Document 6428042

La sospensione della terapia:
il nostro nuovo obiettivo
Gi
Giuseppe
S li
Saglio
Imatinib discontinuation
French STIM experience
The overall probability of maintenance of CMR at 24 and 36
months
h was 39% (95% CI 29
29-48).
48)
39%
Molecular
M
l
l relapse
l
occurred
d iin 61 pts
t with
ith 58 relapses
l
occurring
i d
during
i th
the
first 7 months 3 late relapses at month 19, 20 and 22, respectively
Mahon FX, et al. Blood 2011;118:abstract 603
Imatinib discontinuation
Summary
y of imatinib-discontinuation studies
•
STIM1,2, n=100
– CP-CML, imatinib ≥ 400mg/d frontline or post IFN-α for a least 36 months
– Undetectable BCR-ABL for at least 24 months confirmed at study entry*
•
CML83,4, n=40
– CP-CML, imatinib frontline or post IFN-α for at least 36 months
– Undetectable BCR-ABL on continuing imatinib for at least 2 years**
•
A-STIM,
A
STIM, n
n=34
345
– CP-CML, imatinib frontline or post IFN-α
– MR4.5 or CMR4.5 for at least 24 months
•
Japanese survey6, n=43
– Imatinib stopped for at least 6 months due to any cause except progression,
transplantation or death
– Undetectable BCR-ABL on continuing imatinib for at least 12 months***
months
•
Korean retrospective study7, n=14
– Undetectable BCR-ABL on continuing imatinib for at least 12 months***
1Mahon et al. Lancet Oncol. 2010; 11: 1029‐1035
2Mahon et al. Blood (ASH) 2011; 118: Abstract 603 5Rousselot et al. Blood (ASH) 2011; 118: abstract 3781
3Ross et al. Leukemia 2010; 24: 1719‐1724
6Takahashi et al. Haematologica 2012; 97: 903‐906
4Ross et al. Haematologica 2012; abstract 0189
7Yhim et al. Leukemia Research 2012; 36: 689‐693
*50 000 copies at least of ABL at study entry
**RT‐PCR sensitivity of at least 4.5log
***RT‐PCR sensitivity of at least 4 logs
Imatinib discontinuation
Australian CML8 experience (Twister)
43%
Ross M et al, Haematologica 2012; 97:[abstract 0189].
Prerequisites
q
for TKI discontinuation
Prerequisites for discontinuation
Mahon FX, et al. Blood 2011;118:abstract 603.
Sustained CMR after stopping imatinib
according to duration of CMR before cessation
78% vs. 15%, P = .0002 by Log‐rank test
Takahashi N et al., Haematologica, 2012; 97:903-06.
Factors associated with outcome after
imatinib cessation
Study
Significant factors
STIM study1
Sokal risk group
Imatinib treatment duration
CML8 study2
Sokal risk group
Prior exposure to IFN
Japanese survey3
Imatinib treatment duration
Duration of undetectable BCR
BCR-ABL
ABL transcripts
Imatinib dose intensity
Prior exposure to IFN
Korean retrospective study4
Sokal risk group
Time to undetectable BCR-ABL transcripts
Imatinib
a b treatment
ea e du
duration
a o
1Mahon et al. Blood (ASH) 2011; 118: Abstract 603 3Takahashi et al. Haematologica
2Ross et al. Haematologica
4Yhim et al. Leukemia Research 2012; 36: 689‐693
2012; abstract 0189.
2012; 97: 903‐906
Deep molecular response according to BCRABL transcripts level at 3 months
Branford et al. Blood 2013 121:3818-3824; Prepublished online March 20, 2013
TKI discontinuation: Are there risks?
10
% BCR-ABL/ABL
1
0,1
Start again
Stop
0 01
0,01
0 001
0,001
STIM: A
STIM
Among the
th 59 with
ith recurrence, 49 achieved
hi
d again
i CMR after
ft imatinib
i ti ib
rechallenge. A median time of 4 months (range 0–21) was necessary for CMR to
recur.
