1. Stopping treatment: who and when
Stopping treatment: who and when? CML patient & carer meeting 2016 Manchester, 24th September Richard Clark Royal Liverpool University Hospital 1

2. Can CML patients with consistently undetectable BCR-ABL stop treatment?2

3. STIM Study Design 100 patients
Q- RT-PCR from peripheral blood every month in the first year and every 2 months thereafter
STOP
Start Imatinib
CMR
Sustained deepMR
for ≥ 2 years
Five BCR–ABL analyses by RT-qPCR during these 2 years
Sixth datapoint checked in centralized laboratory
Mahon FX et al. The Lancet Oncology, 2010;11(11):

4. CCR MMR ~MR4 (level of detection in ~2006) 12 15 18 21 24
Time (months)
CCR
100 1
MMR
0.1
~MR4
(level of detection
in ~2006) 30 36 42
BCR-ABL PCR % 4

5. STIM study results (Sept 2015)
100 patients
62 events (61 molecular recurrences)
At 6 months : 43% ( 95%CI  : 33 – 52)
At 24 months : 38% (95%  CI: 32 – 51)
Median follow up: 65 months (range 10-84)
Mahon FX, Personal communication

6. Treatment free remission using loss of MMR to define molecular recurrence
61%
Rousselot P et al., J Clin Oncol Feb 10;32(5):424-30

7. CCR MMR ~MR4 (level of detection) 12 15 18 21 24 Time (months) 30 36
100 1
MMR
0.1
~MR4
(level of detection) 30 36 42
BCR-ABL PCR %

8. DESTINY
De- Escalation and Stopping Treatment of Imatinib, Nilotinib or sprYcel
in patients with excellent control of chronic myeloid leukaemia
CI = Richard Clark, Liverpool 8

9. DESTINY Halve treatment: Imatinib 200mg Nilotinib 200mg 2xday
Dasatinib 50mg
Monitor monthly for 12 months
If PCR remains below 0.1%, then stop.
Further follow-up, monthly for a year then 2-monthly
Associated lab tests that were not attempted in STIM 9

10. DESTINY PCR monthly until month 25
PCR alternate months in months 26-37
De-escalate TKI
(13 months)
Stop TKI
MONTHS

11. DESTINY recruitment: Target = 168
Sites:
Royal Liverpool U Hospital 39
Hammersmith, London 22
Beatson, Glasgow 15
Kent and Canterbury 12
St James, Leeds 12
Nottingham City Hospital 10
King’s College Hospital, London 8
Hereford
Freeman Hospital, Newcastle 7
Heartlands, Birmingham 6
Royal Devon & Exeter 5
Salisbury
Colchester General 5
North Bristol (Southmead) 4
Queen Elizabeth Birmingham 4
UHW, Cardiff 4
Churchill, Oxford 3
Aberdeen Royal Infirmary 3
Manchester Royal Infirmary 2
Addenbrookes, Cambridge 1
TOTAL
Recruitment completed April 2015.
174 patients. 11

12. DESTINY; status 174 patients recruited: 49 to MMR 125 to MR4
Minimum FU to date
Median FU to date
Maximum FU to date
Eligibility assessment
Molecular group assignment
Registration
End of study; primary outcome assessment. Further follow up may be required for relapsed patients that haven’t regained MMR
Determine the safety of proceeding to stopping phase
19 months
Baseline
12 months
24 months
36 months
De-escalation Phase
Stopping Phase
174 patients recruited:
49 to MMR
125 to MR4
Safety & efficacy data from the 12 months de-escalation phase are available on all patients.

