Prospects for stopping treatment : Should this be in a clinical trial? CML patient & carer meeting 2015 Hammersmith Hospital, 14 th November 2015 Richard Clark Royal Liverpool University Hospital

STIM Study Design 100 patients STOP Sustained deepMR 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 RT-qPCR during these 2 years Sixth datapoint checked in centralized laboratory Mahon FX et al. The Lancet Oncology, 2010;11(11):

Time (months) CCR MMR 0.1 ~MR4 (level of detection) BCR-ABL PCR %

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

Definition of molecular recurrence across discontinuation studies Criteria BCR-ABL IS % PILOTSTIM1TWISTERJAPAN ≥ 0.1 at once (loss of MMR) xxx ≥ 0.01 at once (loss of MR4) x ≥ (loss of MR4.5) 2 consecutive points xx and 1 log increase x 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:

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

Disease Burden and Molecular Response Undetectable BCR-ABL mRNA transcript by real-time quantitative and/or nested PCR in 2 consecutive blood samples of adequate quality (sensitivity > 10 4 )* ELN recommendations (optimal response) CHR3 months CCyR12 months MMR18 months MR4.0 and beyond Number of Leukaemic Cells Baccarani M, et al. J Clin Oncol. 2009;27(35): Radich JP. Blood. 2009;114: Overall survival Stable response No risk of progression Possibility to discontinue therapy RUGBY BALL GrapeFruit Walnut Grain of rice Less than grain of sand

Time (months) CCR MMR 0.1 ~MR4 (level of detection) 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

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

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

DESTINY recruitment: Target = 168 Sites: Royal Liverpool U Hospital39 Hammersmith, London22 Beatson, Glasgow15 Kent and Canterbury12 St James, Leeds12 Nottingham City Hospital10 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 Manch’ster Royal Infirmary 2 Addenbrookes, Cambridge 1 TOTAL174 Recruitment completed April patients.

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)

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)

When are the results of DESTINY expected? Trial closed in April No-one has progressed, and no other serious problems. 100 patients will have completed de-escalation by December (next month) I will see results just before Xmas Analysis by end of February 2016: to be shared with scientific teams. De-escalation results on all patients to be made public in June Complete stopping results likely in June 2018.

What next? Prospects for stopping treatment: Should this be in a clinical trial? Ideally yes, to maximise our information/understanding Not possible at present. Need some data from DESTINY: It and EUROSKI will report in June 2016 (European Haematology Association)

What next? Need some data from DESTINY:

Estimations of the future prevalence of CML in the TKI era Huang et al, Cancer 2012; 118: 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

Numbers of patients monitored at Royal Liverpool University Hospital ~ 30 new patients per annum ~ 1 death per annum (often due to ‘natural’ causes)

Improvement of Survival of CML by Therapy 1983 – 2011 German CML Study Group, Year after diagnosis Survival probability n = 3615 Imatinib, 2002 – year survival 90% 8-year survival 88% IFN or SCT, 1997 – year survival 71% IFN or SCT, 1995 – year survival 63% IFN, 1986 – year survival 53% Hydroxyurea, 1983 – 1994, 5 yr surv. 44% Busulphan, 1983 – year survival 38%

Improvement of Survival of CML by Therapy 1983 – 2011 Year after diagnosis Survival probability 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%

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

Time (months) CCR MMR 0.1 ~MR4 (level of detection) BCR-ABL PCR %

The overall probability of maintenance of CMR at 24 and 36 months was 39% (95% CI 29-48). Molecular recurrence occurred in 61 pts with 58 occurring during the first 7 months, and 3 late recurrences at month 19, 20 and 22, respectively STIM: estimates of CMR / MR4 after discontinuation of imatinib

Can we cure CML? “Absence of long-term leukaemia relapse after treatment discontinuation?” Requires at least sustained deep MR in TKI treated patients We may never be able to prove that cure requires the eradication of residual leukaemic cells

The subset of patients with deep MR leading to cessation of treatment is heterogeneous. Around 40% of CML patients with stable deep MR on imatinib for at least 2 years are likely to remain in a prolonged TFR after treatment is stopped. The rate is around 60% if the loss of MMR is the criterion of molecular recurrence. A long-term follow-up of different cessation studies will be necessary to affirm cure. Conclusions

Now that the DESTINY trial is closed to recruitment, what are the options for patients wishing to stop TKI? Need some data from DESTINY: Is de-escalation/stopping safe in MR4 but not MMR patients? Is monthly monitoring essential? If relapse rate on de-escalation is very high, then this needs to be gentler If relapse rate on de-escalation is very low, then could be more rapid/lower dose

EURO-SKI Study update: Final recruitment Patient recruitment (as of June 9, 2015) CountryCentersPreregistrationMR4 confirmation Final inclusio n Czech Republic66462 Denmark Finland France Germany Greece144 Netherlands Norway427 Portugal Spain1999 Sweden TOTAL

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 %) 200 interim patients – overtime, loss MMR=89 Relapses within 6 months, n=77 Mahon et al. Blood (ASH 2014);124:abstract#151. Months from discontinuation of TKI Molecular Relapse Free Survival EURO-SKI

Questions Can all patients be in sustained molecular relapse- free remission ? Is this a realistic goal? Which molecular level is a realistic target to aim for before therapy is stopped? What is the minimal duration of TKI pretreatment before stopping? What is the minimal duration of MR 4 before stopping? Prognostic factors for TFR What is the role of IFN pretreatment ?