deininger (Portland)

Jorge Cortes (Houston)

Stephen O’Brien (Newcastle)

Giuseppe Saglio (Torino)

Brian Druker (Portland)

Michele Baccarani (Bologna)

Imperial CollegeLondon

Non-Hammersmith

Objectives:• Spread information about CML to patients, family

members and doctors in less developed countries• Organise preceptorship programs for experienced

hematologists who want to know more about modern management of CML, and

• Facilitate provision of diagnostic tools and appropriate drugs to patients who could not otherwise afford them

Website: www.CML-foundation.org

http://www.cml-foundation.org/

The end

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Questions restant a résoudre dans le traitement de la LMC - 2010