Mahon et al., Lancet Oncol. 2010; 11:1029-1035.
TKI discontinuation: Are there risks?
9 No events of relapse to AP or BC have been reported
10
9 No acquired drug‐resistance: Sensitivity to imatinib is preserved
% BCR-ABL/ABL
1
0,1
Start again
Stop
0 01
0,01
0 001
0,001
STIM: A
STIM
Among the
th 59 with
ith recurrence, 49 achieved
hi
d again
i CMR after
ft imatinib
i ti ib
rechallenge. A median time of 4 months (range 0–21) was necessary for CMR to
recur.
Mahon et al., Lancet Oncol. 2010; 11:1029-1035.
After discontinuation, some patients may show
fluctuation in MRD
CML patient in CP
CML
patient in CP
31 years old
Low risk Sokal score
Rousselot P, personal data.
Kaplan-Meier estimate of TFR defined as loss of
MMR and defined as loss of CMR
Percent s
survivall
100
80
65%
60
40
37%
20
0
P = 0.003
0
12
24
36
48
60
72
84
96
108
Months
Rousselot P et al., JCO in press
TFR= treatment free remission
(i)
(ii)
(iii)
(iv)
(v)
(vi)
Goh et al. Leukemia &Lymphoma 2011
Goh et al. Leukemia &Lymphoma 2011
Can we improve
p
the discontinuation rate?
ENESTnd: Cumulative incidence of MR4.5
Nilotinib 300 mg
g BID
100
Nilotinib 400 mg BID
Patients W
With MR4.5, %
Imatinib 400 mg QD
80
By 4 Years
By 1 Year
60
40% P < .0001
40%,
0001
40
37%, P = .0002
∆ 14%-17%
∆ 6%-10%
20
11% P < .0001
11%,
0001
23%
7%, P < .0001
1%
0
0
6
12
18
24
30
36
42
48
54
60
Time Since Randomization, Months
Data cutoff: July 27, 2012.
MR4.5,
molecular response of
BCR-ABLIS
≤ 0.0032%.
Hochhaus A, et al. Haematologica. 2013; (s1): [abstract P712].
ENESTnd: MR4.5 by 4 years according to Sokal risk
Pattients W
With MR
R4.5, %
80
70
P = .1688
P = .0004
P = .0183
60
P = .0040
P = .1092
1092
50
P = .0066
30
20
48
45
40
38
34
29
32
31
24
10
13
0 n = 103 103 104
Low Sokal
Nilotinib 300 mg BID
101
100
101
Intermediate Sokal
Nilotinib 400 mg BID
78
78
78
High Sokal
Imatinib 400 mg QD
ƒ Rates of MR4.5 by 4 years were consistently higher with nilotinib vs
i ti ib iin patients
imatinib
ti t with
ith llow, iintermediate,
t
di t or hi
high
hS
Sokal
k l risk
i k scores
Data cutoff: July 27, 2012.
Hochhaus A, et al. Haematologica. 2013; (s1): [abstract P712].
2nd generation TKI discontinuation
STOP 2G-GKI experience
CP‐CML
TKI therapy ≥ 3 years
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
Primary endpoint: survival without loss of MMR
Molecular relapse: loss of MMR
L
Loss
off MMR ttriggered
i
d ttreatment
t
t resumption
ti
M36
M48
M60
Year 3‐5
RQ‐PCR
Every
3‐6 months
*Molecular monitoring performed in local laboratories filling international standardization requirements
international standardization requirements.
*20 000 copies of ABL at least.
