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

Stopping treatment: who and when? CML patient & carer meeting 2016 Manchester, 24 th September 2016 Richard Clark Royal Liverpool University Hospital. Can CML patients with consistently undetectable BCR-ABL stop treatment?. STIM Study Design. 100 patients.

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

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

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

  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): 1029-1035.

  4. 100 CCR 1 BCR-ABL PCR % MMR 0.1 ~MR4 (level of detection in ~2006) 0 12 15 18 21 24 30 36 42 Time (months)

  5. STIM study results (Sept 2015) 100 patients 62 events (61 molecularrecurrences) 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. 2014 Feb 10;32(5):424-30

  7. 100 CCR 1 BCR-ABL PCR % MMR 0.1 ~MR4 (level of detection) 0 12 15 18 21 24 30 36 42 Time (months)

  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

  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

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

  12. DESTINY; status 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 36 months Baseline 12 months 24 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

  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 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). ** = 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 www.euroqol.org

  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.

  24. Molecular relapse free survival EURO-SKI 200 interim patients – overtime, loss MMR=89 Relapseswithin 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.

  25. 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).

  26. ENESTop:

  27. ENEST freedom:

  28. 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)

  29. 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. 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.

  31. 174 CML patients & their 20 teams taking part in DESTINY Acknowledgements

  32. What next? MAYBE: 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

  33. What next? MAYBE: 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

  34. What next?

  35. Serious Adverse Events * Ongoing at death All 15 SAEs (10 patients) were assessed as not related to the trial intervention.

  36. EURO-SKI: Prior treatment

  37. Definition of molecular recurrenceacross discontinuation studies 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.

  38. 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 Initial safety results from the DESTINY trial Professor Richard E. Clark

  39. EURO-SKI Study update: Final recruitment • Patient recruitment (as of June 9, 2015)

  40. EURO-SKI: Patient disposition

  41. EURO-SKI: Patient disposition

  42. 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.

  43. 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.

  44. EURO-SKI: Critical events & safety issues **according to protocol, BCR-ABL > 1% mandated marrow cytogenetics; this was only carried out in a minority of patients.

  45. 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.

  46. 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 Huang et al, Cancer 2012; 118: 3123-7

  47. Improvement of Survival of CML by Therapy 1983 – 2011 n = 3615 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.

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