Stopping TKI treatment in
CML: Who and when?
13th National CML Patient Forum, Newcastle
11th October 2014
Prof. Mhairi Copland
University of Glasgow / Beatson West of Scotland Cancer Centre
Questions
• I’ve had CML for a long time and I’m
doing fine……..
– Could I stop treatment or take less?
– What is the evidence for this?
– What are MMR and MR4?
– How is DESTINY different?
– What will happen in the future?
STopping IMatinib (STIM)
•100 French patients in CMR for at least 2 years
•All were on imatinib for several years
•Some had had previous interferon
•Imatinib stopped, then monthly molecular testing (PCR)
STIM: Stopping imatinib in
CMR/MR4
39%
Mahon et al Lancet Oncology 2010
STopping Imatinib (STIM)
•Imatinib resumed as soon as the PCR became positive
•All 61 relapses responded (56/61 back to CMR/MR4)
•No-one had a more serious deterioration in their CML
TWISTER: Stopping imatinib in undetectable disease
Rate of TFR in all 40 patients.
TFR = treatment-free remission
Ross D M et al. Blood 2013;122:515-522
©2013 by American Society of Hematology
STIM: Can we predict who relapses?
Mahon et al Lancet Oncology 2010
Loss of MMR as trigger for
restarting TKI therapy
65%
61%
Loss of MMR is a practical
and safe criterion for
restarting TKI therapy
55%
If use STIM criteria……… and
restart therapy when BCR-ABL
become detectable
©2014 by American Society of Clinical Oncology
Rousselot P et al. JCO 2014;32:424-430
43%
29%
All patients achieve deep molecular responses after restarting TKI…. But can take time
Rousselot P et al. JCO 2014;32:424-430
©2014 by American Society of Clinical Oncology
Does BCR-ABL need to be negative to stop therapy?
100
CCR
BCR-ABL PCR %
1
MMR
0.1
CMR/MR4
(level of
detection)
0.01
12
15
18
21
24
30
Time (months)
36
42
Does BCR-ABL need to be negative to stop therapy?
100
CCR
BCR-ABL PCR %
1
MMR
0.1
CMR/MR4
(level of
detection)
0.01
12
15
18
21
24
30
36
42
Time (months)
….we don’t know
De-Escalation and Stopping Treatment with
Imatinib, Nilotinib or sprYcel = DESTINY
• CI – Richard Clark, Liverpool
• 2 separate groups; MR4 and MMR; each treated the same
• 84 pts in each group
• 50% treatment dose: IM 200mg; NIL 200mg 2xday; DAS 50mg
• Monitor monthly for 12 months
• If PCR remains below 0.1%, then stop
Check PCR monthly until month 25
De-escalate TKI
(13 months)
Check PCR alternate
months in months 26-37
Stop TKI
MONTHS
DESTINY: key inclusion criteria
CML in first chronic phase only, aged 18 or over
Demonstration of BCR-ABL1 positivity at or shortly after original diagnosis
Must have received TKI treatment for at least 3 years
At least 3 molecular results over the preceding 12 months, that fit either of the
following groups (results from any UK lab are acceptable):
(MR4 group) all the available BCR-ABL1 molecular results over the preceding 12
months are in MR4 (MR4 is defined as a BCR-ABL1/ABL1 ratio of zero, with at
least 10,000 ABL1 control transcripts).
(MMR group) some or all BCR-ABL1 molecular results are in MMR (BCRABL1/ABL1 ratio of 0.1% or less, but not zero, with at least 10,000 ABL1 control
transcripts).
If the results over the preceding 12 months are a mix of MMR and undetectable
BCR-ABL1, then the patient is eligible for the MMR but not the MR4 group.
DESTINY: key exclusion criteria
Any molecular result during the preceding 12 months that is not in either MMR or
MR4.
Treatment with higher than standard TKI doses ('standard' is defined as imatinib
400mg daily, nilotinib 400mg twice daily or dasatinib 100mg daily), unless as part
of a clinical trial of first line therapy, e.g. SPIRIT1.
Patients who switched previous licensed TKI treatment (imatinib, nilotinib or
dasatinib) twice or more because of intolerance.
Patients who switched previous licensed TKI treatment (imatinib, nilotinib or
dasatinib) because of resistance. Patients treated with lower than standard TKI
doses (imatinib 400mg daily, nilotinib 400mg twice daily or dasatinib 100mg
daily) for tolerance reasons may be included.
Previous treatment with ponatinib or bosutinib cannot enter. However, patients
who received interferon prior to commencing TKI (even if resistant to their
interferon) are eligible, provided their response to TKI fits the entry criteria.
Stage 1
Stage 2
Stage 3
Compare first
line intervention
Identify partial
responders
early
Identify ‘best’
responders later
Randomised
Switch
Reduce/stop
SPIRIT 3
Primary endpoint: MR3 (MMR) at 3 years
Secondary: sustained MR3
CMR on reduced dose/stop
(no more bone marrows!)
EFS, PFS, OS
Health Economics, QoL
Stage 1
Stage 2
Stage 3
Randomise
Selective switch
Reduce dose, stop
(500 to each group)
(3 months or later)
(after minimum 3 years)
Imatinib
Imatinib
Group
I
Ponatinib
Ponatinib
Ponatinib
Ponatinib
R
Nilotinib
n=500
Nilotinib
Nilotinib
Primary endpoint
MR3 at 3 years
(if MR3 for at least 1 year)
n=500
Aim to reduce and stop
Imatinib
Group
N
What do you think?