EHA 2023 | Updates in CAR-T and bispecific antibodies for LBCL from EHA 2023

Doctor Iacoboni, It’s a very exciting time for oncologists with an interest in lymphoma. Over the last few weeks, we had the first approval of a bispecific for patients with relapsed refractory large B lymphoma in third line and beyond with epcoritamab, then maybe a second approval later this year. How do you foresee the possibility to intertwine bispecifics with CAR T-cell treatment?

Yeah, thank you Paolo. So I think that’s a very intriguing question. We are also expecting an EMA approval for glofitamab and epcoritamab later this year. But it’s true that at this time point, there is no bispecific antibody which is formally approved for diffuse large B-cell lymphoma in the relapsed/refractory setting.

I think at this time point, given all the robust and mature data we have with car T cell therapy in the third line and now as well in the second line, especially with the overall survival benefit in the Zuma-7 trial for access sell over standard of care. Car T cell therapy remains the go to option in second line if refractory early relapse. And in third line for patients who are, who are candidates, large B-cell lymphoma patients who are candidates for this therapy and bispecific antibodies will still remain the salvage option. A third party cell therapy. However, data is definitely getting more robust and as we get more follow up with bispecific antibody treatment, we may find that some patients could potentially be cured as we’ve seen with CAR T cell therapy. Regarding sequencing, I think that’s a very intriguing question. We have data presented by the French group last year at ASH with identified some patients that received bispecifics before car T cell therapy and it did not seem to impact efficacy or safety. So it seemed to be a safe approach and we have data of CAR-T and then bispecific antibody treatment from the pivotal trials of glofitamab and epcoritamab where we saw a similar rate of progression free survival and and complete response rate. So I think probably in, you know, both orders first bispecifics, first car T cell therapy, it can be an adequate approach. But I think with the more mature data that we have right now with CAR T cell therapy, this should be the go to option and consider bispecific antibodies later on if the patient is not a candidate or has failed car T cell therapy.

Regarding the next topic we wanted to cover if we move into CAR T cell therapy regarding bridging. I think this is a very intriguing question for everyone. How do you handle bridging at your center?

Yeah, that’s a very important question. As you all know in the pivotal trial that brought the approval of axi-cel, Zuma-1 bridging wasn’t allowed beyond use of corticosteroids at low dose. But in real world experience, more than half of the patients do require bridging treatment. And there’s not really currently a standard approach. In the United States there are four agents approved by the FDA in the third line or beyond that could be potentially used as a bridge into CAR-T. One of them targets CD79B like polatuzumab vedotin in combination with BR. Others target CD19 on the same target as axi-cel, tafasitamab and loncastuximab and finally selinexor is an XPO1 inhibitor. In the United States, currently, we don’t prescribe frequently selinexor due to high toxicity profile and limited efficacy. So really the question comes down to when we look into standard treatments, if any of these three will be safe and effective before initiation of car T cell infusion, there’s been recently a European multicenter study UK including 375 patients with relapsed refractory large B cell lymphoma and of interest use of polatuzumab-based regimen as a bridging therapy in a multivariate analysis associated with increased likelihood to achieve a response. So a lot more burden before CAR T-cell infusion, this makes biologically sense. Of course, you want to try to target a different antigen than CD19. Definitely polatuzumab is very easy to use before CAR T-cell, it’s not too myelosuppressive. However, one limitation is that it’s formally approved by the FDA in combination with bendamustine. Definitely Bendamustine is a very lymphodepleting agent. So our practice to usually use Pola in combination with rituximab alone, trying to avoid bendamustine even if their use occurs after leukopheresis. As you mentioned before, there is still an open question whether CD19 targeting agents could be safely and effectively used before CAR T-cell infusion. Limited data are available when it comes loncastuximab. Only 14 patients in the lot proceeded to CAR-T after the use of lonca. And in the 10 patients where CD19 expression was evaluated, the expression was still present, but we need to have larger data sets to make a clear statement that we can use those agents. And finally, when it comes to bispecifics, as you mentioned before, there are some data, they may, they could be safely used. One biological concern is that by using T cell engagers before CAR-T cells, you could exhaust T cells. This is a concern deriving mostly from the B-ALL literature where bispecifics like blinatumomab had been available for a longer time, than large B-cell lymphoma, but it seems to be associated with a continuous infusion. So with intermittent use that we do with either epco or glofi, hopefully we won’t see t cell exhaustion and we may be able in the future. Well, I completely agree. The first use of bispecifics will be in the post-CAR-T setting but potentially to use them as a bridging to CAR-T.