Rea et al. Blood (ASH) 2012; 120: Abstract 916
2nd generation TKI discontinuation
Survival w
without M
MMR losss %
STOP 2G-GKI experience
61.1%
80
95% CI: 45.6‐76.6)
60
40
20
0
•
Survival without MMR loss at 12 months
100
0
6
12
18
24
30
36
42
Months since 2G‐TKI discontinuation
As of November 30, 2012, 39 patients with a minimum follow-up of 6 months
(median 17 months
months, range: 7
7-38)
38) were analyzed
– 16/39 patients lost MMR
– Median time to MMR loss was 3 months (1-25)
Rea et al. Blood (ASH) 2012; 120: Abstract 916
Expectations for best achievable response to
therapy in CML continue to increase
¾ As treatments for chronic myeloid leukaemia (Ph+ CML)
have improved, expectations for responses have
increased: HR → CCyR → MMR1 UMRD
Ph+ CML
Diagnosis
CHR
CCyR
MMR
CMR
MR4.5
UMRD
Time on Treatment
CCyR, complete cytogenetic response; CHR, complete haematologic response;
UMRD, undetectable molecular residual disease; HR, haematologic response; MMR, major molecular response.
Baccarani et al., J Clin Oncol. 2009;27(35):6041-6051.
Expectations for best achievable response to
therapy in CML continue to increase
¾ As treatments for chronic myeloid leukaemia (Ph+ CML)
have improved, expectations for responses have
increased: HR → CCyR → MMR1 UMRD
Ph+ CML
Diagnosis
CHR
CCyR
MMR
TFR: CMR
Treatment‐free
remission
MR4.5
Maintenance
UMRD of MMR without therapy
Time on Treatment
CCyR, complete cytogenetic response; CHR, complete haematologic response;
UMRD, undetectable molecular residual disease; HR, haematologic response; MMR, major molecular response.
Baccarani et al., J Clin Oncol. 2009;27(35):6041-6051.
Medical Rationale and Clinical Benefits
of Treatment-Free Remission
Medical Rationale
• Discontinuation studies
demonstrating proof of concept
regarding successfully stopping
imatinib therapy
• Molecular
M l
l responses ffrom
ENESTnd and ENESTcmr better
with nilotinib
• Patient & Investigator interest
Patient Benefits
• “Operational” cure
• Alleviate chronic low grade AEs
• Reduce risk of developing long
term AEs
• Pregnancy
g
y
• Minimize Drug Drug Interactions
(
(elderly)
y)
• Health economic advantages vs
chronic lifelong TKI therapy
Kamel MALEK / for Business Use Only /Confidential, Do not Circulate / April 13, 2013
ENESTfreedom: Study Design Overview
• MR 4.5 at
study entry
YES
ENRO
OLLMENT
T
• De novo CP
Ph+ CML
adult
patients
treated with
Tasigna®
for ≥ 2 years
Nilotinib Consolidation Phase
Durable
MRD*
52 weeks
• Other I/E
criteria met
TFR Phase
(up to 192 weeks)
NO
Nilotinib
Continuation Phase
(52 weeks)
*Per protocol durable MRD
The 4 llastt quarterly
Th
t l performed
f
d PCR
assessments must fulfill the 3 following
criteria:
1- the last assessment is MR4.5
2 no assessmentt worse than
2th MR4
3- no more than two assessments between
MR4 and MR4.5
E
Enrolling
lli
Kamel MALEK / for Business Use Only /Confidential, Do not Circulate / April 13, 2013
Durable
MRD*
YES
NO
Nilotinib Prolonged
Continuation Phase
TFR-2 Phase
(up to 192 weeks)
ENESTop: Study Design Overview
• MR 4.5 at
study entry
No
Confirmed
Loss of
MR 4.5
Nilotinib Consolidation Phase
52 wks
ENRO
OLLMENT
T
• CP Ph+ CML
adult
patients
treated for ≥
3 years with
TKIs (IM
th
then
Nilotinib for
≥ 2 years)
TFR Phase
(years 2 )
Yes
Not eligible
g
to TFR
• Other I/E
criteria met
Recruitment is ongoing
6 countries
t i in
i EGM including
i l di Australia,
A t li Russia
R
i and
d Tunisia
T i i
KaAustamel MALEK / for Business Use Only /Confidential, Do not Circulate / April 13, 2013
Grazie dell’attenzione
Giuseppe Nicola Saglio