Evolving Therapies in Chronic Lymphocytic Leukemia - Episode 14

BTK inhibitor With vs Without a CD20-Targeted Antibody

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William Wierda, MD, PhD: Dr Allan, let’s talk a little about CD20-targeted monoclonal antibodies. We heard a little about the 3-arm randomized trial with ibrutinib plus rituximab or ibrutinib monotherapy versus BR [bendamustine, rituximab]. What are your thoughts around the utility of a CD20 antibody in the setting of a first-generation BTK [Bruton tyrosine kinase] inhibitor–based therapy and particularly a comparison of rituximab versus obinutuzumab as a partner choice.

John Allan, MD: Absolutely. It’s a great question, and it is something I don’t know if we’ve answered fully yet. To give some context to some of the viewers and physicians and/or patients who may be watching, there’s been a head-to-head study called CLL11 from the German CLL [chronic lymphocytic leukemia] Study Group, where they looked at obinutuzumab-chlorambucil versus rituximab-chlorambucil versus chlorambucil. It’s a 3-arm study in older patients with comorbidities.

CLL11 showed that obinutuzumab seems to be the superior anti-CD20 antibody in terms of its efficacy, with improved response rates as well as progression-free survival and a trend in a very modest potential overall survival benefit in this older, very sick patient population. Obinutuzumab is a glycoengineered antibody with enhanced ADCP [antibody-dependent cell-mediated phagocytosis] and a mechanism of cell kill. In my own anecdotal experience, obinutuzumab appears to be an extraordinarily effective agent.

That brings some context to what I’ll lead into. You mentioned the ALLIANCE A041202 study, where we looked at ibrutinib and ibrutinib-rituximab versus BR [bendamustine, rituximab]. There was no difference with adding rituximab to ibrutinib in terms of response rates, MRD [minimal residual disease] rates, or progression-free survival. Literally, the lines were overlapping, so I still use monotherapy BTK inhibitors, and I’m not using anti-CD20.

That brings us into the fact of the matter: We’ve never seen obinutuzumab-ibrutinib versus ibrutinib alone. There is a study iLLUMINATE, which looked at ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab. We see a little higher response rates at the first data cut, and we’ve seen that’s a better agent, but we don’t have single-agent data. As we know with monotherapy, you continue to deepen the response.

Is it that patients may get to a deeper response faster? Will that mean anything later on, 3 to 4 years later? Or will everyone plateau and get there and you got to that response faster with the better anti-CD20? It remains unknown because we don’t have that monotherapy arm. With that said, the ELEVATE-TN study, which was acalabrutinib-obinutuzumab versus acalabrutinib versus chlorambucil-obinutuzumab, does have that monotherapy arm. We see the response rates are better or deeper and CR [complete response] rates are a little higher.

MRD rates are a little higher in the acalabrutinib-obinutuzumab arm than what we saw with a rituximab-based agent. That study showed, as Dr Burke mentioned, this potential superior progression-free survival. It is very modest, with an absolute difference of only about 6%. The study wasn’t powered to be able to show that statistically, so you can’t really state that’s a true difference. Frankly speaking, follow these patients out another 3 to 4 years, those lines may come together because the anti-CD20 is only 6 months of the overall treatment.

Therefore, it does bring up this question of if you combine the better anti-CD20 agent with the BTK inhibitor, you may be able to impact a longer-term outcome, although I’m a little skeptical of that. There are some issues with it. Anti-obinutuzumab does have infusion reactions and requires an IV [intravenous] administration. There are cytopenias that we have to deal with that can be very problematic for some of our patients. Patients are getting growth factor. They’re getting very thrombocytopenic. They’re on a drug that may enhance bleeding.

We may see more bruising. All these kinds of things that you have to be worried about are the real-world practice of some of these patients who aren’t quite eligible for potential clinical trials that we’re treating in the real world. There’s potential benefit for it. But honestly—and we mentioned this—with a drug like a BTK inhibitor that you’re using for years, I find it hard to believe that 6 months of treatment with an anti-CD20 up front will significantly impact that longer-term outcome.

The longer-term outcome remains to be seen with obinutuzumab. But as the ELEVATE-TN study continues to mature, maybe that slight difference in MRD rate will matter in terms of a longer-term treatment if there is a significant number of patients who achieve MRD. We do know those patients typically do better. If you’re remaining on a treatment and you’re MRD and remain MRD, that line may start to differentiate based on those patients who were able to achieve it.

There are a lot of interesting aspects about that specific anti-CD20. It is a superior drug. I think it is the anti-CD20 we should use when we’re using an agent for CLL, although this does not hold across other histologies. We have not seen obinutuzumab and proved outcomes against rituximab in DLBCL [diffuse large B-cell lymphoma]. We have seen obinutuzumab have some impact in follicular lymphoma, so there are some properties about it that are special, that are unique. It does have some other issues, but I think there’s some value to it.

However, when I am using a BTK inhibitor, I am still typically using it as monotherapy for a lot of reasons, such as infusion reactions and cytopenias. The fact is, a long-term outcome may not actually be impacted by doing this when I’m using a drug that’s continuous. That may change a little if we talk about a BCL2 inhibitor in fixed duration, but I know we’ll be getting to that a little later. Those are my thoughts on that situation in terms of anti-CD20 and BTK.

William Wierda, MD, PhD: Dr Burke, are you using CD20 with your BTK inhibitor–based therapy in the frontline setting?

John Burke, MD: No, I agree 100% with everything Dr Allan just said. I echo his skepticism that adding the anti-CD20 is going to really impact long-term outcomes. Even if there is a small difference in PFS [progression-free survival] that holds or may become a little significant over time, I certainly question whether that will translate to OS [overall survival] benefit. The equation is complicated. It’s not all about PFS. It’s about overall survival. It’s about toxicities. It’s about cost. We say what statement is better, and the definition of better has to do with a lot more than PFS. The short answer to your question is, no, I’m not adding new CD20 to my BTK inhibitors right now as initial therapy.

Transcript Edited for Clarity