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
DR
Current goals of TKI therapy
« Induction » phase
Leukemic burden
CP-CML at
Diagnosis
PFS
« Lifelong maintenance »
EFS
Near-normal life expectancy
CHR,
Minor CyR
PCyR
CCyR
MMR
M3
M6
M12
M18
Stable or improving MMR
> M18
Treatment change upon lack or loss of an optimal response,
progression or unacceptable side effects
Baccarani et al. JCO 2009; 27: 6041-6051
Björkholm et al. JCO 2011: 2514-2420
Gambacorti-Passerini et al. JNCI 2011; 103: 553-561
Time on TKI therapy
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 BCRABL and possess in vivo repopulating capacities in mice6
1Graham
et al. Blood 2002; 99: 319-325
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
2Copland
DR
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
DR
STIM: Stopping imatinib is feasible
Survival without molecular relapse
CP-CML
Imatinib ≥ 3 years
Undetectable BCR-ABL ≥ 2 years
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Survival without molecular relapse:
39% (95% CI: 29-48) at 24 and 36 months
Molecular relapses: n=61
Median follow-up: 34 months (9-50)
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
DR
Factors potentially associated with
outcome
Study
Factors
French prospective STIM
study1
Sokal risk group
Imatinib treatment duration
Australian prospective CML8
study2
Sokal risk group
IFN treatment duration prior to imatinib therapy
Japanese survey3
Imatinib treatment duration
Duration of undetectable BCR-ABL transcripts
Imatinib dose intensity
Prior exposure to IFN
Korean retrospective study4
Sokal risk group
Time to undetectable BCR-ABL transcripts
Imatinib treatment duration
1Mahon
3Takahashi
2Ross
4Yhim
et al. Blood (ASH) 2011; 118: Abstract 603
et al. Haematologica 2012; abstract 0189.
et al. Haematologica 2012; 97: 903-906
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 BCRABL transcripts6,7
4Saglio
1O’Hare
et al. Cancer Res 2005; 65: 4500-4505
2Shah et al. J Clin Oncol 2008; 26; 3204-3212
3Kantarjian et al. Blood 2007; 110: 3540-3546
et al. N Engl J Med 2010; 362: 2251-2259
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
5Kantarjian
DR
STOP 2G-TKI: study design
CP-CML
TKI therapy ≥ 3 years
2G-TKI frontline or
after imatinib intolerance
or resistance
Undetectable
BCR-ABL*
≥ 24 months
•
•
•
STOP
2G-TKI
D1
M12
M24
Year 1
Year 2
RQ-PCR
monthly
RQ-PCR
Every
2-3 months
M36
M48
M60
Year 3-5
RQ-PCR
Every
3-6 months
Primary endpoint: survival without loss of MMR
Molecular relapse: loss of MMR
Loss of MMR triggered treatment resumption
*Molecular monitoring performed in local laboratories
filling international standardization requirements.
*20 000 copies of ABL at least.
DR
Baseline characteristics
Data, 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 diagnosis
Sokal 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 only
Imatinib + dasatinib or nilotinib
Imatinib + dasatinib and nilotinib
2 (5%)
31 (79%)
6 (16%)
Reason for 2G-TKI
Upfront
Intolerance to imatinib
Suboptimal response/resistance to imatinib*
2 (5%)
27 (69%)
10 (26%)
TKI discontinuation
Dasatinib / nilotinib
20 (51%) / 19 (49%)
Median time since diagnosis
Median time since first TKI
Median time since 2G-TKI
Median 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
STOP 2G-TKI
Survival without MMR loss
• Median follow-up was 17 months (7-38)
Survival without MMR loss %
– 16/39 patients lost MMR
– Median time to MMR loss was 3 months (1-25)
100
Month 12: 61.1% (95% CI: 45.6-76.6)
80
60
40
20
0
0
Rea et al. Blood (ASH) 2012; 120: Abstract 916
6
12
18
24
30
36
42
Months since 2G-TKI discontinuation
KM analysis
DR
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 DR
STOP 2G-TKI
Responsiveness to 2G-TKI upon
therapy resumption: patient case
STOP DASATINIB
BCR-ABL/ABL % IS
10
DASATINIB
RESUMPTION
1
MMR
0.1
0.01
MR4.5
0.001
0.0001
0
6
Detectable BCR-ABL
Undetectable BCR-ABL
with at least 32000 copies of ABL
12 18
24
30 36
42
48 54
60
66
Months since dasatinib-induced
undetectable BCR-ABL transcripts
Dr D Rea, Hôpital Saint-Louis, Paris
DR
STOP 2G-TKI
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 intolerance
Suboptimal 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
KM analysis, two-tailed logrank test
Rea et al. Blood (ASH) 2012; 120: Abstract 916 DR
STOP 2G-TKI
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%)
DR
Different outcomes of persistent LSC
CML disease relapse
Self renewal
STOP
TKI
TKI +
BCR-ABL+
LSC
Survival
Ph+ LSCdriven hematopoiesis
Pro
Deep and sustained
Molecular response
STOP
TKI
Inhibited Ph+ LSCdriven hematopoiesis
Why ?
CML-related
factors?
Mat
Mat
Mat
Mat Pre Pre
Pro Pre
Therapy-related
factors?
No
CML disease
relapse
Host-related
factors?
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.
DR