Frontline Venetoclax Plus Obinutuzimab and Bendamustine for Patients With High Tumor Burden FL

Craig A Portell, MD, Associate Professor of Medicine, University of Virginia, Charlottesville, talks about a phase 2 study of venetoclax in combination with obinutuzumab and bendamustine for patients with high tumor burden follicular lymphoma (FL) as frontline therapy.

Transcript
Hi. My name is Craig Portell. I'm an associate professor of medicine at the University of Virginia.

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

Dr Portell: We know that bendamustine and obinutuzumab is a reasonable treatment option for high tumor burden FL from the GALLIUM data.

We wanted to see if we could improve on the response rate, but with the addition of venetoclax, which has been shown in preclinical models to have synergy with chemotherapy.

We went forward with a phase 2 study to combine venetoclax with bendamustine and obinutuzumab for patients who need chemotherapy with FL.

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

Dr Portell: The study added venetoclax to bendamustine and obinutuzumab. Venetoclax was given at 800 mg for 10 days with each cycle of chemotherapy--not continuous and a higher dose than usually is given with other standard treatments.

We initially gave venetoclax with the first cycle, but saw a high degree of tumorlysis syndrome, laboratory evidence of tumorlysis syndrome. Then we modified the study so that it was only given during the second cycle and onward.

The study found a very good (complete response) CR rate of 73% with a response rate of 92%. Rhe progression free survival (PFS) curves with the early estimate looked very good. However, the study did have a high incidence of opportunistic infections, which we think is more related to T cell depletion from the regimen, though we don't have T cell subsets to evaluate for on the study.

We actually think that the study, while having a very good response rate, is a little bit too toxic for this patient population to move forward as it's currently designed.

OLN: Were any of the outcomes particulary surprising?

Dr Portell: We were a bit surprised at the T cell toxicity, to be honest with you. While there's been some kind of circumstantial evidence of some T cell depletion with bendamustine-based chemotherapy, we didn't expect the addition of venetoclax to be quite so toxic.

Now it's a bit of a hypothesis that it's T cell that's causing these issues. We did very carefully evaluate for T cell toxicity, particularly in the maintenance phase of the study with evaluating for hypogammaglobulinemia and not pursuing maintenance if there was significant amount of hypogammaglobulinemia or increased infections.

We saw some very typical infections that are T cell mediated, like PJP pneumonia, CMV, encephalitis, BK nephropathy, that we don't typically see which is T cell depletion. I think that was a pretty surprising finding from the study.

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

Dr Portell: I think, at least for me, it gives me significant pause to think about patients going forward with maintenance strategies after bendamustine and being careful with infectious toxicities, particularly in the era of COVID and the COVID pandemic.

I think we need to be careful to not overly lymphodeplete or overly immunosuppress our patients, though adequately treat their lymphoma. It's a fine line to find.

I do think that there is some opportunities for the combination, could we use Rituxan (rituximab) instead of obinutuzumab? Do we need such a high dose of venetoclax? Could the toxicity profile be different in a different lymphoma? I think those are all things that we can consider with the combination in the future.

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

Dr Portell: We are not going to continue the study of this combination in FL. These are patients that are very well treated with multiple different agents and the degree of toxicity that we saw is just not worth the perceived response benefit.

We are going to continue to follow patients and maybe we'll see some differences in PFS that may change our mind. But at the current time, we think that the toxicity is not quite worth it.

We are evaluating the combination in mantle cell lymphoma (MCL), where the toxicity may actually be worth the benefit and response, with a disease that's a bit more aggressive. But we're also changing the backbone and not using obinutuzumab, but using rituximab instead. We're kind of shifting the treatment, the combination into a slightly different disease and kind of changing the paradigm a bit so it's not quite as toxic.