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iwCLL 2021 | Addressing autoimmune cytopenia in CLL

Kerry Rogers, MD, The Ohio State University, Columbus, OH, discusses the management of autoimmune cytopenia in patients with chronic lymphocytic leukemia (CLL). BTK- and PI3K-inhibitor class CLL drugs such as ibrutinib and idelalisib have been associated with a reduced incidence of autoimmune cytopenia when compared to venetoclax in a clinical trial. This effect may be a result of BTK- and PI3K-inhibitor mediated inhibition of B-cell receptor signalling, with consequent effects on autoimmune cytopenia; however, all three drugs have been found to be associated with improved chronic autoimmune cytopenia control. This suggests that earlier treatment of CLL patients with chronic autoimmune cytopenia using these drugs may improve clinical outcomes. Dr Rogers highlights the potential benefits of primary autoimmune cytopenia drugs, such as fostamatinib, in the treatment of CLL-associated autoimmune cytopenia. This interview was conducted during the 2021 virtual international workshop on CLL (iwCLL).

Transcript (edited for clarity)

I was very excited to give an update at this meeting on the management of autoimmune cytopenias in CLL patients in this era of targeted agents. And there’s really kind of like two aspects to this that I wanted to cover for the talk. One of the most important aspects is just understanding the impact of any new CLL therapy on concomitant autoimmune cytopenias. The information we have is mainly on autoimmune hemolytic anemia and ITP, and really there’s not too much new out there in pure red cell aplasia autoimmune neutropenia, so I focused on the first two...

I was very excited to give an update at this meeting on the management of autoimmune cytopenias in CLL patients in this era of targeted agents. And there’s really kind of like two aspects to this that I wanted to cover for the talk. One of the most important aspects is just understanding the impact of any new CLL therapy on concomitant autoimmune cytopenias. The information we have is mainly on autoimmune hemolytic anemia and ITP, and really there’s not too much new out there in pure red cell aplasia autoimmune neutropenia, so I focused on the first two.

I’m sure everyone’s aware that fludarabine as a single agent was thought to precipitate these. And since this is an important complication of CLL, it’s just something you always got to think about with any new therapy. The really interesting updates that I thought were kind of most relevant was looking at the incidence of these autoimmune cytopenias occurring during treatment with our CLL-directed targeted agents. And then also looking at what happens to patients with chronic autoimmune cytopenias if they start taking one of our newer targeted agents.

So, the CLL focus targeted agents of interest these days, of course, are BTK inhibitors, PI3-kinase inhibitors, and then venetoclax. And in terms of BTK inhibitors, there’s much more information on ibrutinib because it’s been around for longer and it takes a duration of experience with it before we start looking at autoimmune cytopenias and what happens with those. So, both the BTK inhibitor ibrutinib and idelalisib have a lower incidence of treatment-emergent autoimmune cytopenias. And that was actually looked at in a couple of studies.

So, the most recent look at this was a study by the Vitale et al. and they actually broke it down to ibrutinib, idelalisib, and venetoclax in terms of the incidence, and reported it as cases per 1,000 patient years of exposure. And so for ibrutinib that was five, for idelalisib that was six, and for venetoclax that was 69. So ,it’s really quite a higher amount with venetoclax, and that was statistically significant in terms of there being more. So, it’s not really a reason not to use venetoclax, it’s just something else we’ve learned about that agent.

Our institution had previously looked at our experience with treatment-emergent autoimmune cytopenias with ibrutinib. And we had an incidence of 13 per 1,000 patient years. We also had 25% of those patients, roughly, having autoimmune cytopenias prior to starting ibrutinib or having ever experienced them. It was a heavily pretreated high-risk cohort, and we included people with relapsed autoimmune cytopenias and that number. And Vitale actually did it very cleanly, where they only looked at patients that had never had an autoimmune cytopenia. So, that might account for the difference between the 13 and the five and six. Either way, venetoclax is more.

And the theory behind this would be that inhibition of B-cell receptor signaling actually decreases these antibody-mediated autoimmune cytopenias, and actually BTK inhibitors are also developed in different autoimmune diseases based on their immunologic effects. So, that all kind of makes sense. And it’s nice to see this confirmation. PI3-kinase inhibitors also, of course, inhibit B-cell receptor signaling, so it’s probably why you’re seeing the same. The good news is in that study, really, it looked like there was a beneficial effect on ongoing or chronic autoimmune cytopenias with any of the agents starting. And in the venetoclax case, likely due to better CLL control. So, it really isn’t at all discouraging of using any of these drugs.

And this is across multiple studies, you see an improvement, usually in chronic AIC. We looked at this in our study. Dr Hemphill at Mayo Clinic looked at that in a study of non clinical trial patients, ours was clinical trial patients, you know, Vitale’s looked at this. And it really looks like you do get autoimmune cytopenia control for people with chronic ongoing AIC when you start mostly BTK inhibitors and then in the Vitale series, venetoclax.

I think what this really means for the field is that overall, if you have people with chronic autoimmune cytopenias, you treat those kind of distinctly from the CLL. And that makes sense when you’re first treating them as some of them can be completely eliminated and not relapse after treatment with steroids and rituximab; however, in the cases of chronic autoimmune cytopenias, it might actually be better to consider starting CLL-directed therapy with a targeted agent, either a BTK inhibitor, PI3-kinase inhibitor or venetoclax, earlier to avoid chronic toxicity and more and more immunosuppression in this population that’s already susceptible to infections. So, it might be wise to move CLL-directed therapy with these targeted agents earlier into your treatment scheme for autoimmune cytopenias. And also to study these prospectively earlier in that course would be a very valuable thing.

The other thing I wanted to mention that I had talked about was not just our CLL-directed targeted therapies that are antineoplastic treatments and how they impact autoimmune cytopenias and CLL, but also targeted agents being developed in primary autoimmune cytopenias that might benefit our patients. There’s actually been quite a bit of work done in this area recently by people that do work in ITP and autoimmune hemolytic anemia as primary disorders, not as CLL-associated conditions.

And so the two drugs of interest I think right now are fostamatinib, which is a Syk inhibitor. Not only does it inhibit B-cell receptor signaling by inhibiting Syk and that cascade, but also inhibits FC receptor-mediated clearance of antibody coated cells by macrophages. And in mouse models, they’ve demonstrated very nicely that fostamatinib can actually block the clearance of antibody coated cells using a passive model of both ITP and autoimmune hemolytic anemia. Fostamatinib is FDA approved for chronic ITP and is actually in Phase III testing for autoimmune hemolytic anemia and we have the Phase II study open. And it can be very effective, and I think that kind of therapy should be something that we study in our CLL patients. There’s also a BTK inhibitor called rilzabrutinib that has the same kind of effect on macrophages that is now in Phase III testing for ITP.

So, I do think that the CLL community should continue to follow these kinds of things closely and work together with some of the benign hematology community working on therapies for primary ITP and AIHA to see how we might best study or translate some of those advances to help our patient population. I think we all know that autoimmune cytopenias can be more devastating than the actual effects of the leukemia for a subset of our patients. And so continued work in this area, not only to look at how our CLL treatments affect autoimmune cytopenias, but also to look at what new treatments we can bring to our patients with CLL-associated ITP or autoimmune hemolytic anemia, is really important.

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Disclosures

Kerry Rogers, MD, has participated in consultancy work for Acerta Pharma, Pharmacyclics, AbbVie, Genentech, Innate Pharma, and AstraZeneca; has received research funding from Genentech, AbbVie, Novartis, and Janssen; and has received travel funding from AstraZeneca.