13. Study population Patient characteristics at baseline MMR N = 49 MR4
Overall
N = 174
Demographic Characteristics
Age
median (IQR) 57
(45, 66) 61
(51, 68) 59
(50, 68)
Gender
Male [n (%)]
25 (51%)
73 (58%)
98 (56%)
Physical findings
ECOG performance status [n, (%)]
0 - Fully Active
1 - Work Able
2 - Not Work Able
3 - Limited Self Care
4 - Completely Disabled
42 (86%)
7 (14%) -
113 (90%)
10 (8%)
1 (1%)
155 (89%)
17 (9%)
Clinical characteristics
BCR-ABL1 % (Hammersmith results)
median (IQR, range)
0.0047
(0.002, 0.009)
0.001
(0.0003, 0.002)
(0.0006, 0.003)
Medical History
Total time in TKI treatment (years)
Missing
7.7
(5.1, 10.7)
6.5
(4.8, 10.2) 1
6.9
Medication
Imatinib
n (%)
43 (88%)
105 (84%)
148 (85%)
Nilotinib
2 (4%)
14 (11%)
16 (9%)
Dasatinib
4 (8%)
6 (5%)
10 (6%)

14. DESTINY: efficacy
Data are now complete for the de-escalation phase (i.e. until 12 months)
12 molecular recurrences (loss of MR3 on 2 consecutive samples) have occurred between the second and twelfth month of de-escalation.
‘MR3 but not MR4’ at trial entry: 9 of 49 patients (18.4%)
Median time to recurrence: 4.4 months (3.2 – 8.1)
‘MR4 at entry’: 3 of 125 patients (2.4%).
Median time to recurrence: 8.7 months (8.4 – 10.7)

15. DESTINY: Freedom from molecular recurrence

16. DESTINY: Recovery from relapse

17. DESTINY: efficacy
No recurrences have occurred in the quartile with the shortest prior TKI treatment (< 4.8 years) 3
Recurrence according to time in prior MMR/MR4 not yet available; will need a lot of chasing of sites
40 (82%) ‘MR3 but not MR4’ and 118 (94%)  ‘MR4 at entry’ have proceeded to stopping phase.

18. DESTINY: predictors of molecular recurrence
Characteristic
Molecular Relapse
p-value a
Yes
(n = 12) No
(n = 162)
Molecular group: MMR
9 (18%) b
40 (82%)
<0.001
MR4
3 (2%)
122 (98%)
Gender Male
6 (6%)
92 (94%)
0.766
Female
6 (8%)
70 (92%)
ECOG
12 (8%)
143 (92%)
0.366 1+
0 (0%)
19 (100%)
Medication Imatinib
136 (92%)
0.218
Dasatinib/Nilotinib
26 (100%)
Sokal (at diagnosis) Low
45 (100%)
0.131
Intermediate/High
2 (8%)
24 (92%)
Missing 10 93
Hasford (at diagnosis) Low
51 (100%)
0.077
2 (10%)
18 (90%)
Age
60 (46, 69)
59 (50, 68)
0.840
Weight
84 (74, 90)
80 (71, 92)
0.901
Time in TKI (years)
7.6 (6.4, 9.1)
6.8 (4.8, 10.2)
0.365
Haemoglobin
128 (121, 147)
131 (121, 139)
0.888
WBC ×109
6 (4.9, 6.5)
5.7 (4.7, 7.0)
0.883
Platelet count
205 (169, 239)
205 (175, 241)
0.685
Eosinophils
0.10 (0.08, 0.21)
0.20 (0.10, 0.30)
0.059
Lymphocytes
1.6 (1.4, 1.8)
1.6 (1.3, 2.0)
0.617
Frequency & proportion for categorical variables, median (IQR) for continuous variables
P-value: Fisher’s exact test for categorical variables, Mann-Whitney U-test for continuous variables

