MBL: biology, classification & the possibility of early interception

Stephen Ansell: Hi, I’m Steve Ansell from Mayo Clinic, and I’m joined with three of my colleagues. We’re going to talk about monoclonal B-cell lymphocytosis. I’m going to ask each one of them to introduce themselves. Turn over to Andy here.

Andrew Rawstron: Okay hi, I’m Andy Rawstron, I’m a clinical scientist, so mostly involved in laboratory diagnostics. And we came across monoclonal B-cell lymphocytosis essentially because people would refer a sample for a lymphocytosis, and maybe we’d find a small CLL phenotype clone. And at the time 10, 15 years ago, well more now, nobody knew what to do with that situation. So I think a lot of the investigations that have followed come from that issue with does somebody have something that’s clinically significant or is this an unrelated, incidental biological finding?

Fabulous. Setting us up for the discussion. Introduce yourself Paolo.

Paolo Ghia: I’m Paolo Ghia, I’m Professor of Medical Oncology, and I’m the Director of the CLL program at Universita Vita-salute San Raffaele in Milano. And we came across MBL because we did some work in the mouse, and we noticed 25 years ago, unfortunately, that they were developing, monoclonal expansion of B-cells, CD5-positive. And therefore we wondered maybe that’s happening exactly the same in humans. And so that’s where we started.

Thank you. Anton.

Anton Langerak: My name is Anton Langerak. I’m a medical immunologist working at Erasmus Medical Center in Rotterdam in the Netherlands. I’m also much in diagnostics, especially in CLL diagnostics. And recently we’ve embarked upon a project where we are interested in studying the natural CLL development. And that’s why we’ve made studies and looked into MBL stages preceding the CLL diagnosis by using population cohorts where we’ve had some interesting findings in our recent studies.

So, Anton, maybe you just want to share for those that don’t know a lot about MBL, how do we classify MBL? What is MBL? And are there different types of MBL?

Yeah, so MBL is distinguished from CLL by the cell counts, and then it’s below 5000.
And then you have the option to distinguish high count from low count MBLs. Really distinguishing even smaller populations of cells.

Thank you. Paolo, what do we know about the low count versus high count MBL and the differences between those two?

That’s a very good question. So at the beginning, we thought it was flowing from low count, high count and becoming CLL. It would naturally happen having few cells at the beginning, then a little bit more and then a full disease. What we showed, also together with Andy and many others, is that low count seems to be a bird of a different feather, meaning probably they are reflecting more immunosenescence.
These are expansion that can occur in more than 10% of people walking in the street above 40 years of age. So it seems almost a paraphysiological phenomenon. Steve, they have exactly the same phenotype as a full blown chronic lymphocytic leukemia. They may carry the same genetic aberration, but somehow they sit there, very rarely, if ever, they might become really CLL. High count, MBL are really already one step further towards CLL. So they, indeed 1% per year becomes a CLL that needs treatment, so a real disease. So they really are probably, we are making a distinction which is very artificial. With the 5000, less than 5000 or more than 5000. And probably they are part of the same spectrum of a possible disease, because also CLL is not always a disease that needs to be treated. So again, high count MBL are probably similar in that sense.

Right. And Andy, what do you think we know about the high count MBLs that transform and become CLL? Or is there something unique about those cases that we can tell?

I think I mean, so actually what happens in a lot of cases is that people start off as MBL and then their count just drifts above 5000 and they transform. But essentially it’s often then stable for many years thereafter, so the number of cases where it’s driving through to CLL are actually quite rare. And you can usually see that from the start actually. So I think monitoring how people’s counts change, if it’s going up right from the start, then probably that’s a person who’s going to need treatment at some stage, whereas just drifting up and then settling again, those people still, you know, 10, 15 years of follow-up and they haven’t required treatment for the disease. So it’s two different kinetics.

Right. Anton mentioned earlier about the B-cell receptor and engagement. Tell us a little bit more about that and how that actually has a role to play.

