Abstract
Background: The treatment landscape for CLL/SLL has shifted from chemoimmunotherapy to targeted therapies, with BCL-2 inhibitors like Venetoclax (Ven), now widely used in both frontline and relapsed settings. Key trials (MURANO, CLL14, GAIA-CLL13) highlight its fixed duration, tolerability and efficacy in achieving undetectable minimal residual disease (uMRD). However, concerns about tumor lysis syndrome (TLS) identified in early phase I dose escalation trials, and the need for inpatient monitoring have limited its use, particularly in the community setting. Due to the subsequent low rates of reported TLS in phase III and real-world experience, we implemented a novel low-frequency monitoring protocol for outpatient Ven initiation in our CLL population. We herein report on its execution and success.
Methods: Between 2023 and 2025, we implemented a monitoring program for outpatient Ven initiation ramp up. All patients were initiated on cytoreductive therapy before Ven and continued for 2 weeks post Ven initiation. Ven was initiated when the following criteria was met: 1) absolute lymphocyte count <20,000 K/mL, 2) adenopathy <5 cm by physical examination, 3) Spleen size <15cm below the costal margin, per physical exam and 4) CrCl >45mL/min. Once meeting criteria, Ven dosing followed a standardized five-week(W) dose escalation protocol: W1 (20mg), W2 (50mg), W3 (100mg), W4 (200mg), W5 (400mg). Prophylactic allopurinol was initiated one day prior to W1 of Ven induction. Patients were instructed to maintain their average daily fluid intake during dose escalation. Cytoreductive therapy was discontinued on W2D7 of the Ven ramp up. Patients self-administered the initial Ven dose on W1D1 no earlier than 8:00 PM. The following morning (W1D2), patients presented for outpatient evaluation 12 hours after dose administration. Laboratory monitoring included complete blood counts, basic metabolic panel, calcium, uric acid, and phosphorus levels. If laboratory parameters were without TLS, defined as uric acid >9 mg/dL, potassium >6 mmol/L, phosphorus >4.5 mg/dL, or calcium <7 mg/dL- Ven dose escalation proceeded on W2D1with repeat laboratory evaluation on W2D2. This monitoring and dose escalation process was repeated weekly through five weeks. The primary endpoint of this study was to assess the safety and tolerability of Ven dose escalation in the outpatient setting.
Results: As of July 2025, twenty-five patients were transitioned to Ven in the outpatient setting. The median age was 70 (range: 53 – 86) years. 7 patients (28%) were IgVH mutated, 15 (60%) were unmutated, 1 was indeterminate (4%), and 2 were unknown (8%). Cytogenetic risk stratification classified 12 patients (48%) as low risk, 11 (44%) as high-risk, and 2 (8%) had unknown cytogenetic risk status. Most patients (84%) received single-agent Bruton tyrosine kinase inhibition as cytoreductive therapy. Prophylactic allopurinol was maintained for a median of 24 days during the five-week dose escalation period. There was 100% compliance with treatment appointments. No patient required intervention for TLS. Additionally, no patient experienced > grade 1 toxicities, required hospitalization or had dose interruptions. Importantly, there were no treatment discontinuations or deaths during Ven ramp up.
Discussion: Our experience has demonstrated feasibility and safety of outpatient Ven initiation across a heterogenous CLL population. With appropriate cytoreduction, single agent Ven can be safely administered regardless of IGHV mutation status or molecular risk profile. This protocol eliminates the need for hospitalization and minimizes laboratory monitoring, offering a time-limited, oral-only regimen that may improve patient quality of life while reducing financial and logistical burdens. Our findings suggest this approach is well-suited for broader adoption in both academic and community settings.