19. Safety results
The presence and severity of TKI related symptoms are recorded at each monthly visit
Musculoskeletal and connective tissue disorders
53 “new” symptoms have been reported by 36 patients (21%).
43 Grade 1 - Does not interfere with patient's usual function
10 Grade 2 - Enough discomfort to interfere with usual activity.
Most common: cramps, arthritis, musculoskeletal pain.
Lethargy: 25 new symptoms in 24 patients (14%) 23 Grade 1 and 2 Grade 2
Skin disorders: 22 new symptoms in 19 patients (11%) 18 Grade 1 and 4 Grade 2
Nausea/vomiting: 22 new symptoms in 16 patients (9%) 18 Grade 1 and 4 Grade 2.
Diarrhoea: 13 new symptoms in 12 patients (7%) 12 Grade 1 and 1 Grade 2.
Hot flushes/sweats: 8 new symptoms in 8 patients (5%) 7 Grade 1 and 1 Grade 2.
Eye disorders: 7 new symptoms in 6 patients (3%) 6 Grade 1 and 1 Grade 2.

20. EURO-SKI: Adverse events – musculoskeletal symptoms
A TKI withdrawal syndrome consisting of new, mostly transient, musculoskeletal pain or discomfort has been described in EUROSKI patients and other cessation trials (Richter et al JCO 2014 Mori et al 2015, Am J Hematology 2015; Lee et al, Haematologica 2016).
Grade 1-2 %
Grade 3
TOTAL
Musculoskeletal symptoms**
226
29.7 9
1.2
235
30.9
** = musculoskeletal pain, bone and/or joint pain, arthralgia, muscle pain, myalgia, joint stiffness, lumbalgia, articular pain, muscular pain, neck pain, arthromyalgia, pain both arms, pain legs.

21. TKI related symptoms over time (excluding relapsed patients)
Individual side effects (lethargy, diarrhoea, rash, nausea, periorbital oedema, hair thinning) all improve in the first 1-2 months of de-escalation but not significantly thereafter, though the FACT-BRM or EQ-5D Quality of Life data are already optimal at trial entry, suggesting that TKI side effects in entrants do not impact Quality of Life.

22. QoL data over time (EQ-5D questionnaires)
Improvement
Mean EQ-Index and EQ-VAS score profile over time.
The green line corresponds to the mean EQ-VAS Score in the general UK population of any age as published in

23. QoL data over time (FACT-BRM questionnaires)
Improvement
Figure 3. Mean FACT-BRMTOI, FACT-G and FACT-BRM total score profiles over time.
We haven’t found reference values for the general population related to these scores; however, the highest possible value for TOI and G-Score is 108 and the highest possible Total Score is 160.

25. Molecular relapse free survival
EURO-SKI
Molecular relapse free survival
200 interim patients – overtime, loss MMR=89
Relapses within 6 months, n=77
Molecular Relapse Free Survival
 At 6 months : 63 % (95% CI : 55% - 69%)
At 12 months: 56 % (95% CI : 49 % %)
At 18 months : 55 % (95% CI : 47 % %)
Months from discontinuation of TKI
Mahon et al. Blood (ASH 2014);124:abstract#151.

26. ENESTop: Treatment free remission following switch to nilotinib in chronic phase CML
163 entered; 126 entered the TFR phase.
Median duration of TKI = 87 mo; of nilotinib 53.0 mo (median dose 771mg/day during consolidation phase).

27. ENESTop:

29. ENEST freedom:

30. Questions from stopping studies
Do patients feel better on de-escalation/stopping?
How many patients don’t go into stopping studies and why?
Can some patients who relapse on stopping manage well on lower doses?
Is very deep remission (MR 4.5) essential for stopping?
What is the minimum safe time of prior TKI before attempting stopping?
Are ‘hares’ more likely to stop successfully than ‘tortoises’?
Can we predict successful stoppers by:
more sensitive PCR? (Hammersmith)
by immune profile? (Liverpool)
by residual marrow leukaemia? (Glasgow) 30

31. Questions from stopping studies
Do patients feel better on de-escalation/stopping??
How many patients don’t go into stopping studies and why??
Can some patients who relapse on stopping manage well on lower doses??
Is very deep remission (MR 4.5) essential for stopping??
What is the minimum safe time of prior TKI before attempting stopping??
Are ‘hares’ more likely to stop successfully than ‘tortoises’?
Can we predict successful stoppers by:
more sensitive PCR? (Hammersmith)
by immune profile? (Liverpool)
by residual marrow leukaemia? (Glasgow) 31