Now, staying on the CAR-T topic, currently, CAR T-cell treatment is a standard treatment both in US and Europe and even in second line. So definitely the amount of patients who receive CAR T-cell treatment is increasing uh exponentially but one big problem that remains particularly for very active CAR T cell product like axi-cel probably due to the CD28 costimulatory domain there is a high rate of neurotoxicity that in real-world that reporting as many as 60% of patients, which is not trivial. What’s your management in the case of ICANS, in patients with large B-cell lymphoma from after CAR-T?

Yeah, that’s a great question. We still use dexamethasone, I mean steroids. Unfortunately, it’s still our first line. I mean, I think it would be interesting to see the trials which are ongoing with prophylactic anakinra and another agent. But I think it’s kind of universal that steroids remains the first line of treatment with dexamethasone. And we’ve moved into more frequent use of Anakinra in the second line. So for patient’s who are not steroid responsive or are steroid dependent and relapse. Upon tapering, our second line will be Anakinra. A manuscript was published recently working from some sites from Spain and, and the group from Seattle, Fred Hutch. But looking at the different doses of anakinra use across different hospitals and it seems that higher dose of anakinra, the one we use 8 mg per kg, IV, seems to be of larger benefit to the patient’s than lower dose is like 100-200 mg per day. So we do start out with these high doses and then taper the Anakinra when the patient is responding. And then I think another interesting topic would be if anakinra and steroids do not work. Unfortunately, there are some cases like this, we would move into intrathecal chemotherapy. We are using this, we’ve used it in approximately 5-6 patients and it has actually worked nicely. I mean, it’s true that you never know. It’s the intrathecal chemotherapy, the Anakinra or the steroids, the patient is receiving, which finally did the trick. But we think I think this is definitely a good option once we rule out with a lumber puncture, that other causes in the differential diagnosis are not there. So this this would kind of, I mean, be our, our management. It’s true that we don’t wait for an overt symptoms for a grade two or three, we start steroids quite early with grade one ICANS. So I think that’s important as onset and the worsening can be rapid and the coordination, of course with the ICU unit is crucial in these patients. Would you see any different management at your site, maybe?

Now, I would say that that’s exactly also our management. We also tend to use, of course as frontline corticosteroids. There’s some conflicting data as to whether using corticosteroids may impact CAR T-cell amplification and function and maybe the dose and duration. So not every corticosteroid will impact outcome after CAR-T but very high dose and very prolonged treatment may. And exactly as you described, for patients who are corticosteroid refractory or dependent will use anakinra. And as you said that for those, even when anakinra doesn’t work. This number is actually increasing. We do try to offer intrathecal methotrexate or set out a bit. Unfortunately, patients can have very low count, you know, severe thrombocytopenia. So in the case, intrathecal treatment may not be an option and that’s where we’re unfortunately are limited to use of systemic treatments. And is there any room for siltuximab? We are not using it the truth a lot, but I’m keen to know your approach to this agent.

So based on preclinical work, published both by MSK and universities in Italy, and Nature Medicine years ago, very clearly, the biological mechanism of neurotoxicity seems to be driven by tumor associated macrophages under induction of car T cells. And to be mainly driven by interleukin one receptor pathway in preclinical models by using anakinra, there was a decrease both in ICANS and CRS, this has not been replicated in clinical practice. But there’s actually some concern that targeting instead the interleukin six pathway may induce a rebound increase in interleukin one and paradoxically worse than neurotoxicity. You know, may not be the same with siltuximab, the slightly different mechanism of action is compared to tocilizumab but currently we don’t, we’re not using in clinical practice anti interleukin six antibodies to minimize neurotoxicity.

