DR

Discontinuation of second generation tyrosine kinase inhibitors

CML and MPDs UK national meetingNewcastle, March 1st, 2013

Dr Delphine ReaService des Maladies du Sang

Hôpital Saint-LouisParis, France

Fi-LMC (France Intergroupe-Leucémies Myéloïdes Chroniques)

DR

Current goals of TKI therapy

CP-CML atDiagnosis

M3 M6 M12 M18

CHR, Minor CyR

PCyRCCyR

MMR Stable or improving MMR

> M18

PFS EFS

Time on TKI therapy

Leuk

emic

bur

den

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

Near-normal life expectancy

Baccarani et al. JCO 2009; 27: 6041-6051Björkholm et al. JCO 2011: 2514-2420Gambacorti-Passerini et al. JNCI 2011; 103: 553-561

« Induction » phase « Lifelong maintenance »

DR

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: 319-3252Copland et al. Blood 2006; 107: 4532-45393Jorgensen et al. Blood 2007; 109: 4016-40194Konig et al. Blood 2008; 111: 2329-23385Corbin et al. JCI 2011; 121: 396-4066Hamilton et al. Blood 2012; 119: 1501-1510

DR

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

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

0.003% 0.004%

DR

STIM: Stopping imatinib is feasible

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

Sur

viva

l with

out m

olec

ular

rela

pse 1.0

0

0.90.80.70.60.50.40.30.20.10.0

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

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

Molecular relapses: n=61

Survival without molecular relapse:39% (95% CI: 29-48) at 24 and 36 months

Undetectable BCR-ABL: at least 50 000 copies of the ABL control geneMolecular relapse: defined by 2 positive RQ-PCR results over 1 month showing a significant risein BCR-ABL transcripts; triggers imatinib resumption.

CP-CMLImatinib ≥ 3 yearsUndetectable BCR-ABL ≥ 2 years

DR

Factors potentially associated with outcome

Study Factors

French prospective STIM study1

Sokal risk groupImatinib treatment duration

Australian prospective CML8 study2

Sokal risk groupIFN treatment duration prior to imatinib therapy

Japanese survey3 Imatinib treatment durationDuration of undetectable BCR-ABL transcriptsImatinib dose intensityPrior exposure to IFN

Korean retrospective study4 Sokal risk groupTime to undetectable BCR-ABL transcriptsImatinib treatment duration

1Mahon et al. Blood (ASH) 2011; 118: Abstract 603 2Ross et al. Haematologica 2012; abstract 0189.

3Takahashi et al. Haematologica 2012; 97: 903-9064Yhim et al. Leukemia Research 2012; 36: 689-693

DR

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: 2251-22595Kantarjian et al. N Engl J Med 2010; 362: 2260-22706Rea et al. Leukemia 2009; 23: 1158-11597Ross et al. Haematologica 2011; 96: 1720-1722

1O’Hare et al. Cancer Res 2005; 65: 4500-45052Shah et al. J Clin Oncol 2008; 26; 3204-32123Kantarjian et al. Blood 2007; 110: 3540-3546

DR

STOP 2G-TKI: study design

• Primary endpoint: survival without loss of MMR• Molecular relapse: loss of MMR• Loss of MMR triggered treatment resumption

M12 M60D1

STOP2G-TKI

UndetectableBCR-ABL*≥ 24 months

*Molecular monitoring performed in local laboratories filling international standardization requirements.*20 000 copies of ABL at least.

RQ-PCRmonthly

RQ-PCREvery

3-6 months

CP-CMLTKI therapy ≥ 3 years2G-TKI frontline orafter imatinib intoleranceor resistance

Year 1 Year 2 Year 3-5

RQ-PCREvery

2-3 months

M24 M36 M48

DR

Baseline characteristicsData, as of November 30, 2012 Patients with a min. follow-up of 6 months

(median 17: 7-38), n=39

Median age 58 years (34-81)

Gender Male n= 15 (38.5%), Female n=24 (61.5%)

CML phase at diagnosisSokal risk group Low / Intermediate / High / Unknown

CP 100%21 (54%) / 9 (23%) / 6 (15%) / 3 (8%)

