Dr Tedeschi Reviews Zanubrutinib Plus Venetoclax for Patients With CLL

Alessandra Tedeschi, MD, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, reviews early results from arm D of the SEQUOIA trial on zanubrutinib in combination with venetoclax for patients with treatment-naïve chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) with del(17p) aberrations.

Transcript

Dr Alessandra Tedeschi: My name is Alessandra Tedeschi. I work in Niguarda Cancer Center Hospital in Milano, and I deal mostly with lymphoproliferative disorders, mostly CLL and Waldenstrom macroglobulinemia (WM).

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Dr Tedeschi: This is a trial addressed to treatment‑naïve (TN) 17p‑deleted patients. The rationale is based on the efficacy of zanubrutinib showed in monotherapy in these patients with high‑risk features.

The SEQUOIA trial included an arm in which zanubrutinib was given in combination with venetoclax with an aim, if possible, to discontinue treatment when a deep response was achieved based on complete remission and undetectable MRD in peripheral blood and bone marrow.

OLN: Could you briefly describe the study and its findings?

Dr Tedeschi: In this study—I have to say that these are preliminary data of the study—we enrolled as for now 49 patients, and this represents the patients in the safety analysis, while responses of efficacy was done on 36 patients.

What I would like to underline is that this population was characterized of patients with many high‑risk features, not only for the 17p deletion, but also for the presence of a complex karyotype. We had 70% of patients in whom karyotype was performed showing a complex karyotype with 5 or more abnormalities.

This is a very high‑risk population. In this population, we achieved a higher rate of responses, which are about 97% as for now. The median follow‑up is at this stage short, it's 12‑month. What I would like to underline is that in patients in whom treatment was given for 12 months or more—the combination treatment was given for a longer period—we achieved deep responses with 5 patients of the 14 achieving a complete remission (CR).

Those 5 of them had the criteria for a CR, but bone marrow was not performed because of the pandemic and organization related to COVID, because this study was just started before the pandemic, the first wave of pandemic. We are seeing at this moment deep responses in patients achieving in the combination treatment for a long time.

OLN: Were any of the outcomes particularly surprising?

Dr Tedeschi: The outcomes are not surprising, because we are using the best drugs we have in our hands in this moment in the treatment of CLL, the BTK inhibitors, zanubrutinib, and the BCL‑2 antagonist, venetoclax.

What is surprising is that the toxic profile of the combination is very safe. We expect, when we combine treatments, that we may have a higher toxicity related to the combinations, while we saw with zanubrutinib and venetoclax a very well‑tolerated treatment with a rate of diarrhea, neutropenia, and nausea which are very similar to the one‑third when the drugs are used in monotherapy.

We've had only 1 atrial fibrillation, and this is important with atrial fibrillation that was coexisting before treatment, no major hemorrhages. Importantly, after 3 cycles of zanubrutinib, we observed the tumor lysis syndrome related to venetoclax.

It's a very safe combination, and this is very important to have, not only a good combination, but also a combination with a very good toxic profile.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr Tedeschi: I think as for the future, we'll be allowed to combine 2 drugs. We know that there are other studies addressing the combination of ibrutinib with venetoclax.

I'm referring to the CAPTIVATE study that give very high‑order response rates and is a nice study with MRD‑guided responses. As it is of this study, I think that in the future, we will use this fixed‑duration treatment to be able to discontinue and then restart treatment of the 12 patients when necessary.

OLN: Do you and your co-investigators intend to expand upon this research? If so, what will be your next steps?

Dr Tedeschi: The next step is to end this study on the 17p‑deleted patients, but also expand the study to patients without 17p deletion, and this will be very important.

Of course, there is another step that has been done in part, but also it will be of interest to see if we can achieve better results in combining also a monoclonal antibody to venetoclax and zanubrutinib. It has been done in a phase 2 study, but I think that this is a thing that should be expanded, and we will see, of course, other studies, and possibly randomized studies.

OLN: Is there anything else pertaining to your research and findings that you would like to add?

Dr Tedeschi: The field is going on. We have a lot of drugs in CLL, and I don't think that we achieved the curing of CLL in a way, but we are giving to our patients a better prognosis with safe combinations and possibly the rationale to restart treatment when patients need based on undetectable MRD, but this is a thing for the future.