ASH 2022 | Key highlights in NHL: updates in MCL, the role of transplantation, and novel bispecific antibodies

Michael Dickinson:

Hello, I’m Michael Dickinson. I’m a Hematologist from Peter MacCallum Cancer Center in Australia and I’m here at ASH with VJHemOnc.

Tycel Phillips:

And I’m Tycel Phillips, a Lymphoma Physician in the City of Hope in Duarte, California. We’re here with VJHemOnc at the ASH 2022 Hematology meeting.

Michael Dickinson:

And we’re going to give our fresh takes on some of the data that we’ve just seen. We’re still digesting and still thinking about. And I guess we’ll start by just talking a bit about mantle cell lymphoma. So what’s the big hit for you? What do you think?

Tycel Phillips:

So I think the biggest hit, the meeting was a plenary discussion with the Triangle study. There was a well organized study from European countries looking at frontline mantle cell lymphoma. The triangle study designed a three-arm trial looking at R-CHOP with R-HiDAC, followed by autologous stem cell transplantation. There was a standard of care arm and then there was R-CHOP with ibrutinib, high dose Ara-C arm, and then autologous stem cell transplantation. With the second arm they also had ibrutinib maintenance for two years. And then there was a third arm which was R-CHOP, ibrutinib, high dose Ara-C, and then ibrutinib maintenance with an autologous stem cell transplantation.

I think for the last several years, one of the biggest focuses on mantle cell lymphoma was the utility in need for autologous stem cell transplantation. And at least in this study, the standard of care arm, which did not include any ibrutinib maintenance, was deemed to be the inferior of the three arms. And so moving forward, obviously with longer follow up, we’ll look to see if the arm that excluded autologous stem cell transplantation, but included ibrutinib maintenance, will maintain its equivalent PFS and overall survival with the arm that had autologous stem cell transplantation, or if there’s a separation in the curves. Because if there is a separation favoring the arm that has the autologous stem cell transplantation, then again we just added another treatment, being ibrutinib maintenance to what we do already. But if the arms do not separate, then potentially we can move away from autologous stem cell transplantation and some of the risks that come with that treatment in frontline mantle cell lymphoma.

Michael Dickinson:

So this is another study that I guess, is building a case for frontline use of BTK inhibitors to really modify the treatment paradigm. Do you think it’s going to be practice-changing?

Tycel Phillips:

So right now I don’t know if we can necessarily make changes to our practice. I mean, given the approval, if it’s not necessarily in our guidelines, it’s not an FDA-approved indication for the BTK inhibitor. So at this point I think it’s more so cursory that probably we can add BTK inhibitors. Because I do think there was some doubt when the SHINE study came out whether we would be able to get any benefit by adding BTK inhibitors into a frontline study. But in this younger patient population, it appears that there’s some feasibility to that and it may be some added benefit. But I guess, with longer follow up we will see how this will play out.

And then the question comes with, at least within the US, is which BTK inhibitor should move into the frontline study. Because as you know, I mean there’s always the controversy of which BTK inhibitor is the safest for the patients. And with having three options, it gives us more flexibility to try to mix and match. So it’ll be interesting to see how things play out in the next couple of years.

Michael Dickinson:

We don’t have access to BTK inhibitors in the frontline in Australia either. We use them in the second line and beyond. And it’s good also to have that choice now in that setting. Are you still transplanting patients or do patients push back on that idea?

Tycel Phillips:

So we do offer transplant still to some of the patients. I will say for the most part we’ve conducted several clinical trials that have excluded out transplant. But for the standard of care patients, yes, transplant has still been the option that we’ve been referring patients to.

And within the US we’ve also been referring patients to a cooperative group study where they randomize patients who are considered to be minimal residual disease-negative by the adaptive clonoSEQ Assay to transplant versus just maintenance rituximab. So that study has yet to read out. But anybody outside of that, yes, we’ve been still using autologous stem cell transplantation.

Michael Dickinson:

And there’s been some other data that’s come out in the relapsed/refractory setting now with mantle cell lymphoma. Any highlights?

Tycel Phillips:

So we did also present the study looking at glofitamab monotherapy in a relapsed/refractory mantle cell lymphoma patient population. Smaller study compared to what we’ve seen with CAR-T patients. So we have 37 patients, most with advanced-stage disease. But I think the key takeaway that we saw from this is we still had very good overall efficacy in this patient population. And the safety, I think compared to what we see traditionally with CAR-T treatment was very, very encouraging. We have very low rates of grade three to four CRS with pre-treatment with obinutuzumab, either one or two grams. There was some better data with the two grams of obinutuzumab pre-treatment. But we also have very low incidents of ICANS or neurotoxicity. And thus far it appears that the duration of response is durable, but the follow up is still very short. It’s only ten months. So I think we can’t make any firm conclusions of that until we can get more mature data.