Prior IFN (+/- AraC) 12 (33%)

Prior TKI Dasatinib or nilotinib onlyImatinib + dasatinib or nilotinibImatinib + dasatinib and nilotinib

2 (5%)31 (79%)6 (16%)

Reason for 2G-TKIUpfrontIntolerance to imatinibSuboptimal response/resistance to imatinib*

2 (5%)27 (69%)10 (26%)

TKI discontinuationDasatinib / nilotinib 20 (51%) / 19 (49%)

Median time since diagnosisMedian time since first TKIMedian time since 2G-TKIMedian duration of undetectable BCR-ABL transcripts

84 months (31-218)78 months (30-133)37 months (19-72)27 months (19-58)

*ELN 2006 definition Rea et al. Blood (ASH) 2012; 120: Abstract 916

DR

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

0

20

40

60

80

100

0 6 12 18 24 30 36 42

Sur

viva

l with

out M

MR

loss

%

Months since 2G-TKI discontinuation

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

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

DR

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)

STOP 2G-TKI

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

DR

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

Months since dasatinib-inducedundetectable BCR-ABL transcripts

BC

R-A

BL/

AB

L %

IS

Detectable BCR-ABL

Undetectable BCR-ABLwith at least 32000 copies of ABL

DASATINIBRESUMPTION

STOP 2G-TKI

Dr D Rea, Hôpital Saint-Louis, Paris

0 6 12 18 24 30 36 42 48 54 60 660.0001

0.001

0.01

0.1

1

10STOP DASATINIB

MMR

MR4.5

DR

Factors associated with outcome

Factors Estimated survival without MMR loss at 12 months (%, 95% CI) p value

Age: ≤ 58 years vs > 58 68.7 % (44.8-89.7) vs 52.6 % (30.2-75) 0.219

Gender: Female vs male 61.3 % (41.3-81.3) vs 66.7 % (42.8-90.5) 0.901

Sokal risk group: Low vs others 66.7 % (46.5-86.8) vs 52.1 % (29.4-74.8) 0.31

Prior IFN exposure: no vs yes 56.8 % (37.4-76.2) vs 69.2 % (44.1-94.3) 0.581

Reason for 2G-TKI:Frontline/imatinib intoleranceSuboptimal response/resistance to imatinib

68.2 % (51-85.5)40 % (9.6-70.4)

0.0188

Type of 2G-TKI: Dasatinib vs nilotinib 60 % (38.5-81.5) vs 62.7 % (40.8-84.7) 0.599

Time since diagnosis: ≤ 84 months vs > 84 months 63.6 % (41.8-85.4) vs 57.9 % (35.7-80.1) 0.599

Time since first TKI: ≤ 78 months vs > 78 months 63.6 % (41.8-85.4) vs 57.9 % (35.7-80.1) 0.599

2G-TKI duration: ≤ 37 months vs > 37 months 62.2 % (42.7-81.7) vs 66.7 % (42.8-90.5) 0.949

UMRD duration: ≤ 27 months vs > 27 months 70 % (49.9-90.1) vs 52.1 % (-74.8) 0.310

STOP 2G-TKI

KM analysis, two-tailed logrank testRea et al. Blood (ASH) 2012; 120: Abstract 916

DR

BCR-ABL transcripts in patients remaining in MMR

Patients in MMR without therapy(median follow-up 17 months: 7-37) n=23

Always undetectable 7/23 (30.4%)

Occasionally detectable on 1 test 8/23 (34.8%)

Occasionally detectable on ≥ 2 consecutive tests 8/23 (34.8%)

STOP 2G-TKI

DR

Different outcomes of persistent LSC

Self renewal

Survival

TKI + BCR-ABL+LSC

Mat Pre

Pro

CML disease relapse

STOPTKI

STOPTKI

MatMat

Mat

Pre

PrePro

Ph+ LSC-driven hematopoiesis

Inhibited Ph+ LSC-driven hematopoiesis No

CML diseaserelapse

Deep and sustainedMolecular response

Why ?

CML-relatedfactors?

Therapy-relatedfactors?

Host-relatedfactors?

DR

DR

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.