Improved Risk Stratification Models Needed to Predict Baseline Risk of Tumor Lysis Syndrome in Relapsed CLL Treated With Venetoclax

Results of a retrospective study of patients with relapsed chronic lymphocytic leukemia (CLL) treated with venetoclax as part of routine clinical practice suggest that the risk of tumor lysis syndrome (TLS) may not be fully predicted by current risk stratification models.¹  

Tumor lysis syndrome (TLS) is a condition caused by the rapid release of large amounts of potassium, phosphate, and uric acid into the blood from dying cancer cells, and can be associated with acute renal failure, cardiac dysrhythmia, seizures, as well as other clinical sequelae.

According to the Howard criteria, laboratory TLS is characterized by at least 2 metabolic abnormalities including hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia, and clinical TLS is defined as laboratory TLS plus signs of kidney failure as related to specific creatinine clearance levels and oliguria, or clinical signs of cardiac dysrhythmia, neuromuscular irritability, hypotension, and/or heart failure, associated hyperkalemia, or hypocalcemia.²

Notably, TLS has been previously identified as a potential adverse effect associated with use of venetoclax, an oral BCL-2 inhibitor that has received approval by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with CLL and small lymphocytic lymphoma (SLL) and in combination with another agent for some adult patients with acute myeloid leukemia.³

In an attempt to limit the risk of TLS, current venetoclax prescribing guidelines include recommendations for titrating the dose of venetoclax at treatment initiation, along with laboratory monitoring and prophylaxis with hydration, allopurinol, and/or rasburicase according to patient risk of TLS based on the size of the computed tomography (CT)-defined largest lymph node and the absolute lymphocyte count. However, questions remain regarding the risk of TLS in patients with CLL receiving venetoclax outside of the clinical trial setting.

This study included data related to patient-, disease-, and treatment-related characteristics for all patients with relapsed CLL treated with venetoclax outside the setting of a clinical trial at the Mayo Clinic in Rochester, Minnesota, between April 2016 and February 2019, with the exception of patients with Richter transformation or those undergoing rapid escalation of venetoclax dose to prevent ibrutinib flare.

In the cohort of 48 patients with relapsed CLL included in the study, the median age was 70 years and the median number of previous CLL-related therapies was 4. Risk of TLS prior to initiation of venetoclax was low, medium, and high for 21 (44%), 18 (37%), and 9% (19%) of patients, respectively.

Following initiation of venetoclax, 6 (13%) patients developed laboratory TLS, and, of those, 3 (6.5%) also developed clinical TLS, according to the Howard criteria. Of the 3 patients with laboratory TLS alone, the baseline risk of TLS was determined to be either low (2 patients) or medium (1 patient). For the 3 patients developing clinical TLS, baseline risk had been identified as medium (1 patient) or high (2 patients). In the remaining patients, isolated hyperphosphatemia, hyperkalemia, hyperuricemia, and hypocalcemia developed in 19, 13, 2, and 1 patient(s), respectively. Of note, the baseline risk of TLS for 6 of the 19 patients who developed isolated hyperphosphatemia was classified as low, and of the 9 patients who developed isolated hyperkalemia requiring an intervention, 5 were classified as having a low risk of TLS at baseline.

Regarding these findings, the study authors stated that “in our analysis, baseline TLS risk as defined by the package insert did not predict occurrence of TLS, despite all patients undergoing baseline CT scans to assess extent and size of adenopathy.”

Specifically, no association was found between baseline risk of TLS and age, sex, IGHV mutation status, CLL fluorescence in situ hybridization (FISH) findings, Rai stage, beta 2 microglobulin, increasing spleen size, extensive bone marrow involvement, baseline creatinine or glomerular filtration rate, lactate dehydrogenase, absolute lymphocyte count, or largest lymph node size.

In their concluding remarks, the study authors also noted that “current risk stratification models may not predict the incidence of metabolic abnormalities such as hyperkalemia requiring intervention that is not associated with frank TLS.”

Editor’s Note: This article has been corrected to indicate that venetoclax is approved by the FDA for the treatment of adult patients with chronic lymphocytic leukemia and small lymphocytic lymphoma.

References

1. Koehler AB, Leung N, Call TG, et al. Incidence and risk of tumor lysis syndrome in patients with relapsed chronic lymphocytic leukemia (CLL) treated with venetoclax in routine clinical practice. Leuk Lymphoma [published online May 25, 2020]. doi: 10.1080/10428194.2020.1768384
2. Howard SC, Jones DP, Pui C-H, et al. The tumor lysis syndrome. N Engl J Med. 2011;364:1844-1854.
3. Venetoclax (Venclexta). [package insert]. South San Francisco, CA: Genentech, Inc.; 2019.