Discontinuation of Venetoclax Impacts Outcomes of Rituximab Combination in CLL

Anthony Mato, MD

Early discontinuation of venetoclax (Venclexta) was associated with suboptimal outcomes in an analysis of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) in the phase 3 MURANO clinical trial, which was presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. These findings demonstrate the importance of effective management of adverse events (AEs) for patient to experience the full benefit of the combination venetoclax plus rituximab (Rituxan).

Discontinuation or dose interruptions of venetoclax appear to occur frequently in this patient population. This analysis aimed to evaluate how discontinuation or dose interruptions impact outcomes in this patient population.

Out of 194 patients, 140 completed 2 years of the combination regimen; 54 patients discontinued treatment early due to AEs in 29, disease progression in 12, withdrawal in 5, physician’s decision in 3, death in 2, noncompliance in 1, and for other reasons in 2. The median duration of venetoclax in patients who discontinued due to AEs was 11.3 months (range, 0.5-24.6) and 17.1 months (range, 4.6-25.1) for those who discontinued due to progressive disease (P =.08).

Inferior progression-free survival (PFS) was noted in patients who discontinued venetoclax early for any reason except for progressive disease or AEs compared with those who were able to complete treatment. Greater exposure to venetoclax cumulatively reduced the risk significantly of a PFS (HR, 0.93; 95% CI, 0.88-0.99; P =.0168) or overall survival (OS) event (HR, 0.85; 95% CI, 0.79-0.92; P =.0001).

Interruptions due to AEs occurred in 134 patients, which were mostly due to neutropenia (43%). The median duration of venetoclax interruptions was 9 days (range, 1-93). Interruptions did not have an impact on PFS or OS

In an interview with Targeted Oncology, Anthony Mato, MD, director of the Chronic Lymphocytic Leukemia Program, Memorial Sloan Kettering Cancer Center, discussed the findings of venetoclax interruptions or discontinuations observed in patients with relapsed/refractory CLL who received the combination of venetoclax plus rituximab in the phase 3 MURANO study.

TARGETED ONCOLOGY: Could you begin by providing some background on this study?

Mato: The MURANO trial is a trial comparing the combination of venetoclax and rituximab given for a total of 24 months, where the rituximab is given for 6 months and the venetoclax is given for a total of 2 years as compared to bendamustine/rituximab, which is a commonly used chemoimmunotherapy combination in the frontline and relapsed/refractory settings. The trial was conducted several years ago. Now we have 4 years follow up and initially and has subsequently demonstrated success in terms of the primary endpoint, in terms of PFS, as well as an OS advantage, favoring the venetoclax-based therapy, representing a paradigm shift in the management of patients with relapsed/refractory disease, in that we have a new molecule which rivals over a known standard of care, as well as a time-limited therapy approved in the relapsed/refractory setting.

TARGETED ONCOLOGY: Could you shed light on the methods that were used to conduct this particular analysis?

Mato: The analysis that was presented at the ASCO meeting is trying to address the question about whether or not outcomes are impacted for patients who have to undergo dose reductions, dose interruptions, and also for the small subset of patients who discontinue the time-limited therapy prior to the 24 months planned end point for continued therapy. Here we were looking at outcomes, particularly PFS, and how those particular factors might impact the primary end point of the MURANO trial for again, the small subset of patients who did require interruptions, reductions, and early or premature discontinuation.

TARGETED ONCOLOGY: What were some of the main reasons for discontinuing or interrupting treatment with venetoclax?

Mato: In most of the novel agents that have been approved for CLL, there's always 2 competing factors that seem to lead to most of the dose reductions or interruptions and/or discontinuation, and those always seem to include AEs or progression of disease.

TARGETED ONCOLOGY: What do the results show in terms of the impact on outcomes?

Mato: The take home message from this trial is that it's really best to try to understand how to use the label of venetoclax effectively to maintain continuous dosing for the 24 months. If patients required brief interruptions or dose reductions to try to find that right balance between AEs and continued exposure to this active agent, they were able to do just fine, and there was no significant impact on the outcomes. For patients who had to discontinue early, , those patients did have an impact on their outcomes. The lesson learned here is that if a patient requires a dose reduction due to neutropenia or diarrhea for example, it's better to understand the label and appropriately apply supportive care and to dose reduce, rather than to just give up on using the combination all together.

TARGETED ONCOLOGY: Could you elaborate on what those supportive care measures would entail?

Mato: It depends on the AE. Frequently, in clinical practice, if a patient experiences neutropenia, for example, which is probably the most common AE, one can use growth factors like filgrastim (Neupogen) or pegfilgrastim (Neulasta) to support the white blood cell count. Fortunately, with venetoclax, you don't need a lot of growth factor in order to maintain an absolute neutrophil count of about 1000, so sparing use once or twice a week might do it to maintain a dose of 400 mg. If the patient continues to experience neutropenia, then one might consider also reducing the dose from 400 mg, for example, to 300 mg or 200 mg. That might be 1 strategy.

Another supportive care measure is working with a clinical pharmacist to verify that there aren't particular medication interactions that might increase the venetoclax dose or level such that you may experience AEs. Patients who have diarrhea, for example, might benefit from a brief hold, a dose reduction, a brief interruption, or use of supportive care. Like with any novel agent, there's a learning curve associated with use of venetoclax, but once you're able to understand the AEs, which are fairly predictable and it's not like there's hundreds of AEs associated with this drug, you can come up with measures related to dose reductions, interruptions, or adding in medications or supportive measures that allow patients to stay on drug.

TARGETED ONCOLOGY: Is there anything else you wanted to emphasize?

Mato: It's important that these types of analyses are conducted when exploring the use of novel agents after the initial results of key trials are reported, particularly with the BTK inhibitors. We've seen similar types of analyses conducted, as well as less so with the Pi3K inhibitors, but I think it does provide an important framework for those practicing and taking care of patients who may require these types of measures in order to stay on drug to really help provide reassurance that outcomes are not compromised if you're following the label and are able to stay on drug at a dose that's right for a particular patient.