Clinical Challenge: Risk of Tumor Lysis Syndrome With Venetoclax in CLL

Venetoclax (Venclexta), a potent oral BCL2 inhibitor, is increasingly being used for the treatment of patients with chronic lymphocytic leukemia (CLL). However, its efficacy at inducing apoptosis in CLL cells increases the risk for tumor lysis syndrome (TLS), a potentially fatal complication discovered in early clinical trials.

To prevent TLS, protocols have been developed for administering venetoclax, detailed in the FDA package insert. These include a gradual ramp-up strategy for dosing the drug, as well as instructions for risk assessment and monitoring, noted Jeff Sharman, MD, medical director of hematology research at the U.S. Oncology Network in Eugene, Oregon.

“With that strategy, in the context of clinical trials, the rates of tumor lysis have been exceptionally low. Yet even with those protocols, you still have to remain vigilant and aware of the risk,” he told MedPage Today.

“From a realistic perspective, it has made it challenging to utilize the therapy because the monitoring burden is not trivial, and oftentimes this is not work you can outsource to a hospitalist to admit the patient and manage correctly, so you really have to remain hands on if you’re going to admit the patient to the hospital. And then if you’re going to do it in the clinic, it takes a fair bit of work, too,” he added.

However, “I think once anybody has done it a couple times, you can get to be quite comfortable with it. The trick is, like anything, you have to learn something new,” Sharman noted.

Kanti Rai, MD, developer of the Rai staging system for CLL and a hematologist and researcher at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, said that adhering to the protocols for administering venetoclax is important, even if some patients — who may need to receive initial doses in the hospital depending on their level of risk — complain about the inconvenience.

“There are some patients who question whether it is necessary to be hospitalized,” Rai told MedPage Today. “And the doctor has to take time to explain that, initially, when venetoclax clinical trials started, a few patients died of tumor lysis syndrome a short time after starting, because we didn’t know the risk when we started patients right away on the standard therapeutic dose of 400 mg.”

For patients with CLL, the FDA recommends a starting dose of 20 mg for the first week, and then a weekly ramp-up schedule with close monitoring over 5 weeks to the 400-mg dose. “So we can explain to a patient that, inconvenient as it is to take these precautions, which last approximately a month all in all, they are necessary,” Rai said. “If we follow the FDA requirements, we are keeping our patients quite safe from the risk of tumor lysis syndrome.”

Risk Assessment: Advice on CT Scans

Risk of TLS is based on multiple factors, including tumor burden, renal function, and other comorbidities, as stated in the venetoclax package insert. Therefore, physicians should perform tumor burden assessments, including a radiographic evaluation such as a CT scan. Physicians should also assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine), and correct any pre-existing abnormalities prior to treatment. Reduced renal function (creatinine clearance less than 80 mL/min) further increases TLS risk.

According to FDA recommendations, patients can be categorized as low risk, medium risk, or high risk based on absolute lymphocyte count (ALC) and number of lymph nodes >5 cm:

• Low risk: All lymph nodes <5 cm or ALC <25 × 10⁹/L
• Medium risk: Any lymph node 5 cm to <10 cm or ALC ≥25 × 10⁹/L
• High risk: Any lymph node ≥10 cm or ALC ≥25 × 10⁹/L and any lymph node ≥5 cm

However, Sharman offered a word of caution about radiographic imaging in this context. “Radiologists are not familiar with the tumor lysis risk associated with CLL, nor do they understand that how you provide radiographic measurements of lymph nodes influences patient risk stratification. Consequently, there’s a high degree of variability in how radiologists will report lymphadenopathy, in particular lymph nodes within the retroperitoneum,” he said.

Therefore, it is important for treating physicians to look at the images themselves, Sharman advised. “The reason for that is you may have 3- or 4-cm lymph nodes in isolation, or you could have 3- or 4-cm lymph nodes that are really part of a much larger mass that is 18 cm. So you could potentially consider a patient low risk when in fact they are very high risk. You really can’t trust a radiology interpretation to adequately characterize bulky or matted adenopathy. They may be measuring independent small nodes and miss or fail to characterize that it’s really matted adenopathy that is much larger.”

