AML-212: Treatment Free Remission (TFR) After Ceasing Venetoclax-Based Therapy in Responding Patients with Acute Myeloid Leukemia

Abstract

<h3>Context:</h3> Ph3 studies confirmed the benefit of adding venetoclax (VEN) to hypomethylating agents (HMA) or low-dose cytarabine (LDAC) in older/unfit patients with newly diagnosed AML with a median response duration of 12-18 months(mo). It is currently unknown whether patients should continue therapy until progression and whether elective therapy cessation could detrimentally impact outcomes. <h3>Objective:</h3> To compare the natural history of patients receiving ≥12mo of VEN-based therapy in first remission. <h3>Design, Setting and Patients:</h3> Retrospective analysis of patients with AML receiving VEN plus HMA or LDAC for ≥12mo and in sustained first remission from three institutions. Two treatment approaches were compared: elective therapy cessation in remission followed by monitoring (STOP) or continued therapy until relapse (CONT). <h3>Main Outcome Measures:</h3> Primary: treatment free remission (TFR), progression free survival (PFS). Secondary: overall survival (OS), molecular correlates of PFS. <h3>Results:</h3> 28 patients were identified: 14 in STOP, 14 in CONT. Median follow-up was 60.9mo. Treatments included VEN-HMA (68%) or VEN-LDAC (32%). Median time on therapy (TOT) was shorter in STOP (19.0mo <i>vs</i> 32.7mo) and fewer cycles were received in STOP (median 17 <i>vs</i> 30). In STOP, treatment cessations were due to patient request (43%) or medical (57%), with a median TFR of 45.8m (95%CI 9.5-not reached). 7/14(50%) have relapsed, with 3 relapsing >31mo of TFR. In CONT, 9/14(64%) have relapsed, with 6 relapsing >24mo of therapy. Cytogenetic evolution was more frequently observed at relapse in CONT (67% <i>vs</i> 43%). A landmark analysis was performed (landmarked at median TOT in STOP to exclude lead-time bias from early relapses in CONT), which revealed no significant difference in PFS (p=0.14) or OS (p=0.24). 10/15 patients with <i>NPM1</i> and/or <i>IDH2</i> mutations remain in remission (6/8 STOP, 4/7 CONT), of which 9/10 achieved undetectable MRD (by flow/qPCR). 1 had detectable <i>IDH2</i> mutation at pre-leukemic levels. Multivariate analysis showed that mutant <i>NPM1</i> is an independent predictor of OS (HR for death 0.002, p=0.037) and PFS (HR for relapse 0.012, p=0.024). <h3>Conclusion:</h3> Durable TFR is highest among patients with <i>NPM1/IDH2</i> mutations and MRD negative after ceasing >12 months of VEN-based treatment. A prospective, randomised, discontinuation study in pts in CR_MRDneg after 12 months of VEN-based therapy should be considered.