leucemia mieloide cronica - siematologia · leucemia mieloide cronica. bcr-abl loading in cml...
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Dati sulla sospensione della
terapia
Gianantonio Rosti, Bologna
Leucemia Mieloide Cronica
BCR-ABL Loading in CML Patients
100%
10%
1%MR4
MR4.5
MMR
STIM study designN=100
STOPSustained CMR
for ≥ 2 years
Start Imatinib
CMR
Q- RT-PCR from peripheral blood
every month in the first year and
every 2 months thereafter
Five BCR–ABL analyses by
Q- RT-PCR during these 2
years
Sixth datapoint checked in
centralized laboratory
Mahon FX et al. The Lancet Oncology, 2010;11(11): 1029-1035.
Molecular recurrence: positivity of
BCR–ABL transcript in Q-RT-PCR
confirmed by a second analysis point
indicating the increase of one log in
relation to the first analysis point, at
two successive assessments, or loss
of MMR at one point.
Treatment-free survival
At 60 months 40% ( 95% CI: 30-49)
Median follow up: 55 months (range 9-72)
Mahon, ASH 2013
Follow-up of the non-molecular relapse
patients (n= 39)
• Follow-up: mean 56, median 58 (9-72)
months
• 38 patients are still in CMR i.e., UMRD
(sensitivity > 4.5 log)
• 1 patient died in CMR after 9 months of
imatinib cessation due to myocardial
infarction
£ factors included when p<0.2 in univariate analysis# Acounting for competing risk
Univariate
analysis
P value
Multivariate analysis
(final model)
-
Gender£0.103 0.08
Sokal score£0.0076 0.0037
Interferon 0.2426 -
Time to CMR 0.2880 -
CMR duration 0.2345 -
IM duration£ 0.1357 0.1
Regression model# of molecular relapse at 24 months
STIM: Low Sokal Score and Previous Imatinib ≥ 5 y Are Prognostic For Reduced Relapse Risk
Mahon FX, et al. Blood 2011;118:abstract 603.
Multivariate analysis (Cox model)
Hazard ratio (95% CI) P value
Sokal score 2.555 (1.278 -5.119) 0.008
IM duration (≥ 5 y vs < 5 y) 0.582 (0.340 -0.995) 0.047
At 24 Months:
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Su
rviv
al W
ith
ou
t M
ole
cu
lar
Re
lap
se
0 3 6 9 12 15
Sokal Low + IM > 5 y:
Others
68% (95%Cl: 45–83)
33% (95%Cl: 22–42)
18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Months Since Discontinuation of Imatinib
P = .007
Sustained CMR after stopping imatinib
according to duration of CMR before cessation
78% vs. 15%, P = .0002 by Log-rank testTakahashi N et al., Haematologica, 2012; 97:903-06.
Kumari A et al, Blood. 2012 Jan 12;119(2):530-9.
Stem cell persistence is associated with
low BCR-ABL expression
CFUApoptosis
Hypothetical Model of CML persistence and recurrence
versus extinction
Deininger, M. Nat. Rev. Clin. Oncol. advance online publication 1 February 2011;
doi:10.1038/nrclinonc.2011.17
The eradication of the leukemic clone may depend on inherent features of
the disease or on the duration of therapy, or both.