Prophylaxis: Matching Patient to Strategy

The two main FDA-recommended strategies for mitigating TLS risk are oral and/or intravenous hydration 2 days prior to treatment and uricosuric agents to manage high uric acid levels 2 to 3 days prior to treatment. Specific recommendations for these measures are based on risk category.

• Low risk: Oral hydration with 1.5 to 2 liters of water daily and allopurinol or other xanthine oxidase inhibitor
• Medium risk: Same as for low risk, but consider adding intravenous hydration
• High risk: Oral hydration 1.5 to 2 liters of water daily, intravenous hydration 150 to 200 mL/hour as tolerated, and consider adding rasburicase if the baseline uric acid is elevated

Another prophylactic strategy being studied is tumor debulking prior to venetoclax, especially with anti-CD20 antibodies and Bruton tyrosine kinase (BTK) inhibitors, said Sharman, who has conducted studies in this area. His recent research suggested that each of these approaches may be suited to specific patients.

“In the frontline setting, we know that obinutuzumab, which is approved in combination with venetoclax, will take somebody’s lymphocyte count down to normal by the time they start venetoclax. So it has the potential to lower a patient’s risk characteristics. What obinutuzumab fails to do, however, is change lymph nodes much over the course of a month,” Sharman explained. “That is information we have presented in abstract form, but [it] hasn’t been published.”

“Another combination therapy that venetoclax is being studied with is BTK inhibitors. And with BTK inhibitors given for 3 months prior to venetoclax, which is how most of the studies are being done, you do get a significant reduction in the lymph node size, but the lymphocyte count is more variable,” he added.

“So if you want to think about debulking, you can consider how you’re doing it,” Sharman advised. “Those patients with bulkier adenopathy are more likely to debulk with BTK-based strategies, whereas patients who have more lymphocyte-predominant disease are going to debulk very well with an anti-CD20-based approach.”

Monitoring: A Word About Potassium

Careful monitoring of patients for TLS as venetoclax therapy precedes is necessary, especially after the initial dose and each weekly ramp-up dose. For low- and medium-risk patients, blood chemistry should be monitored 6 to 8 hours and 24 hours after the initial dose and each ramp-up dose. For medium-risk patients with renal impairment, the FDA package insert says to consider administering the initial 20-mg dose and 50-mg ramp-up dose in the hospital.

High-risk patients should receive their initial 20-mg and 50-mg doses in the hospital, and blood chemistry should be monitored at 4, 8, 12, and 24 hours. Subsequent doses can be given in the outpatient setting, but blood chemistry should be monitored at 6 to 8 hours and 24 hours after each ramp-up dose, according to the FDA.

When monitoring potassium, pay attention to the rate of any change, Sharman advised. “One of the things that’s a little bit tricky is you can have a potassium in the normal range that could actually be quite dangerous. What you need to do is evaluate the rate of change after taking the drug, more than the level. So someone who went from a low potassium of 2.9 up to 4.0 could potentially be in significant trouble even though 4.0 is a normal number. The rate of change is key.”

If you do see a significant change in potassium, quick action is required, Sharman said. “It’s not ‘let’s just check this patient the next day.’ At that point it’s getting the patient into the emergency room quickly, so you can manage possible hyperkalemia. And it’s probably a weird experience to talk to the emergency room and say, ‘hey, I’m really worried about this patient with tumor lysis, even though their potassium is more or less in the normal range, or isn’t particularly high.’ But it’s knowing where they’re going and if the risk is going to worsen that’s really important.”

Finally, dose modifications are recommended in any patient with blood chemistry changes or symptoms suggestive of TLS, which could include renal, cardiac, and neuromuscular symptoms. If these occur, the FDA recommendation is to withhold the next day’s dose. If the blood chemistry changes or symptoms resolve within 24 to 48 hours, the same dose can be resumed. “For any blood chemistry changes requiring more than 48 hours to resolve, resume venetoclax at a reduced dose. For any events of clinical TLS, resume at reduced dose following resolution,” according to the recommendations.