Yeah I think so what we learned from our studies is that the B-cell receptor is detectable many, many years before diagnosis. And an interesting finding was that it is not restricted to the more indolent type of CLLs that finally developed, but even the more aggressive types and high-risk subsets that one could define in the CLL stage were already detectable long before. So I think it’s a very early marker of a cell that that kind of develops over time into that CLL. And I think it’s a very early event, as we could deduce from our genetic studies that we combined with the B-cell receptor analysis, where we saw that, acquisition of genetic events is a later process than the very early event where the immune globulin or the B-cell receptor is the kind of defining factor in the very beginning. So I think the order is that the cell depends on the B-cell receptor as the first signal through antigenic stimulation and then later on acquires further genetic events that might transform the whole process.

Right. Now, we’ve spoken a lot about the genetic events and the B-cell signaling, etc. but Paolo, maybe where is the immune system in all of this? Why is, you know, why are these cells not edited out by the immune system? Any thoughts about that?

Yeah, we are actually asking, meaning that what we see that is interesting is that already at the level of MBL and particularly high count, where there is data, the immune system is already somehow corrupted. And the corruption is very similar to what we see in CLL. So everything is a little bit, altered, which we know in CLL, we know patients who are more prone to develop infections, are not responding so well to immunotherapies. And the same thing appears to be true in MBL and in fact, even low count MBL, if they have any risk in clinical terms, is really a higher risk of infection. So it seems, and Andy and others have shown, that is that there is patients, individuals, with low count MBL, they are not patients, they tend to die earlier, probably because of an increased infection. So they don’t have a risk of hematological disorder, but they have already a risk of immunodeficiency, which probably again tells us that it’s more related to the aging of the immune system than a real hematological disorder.

Right. And, Andy, you know, interception is the new buzzword and the thing that we’re all looking to do. Do you think there’s an opportunity for MBL to be intercepted?

I think that would be, so you’ve got an opportunity to catch a subset of people. I mean, for most people, the overall survival is very similar to the general population. And maybe the risks of intervention are quite high relative to the potential gains. But there’s a definite subset of people who’ve got severe immune suppression, increased risks of infection and worse overall survival. So it’s somewhere between the low count MBL, it has very similar survival to the general population, and most of the higher count MBL, but within that there’s a group that they think would benefit from intervention. And especially now that you have treatments that can be given in a short time frame, you know that normal immune system recovers after treatment in people with more extensive disease, and the toxicity is relatively low. I think the opportunities are really starting to arise for investigation at the moment.

You know, I think it’s really exciting that lots of things are being learned about the genetics and the biology and the opportunity for interception intervention now exists. So I think these are interesting and exciting times. So thank you very much to my colleagues for joining us and thank you for you listening to this discussion.

Richter’s transformation: biology & ongoing trials in the field

Matthew Davids: I’m Dr Matthew Davids from Dana-Farber Cancer Institute in Boston, here in Lisbon for the 2024 Intercepting Blood Cancers IBC conference. I’m very happy here to be joined by my colleague Dr Erin Parry from Dana-Farber in Boston, as well as Dr Carsten Niemann from Copenhagen, and we’re here to be talking about Richter’s transformation.

So we know that CLL, which is a more indolent B-cell malignancy, can sometimes transform into an aggressive lymphoma, typically diffuse large B-cell lymphoma, and historically this has been a very challenging entity to treat. Fortunately, over the last few years, there’s been a number of new insights into the biology of this transformation and this is being reviewed here at this meeting. We’re also discussing some of the exciting new clinical trial opportunities. So I’m going to bring Erin first into the conversation here, and we’ll talk about the biology of Richter’s. We’ve learned a lot in the last few years about this transition. So maybe you can kind of summarize for us some of the key insights.

Erin Parry: Sure. So there’s been I think a number of different studies, both in sort of animal models as well as using patient samples, focusing on tracing that evolution of CLL to Richter’s, and looking at the different processes that are going on there.