Treatment-free survival
At 60 months 40% ( 95% CI: 30-49)
Median follow up: 55 months (range 9-72)
Mahon, ASH 2013
Summary of treatment suspension trials
Study Therapy Duration of tx
Inclusion criteria and duration
N patients
Primary Endpoint Molecular Relapse Rate
STIM1 (IFN) IM >3 years Stable CMR> 2 years
100 Survival without loss of CMR
61% at 5 year
STIM22 IM >3 years Stable CMR >2 years
124 Survival without loss of CMR
38.7% at 1 year
A-STIM3 IM >3 years Stable CMR>2 years
80 Survival without loss of MMR
39% at 3 years
STOP 2G-TKI4 2TKI: I or II line
>3 years Stable CMR >2 years
33 Survival without loss of MMR
38.9% at 1 year
TWISTER5 (IFN) IM >3 years Stable CMR>2 years
40 Survival without loss of CMR
52.9% at 2 years
EUROSKI IM, 2TKII or II line
>3 years Stable MR4.0>1 year
500 Survival without loss of MMR
/
DASFREE DAS I or II line
> 2 years Stable MR4.5>1 year
74 Survival without loss of MMR
/
ENEST Freedom
NIL >3 years Stable MR4.5 >1 year
206 Survival without loss of MMR
/
ENESTop IMNILNIL
IM NIL >3 years
Stable MR4.5>1 year
117 Survival without loss of MR4.0
/
ENESTPath IMNIL IM 2 NIL 2 vs 3 y
Stable MR4.0 >1 vs 2 years
1058 Survival without loss of MMR
/
1.Mahon et al ASH 2013. 2.Mahon et al Blood (2013) abs #654 3.Rousselot et al J.Clin Oncol (2013) e-pub ahead of print. 4.Rea etal Blood (2012) abs #916 5.Ross et al Blood (2013) 122:515-522
Summary of treatment suspension trials
Study Therapy Duration of tx
Inclusion criteria and duration
N patients
Primary Endpoint Molecular Relapse Rate
STIM1 (IFN) IM >3 years Stable CMR> 2 years
100 Survival without loss of CMR
61% at 5 year
STIM22 IM >3 years Stable CMR >2 years
124 Survival without loss of CMR
38.7% at 1 year
A-STIM3 IM >3 years Stable CMR>2 years
80 Survival without lossof MMR
39% at 3 years
STOP 2G-TKI4 2TKI: I or II line
>3 years Stable CMR >2 years
33 Survival without lossof MMR
38.9% at 1 year
TWISTER5 (IFN) IM >3 years Stable CMR>2 years
40 Survival without loss of CMR
52.9% at 2 years
EUROSKI IM, 2TKII or II line
>3 years Stable MR4.0>1 year
500 Survival without lossof MMR
/
DASFREE DAS I or II line
> 2 years Stable MR4.5>1 year
74 Survival without lossof MMR
/
ENEST Freedom
NIL >3 years Stable MR4.5 >1 year
206 Survival without lossof MMR
/
ENESTop IMNILNIL
IM NIL >3 years
Stable MR4.5>1 year
117 Survival without loss of MR4.0
/
ENESTPath IMNIL IM 2 NIL 2 vs 3 y
Stable MR4.0 >1 vs 2 years
1058 Survival without lossof MMR
/
1.Mahon et al ASH 2013. 2.Mahon et al Blood (2013) abs #654 3.Rousselot et al J.Clin Oncol (2013) e-pub ahead of print. 4.Rea etal Blood (2012) abs #916 5.Ross et al Blood (2013) 122:515-522
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
Rea, ASH2013
Patient characteristics A-STIM* STIM°
Patients, n 80 100
Gender, M/F ratio 0.52 0.6
Median age at diagnosis, y (range) 56 (27 – 78) 62 (29 – 80)
Sokal Score, %
Low risk 52 49
Intermediate risk 27 39
High risk 18 11
Previous therapy, n (%)
Interferon (or IFN/Ara-C) 43 (53.1) 34 (44.9)
Autologous HSCT 3 (3.7) 0
Median duration of imatinib, mo (range) 77 (30 – 145) 50 (36 – 90)
Median duration of CMR, mo (range) 40.1 (20 – 96) 35.5 (24 – 85)
Median follow-up after imatinib
discontinuation, mo (range) 22 (1 – 97) 34 (9 - 50)
Baseline characteristics
in A-STIM and STIM
Mahon FX et al., Lancet Oncol., 2010; 11:1029-35 & Blood 2011; 118 [abstract 603].Rousselot P et al. 2014 JCO
Months
Perc
en
t su
rviv
al
0 12 24 36 48 60 72 84 96 1080
20
40
60
80
100
Kaplan-Meier estimate of TFS defined as loss of
MMR and defined according to STIM criteria after
imatinib discontinuation in 81 CML patients.
