Prolonged Survival Following Imatinib Failure for CML Patients in CP May Require Multiple TKI Strategies for Responding Patients,
Authors: Milojkovic Dragana , Apperley Jane F , Ibrahim Amr R , Bua Marco , Reid Alistair , Gerrard Gareth , Foroni Letizia , Rezvani Katy , Goldman John M , Marin David 
Published: October 2019

Abstract
Abstract 3777
2G-TKI are proven to be effective in inducing complete cytogenetic responses (CCyR) in approximately half of the patients treated. What is less clear is whether these responses are durable and/or whether the first choice 2G-TKI can be maintained long-term without unacceptable side-effects. We report the clinical outcome of 119 patients who received a 2G-TKI following imatinib failure with a median follow-up of 36m (3–73) and 75% of patients were followed-up for more 48m. 91 patients initially received dasatinib, 25 nilotinib and 3 patients bosutinib. The median patient age was 48 yrs (14–78). The reasons for imatinib failure were primary resistance (n=43), acquired resistance (n=34) and intolerance (n=42). 30 patients were in CCyR at the time of starting a 2G-TKI. The TKI doses were in accordance with manufacturers' recommendations and the dose was adjusted according to tolerability and response. OS was defined as alive at time of last follow-up, PFS as alive and lack of progression to advanced phase at last follow-up. EFS was defined as freedom from death, progression to advanced phase, loss of a previously achieved cytogenetic response (CyR) or discontinuation of first 2G-TKI. The 4-yr probabilities of OS, PFS and EFS were 82%, 81% and 35% respectively. The 4-year CI of CCyR in patients who were not in CCyR at the time of starting 2G-TKI was 50% (in accordance to previous studies) and 63% if all patients were included. The 4-year CI of MMR and CMR were 32% and 7% respectively.
As previously reported haematological and cytogenetic resistance on imatinib predicted for the achievement of cytogenetic response (data not shown). However, neither factors at diagnosis nor at start of 2G-TKI therapy predicted for survival. Analysis of the molecular responses at 3m were highly predictive of OS, PFS and EFS. 77 patients with a BCR-ABL/ABL ratio of ≤10% on the international scale had a significantly superior OS (91% vs 72%, p=0.02), PFS (91% vs 68%, p= 0.007)and EFS (49% vs 13%, p<0.001) than the 33 patients with values greater than 10%. 62 patients (52%) discontinued the first choice 2G-TKI on account of primary resistance (n=23), acquired resistance (n=8) and intolerance (n=31) and 57 patients were on first choice 2G-TKI therapy at last follow-up. ABL KD mutations were identified in 26 patients prior to 2G-TKI therapy and 16 of these (62%) developed further mutations on subsequent therapy in contrast to only 10 (11%) of the 93 patients without mutations at start of 2G-TKI (p<0.001). 74 patients achieved/maintained CCyR on first choice 2G-TKI therapy. Of these 8 have subsequently lost CCyR (3 patients regained CCyR on alternative therapy). Of the remaining 68 patients, 14 changed 2G-TKI as a result of intolerance, and 54 continued on first choice 2G-TKI. 45 patients did not achieve CCyR on first choice 2G-TKI, of whom 32 then received third line therapy (alternative TKI, allo-SCT and others).
As we have shown previously, the discontinuation rate of the first choice 2G-TKI is relatively high and to further explore the durability of CyR, irrespective of the need of an alternative TKI, we have used the concept of current CCyR-Survival (cCCyR-S) which is defined as the probability of being alive and in CCyR at a given time point. This is the analogue of current leukaemia-free survival, a term developed to describe the behaviour of patients following allo-SCT which recognises the fact that patients may relapse and regain remission with alternative therapy. The cCCyR-S at 4-years was 54% (Figure 1). In a landmark analysis of patients in CCyR at 12 months the cCCyR-S at 4 years was 90% (3 deaths due to non-leukaemia causes). This outcome strongly suggests that patients should be given the opportunity of more than one 2G-TKI after imatinib failure in order to achieve an optimal outcome.Figure 1.OS, EFS and cCCyR-S in the cohort of 119 patientsFigure 1. OS, EFS and cCCyR-S in the cohort of 119 patients

Disclosures:
No relevant conflicts of interest to declare.