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

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

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): 1029-1035.

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

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

Treatment free remission using loss of MMR to define molecular recurrence 61% Rousselot P et al., J Clin Oncol. 2014 Feb 10;32(5):424-30

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 %

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

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

DESTINY PCR monthly until month 25 PCR alternate months in months 26-37 De-escalate TKI (13 months) Stop TKI 0 12 13 37 MONTHS

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 7 Freeman Hospital, Newcastle 7 Heartlands, Birmingham 6 Royal Devon & Exeter 5 Salisbury 5 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 174 Recruitment completed April 2015. 174 patients. 11

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.

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%)

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)

DESTINY: Freedom from molecular recurrence

DESTINY: Recovery from relapse

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.

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 0 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

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.

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.

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.

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 www.euroqol.org

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.

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 % - 63 %) At 18 months : 55 % (95% CI : 47 % - 61 %) Months from discontinuation of TKI Mahon et al. Blood (ASH 2014);124:abstract#151.

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).

ENESTop:

ENEST freedom:

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

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

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

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

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

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

What next? 37

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.

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

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) ≥ 0.0032 (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; 11:1029-35. Ross D, et al. Blood. 2013;122:515-522. Takahashi N, et al. Haematologica. 2012;97:903-906.

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

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

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

EURO-SKI: Patient disposition Years (range) Gender: % female 47.8% Median age at diagnosis 52.0 (11.2 -85.5) Median age at stop 60.3 (19.5-89.9) 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 (1.0-13.3)

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 1.08-1.25), 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

EUROSKI: Prognostic modelling 2 (n=448; imatinib only) The odds ratio for MR4 duration was 1.16 (95% CI 1.076-1.253), 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

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.

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

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. © IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSION' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. Huang et al, Cancer 2012; 118: 3123-7 49

Improvement of Survival of CML by Therapy 1983 – 2011 Imatinib, 2002 – 2011 5-year survival 90% 8-year survival 88% IFN or SCT, 1997 – 2003 5-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 – 1994 5-year survival 38% Year after diagnosis German CML Study Group, 2011. 50

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

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

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):6041-6051 Radich JP. Blood. 2009;114:3376-3381

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

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) ≥ 0.0032 (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; 11:1029-35. Ross D, et al. Blood. 2013;122:515-522. Takahashi N, et al. Haematologica. 2012;97:903-906.

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