37%
65%
P = 0.003
TFS= treatment free survivalRousselot P et al., JCO 2014
How many patients on imatinib achieve deep responses?
Branford et al, Blood 2013;121:3818
Years after commencing imatinib
Cum
ula
tive
Incid
en
ce
%
0
20
40
60
80
100
0 4 5 6 7 81 2 3
Confirmed undetectable MR4.5
52% (CI 43 - 60%)
n=423 patients
37%
Stable
2 years
Deep Molecular Response
Cumulative incidence of MR4.0 342/559 (61%)
Stable MR4.0 (> 18 mos; > 3 samples) 108/559 (19%)
Fluctuating MR4.0 in stable MMR 153/559 (27%)
Episodic MR4.0 (one sample only) 81/559 (14%)
METHODS:
- QPCR every 6 months
- MR4.0: ≤ 0.01% BCR-ABLIS or undetectable BCR-ABL transcript
with ≥10,000 ABL transcripts
GIMEMA CML WPCastagnetti on begalf of GIMEMA , ASH 2013
Factors associated with deep responses
Branford et al, Blood 2013;121:3818
– strongest independent predictor was the
3 month BCR-ABL1 value, P < .001
Years after commencing imatinib
4 5 6 7 81 2 3Cum
ula
tive
Incid
en
ce
%
0
20
40
60
80
100
0
MMR, 78%
>10%, 9%
>0.1-1.0%, 53%
>1-10%, 29%
Stable undetectable MR4.5 for 2 years
n=423
Susan Branford, GOLS 2014
Proportion of Patients With MR4.5
by BCR-ABL Levels at 3 Months
58%
28%
4%
P = .0001
P = .0135
70%
52%
8%
P = .0046
P = .0001
MR4.5 by 4 Yearsa
MR4.5 by 5 YearsaBCR-ABL Level
≤ 1%
> 1% to ≤ 10%
> 10%
Pts
144
89
24
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6
Pa
tie
nts
With M
R4
.5,
%
Time Since Randomization, Calendar Years
MR4.5 by 4 Yearsa
MR4.5 by 5 Yearsa
65%
24%
5%
P < .0001
P =
.0001
67%
34%
15%
P = .0001
P = .0016
BCR-ABL Level
≤ 1%
> 1% to ≤ 10%
> 10%
Pts
43
133
88
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6P
atie
nts
With M
R4
.5,
%
Time Since Randomization, Calendar Years
a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.
BCR-ABLIS ≤ 1%:
16% of ptsBCR-ABLIS ≤ 1%:
56% of pts
Nilotinib 300 mg BID Imatinib 400 mg QD
Patients with BCR-ABL ≤ 1% at 3 months have significantly higher rates
of MR4.5 by 5 years
More patients achieve BCR-ABL ≤ 1% at 3 months on nilotinib 300 mg
BID vs imatinib
20 Saglio G, et al. Blood. 2013:[abstract 92].
Cumulative Rate of MR4 and MR4.5
% W
ith
MR
4.5
Months
P=0.030
0 12 24 36 48 60
Dasatinib 100 mg QD Imatinib 400 mg QD
MR4 = BCR-ABL (IS) ≤0.01%;
MR4.5 = BCR-ABL (IS) ≤0.0032%;
IS = International Scale.
0
20
10
30
40
50
60
3%
2%
18%
9%
23%
12%
34%
21%
37%
30%
% W
ith
MR
4
Months
P=0.0021
0
20
10
30
40
50
60
12%
5%
28%
17%
35%
22%
47%
35%
0 12 24 36 48 60
53%
42%
MR4 MR4.5
• Treatment discontinuation is a real opportunity:
No exposure to long term toxicities
Better QOL
Reduced costs of treatment
• “CMR” is the absolute prerequisite
• Second generation TKIs allow to a much higher rate of “CMR”
We do not know something relevant:
• Why the duration of TFR is so different?
