CONTEXT: Despite many novel therapeutic agents, children and adults with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) continue to have poor outcomes, therefore, a significant unmet medical need remains for these patients. Venetoclax (highly selective BCL-2 inhibitor) or navitoclax (BCL-2, BCL-XL, and BCL-W inhibitor) monotherapy showed activity in a variety of preclinical ALL models, and the combination of BCL-2 and BCL-XL inhibitors resulted in synergistic antitumor activity in ALL xenografts.OBJECTIVE: Present preliminary safety (primary) and efficacy (secondary) data, evaluating venetoclax in combination with navitoclax and chemotherapy in patients with R/R ALL.DESIGN: Phase 1, open-label, multicenter, dose-escalation study (NCT03181126).SETTING: Fifteen academic institutions.PATIENTS: Pediatric and adult patients (u22654years; u226520kg); R/R ALL or LL.INTERVENTIONS: Oral venetoclax is administered daily starting with 200mg weight-adjusted equivalent (Day1), and 400mg-equivalent thereafter. Oral navitoclax is administered daily (Day3 onwards), with up to 3 dose levels for patients u226545kg (25,50,100mg) and up to 2 dose levels for patients <45kg (25,50mg). Chemotherapy may be administered (peg-asparaginase:1,250IU/m2; vincristine:1.5mg/m2; dexamethasone:20mg/m2/day) based upon investigator discretion.MAIN OUTCOMES MEASURES: Safety and efficacy.RESULTS: Four patients have been enrolled and treated, having previously failed multiple lines of therapy; three patients had pre-B-cell ALL, and one had T-cell ALL. All patients experienced u22651 adverse event (AE), with nausea having the highest occurrence. Serious AEs were nausea, vomiting, abdominal pain, abdominal pain upper, pseudomonal sepsis, and somnolence. All patients achieved either complete response (CR), CRi (CR-incomplete marrow recovery), or CRp (CR-no platelet recovery), with response duration 0.3u20132.6 months. Two patients achieved minimal residual disease (MRD) negativity (threshold:10-4). While one patient discontinued due to disease progression (3.4 months), the other three patients remain on study (2.3u20134.2 months).CONCLUSIONS: The observed safety profile of venetoclax+navitoclax is consistent with prior reports, without unexpected AEs to date; further details will be provided at the meeting. Preliminary data suggest the combination of venetoclax+navitoclax is efficacious in R/R B- and T-cell ALL patients who have failed multiple prior therapies. Long-term follow-up of safety and response durability is ongoing, as is study enrollment.