We know that there is additional mutations and copy number alterations that occur along the way that sort of shape that evolutionary process and I think it’s highlighted a lot of the pathways that are dysregulated in that transition, including things like MYC signaling, oxidative phosphorylation, cell cycle dysregulation that lead to sort of that indolent to aggressive transformation.

I think the other thing that’s come out of some of these different studies is sort of focusing on something that we knew years ago that there’s two sort of different types of Richter’s: one that sort of seems clonally related, meaning it sort of emerges out of that preexisting CLL. And then a second, but less common type of transformation in which the CLL and the Richter’s are actually distinct malignancies, meaning that they don’t share that sort of common evolutionary genetic past.

And that has really important prognostic implications, right?

Yeah, and so these studies have sort of suggested that that clonally unrelated Richter’s the one that doesn’t sort of share the genetic basics, looks more like large cell lymphoma, both sort of epigenetically and genetically, and we know from some of the clinical studies, although small numbers, it sounds like that sort of those patients tend to do a lot better with our sort of standard of care therapies.

And then there’s also been some really interesting data published recently suggesting that these Richter’s precursor cells can be identified, sometimes many years before the actual Richter’s transformation, maybe you could speak to that a little bit.

Yeah, I think that’s an exciting, potentially interesting finding. At least on the research side, it looks like we can either by sort of very sensitive single-cell methods, people have been able to detect sort of some of those early genetic events that later mark the Richter’s clones even years prior. And there’s also some emerging literature for cell-free DNA, so it’s exciting about whether, on a research side, we can be able to detect changes early that maybe someday we can sort of bring to the clinic.

And then the other question that’s come up recently is with this era of targeted therapies that we now have in CLL, is that risk of Richter’s going down over time?

What’s your perspective on that so far?

So far, I don’t know that I’ve seen evidence that it’s going down, but it certainly seems that, the targeted therapies are not necessarily preventing Richter’s and that we’re still seeing Richter’s emerge even in these targeted trials, and it’d be interesting to hear your perspectives on that as well.

Yeah, absolutely, so, Carsten, maybe I’ll bring you into the conversation here. What’s your perspective in terms of this, you know, the frequency of Richter’s, are we still seeing it as frequently with targeted agents?

Carsten Niemann: So I think we saw a few years ago after the first concerns on BTK inhibitors that from the MD Anderson data that upon FCR chemoimmunotherapy for de-novo CLL, we saw in the relapsed/refractory setting, we saw more, Richter’s than what we saw in the relapsed/refractory trials treated with BTK inhibitors. And that’s essentially the best data we have at the moment from the GAIA CLL13 trial. We don’t have enough follow up where we have the direct comparison between the BTKi, the BCL2i, and chemoimmunotherapy arms. There might be a slight indication at least we’re not seeing more, so I think it’s safe to say we are not seeing more Richter’s [inaudible] treatment with BTK and BCL2 inhibitors in the frontline or later line settings.

Okay. Yeah.

The other thing, building on your, perspectives there and looking at the genetic instability in Richter’s, I think that’s really promising, taking it together with some of the clinical trials where we have seen in solid cancers that using genetic instability might be a marker for PD-1 or checkpoint inhibitors, and we might maybe have some implications that we could see the same in Richter’s, and I think that’s might really be promising going forward.

So I’m glad you brought up the idea of clinical trials in Richter’s you know, for a long time we didn’t have too much investigation going on in this disease, we were just using chemoimmunotherapy and it was not very effective. But it has been great to see over the last few years, a number of new clinical trial data sets being presented, including some featuring PD-1 and Pd-L1 blockade. So maybe you could speak a little bit to some of the exciting clinical trials in the space now.