32. When are the final results of DESTINY expected?
The trial closed in April 2015.
No-one has progressed, and no other serious problems.
Everyone has completed the de-escalation phase.
100 patients will have completed one year of stopping by December 2016
Data Monitoring Committee won’t release results to me until ??May 2017
Analysis by ~July 2017: to be shared with scientific teams.
Complete de-escalation & 1st year stopping results could be presented in Dec 2017.
Complete stopping results likely in June 2018. 32

33. Acknowledgements
174 CML patients & their 20 teams taking part in DESTINY

35. What next? MAYBE: PROBABLY NOT: More aggressive de-escalation
Earlier de-escalation (< 3 years on TKI)
Broader entry criteria:
allow patients who have switched for resistance
allow previous BMT
More sites (= more expensive)
Less frequent PCR monitoring
Not stop the MMR patients?
PROBABLY NOT:
If not in stable MMR
If not in CP1
If not in stable remission for < 1 year 35

36. What next? MAYBE: PROBABLY NOT: More aggressive de-escalation
Earlier de-escalation (< 3 years on TKI)
Broader entry criteria:
allow patients who have switched for resistance
allow previous BMT
More sites (= more expensive)
Less frequent PCR monitoring
Not stop the MMR patients?
PROBABLY NOT:
A huge study
If not in stable MMR
If not in CP1
If not in stable remission for < 1 year 36

37. What next? 37

38. Serious Adverse Events
Severity: No. of SAEs (No. of patients)
CTCAE
short name (No. of SAEs)
Treatment
Arm 1 2 3 4 5
Myocardial infarction (2),
Syncope (1)
MMR -
MR4
1 (1)
2 (2)
Abdominal pain (1)
Pain in lower limbs* (1)
Gallbladder pain (1)
Allergic reaction (1)
Sepsis (3),
Urinary tract infection (1),
Skin Infection (1)
2 (1)
Bone pain (1),
Other (1)
Urinary retention (1)
Total
5 (4)
8 (7)
* Ongoing at death
All 15 SAEs (10 patients) were assessed as not related to the trial intervention.

39. EURO-SKI: Prior treatment%
Treatment before TKI: TOTAL
395
52.0 HU
272
35.8
HU + IFN 65
8.6
IFN 22
2.9
Other 20
2.6
Unknown 16
2.1
TKI first line
Imatinib
710
93.5
Nilotinib 35
4.5
Dasatinib 14
1.9 1
0.1
TKI second line 7 47 57

40. Definition of molecular recurrence across discontinuation studies
Criteria
BCR-ABL IS %
PILOT
STIM1
TWISTER
JAPAN
≥ 0.1 at once (loss of MMR) x
≥ 0.01 at once (loss of MR4)
≥ (loss of MR4.5)
2 consecutive points
and 1 log increase
Rousselot P et al., Blood. 2007;109:58–60.
Mahon FX, et al, Lancet Oncol. 2010; 11:
Ross D, et al. Blood. 2013;122:
Takahashi N, et al. Haematologica. 2012;97:

41. Safety results TKI withdrawal effects at half dose
The presence and severity of TKI related symptoms are recorded at each monthly visit.
Any previously unreported TKI symptom is recorded as a “new” symptom.
Some sites tend to report non serious AEs as TKI symptoms (due to the fact that we don’t ask non serious AEs to be reported).
Hence, “new” TKI symptoms during de-escalation include a mixture of common AEs (e.g. injuries, infections, etc.), TKI symptoms that occur periodically but were not present at the time of study entry and symptoms that could be attributed to halving the standard TKI dose.
A clearer and more consistent way for capturing TKI withdrawal effects has been recently implemented; a retrospective review of patients’ notes is performed at 12 months after complete treatment cessation. However, these results are not available yet.
The most commonly reported “new” TKI symptoms are summarised in the next slide
Professor Richard E. Clark
Initial safety results from the DESTINY trial

