Ultimately, we propose specific recommendations for the management of venetoclax-based therapy, to tailor prophylaxis and mitigate risk for patients with CLL. prevent and monitor for tumor lysis syndrome and Fludarabine (Fludara) other toxicities of venetoclax Introduction Because of the availability of numerous therapies for patients with chronic lymphocytic leukemia (CLL), it is important to develop a tailored treatment strategy for the individual patient that considers balance of efficacy, toxicity, and the patients preference.1 Two different approaches can Fludarabine (Fludara) be considered: continuous treatment with Brutons tyrosine kinase (BTK) inhibitors until disease progression or fixed-duration combination treatment with venetoclax and obinutuzumab. Despite the amazing progress that has been made with these novel targeted therapies, neither is considered curative.2,3,4 Moreover, it is important to note that each approach has a distinctive toxicity profile. In addition, hematological toxicities such as neutropenia and thrombocytopenia and also infections are often similar in frequency and severity when compared with chemoimmunotherapy.5-9 Although tumor lysis syndrome (TLS) has not been a frequent complication in the management of indolent lymphoma,10 early trials of venetoclax in patients with relapsed/refractory CLL reported a few cases of TLS, some of them fatal.11 Based on these early observations, subsequent trials have implemented various measures of monitoring and mitigation to control venetoclax-associated TLS. With the drug now approved and widely available for routine clinical use, various procedures have been recommended to avoid or treat TLS in patients with CLL.12-14 With venetoclax increasingly becoming the backbone of many different combination regimens for CLL, a solid understanding of the best ways to mitigate toxicities is increasingly important to the practicing hematologist. We summarize the current evidence with regard to preventing and monitoring TLS and other toxicities related to venetoclax. Ultimately, we propose specific recommendations for the management of venetoclax-based therapy, to tailor prophylaxis and mitigate risk for patients with CLL. Particular emphasis will be on the discussion of toxicity data and risk reduction strategies of venetoclax-based therapies of recently published clinical trials that have defined the prevalent standard of care and the ongoing trials that may influence the next generation of treatment options. Clinical case A 75-year-old female patient with a diagnosis of CLL was referred to our cancer center evaluation of her treatment. The patient had been diagnosed with stage Binet A/Rai I CLL 5 years ago with moderate lymphocytosis of 12 109/L. Initiating frontline therapy To date, there is no evidence of a potential benefit of early intervention for asymptomatic CLL.15-17 Therapy initiation should be postponed until active disease, defined according to International Workshop on CLL (iwCLL) guidelines, is observed.18 Clinical trials evaluating the early use of novel inhibitors are currently ongoing, but so far, neither of these includes the BCL-2 inhibitor venetoclax or provides evidence that Fludarabine (Fludara) alters the current watch and wait standard of care.16 Clinical case (continued) During the most recent watch-and-wait visits, an increasing lymphocyte count up to 80 109/L, hemoglobin of 8.5 103/L, and a platelet count of 70 109/L were observed. Moreover, the patient reported fatigue that impaired her mobility and well-being. Based on the symptom burden and cytopenias with stage Binet C/Rai IV disease, the need for leukemia treatment was discussed with patient. Biologic and clinical factors guiding individualized treatment At present, a tailored treatment approach requires knowledge of the patients condition including the following Pfkp parameters19: (1) the clinical stage, (2) the presence of mutation and/or deletion, (3) the fitness (ie, coexisting conditions, such as cardiac conditions, or renal dysfunctions) of the patient, (4) the immunoglobulin heavy chain variable (IGHV) mutational status, and (5) the symptoms of CLL. The selection of the appropriate treatment paradigm (continuous indefinite vs fixed-duration treatment) follows these characteristics, because advanced age and poor performance status, among other factors, confer the highest risk of increased toxicity and intolerance. Clinical case (continued) A molecular and.