That’s, that’s very interesting. Thank you, Paolo. My last question was regarding cytopenias. I mean, this is I think a really hot topic when it comes to CAR-T, it’s going to be the main issue and long term follow up. I think management is quite heterogeneous across sites. So I’d love to know your insights on cytopenias of the car T cell therapy. Yeah, I agree that this is the new hot topic in the car T cell space. As we understand more about the pathophysiology and the management of serious ICANS or CRS, the mechanism of cytopenia remains quite unknown. There are really three types of cytopenia, early cytopenia, most likely due to myelosuppression from lymphodepleting chemo but then late cytopenia starting day 30 or persisting a data or beyond a very late cytopenia beyond day 19. What is interesting is that no matter what product we use, 30% of patient’s 30 days after CAR T-cell infusion will have grade three or higher cytopenia. So, either neutropenia and or thrombocytopenia. For years, we have assumed that this was just a consequence of the use of fludarabine-cyclophosphamide as lymphodepleting chemotherapy strategy. However, that and duration of cytopenia that we see tends to be much higher than what we see. For example, with the use of the same agents like FCR in patients with CLL where you could actually spend even more cytopenia, do two more frequent bone marrow involvement and actually repeated cycles of treatment. Finally, some light has been shed by some translational work. There’s been a publication from Doctor Rejeski and we also recently published our own single cell RNA sequencing data. So, by collecting bone marrow samples, prospectively in patients will large B-cell lymphoma who develop or did not develop prolonged cytopenias after CAR-T by single-cell sequencing, we were able to identify an oligoclonal CD8 positive T cell population that has increased pathway and increased expression on the interferon gamma pathway. We don’t have functional data, but these are just target interferon gamma may translate into resolution of cytopenia. Now, there are agents available like emapalumab, but you know it’s an antibody targeting interferon gamma currently approved in the United States for primary HLH but not for secondary. Of course, neither for CAR-T related cytopenia. So there will be an option, an easier option TPO agonists such as eltrombopag or romiplostim because they also target the interferon gamma pathway. It may sound counter intuitive using a TPO agonist for somebody, let’s say with isolated neutropenia. But translational data suggest that this may work. And actually now there are finally some case series published either with eltrombopag romiplostim showing some resolution of this persistent cytopenia. I think investigating this further is going to really help to resolve a highly met need because these patients maybe here cured for their lymphoma and still have to be managed like patients with myelodysplastic syndromes, with very frequent transfusions or hospitalization for infectious complications. And most importantly, there’s been a recent publication by the Mayo Clinic showing that the main reason why patients will large B-cell lymphoma relapse after Car-T are ineligible for clinical trials that may be potentially life saving So on one side, we need to try to address better this complication and on the other, probably also have to be more flexible when it comes to eligibility for trials after CAR-T. What has been your standard approach for this prolonged cytopenia Doctor Iacoboni?

Yes. So very similar to what you have mentioned. Usually during the first month, we give the patient G-CSF support for neutropenia and transfusion support for the anemia or thrombocytopenia and then after one month, if cytopenias are persistent, we do recommend carrying out a bone marrow aspirate and or biopsy if necessary. …To rule out, as you mentioned, other causes, we have to remember that these patients have not only received car T cell therapy but also previous lines of immunochemotherapy and could have developed a myelodysplastic syndrome. So I think this, this, you know, full work up is very important. If this is ruled out, then we do consider romiplostim or eltrombopag, TPO analogs which we have administered in a few patients. for these patients, we also consider a stem cell boost if it’s available. It’s true. Unfortunately, it’s not available for many patients but some worry for instance, an autograft which never was eventually carried out. So they have these cryopreserved stem cells and this could be, you know, one consideration to take into account for, for some patients who have persistent cytopenias prolonged after one month, post car T cell infusion. The truth is we don’t have experience with other agents. There are other reports and some immunosuppressive agents that could be considered or even dasatinib as an on switch, off switch for Car T. There’s some pre clinical data and case reports with that. But it’s true that I think it becomes quite uncertain after TPO analogs, there are not many, not many agents which have really sufficient evidence to be used in that setting.

And as you mentioned, I think this is a key factor to remember, because it will kind of be key when we’re following that patient, long term follow up after car T cell infusion, the cytopenia kind of mandates how often we have to see the patients, eventually we can see them every month and we have to see them more often and can condition higher risk of infections which many times is the grade five unfortunately adverse event. As we’ve seen in the clinical trials, which can potentially limit the patient’s life and quality of life. So I think infections and underlying side opinions are really, really important in long term follow up of car T cell patient’s.

Thank you for your time. Thank you Paolo for the interview and look forward to seeing you on VJHemOnc.

Thank you, everybody