42. EURO-SKI Study update: Final recruitment
Patient recruitment (as of June 9, 2015)
Country
Centers
Preregistration
MR4 confirmation
Final inclusion
Czech Republic 6 64 62
Denmark 4 33 28 27
Finland 1 31 30
France 17
204
199
193
Germany 21
217
209
195
Greece 44
Netherlands 3 96 85 81
Norway
Portugal 26
Spain 9
Sweden
116
114
TOTAL 68
868
836
806

43. EURO-SKI: Patient disposition
Comment
Pre-registered
868 64
Final registration
821
47 screen failures (46 because not in MR4)
Descriptive statistics
760
20 excluded as TKI <3 yrs, > 2 TKIs, MR4 <1 yr, TKI switch not due to intolerance; atypical transcript.
41 have data pending
Assessible for molecular outcome
750
9 had inadequate molecular data
1 did not stop TKI
Prognostic modelling
448
Imatinib treated patients only

44. EURO-SKI: Patient disposition
Years (range)
Gender: % female
47.8%
Median age at diagnosis
52.0 ( )
Median age at stop
60.3 ( )
Median time from diagnosis to stop
7.7 (3.1 – 22.6)
Median duration of TKI therapy
7.6 (3.0 – 14.2)
Median duration of MR4 before stop
4.7 ( )

45. EUROSKI: Prognostic modelling 1 (n=448; imatinib only)
Univariate analysis showed no significant association between molecular relapse-free survival at 6 months and age, gender, depth of molecular response (MR4.5 vs not in MR4.5), or any variable parts of the Sokal, EURO, EUTOS or ELTS scores.
However, treatment duration with imatinib and MR4 duration were significantly (p < 0.001) correlated with MMR status at 6 months.
The odds ratio for treatment duration was 1.16 (95% CI ), meaning that 1 additional year of imatinib treatment increases the odds to stay in MMR at 6 months by 16%.
Molecular relapse free survival at 6 months was 65.5% for imatinib treatment > 5.8 yrs and 42.6% for treatment <5.8 yrs. This cut-off was identified with the minimal p-value approach. 45

46. EUROSKI: Prognostic modelling 2 (n=448; imatinib only)
The odds ratio for MR4 duration was 1.16 (95% CI ), which means that also one additional year in MR4 before TKI stop increases the odds to stay in MMR at 6 months by 16%.
Of note, treatment duration and MR4 duration were highly correlated, preventing a significant multiple model incorporating both.
Further analysis is in progress in order to:
Suggest an optimal cut-off for MR4 duration
Overcome the correlation between the two variables
Additionally, more data on IFN pre-treatment will be collected; there is reason to suspect its influence on MMR duration after TKI stop. 46

47. EURO-SKI: Critical events & safety issues
No. of patients
BCR-ABL >1%** 72
Loss of complete cytogenetic response 11
Restart of TKI without loss of MMR 14
Progression to accelerated phase or blast crisis
Deaths on trial, total 9
CML-related deaths
**according to protocol, BCR-ABL > 1% mandated marrow cytogenetics; this was only carried out in a minority of patients.

48. EUROSKI: Conclusions EHA 2016
With inclusion and relapse criteria less strict than in many previous trials and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a very large cohort of CML patients appears feasible and safe.
The proportion of patients without relapse (loss of MMR) after 6 months is 62% and after 12 months 56%.
Longer duration of imatinib therapy (optimal ≥ 5.8 years) prior to treatment cessation correlates to a higher probability of relapse-free survival.
Gender, age or any of the variables in EUTOS or Sokal scores do not predict the probability of successful TKI stop. 48

