Discontinuation of second generation tyrosine kinase inhibitors
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Discontinuation of second generation tyrosine kinase inhibitors. Dr Delphine Rea Service des Maladies du Sang Hôpital Saint-Louis Paris, France Fi-LMC (France Intergroupe-Leucémies Myéloïdes Chroniques). CML and MPDs UK national meeting Newcastle, March 1 st , 2013.

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Discontinuation of second generation tyrosine kinase inhibitors

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Discontinuation of second generation tyrosine kinase inhibitors

Discontinuation of second generation tyrosine kinase inhibitors

Dr Delphine Rea

Service des Maladies du Sang

Hôpital Saint-Louis

Paris, France

Fi-LMC (France Intergroupe-Leucémies Myéloïdes Chroniques)

CML and MPDs UK national meeting

Newcastle, March 1st, 2013


Current goals of tki therapy

Current goals of TKI therapy

« Induction » phase

« Lifelong maintenance »

CP-CML at

Diagnosis

Near-normal life expectancy

PFS

EFS

CHR,

Minor CyR

PCyR

CCyR

MMR

Leukemic burden

Stable or improving MMR

> M18

M3

M6

M12

M18

Treatment change upon lack or loss of an optimal response, progression or unacceptable side effects

Time on TKI therapy

Baccaraniet al. JCO 2009; 27: 6041-6051

Björkholm et al. JCO 2011: 2514-2420

Gambacorti-Passerini et al. JNCI 2011; 103: 553-561


Evidence that tkis may not be curative

Evidence that TKIs may not be curative

  • Primitive CD34+CD38- BCR-ABL+ cells are insensitive to imatinib-, dasatinib-, nilotinib- and bosutinib-induced cell death in vitro1-4

  • CD34+CD38- BCR-ABL+ cells escape from TKI-induced cell death is independent from BCR-ABL in vitro5

  • CD34+CD38- BCR-ABL+ residual cells in optimal responders to imatinib survive independently from BCR-ABL and possess in vivo repopulating capacities in mice6

1Graham et al. Blood 2002; 99: 319-325

2Copland et al. Blood 2006; 107: 4532-4539

3Jorgensen et al. Blood 2007; 109: 4016-4019

4Konig et al. Blood 2008; 111: 2329-2338

5Corbin et al. JCI 2011; 121: 396-406

6Hamilton et al. Blood 2012; 119: 1501-1510


Median bcr abl is transcript levels over 84 months in the iris trial

Median BCR-ABL (IS) transcript levels over 84 months in the IRIS trial

0.003%

0.004%

Hughes et al. Blood 2010; 116: 3758-3765


Stim stopping imatinib is feasible

STIM: Stopping imatinib is feasible

CP-CML

Imatinib≥3 years

Undetectable BCR-ABL≥2 years

1.0

Survival without molecular relapse:

39% (95% CI: 29-48) at 24 and 36 months

0.9

0.8

0.7

0.6

Survival without molecular relapse

0.5

0.4

0.3

0.2

Molecular relapses: n=61

0.1

Median follow-up: 34 months (9-50)

0.0

0

3

6

9

12

15

18

21

24

27

30

33

36

39

42

45

48

51

54

57

60

Months since discontinuation of imatinib

Undetectable BCR-ABL: at least 50 000 copies of the ABL control gene

Molecular relapse:defined by 2 positive RQ-PCR results over 1 month showing a significant rise

in BCR-ABL transcripts; triggers imatinib resumption.

Mahon et al. Blood (ASH) 2011; 118: Abstract 603


Factors potentially a ssociated w ith o utcome

Factors potentially associated with outcome

1Mahon et al. Blood (ASH) 2011; 118: Abstract 603

2Ross et al. Haematologica 2012; abstract 0189.

3Takahashi et al. Haematologica 2012; 97: 903-906

4Yhim et al. Leukemia Research 2012; 36: 689-693


Rationale for 2g tki discontinuation

Rationale for 2G-TKI discontinuation

  • Dasatinib and nilotinib display increased potency in vitro against BCR-ABL compared with imatinib1

  • Dasatinib and nilotinib are efficient salvage therapies in patients with intolerance or resistance to imatinib2,3

  • Frontline dasatinib and nilotinib induce higher rates of deep molecular responses than imatinib4,5

  • Case reports on dasatinib cessation in 4 patients with imatinib-resistant CML with very low or undetectable BCR-ABL transcripts6,7

