Stopping TKI treatment in CML: Who and when 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

Rate of TFR in all 40 patients. TWISTER: Stopping imatinib in undetectable disease Rate of TFR in all 40 patients. Rate of TFR in all 40 patients. Actuarial estimate of the rate of TFR. The 95% CI is indicated by dashed lines. 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 Kaplan-Meier estimates of RFS defined (A) as loss of major molecular response (MMR) and (B) according to STIM (Stop Imatinib) study criteria after imatinib discontinuation in 80 patients with chronic myelogenous leukemia (CML). (A) Overall probability of maintaining MMR in patients with stable confirmed complete molecular response (cCMR; 38 patients) and unstable cCMR before study entry (42 patients) was estimated as 65% (95% CI, 47% to 78%) and 64% (95% CI, 48% to 77%) at 12 months, respectively (P = .75). (B) Overall probability of maintaining CMR in patients with stable cCMR (39 patients) and unstable cCMR before study entry (42 patients) was estimated as 55% (95% CI, 38% to 69%) and 43% (95% CI, 28% to 57%) at 12 months, respectively (P = .18). 43% 29% Rousselot P et al. JCO 2014;32:424-430 ©2014 by American Society of Clinical Oncology

All patients achieve deep molecular responses after re-starting TKI… All patients achieve deep molecular responses after re-starting TKI…. But can take time Cumulative incidence of complete molecular response (CMR) in patients re-treated after loss of major molecular response. Median time to regain CMR was estimated as 7.3 months. 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? 12 15 18 21 24 Time (months) CCR 100 1 MMR 0.1 CMR/MR4 (level of detection) 0.01 30 36 42 BCR-ABL PCR %

Does BCR-ABL need to be negative to stop therapy? 12 15 18 21 24 Time (months) CCR 100 1 MMR 0.1 CMR/MR4 (level of detection) 0.01 30 36 42 BCR-ABL PCR % ….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 alternate months in months 26-37 Check PCR monthly until month 25 De-escalate TKI (13 months) 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 (BCR-ABL1/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.  

SPIRIT 3 Stage 1 Stage 2 Stage 3 Compare first line intervention Randomised Stage 2 Identify partial responders early Switch Stage 3 Identify ‘best’ responders later Reduce/stop 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 SPIRIT 3

(if MR3 for at least 1 year) Stage 1 Randomise (500 to each group) Stage 2 Selective switch (3 months or later) Stage 3 Reduce dose, stop (after minimum 3 years) Imatinib Imatinib Group I Imatinib n=500 Ponatinib Ponatinib R Aim to reduce and stop (if MR3 for at least 1 year) Ponatinib Ponatinib Switch if: Partial response >10% @ 3 months >1% at 12 months Intolerance (dose reduction, no switch – stuff to be pulled in from S2 protocol) When ‘go to trial office’. Standard ‘script’ required. ‘Authorisation’. This is required. Single medic approval. Monthly review of switch events. Can’t force to switch. Loss of response CHR easy Loss of MR3 if on two occasions, 3 months (NOT 1 month) apart If a samples is 0.1 – 1.0 then 3 months, if over 1.0 then repeat within a month. Group N Nilotinib n=500 Nilotinib Nilotinib Primary endpoint MR3 at 3 years

What do you think?