Role of Venetoclax in Chronic Lymphocytic Leukemia


Experts comment on the use of venetoclax-based therapy in treating chronic lymphocytic leukemia.

Jennifer Brown, MD, PhD: The biggest recent approval in the frontline setting is certainly venetoclax/obinutuzumab, which is a 1-year, time-limited regimen combining anti-CD20 antibody obinutuzumab with venetoclax. This results in about a 75% rate of undetectable MRD [minimal residual disease] at the 1-year point in patients who discontinued at that point. Those patients who are with undetectable MRD have a 90% progression-free survival from that point of discontinuation. Those who still have detectable MRD tend to show steady relapse, which is not surprising for a time-limited therapy. That is similar to what we saw with chemoimmunotherapy, but if you have a long enough duration of remission, that is still a substantial benefit for 12 months of therapy.

The other recent registration trial for which we have just heard the results at ASH [the American Society of Hematology annual meeting] 2020 are from the UNITY trial, which has been long-awaited. This is a randomized comparison of a next-generation PI3 kinase delta inhibitor called umbralisib, which also inhibits casein kinase 1 epsilon together with the anti-CD20 antibody ublituximab. The regimen was compared to obinutuzumab/chlorambucil in both treatment-naïve and relapsed/refractory patients. It is a little unusual. The study was about half and half patients who were untreated vs relapsed/refractory.

The regimen was pretty well tolerated. It showed some of the known PI3 kinase adverse effects: diarrhea in more than half the patients, but high grade in only 12%, and transaminitis in about 8%. The discontinuations for adverse events were only 17%, and so the safety even in the frontline setting definitely appears to be improved compared to other PI3 kinase inhibitors. 

The progression-free survival in the overall study was 32 months. For the frontline cohort, it was 36 months. This is not as long as we have seen in most of our BTK [Bruton tyrosine kinase] or BCL2-based studies, but it is another option for our patients. It will probably be used mostly in later lines of treatment, but there may be a subset of older patients with significant cardiac or renal comorbidities in whom this would be a good option even in the frontline setting.

The venetoclax/obinutuzumab regimen involves some significant monitoring at the initiation of therapy. Obinutuzumab starts first, with 3 consecutive weekly doses, and depending on the tumor burden, one needs to be careful for infusion-related reactions as well as tumor lysis. I usually use prophylaxis for tumor lysis even with the obinutuzumab, and I will check laboratory test results on the evening of the infusion and the next day, at least in the first week or two. It has the benefit that it reduces the disease burden when it comes to be time for the venetoclax.

Patients still require the typical monitoring of labs prior to dosing, followed by labs in 6 to 8 hours, and the following day. That is assuming that they have been reduced to medium-risk criteria. One needs to follow the package insert in terms of low, medium, or high risk for tumor lysis. High-risk patients still get admitted. Fortunately, my patients have mostly been reduced from the high-risk group by the prior obinutuzumab, but I always get my CT scan after the obinutuzumab and before the venetoclax, rather than prior to therapy, so that I can make sure that they are in good shape for outpatient venetoclax.

The monitoring obviously requires some effort, so getting the labs done and seeing the results in a timely fashion is one of the barriers to community use of the regimen, although we certainly have some community doctors in my area who are able to do it. That is one of the barriers that we need to overcome, or we will need to get more lead-in strategies that reduce all patients to low enough risk that we can skip the monitoring. So far, none of us are comfortable skipping the monitoring with any of the regimens, so that is an area for further investigation.

Stephan Stilgenbauer, MD: Next to targeting BTK, the other new revolution, I would say, in CLL [chronic lymphocytic leukemia] treatment is the principle of targeting apoptosis. The BCL2 inhibitor venetoclax is the lead compound in this class of agents. 

Venetoclax has been approved by the FDA and by the EMA [European Medicines Agency] in the frontline treatment setting of CLL based on the CLL14 study data. CLL14 was a randomized trial comparing chlorambucil plus obinutuzumab versus venetoclax plus obinutuzumab, in an elderly patient population defined by a significant degree of comorbidities.

In this population the CLL14 trial showed that there is significantly superior progression-free survival with venetoclax plus obinutuzumab compared to chlorambucil plus obinutuzumab. The tolerability of both treatment arms was similar with a manageable safety profile for both agents. An important thing when it comes to venetoclax compared to other monotherapies, such as the BTK inhibitors, is that venetoclax provides the option of limited treatment duration. Venetoclax plus obinutuzumab is licensed as a fixed-duration, 12-month treatment, and it obviously provides the opportunity for our patients to get off therapy. Time off therapy is obviously time where the adverse effects of treatment are much reduced; they are usually not present at all, and it allows patients to lead a normal life. 

When looking at the genetic risk factors, one has to say that patients with high-risk genetic features, such as unmutated IGHV status or those with 17p deletions, benefit particularly from venetoclax-based therapy compared to chemoimmunotherapy. Nevertheless, the outcome of patients with a 17p deletion or TP53 mutation is somewhat inferior with venetoclax treatment compared to patients without these abnormalities. However, this difference was also seen with BTK inhibitor-based therapy, so we have to say that, even with the novel agents targeting BTK or targeting BCL2, the subgroup of patients with a 17p deletion and/or a TP53 mutation are still patients who need further development and further improvement in the efficacy of our treatments.

Transcript edited for clarity.

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