Dr Jain on Current Challenges in Defining Venetoclax Failure in CLL

"What often occurs is that patients do well [as they receive] venetoclax for the designated 1- to 2-year treatment period, but [they] experience disease progression after completing therapy. The challenge is how to define treatment failure in this context. With venetoclax, it can be a bit challenging to define failure, and as a CLL community, I don't think we have standard definitions for failure yet in that setting.”

Nitin Jain, MD, a professor of medicine in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the current challenges in defining venetoclax (Venclexta) failure in chronic lymphocytic leukemia (CLL) and highlighted the need for consensus within the CLL community to guide clinical practice and research.

Unlike BTK inhibitors, which are administered continuously, venetoclax is typically given as part of a time-limited regimen, often in combination with agents such as obinutuzumab (Gazyva) or rituximab (Rituxan) for a fixed duration of 1 to 2 years, Jain explained. He noted that disease progression with BTK inhibitors is generally easier to identify, as disease progression during active therapy—evidenced by rising lymphocyte counts or lymphadenopathy—can serve as a clear reflection of treatment resistance. However, ambiguity can arise when patients discontinue BTK therapy due to intolerance and later experience disease progression. In these cases, it is important to distinguish true resistance from progression following intolerance, Jain explained.

In contrast, defining failure on venetoclax-based regimens remains more complex, he continued. Since venetoclax is administered as a fixed-duration therapy, patients often complete and remain off treatment until disease progression.

Jain highlighted the clinical uncertainty surrounding whether relapse occurring after treatment completion constitutes true venetoclax failure. Some clinicians propose that a relapse within 1 to 2 years of discontinuation should be considered venetoclax failure, although Jain cautions that this remains an informal framework without standardized criteria.

Jain concluded by noting that the lack of a universally accepted definition of venetoclax failure complicates treatment sequencing and clinical trial eligibility. Without clarity on what constitutes venetoclax failure, it becomes difficult to compare outcomes across studies or determine optimal salvage strategies.