49. Estimations of the future prevalence of CML in the TKI era
Based on: The annual mortality rate on TKI therapy compared with a age-matched, non-CML population
The incidence of CML (4800 new cases per annum in the USA)
The anticipated population growth
The ageing of the population
The estimated prevalence of chronic myeloid leukemia in the United States by calendar year is illustrated.
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Huang et al, Cancer 2012; 118: 49

50. Improvement of Survival of CML by Therapy 1983 – 2011
Imatinib, 2002 – 2011
5-year survival 90%
8-year survival 88%
IFN or SCT, 1997 – year survival 71%
Survival probability
IFN or SCT, 1995 – 2001
5-year survival 63%
IFN, 1986 – 1994
5-year survival 53%
Hydroxyurea, 1983 – 1994, 5 yr surv. 44%
Busulphan, 1983 – year survival 38%
Year after diagnosis
German CML Study Group, 2011. 50

51. Improvement of Survival of CML by Therapy 1983 – 2011
Imatinib, 2002 – 2011 (CML IV)
5-year survival 90%
8-year survival 88%
Age matched non-CML population
(US data) 5-year survival 93%
8-year survival 87%
Survival probability
Year after diagnosis 51

52. EURO-SKI Study update: Final recruitment
Patient recruitment (as of June 9, 2015)
Country
Centers
Preregistration
MR4 confirmation
Final inclusion
Czech Republic 6 64 62
Denmark 4 33 28 27
Finland 1 31 30
France 17
204
199
193
Germany 21
217
209
195
Greece 44
Netherlands 3 96 85 81
Norway
Portugal 26
Spain 9
Sweden
116
114
TOTAL 68
868
836
806

53. Disease Burden and Molecular Response
Number of Leukaemic Cells
ELN recommendations
(optimal response)
CHR
3 months
CCyR
12 months
MMR
18 months
MR4.0 and beyond
1012
1011
1010
109
108
107
106
RUGBY BALL
GrapeFruit
Walnut
Overall survival
Grain of rice
Stable response
No risk of progression
Less than grain of sand
Undetectable BCR-ABL mRNA transcript by real-time quantitative and/or nested PCR in 2 consecutive blood samples of adequate quality (sensitivity > 104)*
Possibility to discontinue therapy
Baccarani M, et al. J Clin Oncol. 2009;27(35):
Radich JP. Blood. 2009;114:

54. EUROSKI: Entry criteria: (in red if differing from DESTINY)
Main Eligibility Criteria:
CML in first chronic phase.
TKI treatment for at least 3 years.
Must have b3a2 (e14a2) or b2a2 (e13a2) transcript (i.e. rare ones excluded even if monitorable)
At least 3 molecular results in the preceding 12 months showing BCR-ABL1/ABL1 ratio 0.01% or less (reported to IS where possible). Minimum control transcript number not specified (>104 in DESTINY).
Only one TKI treatment change AND only if due to intolerance; changes due to resistance are an EXCLUSION.
Parameters for the Sokal & EUTOS scores should have been recorded at diagnosis.
Previous or planned allograft is an EXCLUSION.
PCR monitoring = 4-weekly for 6 months, 6-weekly for 6 months, then 3-monthly for 2 years
Recruited May 2012 – Dec 2014
Professor Richard E. Clark
Initial safety results from the DESTINY trial

55. Definition of molecular recurrence across discontinuation studies
Criteria
BCR-ABL IS %
PILOT
STIM1
TWISTER
JAPAN
≥ 0.1 at once (loss of MMR) x
≥ 0.01 at once (loss of MR4)
≥ (loss of MR4.5)
2 consecutive points
and 1 log increase
Rousselot P et al., Blood. 2007;109:58–60.
Mahon FX, et al, Lancet Oncol. 2010; 11:
Ross D, et al. Blood. 2013;122:
Takahashi N, et al. Haematologica. 2012;97:

56. CCR MMR ~MR4 (level of detection) 12 15 18 21 24 Time (months) 30 36
100 1
MMR
0.1
~MR4
(level of detection) 30 36 42
BCR-ABL PCR % 56