Benefit of Venetoclax Addition ("Benefit VA") in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an incurable, prevalent B-cell malignancy. Inhibitors of Bruton’s tyrosine kinase (BTKi) are commonly used oral therapies used to treat CLL/SLL and are continued indefinitely, but can cause toxicities, symptoms, and impaired quality of life (QoL) in a significant subset of patients. Since BTKi have modest responses, there drugs are used continuously. Long- term therapy with BTKi exposes patients to its long-term toxicities, thereby compromising patient experience during continuous therapy. CLL/SLL and its optimal therapy is of particular interest to the Veterans Administration (VA) because of the higher incidence of CLL/SLL in Veterans and its relationship with Agent Orange. CLL/SLL patients are interested in initial therapy that is easy to take, has a fixed duration, effectively treats the CLL/SLL, minimizes long-term toxicities, and improves symptoms and QoL. Our overall goal is to care for Veterans with CLL/SLL in an evidence-based patient-centric approach. Our central hypothesis is that in CLL/SLL patients, who are already receiving initial therapy with and responding to BTKi, the addition of Venetoclax (Ven) and then discontinuation of both medications after one year will lead to increase in the depth of response measured as minimal residual disease (MRD) and will improve patient’s experience, as compared to those patients receiving BTKi alone. In the proposed phase II, multi-site clinical trial in Veterans with CLL/SLL, patients will be randomized 1:1 to either continue BTKi (arm A) alone or to continue BTKi at the same dose and to initiate Ven ramp up per the manufacturer’s label (arm B). Patients on arm A will continue BTKi for three years, whereas patients on arm B, BTKi and Ven will be discontinued after 12 cycles. Patients will be recruited from hematology-oncology VA clinics across the US, and the study will allow for a decentralized research process to maximize Veteran access to this study. Eligible patients will have measurable disease and belong to the low tumor lysis syndrome (TLS) risk group. In arm B (investigational arm), consenting patients will continue on a 28-day cycle with the BTKi they are already receiving, at the same dose, and will add Ven with the standard ramp-up dosing in cycle one, and then continue full dose thereafter. After 12 cycles of combination therapy, both BTKi and Ven will be discontinued, and patients will enter long-term follow up. The primary objective is to compare disease response between the two arms by measuring minimal residual disease in the blood (primary outcome). The secondary objectives are to measure patient experience through patient reported outcomes, assessment of cancer symptoms (measured by VSAS), QoL (measured by EORTC QLQ- C30, QLQ-CLL17), financial toxicity (measured by FACIT-COST), adverse events (CTCAE v5.0), and overall response rates, progression-free and overall survival. Patient demographic and CLL/SLL molecular risk factors will be collected to evaluate their association with the objectives. The results of this study will inform best practices for treating CLL/SLL patients, focusing on optimizing the patient experience while providing highly effective therapy. The VA is uniquely poised to perform this study, demonstrating potential benefits to Veterans and potential long-term medication cost savings to the health-care system. Project Number: 1I01CX002685-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: SUMAN KAMBHAMPATI (+1 co-PI) | Institution: KANSAS CITY VA MEDICAL CENTER, KANSAS CITY, MO | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 HEMA-G (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/10801637