BCR-ABL1 Transcript Kinetics and Treatment-Free Remission in Patients with Chronic Myeloid Leukemia

Abstract

Early BCR-ABL1 kinetics predict which patients will reach a deep molecular response, and reaching one is the entry requirement for attempting to stop treatment. It does not follow that kinetics predict who will stay in remission after stopping, and the largest comparison found that they do not. Objectives: To review the published evidence on BCR-ABL1 transcript kinetics and treatment-free remission in chronic myeloid leukaemia: what proportion of patients maintain remission after stopping, when relapse occurs, which variables predict it, and whether early kinetic measures add anything to the prediction. Material and Methods: Narrative review of discontinuation trials, real-world cohorts, modelling studies and consensus recommendations indexed in PubMed and the major haematology journals. Studies were eligible if they reported treatment-free remission outcomes after tyrosine kinase inhibitor discontinuation in a defined chronic myeloid leukaemia population, or the predictive performance of molecular response measures. No new patient data were generated and no patients were recruited; every estimate quoted is one published by the original investigators.
Results: In the largest discontinuation trial, 434 of 728 patients (61 per cent, 95% CI 57-64) remained in major molecular response at 6 months and 309 of 678 (46 per cent, 42-49) at 36 months. Duration of tyrosine kinase inhibitor treatment and of deep molecular response before stopping were confirmed as predictors of loss at 6 months, with transcript type added as a third. In the earliest trial, molecular relapse occurred in 61 of 100 patients and 80 per cent of those relapses fell within the first 6 months. Where deep response had been sustained for only one year and total treatment was under three years, relapse-free survival was 16.7 per cent at 12 months and the trial was terminated early. Comparing early measures in 408 real-world patients, halving time and residual disease at month 3
performed similarly and residual disease at month 6 performed best for predicting deep response, with areas under the curve of 0.81 to 0.92, but the initial molecular response did not predict treatment-free remission maintenance. Conclusion: Early kinetics identify who will achieve a deep response and are useful for that purpose. What predicts staying in remission after stopping is duration, of treatment and of deep response, rather than how quickly the transcript fell in the first months. Abbreviations: CML – Chronic Myeloid Leukaemia, CML-CP – Chronic Phase CML, TKI – Tyrosine Kinase Inhibitor, TFR – Treatment-Free Remission, MMR – Major Molecular Response, DMR – Deep Molecular Response, MR4 – BCR-ABL1 IS ≤0.01 Per Cent, MR4.5 – BCR-ABL1 IS ≤0.0032 Per Cent, IS – International Scale, HT – Halving Time, ELTS – EUTOS Long-Term Survival Score, KDm – Kinase Domain Mutation.