Case 1: Ibrutinib +/- CD20 Antibodies in CLL



Anthony Mato, MD, MSCE:One of the controversies that you brought up, because you talked about ibrutinib-based therapy, and I think the subtlety there was that this is either ibrutinib or ibrutinib plus rituximab. Well, let’s touch, tackle rituximab first. Any value in adding rituximab to ibrutinib in the frontline setting, and what’s that based on?

Sameer A. Parikh, MBBS:Based on the Alliance [A041202] study that had patients randomized to ibrutinib versus ibrutinib and rituximab, compared to bendamustine and rituximab in a 3-arm study. There were no differences noted in the progression-free survival between the 2 ibrutinib regimens. So ibrutinib versus ibrutinib plus rituximab, there was no improvement. In practice improvement in progression-free survival; so in practice, I don’t see the role of rituximab being added routinely in the management of patients who are about to start therapy. We would typically recommend starting an ibrutinib as a single agent.

Anthony Mato, MD, MSCE:I agree, and that was also found similarly in the relapsed-refractory setting with ibrutinib plus or minus rituximab—no difference in progression-free or overall survival. Maybe subtle differences in terms of depth of response, but not worth I think the addition.

Sameer A. Parikh, MBBS:The really group of patients where I would sometimes consider adding rituximab would be patients where I want a rather quick response to therapy. I have had patients where they started a white count of 500,000, and then their white count because of ibrutinib related lymphocytosis would climb up to 700,000, or something like that, and there you would consider maybe potentially adding rituximab to gain faster disease control.

Another group of patients where I’ve sometimes use it in patients who have membrane proliferative glomerulonephritis or other autoimmune processes that may need the addition of an anti-CD20 monoclonal antibody.

Anthony Mato, MD, MSCE:Well rituximab is not the only approved anti-CD20 antibody. Obinutuzumab has some interesting data with ibrutinib in the frontline setting ILLUMINATE trial. Do you want to touch on that one?

Shuo Ma, MD, PhD:The ILLUMINATE study is actually combining ibrutinib with obinutuzumab, a novel anti-CD20 antibody, in comparison to chlorambucil plus obinutuzumab. As we all know that the previous CLL11 study has established obinutuzumab combining with chlorambucil is superior over chlorambucil alone, and also superior to chlorambucil plus rituximab. That study established obinutuzumab is a superior antibody in combination with chemotherapy, at least in the frontline treatment of chronic lymphocytic leukemia [CLL].

Based on that, this ILLUMINATE study used chlorambucil plus obinutuzumab, an FDA-approved combination as a control arm, and then comparing to ibrutinib plus obinutuzumab. This included patients who had treatment-naïve CLL, or 65 years or older, or for younger patients who has comorbid conditions.

With a median follow-up of 31 months the ibrutinib plus obinutuzumab arm significantly prolonged

the progression-free survival compared to the chlorambucil/ obinutuzumab arm. An estimated 30-month progression-free survival was 39% in the ibrutinib-containing arm, versus 31% in the chlorambucil containing arm.

Based on this study actually the FDA has approved this combination of ibrutinib and obinutuzumab as an option for frontline treatment of CLL. Whether that is better or equivalent to ibrutinib single arm, there hasn’t been a study to compared those 2 side by side, so we don’t really know the answer to that.

Anthony Mato, MD, MSCE:In your current practice then are you using ibrutinib as a monotherapy, or ibrutinib plus obinutuzumab.

Shuo Ma, MD, PhD:I’m using pretty similar to Sameer’s that for most patients I use ibrutinib as a single agent. But for a patient who has an extremely high white cell count to start with, I will add the obinutuzumab to help have a quicker cytoreduction.

Anthony Mato, MD, MSCE:Then just to press Sameer a little bit more, because he did mention the use of rituximab in autoimmune conditions. Are you using rituximab or is it obinutuzumab, just for teaching purposes?

Sameer A. Parikh, MBBS:I think the ibrutinib-obinutuzumab data has just come out recently so I’m more inclined to use obinutuzumab if I really have to use an anti-CD20 monoclonal antibody therapy. And, again, this is cross-trial comparison so we, like you mentioned, don’t have any data to support the use of obinutuzumab compared to rituximab with ibrutinib. There is the data from the ILLUMINATE study suggest that there is a higher rate of minimal residual disease [MRD]-negativity that happens after 18 months or so, compared with, again, this cross-trial comparisons, but I think if I had to use an anti-CD20 monoclonal antibody, I would potentially pick obinutuzumab.

Transcript edited for clarity.

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