• Which mechanisms contribute to a sustained TFR?
• TFR rates in a head-to-head comparison of IMA vs 2^ Gen TKIs
• 2^ Gen TKIs: same (long) duration of tx as for ima to allow a long TFR?
• What about the impact of the risk (Sokal/Euro) on TFR duration?
• The added value of IFN or drugs active against leukemic SCs under.
We know that:
Dati sulla sospensione della
terapia
Gianantonio Rosti, Bologna
Leucemia Mieloide CronicaGrazie per l’attenzione
1. Milojkovic D, et al. Blood. 2011;118(21): abstract 605. 2. Goh HG, et al. Leuk ymphoma. 2009;50(6):944-951.3. Koskenvesa P, et al. Blood.
2008;112(11):738 [abstract 2121]. 4. Kuwabara A, et al. Blood. 2010;116(6):1014-1016. 5. Mahon FX, et al. Blood. 2011;118(21): [abstract 603] 6. Rousselot
P, et al. Blood. 2011;118(21): abstract 3781. 7. Goh H-G, et al. Blood. 2011;118(21): abstract 2763. 8. Matsuki E, et al. Blood. 2011;118(21): abstract 3765.
Response at Time of Treatment
Discontinuation
Patients With Molecular and/or
Cytogenetic Relapse, %
CCyR2 100%
MMR3 100%
MMR, CCyR, MCyR4 100%
CMR for ≥ 2 years on imatinib5-8 ~30%-65%
CCyR, complete cytogenetic response; CMR, complete molecular response;
MCyR, major cytogenetic response; MMR, major molecular response.
Defining Molecular Response Requirements
for Potential Treatment Discontinuation
ENESTnd 5-Year Update
Data cutoff: May 22, 2013
BCR-ABL Categories at 3 Months*
0
20
40
60
80
100
Pati
en
ts, %
BCR-ABL Level at 3 Months
n 176 234 88 24
BCR-ABL >10%
91
67
9
33>1- ≤10%
≤1%
Nilotinib 300 mg BID (n=258)
Imatinib (n=264)
Reasons for unevaluable samples included:
• Atypical transcripts: 5 patients on nilotinib, 2 patients on imatinib
• Missing samples: 4 patients on nilotinib, 5 patients on imatinib
• Discontinuation: 15 patients (including 1 progression) on nilotinib, 12 patients (including 1 progression) on
imatinib
*Calculated from total number of evaluable patients with PCR assessments at 3 months.
BCR-ABL ≤10%
>1- ≤10%
≤1%
25 Saglio G, et al. Blood. 2013:[abstract 92].
Characteristics of patients included in the STIM Study
A prospective, multicentre, non-randomized study with 19
participating institutions in France:
•100 patients enrolled between July 2007 and Dec 2009
•Median age (range): 63 years (29–80)
•Gender distribution: 48 males, 52 females
•Patients with previous IFN treatment: 51
•De novo CML patients: 49
•Median follow up: 55 months (range 9-72)
Frequent and sustained drug-free remission in the
Australasian CML8 trial of Imatinib withdrawal
Median follow-up of 42 months (range 15 – 72 months)
Ross DM et al. Blood. 2013 Jul 25;122(4):515-22.
CML-IV: Survival by Confirmed Response at 4 Years
Achievement of confirmed MR4.5 at 4 years predicted significantly
higher survival probabilities at 8 years vs 0.1% to 1% BCR-ABLIS
(92% vs 83%; P = .047)
Hehlmann R, et al., JCO, 2014;32(5):415-423.