So to be honest, I’ve been quite surprised to see what we have seen in the last few years in terms of clinical trials, because from my perspective, diffuse large B-cell lymphoma, Richter’s transformation, you would need chemoimmunotherapy. But we just saw the publication of the RT1 trial in Nature Medicine a few months back where the testing was, it’s a Phase II trial design, there’s no comparator arm where you could be critical about the primary outcome, because it’s restricted to only report on the patients who could continue at least two cycles of treatment, as I would recommend also to go for the supplementary, where you can actually see the intention to treat population. But what we saw here is combining a BTK inhibitor and a checkpoint inhibitor actually gave for the intention to treat population 40% or higher durable remissions. And what was really strange to see, we had, I think, ten patients on that trial at our institution was that some of the patients had partial remissions. I’ve never seen sustainable partial remissions in Richter’s before.

If you had a partial remission, the patient would progress. You would not even be able to bring the patient for an allogeneic transplant, but here we have seen for years patients staying on treatment even with PET positive partial remissions, so it means it’s maybe changing the perspective. We might be able for some patients to turn Richter’s into a chronic disease and that really also speaks to the like decades before Richter’s clinical diagnosis, seeing the markers, seeing the development.

Thus, we might maybe by combining targeted agents, maybe some debulking by chemoimmunotherapy be able to turn Richter’s into a treatable disease. And I’m very much looking forward to seeing the next combination trials coming up, also, the ones where it will be triplets both having BTK inhibitors, BCL2 inhibitors, and checkpoint inhibitors in the same treatment regimen.

Yeah, I think that’s all very exciting data with the checkpoint inhibitors. What about also the early data we’ve seen with bispecific CD20xCD3 targeting antibodies?

So unfortunately the first data have been obviously with just monotherapy, and from my perspective I have seen monotherapy as a bridging towards allogeneic transplant. Because for the Richter’s patients have had on those trials and from the reports on the trials, we see like half a year, a year of response. I’m not really convinced that we’ll see durable responses just on monotherapy, but we definitely see an efficacy with the bispecifics, and then we just need to figure out which combination partners we’re going for. I’m quite excited about seeing also the combinations with lenalidomide. Again, taking like the idea to combine a immunotherapy with immune modulator. And that way trying to get maybe not away from chemoimmunotherapy, but only using the chemoimmunotherapy for the debulking part. And I think that speaks very well into like the biological understanding of Richter’s, trying to use that as soon as possible to bring it into the clinical trial design.

We share your enthusiasm for combinations with bispecific antibodies. We recently opened a study of glofitamab at Dana-Farber starting as monotherapy, but with the plan to build in combinations, including with polatuzumab as well as with atezolizumab, the PD-L1 monoclonal antibody. So we’ll see, but it looks promising.

But maybe to that end we really need to figure out how can we make the randomized trials in Richter’s, because it’s so hard to actually get large enough collaborations to have randomized trials. And obviously with all the different, combinations coming up, maybe we would need some kind of like a platform trial, an international platform trial that would best be driven by academic insights.

Since then, taking in the different pharma companies, maybe build on what we’ve seen for Covid, because otherwise we risk having a lot of Phase II trials, but not knowing what would actually be the most efficient treatment for specific subgroups.

Yeah. Totally agree and yeah, a lot, a lot to study in the future. So hopefully outcomes for Richter’s patients will continue to improve as we develop these promising new regimens.

And we’ll definitely need you, Erin, to run all these translational trials on that because that would really like having a lot of biological samples from such trials would help us understand which subgroups would really benefit from which combinations.

Yeah, I think that’s an important thing. I think one of the reasons that our knowledge about Richter’s had lagged behind our knowledge of CLL, had to do a lot with sample acquisition, and so being able to do as we do, these great clinical trials have good biobanking where we can learn in parallel will be important.

Have you thought that that in terms of repeated lymph node biopsies from your patients during targeted treatment for Richter’s? Because I would really love to understand what’s going on in the lymph node of these patients with partial remissions.

Yeah, we have some limited experience with that, but it is challenging to do these serial lymph node biopsies, but it’s definitely a priority to try to understand the biology. Well, I’d like to thank you, Erin and Carsten, great discussion and we look forward to future studies in Richter’s going forward.

Thank you so much. Thanks.