BSH 2022 | Updates from the lymphoma & CLL session: clinical trials, novel agents, and more

Andrew Davies:

Hi, I’m Andrew Davies from the University of Southampton. And we’re here at the BSH in April 2022 and we’re here with VJHemOnc and Kate Cwynarski from University College Hospital is here with me. So Kate, you chaired this morning, the lymphoma and the CLL session, what came out of that was interesting for you?

Kate Cwynarski:

Well, the first talk was POLARIX, which of course Graham Collins presented. And I was interested particularly that the very impressive PFS and EFS advantage was not mirrored by an overall survival advantage. And I just wonder what you thought of that.

Andrew Davis:

Yeah, I think this is really interesting because we can see a 6.5% improvement in absolute PFS when everybody’s been followed up for two years, but no overall survival advantage. So that’s interesting. I mean we could see that there was less use of second and subsequent line therapies such as autografts and CAR-T in the population that received polatuzumab. And I would’ve thought that would start to have had an impact upon overall survival. And actually all the patients had been followed up for 24 months. So you kind of thought there might be some separation in the curve, but maybe actually because of the effectiveness of second and subsequent lines of therapy, that actually we’re just not there yet. And we perhaps need a bit more time to follow-up this data. I think the heterogeneity in clinical effect is really interesting in this study.

We saw that some subgroups clearly benefited, and some subgroups didn’t. And so we saw that the IPIs who were three to five, had a very clear benefit. Whilst those patients who had IPI scores of two didn’t. The ABC subgroups appeared to benefit, those who didn’t have bulk and those who were older patients. Now what to make of all of that subgroup analysis, I think is going to be really interesting when it goes to the funders. But of course, some key demographics such as being female and being younger were the groups of patients who didn’t benefit. And I don’t know how the funders is going to make anything of this clinical heterogeneity.

Kate Cwynarski:

Yeah. I was going to ask you, do you think it’s robust enough to even know that, as you say, you could deny it to the people who don’t have those characteristics?

Andrew Davies:

Well trying to pull apart subgroup analysis is absolutely full of pitfalls. These are completely underpowered and I think we should limit what conclusions we draw from this data.

Kate Cwynarski:

Yeah. So one of the exciting things for us, we’ve just opened REMoDL-A. And we are delighted to have REM0DL-A open for many reasons. I just wondered if you would just summarize sort of details of the study.

Andrew Davies:

Brilliant. Well, thanks Kate. I mean, the REMoDL-A study is asking the question, if you add acalabrutinib to R-CHOP chemotherapy, can you improve outcomes in previously untreated patients with diffuse large B-cell lymphoma? Because I really believe there’s an important message in the BTK inhibitor story in diffused large B-cell lymphoma. And you may say, well, the PHOENIX study with ibrutinib didn’t really work out for frontline approach. But actually if you look at younger people, we saw that there was a clear EFS advantage and overall survival advantage. The difficulty was the toxicity from the ibrutinib, which compromised the delivery of the R-CHOP chemotherapy, but actually with acalabrutinib as a next generation BTK inhibitor, which has a much tighter kinase selectivity, and much less off target side effects, we hope that we can gain the benefits of the BTK inhibitor without the toxicity and without the need to reduce any doses of R-CHOP. And we’ve seen that in the Phase IB exploratory study of acalabrutinib with R-CHOP chemotherapy that we actually didn’t compromise delivery of chemotherapy if you were older. And the event profile was the same in the older and the younger patient group. So it seems to me a very attractive way of getting the advantages of the BTK inhibitor.

Kate Cwynarski:

So we recruited to FLAIR and in the abstract session this morning, Pete Hillman presented on behalf of Talha Munir, the premature cardiac death in the FLAIR study in patients who were treated with ibrutinib compared to FCR. And I just wondered whether you would reflect on that when we counsel our patients in the REMoDL-A study to be included to enroll into that study?

Andrew Davies:

So I think this is really important. And I think that it is great that FLAIR was such a big data set that you are able to look back and to look for these patterns. I think what’s really important and reflecting on this for REMoDL-A is of course that the exposure to acalabrutinib is much less, but is only a short duration of exposure as it is for DLBCL therapy, compared with the exposure that there is for CLL therapy. And of course because acalabrutinib has this tighter kinase selectivity, we hope that it has much less cardiovascular toxicity, and that’s been demonstrated in a simple head to head randomization between ibrutinib and acalabrutinib in CLL, much less cardiac toxicity. So I think it’s important that we counsel patients, but I think I have less concerns about this in DLBCL.

Kate Cwynarski:

And so just as our session finished this morning, I had notification that one of my patients who I’ve just recruited to REMoDL-A has been randomized to the acalabrutinib arm. Now that’s two to one randomization. And part of the reason is there was sort of much discussion at ASH about CNS prophylaxis. There seems to be very scant evidence that high dose methotrexate or IT’s are effective, but I do know that acalabrutinib and other BTK inhibitors do cross the blood brain barrier. And it’s quite possible that my patients are going to potentially gain in a CNS prophylaxis way if they’re randomized to the acalabrutinib arm, could you share my enthusiasm for that?

Andrew Davies:

Yeah. I think we need to resolve this question and find new ways of reducing CNS risk. We know that acalabrutinib crosses the blood brain barrier and we hope that this is going to be an effective agent potentially at reducing the risk of CNS episodes. I don’t know that doing trials in this group is really difficult.

Kate Cwynarski:

Yeah.

Andrew Davies:

Cause the event rate is very low, but you know, I’m hoping that’s potentially one advantage of using acalabrutinib. So let’s wait and see.

Kate Cwynarski:

I mean, we’re going to open the PRiZM study, the CI is Chris Fox, that’s later this year in primary CNS lymphoma in the relapsed/refractory setting and that’s with zanubrutinib. So certainly there’s data on other BTK inhibitors in primary CNS lymphoma and certainly I’d love access for it in secondary CNS lymphoma. So I’m sort of certainly delighted to discuss REMoDL-A with my patients.

Andrew Davies:

Great. And of course you’ve said at the beginning, it’s a two to one randomization, so great advances in terms of getting experimental arm. So, Kate, whilst we’re just talking about CNS lymphoma, I just wondered if there was anything that was on the horizon in terms of secondary CNS lymphoma after the publication of the MARIETTA study?

Kate Cwynarski:

Yeah. So after the MARIETTA study we’ve had a number of other sort of small studies published. We’re just finishing our last draft of a good practice paper in secondary CNS lymphoma, which I have to say was one of my most challenging because we’ve really sort of come from, there really aren’t many other guidelines in that setting. Certainly we have data on over 125 patients who’ve had an autograft with thiotepa based conditioning and we’re just finishing our review of that data set. And also we are exploring the role of CAR-T cell therapy for our patients with secondary CNS lymphoma, both on the national panel and also in the trial access setting.

Andrew Davies:

So really important data. And I look forward to being able to see that. Kate as always, it’s a great pleasure to be catching up with you. Thanks very much. Enjoy the rest of your meeting.

Kate Cwynarski:

Thank you, Andy. Pleasure shared.