S157: BCR::ABL1 DIGITAL PCR IDENTIFIES CHRONIC PHASE CML PATIENTS SUITABLE FOR AN EARLY TKI DISCONTINUATION ATTEMPT: A PATIENT-LEVEL META-ANALYSIS

Background: Digital PCR (D-PCR) is an emerging technique that delivers a highly accurate BCR::ABL1 quantification, even in CML patients with low residual disease. This is crucial in the context of treatment-free remission (TFR) for the selection of patients who may successfully discontinue TKI therapy. However, it is unclear how its prognostic value relates to time variables such as treatment duration prior to the TFR attempt. Current guidelines suggest aiming for a TKI treatment duration >6 years to increase TFR success rate. Aims: In current analysis, we aimed to assess the prognostic value of BCR::ABL D-PCR in relation to prior TKI treatment duration. Methods: We performed an Individual Patient Data Meta-Analysis (IPD-MA) combining data from different study cohorts in which BCR::ABL1 was assessed by D-PCR prior to TKI discontinuation. Eligibility criteria included age ≥18 years and CML diagnosed in chronic phase. Data of the participating studies were pooled and stratified based on D-PCR and/or treatment duration. BCR::ABL1 D-PCR was dichotomized based on each study-defined prediction cut-off. Strata were assessed for molecular relapse (MolR) with Kaplan-Meier estimates and with cox regression analysis including a frailty term for correction for between-study heterogeneity and including confounding variables: age at diagnosis, gender, Sokal score, TKI generation, treatment duration, DMR duration (model 1) and BCR::ABL1 transcript type (model 2). MolR was defined as a BCR::ABL1 >0,1%IS or a 1-log BCR::ABL1 increase in two consecutive analyses. Patients were censored at last follow-up. Results: For this meta-analysis, data were combined from five cohorts: four published cohorts (STIM2 cohort [Nicolini et al.], n=175; ISAV cohort [Diral et al.], n=107; Bernardi et al., n=111; Colafigli et al., n=50) and 1 unpublished cohort (Dutch cohort; n=40). The pooled dataset comprised 483 patients (Table). A total of 205 patients (42%) experienced MolR with a median time to relapse of 3 months. Median follow-up duration for TFR patients was 27 months. MolR patients had a significantly shorter treatment duration prior to TKI discontinuation (6,7 vs 7,9 years, p=0.006) and more often presented a BCR::ABL1 D-PCR above the study-defined prediction cut-off (34% vs 19%, p<0.001). Interestingly, the median treatment durations were almost identical in patients with a BCR::ABL1 below or above the cut-off (7.0 vs 7.5 years, p = 0.470). The probability of MolR at 24 months was 38% versus 58% for patients with a D-PCR BCR::ABL1 below versus above the prediction cut-off (p <0.001). In the cox regression analysis, the HR of D-PCR BCR::ABL1 below the cut-off for MolR was 0.48 (95% CI 0.35-0.66, p<0.001). Treatment duration and BCR::ABL1 transcript type also remained independent predictors, but TKI generation and DMR duration did not. When stratifying into 4 groups based on the D-PCR result and treatment duration, patients with a TKI treatment for ≥6 years and low D-PCR result had the lowest MolR rate (33% at 24 months, figure). Patients treated <6 years and with a low D-PCR result had a rate of 48% at 24 months, while patients treated <6 years and a D-PCR result above the cut-off had the highest MolR rate of 72% at 24 months. Summary/Conclusion: These combined patient-level data of multiple CML cohorts further support the independent prognostic value of BCR-ABL1 D-PCR for TFR success rate. Importantly, patients with a TKI treatment duration <6 years and a low D-PCR result were found to have a clinically acceptable MolR rate (48%).