Venetoclax and Obinutuzumab in CLL

William Wierda, MD, PhD: I’m struck when I sit with a patient and I talk about them going on a BTK [Bruton tyrosine kinase] inhibitor–based therapy as their frontline therapy. They’ll ask me how long this is going to work. In the frontline setting, I have to answer that I don’t know because even the long-term data we have, we don’t know what the median is in terms of progression-free survival [PFS]. We’ve never been in that situation before. But let’s switch gears and talk about a BCL2 inhibitor–based therapy, venetoclax.

Venetoclax is approved in the frontline setting, and that was based on the CLL14 trial. We have seen some recent updates regarding CLL14. Maybe Dr Shadman can summarize what we know in the frontline long-term follow-up from CLL14, the trial design, and what it showed.

Mazyar Shadman, MD, MPH: The CLL14 study, in my opinion, is 1 of the most important studies for CLL [chronic lymphocytic leukemia]. It brought time limits and nonchemotherapy, or chemotherapy-free treatment, into the first-line setting. That’s very important for our patients. The study was done by the German CLL Study Group. Patients with comorbidities, defined as CIRS [cumulative illness rating scale] score of more than 6 or kidney function with the creatinine clearance of less than 70 mL/min, were randomized to receive either venetoclax and obinutuzumab as a combination therapy for a fixed 1-year duration without any role from MRD [minimal residual disease] in terms of stopping the treatment.

Every participant received 1 year of treatment, starting with obinutuzumab, and then venetoclax was added. The control arm was chlorambucil and obinutuzumab. The primary end point of the study was progression-free survival with MRD, overall survival, and response rates as other end points. It’s important to mention that roughly 12% of patients had abnormal TP53, either mutation or deletion, and 60% of patients overall had an unmutated IGHV gene without much difference between the 2 arms.

The initial report we had from this study showed that the study met the primary end point with a 3-year PFS of greater than 80%: 82% in the VenG [venetoclax-obinutuzumab] arm and 50% in the chlorambucil-obinutuzumab arm. The benefit was seeing all the known risk groups for CLL, including TP53 abnormal or unmutated IGHV gene. Because we are talking about the fixed-duration therapy, the depth of response becomes very important. Therefore, the rate of MRD eliminations is a particularly important end point.

So in peripheral blood, the percentage of patients who received VenG [venetoclax-obinutuzumab] had 76% undetectable MRD with the sensitivity of 10-4, and then the percentage of patients with MRD negativity in bone marrow was 57%. This is very impressive because what we know from venetoclax-based therapies and from this study is that the duration of response and PFS is directly correlated with the depth of response, meaning that if you achieve that undetectable MRD, the PFS would be longer. In the recent ASCO [American Society of Clinical Oncology] Annual Meeting, we saw that 18 months after finishing therapy, 47% of patients on the VenG [venetoclax-obinutuzumab] arm were still in the undetectable MRD status, which is very impressive.

For the CLL14 study, we don’t have the actual estimates as we do for MURANO, such as the exact PFS for each category of undetectable or low MRD or high MRD, but we know that they are significantly different. Unlike the discussion we had about BTK inhibitors, achieving an MRD or adding a second agent really doesn’t help the overall benefit. I agree that the benefit is not necessarily PFS. Here with a venetoclax-based therapy, we are in a very different situation because the goal is to give a fixed-duration therapy and stop.

Therefore, it does matter how good that response is. The most recent follow-up at ASCO showed that undetectable status could be durable. We’re still not seeing any new safety signals with the current follow-up, which is important. There was some report of secondary malignancies, which the numbers I believe are in the 17% range for the treatment arm versus 10%, but they are mainly skin cancers. I don’t believe there were any concerns, from what I reviewed, that there is a specific type of secondary malignancy that is more prevalent in the treatment arm.

Overall, as I mentioned, this study gives us an opportunity to offer a treatment that finishes at some point, and it’s not chemotherapy. As part of the conversation that you mentioned earlier about the decision between BTK inhibitors or venetoclax-based therapy, 1 of the factors to consider is that while venetoclax-based therapy is a great treatment and we talked about the benefits, it’s not as easy to start as BTK inhibitor–based therapy. As we discussed in regard to the coronavirus pandemic, you can start patients on treatment without even seeing them.

Hopefully that won’t happen, but it’s not impossible. You can follow patients’ labs and start them on treatment. With venetoclax, you need teamwork. You need a lot of coordination. There is a risk of tumor lysis syndrome [TLS], and there are strategies that you must follow to decrease that risk. One would be choosing the right patient for treatment. If you have a patient who’s not able to follow the recommendations in terms of coming to the clinic and following the ramp-up protocol, or they have unstable kidney function, maybe venetoclax-based therapy is not the best treatment option for them. Most important, involve the patient.

One of the differences in CLL14, which is a frontline study, and MURANO, which is a relapse study—we’ll talk about it later, I believe—is that CLL14 starts patients with obinutuzumab. With this approach, from the lymphocyte count standpoint, we’re able to downgrade these patients in terms of TLS risk. In the real practice, this approach may not be adequate in patients who have significant bulky disease, so in those cases, you add more time to that antibody or use other strategies.

In general, it is important to follow the CLL14 schedule and regimen—I follow it religiously—until we have more data. As great of a drug venetoclax is, we don’t want a situation where a patient develops TLS when it was preventable. Venetoclax is a new option for us and is that initial phase of debulking and ramp-up that we have as part of the conversation with patients.

Transcript Edited for Clarity