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• W3155962936 abstract "Discontinuation of imatinib treatment after a sustained deep molecular response enables a proportion of people with chronic myeloid leukaemia (CML) to achieve treatment-free remission (TFR).1 Other patients experience a molecular relapse with rising BCR-ABL1 levels by reverse transcriptase quantitative polymerase chain reaction (Q-PCR), and need to resume treatment to regain a deep molecular response. Since a TFR attempt has become an accepted part of the treatment pathway,2 physicians need to be able to provide information to their patients in order for them to decide when is the right time to stop.3 Multiple studies have now explored the question of how much imatinib is enough. Dennis Kim and his co-investigators in the Canadian TRAD study have added additional data and an alternative perspective on how to answer this question.4 The first part of the TRAD study, involving 131 imatinib-treated patients, was reported in the British Journal of Haematology, showing results that compared favourably with other imatinib discontinuation clinical trials: molecular relapse-free survival was 56·8% at 12 months,4 compared with 50% at 24 months in both STIM2 and EuroSKI.5, 6 In the second part of the TRAD study those patients who experienced molecular relapse will resume tyrosine kinase inhibitor (TKI) therapy with dasatinib instead of imatinib with the aim of enabling a successful second TFR attempt in the future. Comparing TFR studies is complicated by varying definitions of eligibility and molecular relapse.1 Patients entering the TRAD study had a deep molecular response (MR4.5) for two years or more and the trigger to resume TKI was loss of MR4.0 on two occasions or loss of major molecular response (MMR) on a single occasion.4 These entry criteria are more stringent than in EuroSKI, which required at least 12 months of MR4.0.6 The cumulative incidence of molecular relapse by the two different definitions used in TRAD was 29·2% and 34·8%,4 indicating that most people with confirmed loss of MR4.0 will lose MMR. Interestingly, there were no cases of loss of MMR after six months in the TRAD study, unlike in EuroSKI, suggesting that either the deeper response at study entry or the more stringent relapse definition reduces the incidence of late relapses. The median duration of imatinib treatment in the TRAD study was 9·2 years,4 compared with 7·5 years in EuroSKI.6 This enabled the authors to calculate the odds of molecular relapse according to duration of imatinib treatment and duration of MR4.0 up to 12 years (Table I). As in EuroSKI, the duration of MR4.0 was a better predictor of TFR than the duration of imatinib treatment. The hazard ratio for molecular relapse for each additional year of MR4.0 was 0·86 in TRAD,4 and the odds ratio for relapse-free survival was 1·13 in EuroSKI, indicating that the odds of molecular relapse reduce by approximately 13% for each additional year of MR4.0 prior to imatinib discontinuation. The proportion of patients remaining in TFR increased from 57·8% for those stopping after 3+ years of MR4.0 to 90% after 12+ years.4 In a novel analysis the TRAD authors explored the duration of MR4.0 that optimised diagnostic accuracy (the chance of correctly predicting the outcome after TKI discontinuation). For each year of MR4.0 at study entry they calculated the positive predictive value (PPV) to identify molecular relapse and the negative predictive value (NPV) to identify successful TFR outcome, aiming to find the point at which both predictions (relapse/remission) will be correct more often than not. It is apparent from the data described above that the NPV gradually rises with each passing year, whereas the PPV falls. Since diagnostic accuracy requires both PPV and NPV to be high the authors chose 4·5 years of MR4.0 as the shortest duration that gave an adequate level of diagnostic accuracy (62·6%). This means that most of those patients with <4·5 years of MR4.0 relapsed (64·8%) and most of those patients with >4·5 years of MR4.0 remained in TFR (58·1%).4 A longer duration of deep molecular response is an important predictor of TFR, but in the TRAD study half of the patients with only three years of MR4.0 remained in TFR, whereas 13% of patients with more than 10 years of MR4.0 still relapsed. These outliers highlight the need to consider additional factors that might influence TFR outcome. Recently it was reported that the kinetics of initial response to TKI (BCR-ABL1 halving time in the first three months of treatment) improve prediction of the outcome of a TFR attempt.7 The quartile of patients with the shortest BCR-ABL1 halving time (<9·35 days) had a higher chance (80%) of TFR.7 The two first clinical trials of discontinuation of first-line nilotinib and dasatinib showed rates of TFR comparable to those seen with imatinib, but with a much shorter median duration of treatment of 43·5 and 40·4 months, respectively.8, 9 One could infer that those patients who remained in TFR after relatively early TKI discontinuation were predominantly those patients who had a short halving time. It may be useful to visualise this interaction as an ‘area under the curve’ that is deeper if the initial response is very steep, and longer if the duration of treatment is prolonged after achievement of deep molecular response, with a greater area under the curve being predictive of TFR. The data from the first part of the TRAD study are a valuable confirmation of the important EuroSKI analysis showing the interaction between duration of deep molecular response and TFR outcomes. They extend the data by including a proportion of patients with extremely long duration of MR4.0. It is becoming clear that the important question for predicting TFR is not ‘how much imatinib’, but rather ‘how much deep molecular response’ is enough. It remains to be seen whether the odds ratio per year of MR4.0 will be similar or different with more potent TKIs." @default.
• W3155962936 created "2021-04-26" @default.
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• W3155962936 date "2021-04-19" @default.
• W3155962936 modified "2023-10-18" @default.
• W3155962936 title "How much imatinib is enough?" @default.
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• W3155962936 doi "https://doi.org/10.1111/bjh.17444" @default.
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