4Saglio et al. N Engl J Med 2010; 362: 2251-2259

5Kantarjian et al. N Engl J Med 2010; 362: 2260-2270

6Rea et al. Leukemia 2009; 23: 1158-1159

7Ross et al. Haematologica 2011; 96: 1720-1722

1O’Hare et al. Cancer Res 2005; 65: 4500-4505

2Shah et al. J ClinOncol 2008; 26; 3204-3212

3Kantarjian et al. Blood 2007; 110: 3540-3546


Stop 2g tki study design

STOP 2G-TKI: study design

Primary endpoint: survival without loss of MMR

Molecular relapse: loss of MMR

Loss of MMR triggered treatment resumption

CP-CML

TKI therapy ≥ 3 years

2G-TKI frontline or

after imatinib intolerance

or resistance

D1

M12

M24

M36

M48

M60

Undetectable

BCR-ABL*

≥ 24 months

STOP

2G-TKI

Year 1

Year 2

Year 3-5

RQ-PCR

monthly

RQ-PCR

Every

2-3 months

RQ-PCR

Every

3-6 months

*Molecular monitoring performed in local laboratories filling international standardization requirements.

*20 000 copies of ABL at least.


Baseline characteristics

Baseline characteristics

*ELN 2006 definition

Rea et al. Blood (ASH) 2012; 120: Abstract 916


Survival without mmr loss

Survival without MMR loss

Median follow-up was 17 months (7-38)

16/39 patients lost MMR

Median time to MMR loss was 3 months (1-25)

STOP 2G-TKI

100

Month 12: 61.1% (95% CI: 45.6-76.6)

80

60

Survival without MMR loss %

40

20

0

0

6

12

18

24

30

36

42

KM analysis

Months since 2G-TKI discontinuation

Rea et al. Blood (ASH) 2012; 120: Abstract 916


Outcome after mmr loss

STOP 2G-TKI

Outcome after MMR loss

  • Median BCR-ABL transcript level at MMR loss:

    • 0.35% IS (0.12-1.95)

  • TKI therapy resumption in 15/16 patients

    • Median time between MMR loss and therapy resumption: 1 month (0-4)

    • Same 2G-TKI used prior to discontinuation in all patients but 1

  • No loss of CHR or progression to AP/BP

  • With a median follow-up of 7 (1-35) months after therapy resumption:

    • MMR regained in14 patients, median time to MMR 2 (1-6) months

    • Undetectable BCR-ABL transcripts in 14 patients after a median time of 4 months (3-10)

Rea et al. Blood (ASH) 2012; 120: Abstract 916


Responsiveness to 2g tki upon therapy resumption patient case

STOP 2G-TKI

Responsiveness to 2G-TKI upon therapy resumption: patient case

STOP DASATINIB

10

DASATINIB

RESUMPTION

1

MMR

0.1

BCR-ABL/ABL % IS

0.01

MR4.5

0.001

0.0001

0

6

12

18

24

30

36

42

48

54

60

66

Detectable BCR-ABL

Months since dasatinib-induced

undetectable BCR-ABL transcripts

Undetectable BCR-ABL

with at least 32000 copies of ABL

Dr D Rea, Hôpital Saint-Louis, Paris


Factors associated with outcome

STOP 2G-TKI

Factors associated with outcome

KM analysis, two-tailed logrank test

Rea et al. Blood (ASH) 2012; 120: Abstract 916


Bcr abl transcripts in patients remaining in mmr

STOP 2G-TKI

BCR-ABL transcripts in patients remaining in MMR


Different outcomes of persistent lsc

BCR-ABL+

LSC

Different outcomes of persistent LSC

CML disease relapse

Mat

Mat

Self renewal

Mat

Ph+ LSC-

driven hematopoiesis

STOP

TKI

Pre

Mat

Pre

Pro

Pre

Pro

Deep and sustained

Molecular response

TKI +

Inhibited Ph+ LSC-

driven hematopoiesis

No

CML disease

relapse

Survival

STOP

TKI

Why ?

CML-related

factors?

Therapy-related

factors?

Host-related

factors?


Conclusions

Conclusions

  • Discontinuation of 2G-TKI in patients with deep and sustained molecular responses is possible without jeopardizing short-term outcome, under strict monitoring conditions.

  • TKI discontinuation may not be a realistic goal for all patients but the increasing use of 2G-TKI may broaden access to treatment discontinuation attempts.

  • Patients who successfully stop TKI may not be definitively cured, likely because of LSC persistence.

  • Unknown long-term risk of relapse, acquired resistance and progression to AP/BP after TKI discontinuation.

  • Targeting residual LSC with specific compounds may offer a chance for a definitive cure.


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