Transcriptome-based prediction model for treatment-free remission in chronic myeloid leukemia

Treatment-free remission (TFR) is a major therapeutic objective in chronic myeloid leukemia (CML). However, nearly 50% of patient relapse after TKI discontinuation, an no robust predictive biomarker is currently available. Analysis of peripheral blood cell transcriptomes at imatinib discontinuation in participants of the French STIM2 study was used to develop a transcriptome-based model to predict TFR by 2 years. A 50-gene signature discriminated patients with sustained TFR from those experiencing molecular relapse: AUROC 0.83 (95% CI 0.73-0.93) and 0.75 (0.55-1.00) in the training and internal validation cohorts, respectively. The discriminative performance was confirmed in an external test cohort of 70 patients attempting imatinib or nilotinib cessation, both as a binary predictor of 2-year TFR (AUROC 0.71; 95% CI 0.58-0.83) and as a time-to-event predictor (log-rank p=0.0042). The high TFR-signature group showed a higher proportion of myeloid immune cells and natural killer T cells, with an enrichment in Hedgehog signaling, whereas the low TFR-signature group demonstrated a higher proportion of lymphoid cells with an enrichment in mTOR signaling. The authors conclude that these findings demonstrate that transcriptomic profiling at TKI discontinuation can predict TFR outcomes in patients with CML and provide biologic insights into the mechanisms underlying sustained TFR.