Michael Dickinson:

What do you think about for people watching, I’m an investigator on this trial as well, I should reveal. So for me, the response rates were very exciting, particularly because many patients had been exposed to BTK inhibitors before.

Tycel Phillips:

So two thirds of the patients had BTK inhibitor exposure. Ideally, our study, as you know, wasn’t necessarily designed to dig in deep into the mantle cell patient characteristics that we normally would do in a mantle cell derived study. But very, very, very encouraging because again, in the post BTK setting, we don’t necessarily have a lot of fundamentally sound data about other agents that can give us very durable responses. So quite curious to see how things play out.

And speaking of glofitamab, I mean ideally there was a very nice presentation by Martin Hutchings looking at that in large cell lymphomas. What do you think about that data and how it compares to some of the other bispecifics on the market?

Michael Dickinson:

Well, so I’m an investigator on the glofitamab study and the pivotal data have just been published just in the last 24 hours while we’ve been here at ASH ’22, in the New England Journal, which we are excited to have out there. And what was presented here at ASH was really a re-analysis of that pivotal data, asking the question, whether patients would retain complete remission.

So obviously we were focusing on a subset of patients. We really focused down on those patients where complete remission had been achieved. Because here a topical question is, should bispecifics, this new class of agents, be given continuously in patients with aggressive B-cell lymphomas or is having a fixed course therapy a defensible approach? And so we wanted to zoom in on whether patients relapsed after finishing their fixed course treatment.

So glofitamab’s given for 12 three-weekly cycles as an intravenous infusion and there’s this desire for pretreatment as you’ve already highlighted. And so it’s a fixed course and patients just stop. And in that it’s different from epcoritamab, which is given indefinitely, and odronextamab, where we’ve seen some further data at this meeting. And these different companies have taken different approaches to dosing and scheduling in diffuse large B-cell lymphoma.

What Martin showed in his presentation is that relapse in patients who are in a complete remission at the landmark of end of treatment, patients who are in that complete remission, relapse is very, very rare. And so that it is defensible then to stop treatment. And I think that was an exciting finding. Obviously we’re looking at the best of the best. It wasn’t replacement or really even an update of the pivotal data. It was about asking that question, what can we say to patients who are in a complete remission who are perhaps coming to their 12th cycle and going to stop treatment? Is it safe? And I think that data set was quite reassuring.

Tycel Phillips:

No, I agree. I think it was very, very encouraging in that situation to have that time period of patients off treatment. And I guess, another good question for you, long-term follow up and how that plays out. I mean, given some of the logistical issues we’ve all experienced with CAR-T, it gives another good option for some of these patients. How do you see that if this data is very mature and plays out, how that forks in that plan with the sequencing of the CAR T treatment?

Michael Dickinson:

Well, so I think this is going to be something that is different in different regions around the world. And it will be different for different treatment settings, I think. I think one of the great appeals of the bispecific agents is their off-the-shelf availability. We see complete remission rates that are within the range of what can be achieved with CAR T-cell treatment in the third line. And importantly, the bispecifics are showing activity in patients who’ve received CAR T-cell products before.

And so I think, very neatly, I think very confidently we can say bispecifics can be given to patients who’ve had CAR T-cells before, which is perhaps the current situation where third-line CAR T-cells are available. And in some regions second line CAR T-cells are available so bispecifics could confidently be used after that I think, pending future approvals.

And then, I think there will be some regions in the world where it is just easier to reach for a bispecific than a CAR T-cell therapy for reasons of reimbursement status and those sorts of things. And it’s hard and I think it’s hard to access CAR-T in every setting and I think bispecifics will slip in there, potentially in the third line in some regions before CAR T-cell therapy.

And I guess it remains to be seen whether there’ll be a role for bispecifics in combination. We’ve just seen data from several companies about the combination of bispecifics with frontline chemotherapy regimens.

Tycel Phillips:

I wholeheartedly agree. I think the combinability of bispecifics makes it an attractive agent and I think moving forward we probably will see it littered in multiple lines of therapy for all our patients.

Michael Dickinson:

It feels like a new era for patients with aggressive B-cell lymphomas, which I think’s great.

Tycel Phillips:

Wholeheartedly agree.