0 1
1.0
0.8
0.6
0.2
0
Su
rviv
al
Pro
bab
ilit
y
Time Since Diagnosis, Years
2 3 5 6 7 8
0.4
4
No. at risk
< 0.0032%
8-year survival
9
0.0032%-0.01%
0.01%-0.1%
0.1%-1%
> 1%
198
191
260
55
44
163
149
206
41
32
69
69
106
24
16
40
41
67
17
8
< 0.0032%0.0032% -0.01%0.01%-0.1%0.1%-1%
All patients with primary imatinib (n = 1,194)
4-year survival, 93%
8-year
survival (%)
> 1%
BCR-ABLIS
92
90
88
83
78
NSNSNS
P
.047
.001
MR4.5 at 4 years
No MMR at 4 years
MR4.5 vs no MMR
92% vs 83%, P < .047
Disease burden and cytogenetic response
1012
1011
1010
109
108
107
106
(Complete molecular response)
• Undetectable BCR-ABL mRNA transcript by real-time
quantitative and/or nested PCR in 2 consecutive blood
samples of adequate quality (sensitivity > 104)*
ELN recommendations(optimal response)
CHR 3 months
CCyR 12 months
MMR 18 months
CMR
Number of Leukemic Cells
Baccarani M, et al. J Clin Oncol. 2009;27(35):6041-6051
Radich JP. Blood. 2009;114:3376-3381
Overall survival
Stable responseNo risk of progression
STOP 2G-GKI experience
2nd generation TKI discontinuation
Rea et al. Blood (ASH) 2012; 120: Abstract 916
0
20
40
60
80
100
0 6 12 18 24 30 36 42
Surv
ival
wit
ho
ut
MM
R lo
ss %
Months since 2G-TKI discontinuation
95% CI: 45.6-76.6)61.1%
Survival without MMR loss at 12 months
• As of November 30, 2012, 39 patients with a minimum follow-up of 6 months
(median 17 months, range: 7-38) were analyzed
– 16/39 patients lost MMR
– Median time to MMR loss was 3 months (1-25)
ENESTnd 5-Year Update
Data cutoff: May 22, 2013
PFS (AP/BC or Death) on Study
by BCR-ABL Levels at 3 Months
Nilotinib 300 mg BID Imatinib 400 mg QD
BCR-ABL Level
≤ 1%
> 1% to ≤ 10%
> 10%
Censored
Observations
Pts Evt Cen
145 7 138
89 4 85
24 6 18
P = .9814
P = .0010
PFS by 5 Yearsa
94.6%95.3%
78.3%
100
90
80
70
60
50
40
30
20
10
00 1 2 3 4 5 6
Pa
tie
nts
Witho
ut P
rog
ressio
n, %
Time Since Randomization, Calendar Years
100
90
80
70
60
50
40
30
20
10
00 1 2 3 4 5 6
Pa
tie
nts
Witho
ut P
rog
ressio
n, %
Time Since Randomization, Calendar Years
PFS by 5 Yearsa
P = .2338P < .0001
98.5%95.3%
80.1%
BCR-ABL Level
≤ 1%
> 1% to ≤ 10%
> 10%
Censored
Observations
Pts Evt Cen
43 2 41
133 2 131
88 16 72
EMR Failure EMR Failure
Cen, censored; EMR, early molecular response; Evt, events; Pts, patients.a PFS rates reported consider each year to consist of twelve 28-day cycles.
Patients with EMR failure (BCR-ABL > 10% at 3 months) have
significantly worse 5-year PFS
Rates of EMR failure are lower on nilotinib 300 mg BID vs imatinib
31 Saglio G, et al. Blood. 2013:[abstract 92].
NK CELL COUNTS AT THE TIME
OF IMATINIB DISCONTINUATIONNK cells
No relapse Relapse0
200
400
600
800
CD
3- /C
D5
6+/m
m3
p=0.0135
NK cells CD56dim
No relapse Relapse0
200
400
600
800
CD
3- /C
D5
6dim
/mm
3
p=0.011
NK cells CD56bright
No relapse Relapse0
10
20
30
40
CD
3- /C
D56
bright /m
m3
p=0.366
All No relapse Relapse
Median CD3-CD56+/mm3 (range) 174 (67-727) 233 (70-727) 145 (67-450)
Median CD3-CD56dim/mm3 (range) 162 (55-723) 216 (55-723) 139 (58-438)
Median CD3-CD56bright/mm3 (range) 7 (2-31) 7 (2-30) 8 (2-31)
Delphine Rea et al for STIM Investigators, ASH 2013 (abs 856)
ENESTnd 5-Year Update
Data cutoff: May 22, 2013
Cumulative Incidence of MMR
MMR, major molecular response (BCR-ABLIS ≤ 0.1%).a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.
