Venetoclax Salvage Therapy as a Fourth-Line Treatment in a Patient with Multiply-Relapsed Chronic Lymphocytic Leukemia: A Detailed Case Report

By MD Resmije TOZHARAKU, PhD Elvana RISTA, MD Blerim ARAPI

Abstract
Background: Chronic lymphocytic leukemia (CLL) is a heterogeneous B-cell malignancy characterized by progressive lymphocytosis, lymphadenopathy, and evolving therapeutic requirements over time. Although chemoimmunotherapy historically represented frontline management, targeted therapies such as BTK inhibitors and BCL-2 inhibitors have reshaped treatment landscapes. Venetoclax, a selective BCL-2 antagonist, has demonstrated high efficacy in relapsed and refractory CLL but is associated with tumor lysis syndrome (TLS), especially in patients with very high tumor burden.
Case Presentation: We report the case of a 69-year-old man with CLL diagnosed 9 years earlier, initially treated with fludarabine–cyclophosphamide–rituximab (FCR) achieving remission for 3 years. Subsequent relapse was managed with bendamustine–rituximab (BR) with a 2-year remission. A second relapse was successfully controlled with ibrutinib for several years until a third aggressive relapse occurred. The patient presented with massive hyperleukocytosis (300,000/mm³), bulky lymphadenopathy, and clinical deterioration. One cycle of bendamustine successfully reduced leukocyte count to 30,000/mm³, allowing venetoclax initiation. Despite adherence to TLS prevention protocols, he experienced severe laboratory and clinical TLS accompanied by a malignant hyperthermia–like syndrome requiring intensive care and Prismaflex continuous renal replacement therapy. After recovery and cautious resumption of venetoclax, he achieved complete clinical remission with undetectable minimal residual disease (MRD).
Conclusion: This case highlights the therapeutic challenges of multi-relapsed CLL and demonstrates the capacity of venetoclax to induce deep MRD-negative responses even as fourth-line therapy. The report emphasizes the importance of tumor debulking, aggressive TLS surveillance, and multidisciplinary ICU management in high-risk patients. The malignant hyperthermia–like presentation underscores the expanding clinical spectrum of TLS and the need for heightened clinician awareness.