Venetoclax is among the most exciting novel agents in the treatment of patients with CLL. The combination of venetoclax and obinutuzumab in a fixed-duration regimen leads to very deep, durable remissions. And the ability to take a medication for a defined period and then stop taking it is appealing to many patients.

Nonetheless, venetoclax can lead to very rapid cellular death that may manifest with laboratory and/or clinical evidence of TLS. During the early clinical development of venetoclax, TLS risk mitigation slowed the development of the drug, resulting in what we now recognize as the venetoclax ramp-up. This entails starting at a lower dose of venetoclax than was used in early phase studies and following a stepwise dose increase over a period of 5 weeks. Using the venetoclax dose ramp-up, the rates of TLS have been low, but they have not been 0. So, it is important for practicing clinicians to be aware of the risk of TLS and to have access to the appropriate resources for stat monitoring and management in high-risk scenarios.

Prior to treatment, patients with CLL should be risk stratified into high-, medium-, and low-risk TLS groups based on the tumor burden (ie, lymph node size and absolute lymphocyte count). Other clinical factors, such as the patient’s renal function, should also be considered when assessing the patient’s risk of TLS.

When patients are started on venetoclax, clinicians need to carefully monitor them in either an inpatient or outpatient setting, depending on risk category. It is generally recommended that high-risk patients be treated in a hospital that has rapid access to emergency dialysis and the capacity for the acute management of hyperkalemia or hyperuricemia. For those who are at medium risk for TLS, there is more room for individualized decision making with regard to the appropriate treatment and treatment setting, but those patients with glomerular filtration rates that are less than or equal to 80 mL/min may benefit from closer monitoring.

During the 5‐week venetoclax ramp-up period, monitoring laboratory values at 6 to 8 hours and at 24 hours after each first new weekly dose level has been recommended. At 6 to 8 hours, even relatively modest changes in potassium levels may be clinically meaningful. For example, seeing a 0.5-mEq/L difference in potassium level at 6 to 8 hours is potentially a high-risk scenario, and lab results that do not come back until the following day are inadequate in the acute management of potassium elevations. If a clinic is not able to obtain stat labs on potassium and uric acid levels, hospitalization may be required for treatment.

In concert with TLS risk assessment and laboratory monitoring, the most fundamental part of TLS prevention and management is probably maintaining adequate hydration. Preventive therapies for hyperuricemia, such as allopurinol, should also be considered. And, in select cases, patients may benefit from therapy with rasburicase, a recombinant urate oxidase enzyme. In clinical trials, we have observed low rates of TLS with this approach. In the general population, where practices and interventions may be more variable, we have seen evidence from retrospective data sets suggesting that somewhat higher rates of TLS have been observed than the rates reported in clinical trials. For clinicians who are practicing in an environment with limited access to resources, it may be advisable to ask the nearest university center to help with the dosage ramp-up, to ensure that it is done safely.