By 1 Yeara By 5 Yearsa
55%, P < .0001
51%, P < .0001
27%
Δ 24% to 28%
60%
77%, P < .0001
77%, P < .0001
Δ 17%
By 4 Yearsa
76%, P < .0001
73%, P < .0001
56%
Δ 17% to 20%
100
0 2 6
90
80
70
60
50
40
30
20
10
0
Pati
en
ts W
ith
MM
R,
%
Time Since Randomization, Calendar Years
31
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
4 5
33 Saglio G, et al. Blood. 2013:[abstract 92].
ENESTnd 5-Year Update
Data cutoff: May 22, 2013
Cumulative Incidence of MR4.5
MR4.5, molecular response ≥ 4.5-logs (BCR-ABLIS ≤ 0.0032%).a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.
By 5 Yearsa
11%, P < .0001
7%, P < .0001
1%
Δ 6% to 10%
31%
52%, P < .0001
54%, P < .0001
Δ 21% to 23%
By 4 Yearsa
40%, P < .0001
37%, P = .0002
23%
Δ 14% to 17%
100
0 2 6
90
80
70
60
50
40
30
20
10
0
Pati
en
ts W
ith
MR
4.5
, %
Time Since Randomization, Calendar Years
31
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
4 5
By 1 Yeara
34 Saglio G, et al. Blood. 2013:[abstract 92].
ENESTnd 5-Year Update
Data cutoff: May 22, 2013
12
17
233
5
0
5
10
15
20
25
Including Clonal Evolution
Pati
en
ts, n
Progression to AP/BC on Core Treatmenta
a Includes progression to AP/BC or deaths in patients with advanced CML occurring on core treatment.
P = .0059
P = .0185
P = .0009
P = .0085
4.2% 0.7% 1.1% 6.0% 1.1% 1.8%
Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281)
No new progressions on core treatment (excluding or including clonal evolution) in year 5
Imatinib 400 mg QD (n = 283)
35 Saglio G, et al. Blood. 2013:[abstract 92].
Disease burden and cytogenetic response
1012
1011
1010
109
108
107
106
(Complete molecular response)
• Undetectable BCR-ABL mRNA transcript by real-time
quantitative and/or nested PCR in 2 consecutive blood
samples of adequate quality (sensitivity > 104)*
ELN recommendations(optimal response)
CHR 3 months
CCyR 12 months
MMR 18 months
CMR
Number of Leukemic Cells
Baccarani M, et al. J Clin Oncol. 2009;27(35):6041-6051
Radich JP. Blood. 2009;114:3376-3381
Overall survival
Stable responseNo risk of progression
Possibility to discontinue
therapy
Cumulative Incidence of MR5.0
Achievement According to 6 Month Response
Muller MC, et al. Blood. 2013: 122(21): [abstract 4008].
1.0
0 3 41
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Cu
mu
lati
ve i
ncid
en
ce
of
MR
5
Years after diagnosis
52 6 7 8
< 0.1%IS at 4.5 to 7.5 months, n = 255
0.1%-1%IS at 4.5 to 7.5 months, n = 254
1%-10%IS at 4.5 to 7.5 months, n = 211
> 10%IS at 4.5 to 7.5 months, n=107
6 mo
MMR
at 6 mo
No MMR
at 6 mo
RANDOMIZE
Imatinib continue same dose (n = 103)
Nilotinib 400 mg BID (n = 104)
4-year study
BID, twice daily; CCyR, complete cytogenetic response; MMR, major molecular response; RQ-PCR,
real-time quantitative polymerase chain reaction.
