Background: Venetoclax (VEN)-based regimens are highly effective for patients (pts) with treatment naïve (TN) and relapsed/refractory (R/R) CLL. Despite high rates of undetectable minimal residual disease (uMRD) and durable responses even with time-limited therapy, uptake of VEN in routine clinical practice has been relatively low, in part due to the inconvenient 5-week dose ramp-up used to reduce the risk of tumor lysis syndrome (TLS). Accelerated ramp-up schedules have been evaluated in retrospective studies (Davids et al., AJH, 2022), but prospective studies are lacking. Here we present initial results of SAVE: Safe Accelerated Venetoclax Escalation, a phase Ib study of VEN with an accelerated dose ramp-up in pts with CLL. Methods: This is an ongoing phase Ib investigator-sponsored trial for pts with TN and R/R CLL (NCT04843904). Key eligibility include CLL requiring therapy per 2018 iwCLL criteria and adequate renal function. The primary endpoint is the highest risk TLS group that can safely tolerate an accelerated VEN ramp-up. Secondary endpoints include safety and tolerability and rates of ORR/CR/uMRD after 3 months of VEN-based therapy. Patients are treated inpatient with a 5-day daily VEN ramp-up schedule (20-50-100-200-400 mg). TLS labs are monitored pre-dose and at 4, 8, 12, and 24 hours following each dose. Anti-CD20 antibody is given per SOC. At least 5 pts from cohort A (low TLS risk using standard assessment) were required to enroll prior to opening cohort B (medium and high TLS risk). Efficacy is assessed using 2018 iwCLL criteria, toxicity using iwCLL and CTCAE v5, and MRD using central 8-color flow at 10^-4. Results: As of 2/2/2023, 20 pts have been treated (10 each from cohort A and B) (Table). 19 pts received obinutuzumab with VEN, and 1 pt received VEN monotherapy. All pts completed an accelerated VEN ramp-up without any clinical TLS. One pt with medium TLS risk had lab TLS (phos and uric acid peaked at 8.7 mg/dL) after the first VEN 400 mg dose, which resolved with sevelamer and rasburicase, thereby prolonging the ramp-up to 6 days. Median inpatient time was 6 days (range 5-8). All grade heme tox: neutropenia (45%; 20% G3/4), thrombocytopenia (35%; 10% G3/4). One pt died 2 months into treatment due to complications of a bowel obstruction unrelated to study treatment. ORR after 3 mo. was 89% in 19 evaluable pts including 2 CRs. Among 19 evaluable patients after 3 mo., 74% and 42% had uMRD in PB and BM, respectively. Conclusions: Our early data suggest that an inpatient, accelerated 5-day VEN ramp-up is feasible in CLL, with a low rate of TLS, even among patients with medium or high risk of TLS. The study is currently ongoing. Clinical trial information: NCT04843904.