Patients
treated with
imatinib for ≥ 2
years who
achieved CCyR
but have
detectable
BCR-ABLa
(N = 207)
a By RQ-PCR with sensitivity of ≥ 4.5 logs.
Crossover from imatinib to nilotinib for:• Detectable BCR-ABLa at year 2• Treatment failure, confirmed loss of
response
Year 2
Study Schema
The kinetics of molecular relapse
0,001
0,01
0,1
1
10
BCR-ABL / ABL(%)
CyclicNo imatinib
0,001
0,01
0,1
1
10BCR-ABL/ABL (%)
FluctuatingNo imatinib re-treated
0,001
0,01
0,1
1
10
BCR-ABL / ABL(%)
1
3
2Logarithmic
Mahon ASH 2009
Cumulative Incidence of MR4.5
in Patients Without MR4.5 at Baseline (ITT analysis)
ITT, intention-to-treat.
Pa
tie
nts
Wit
h M
R4.5
, % P = .0006
By 12 Months By 24 Months
Δ 14%
By 36 Months
Δ 19%
P = .0020
Δ 22%
Nilotinib Imatinib
Crossover to nilotinib
33%
P = .0453
• In a subgroup analysis when only responses up to crossover were counted, 47% versus
24% of patients in the nilotinib and imatinib arms, respectively, achieved MR4.5 (P = .0003)
ENESTcmr 3-year follow-up
Leber B, et al. Blood. 2013;122(21):[abstract 94].
98 989896 9696n
Follow-up of the molecular-relapse patients (n=61)
Among the 57 patients alive another attempt of TKI discontinuation was
proposed for 16 patients in sustained CMR
Patients Treatment in
progress
Molecular response
Sustained treatment 40 27 Imatinib
8 Nilotinib
5 Dasatinib
31 CMR
9 MMR
2nd Stop without molecular
relapse9 NA 7 CMR
2 MMR
2nd Stop with molecular relapse 7 5 Imatinib
1 Nilotinib
1 Dasatinib
3 CMR
1MMR
No response*
3rd Stop 1 NA 1 CMR
No treatment 1 NA 1 CMR
Deaths 4 stroke,
mesothelioma,
gastric carcinoma,
elderly woman
general deterioration
Strategies to Try to Silence / Eradicate
Ph+ Stem Cells
- Ph+ stem cell eradiction may occur
spontaneously after TKI therapy in some cases
(how many?)
- It may be “stimulated” by immunomodulatory
agents like IFN
- We may try to force it:
- Through vaccination processes
- Adoptive immunotherapy with antibodies directed
against Ph+ Stem cells antigens (IL1R*)
- Drugs affecting stem cell activated pathways
*Fioretos et al. Blood (ASH) 2010.
+ imatinib
CD
34-P
E
CFSE
- imatinib
CML Stem Cells are Resistant to Imatinib: Experimental Approaches
Imatinib/GF insensitive CML stem cells
Graham. Blood 2002;99(1):319-25 (modified)
Reversible G1 arrest –anti-proliferative effect“accumulation”
10mM 10x IC50+/- GFs
Recruitment out of niche/into cycle:+ IFN-alpha+ Plerixafor +/- G-CSF+ PLGF-Inhibitor....
Targeting of quiescent LSC:+ JAK2 Inhibitors.+ IFN-alpha+ Vaccination+ Autophagy inhibitors+ earlier acting TKIs
Clonal exhaustion:Telomerase inhibitors
JAK2-Mediated Extrinsic Survival of CML Stem Cells
Stromal cells protect CML stem/progenitors cells by producing cytokines which
activate JAK2 pathway: rational for combining Bcr-Abl and JAK2 inhibitor
Traer E, Mackenzie R, Snead J et al. Blood 2010; 116: abstract 199