Novel and emerging strategies for diffuse large B-cell lymphoma (DLBCL)

DR SALLES: Hello, I’m pleased to review with you today the novel and emerging strategies for diffuse large B-cell lymphoma. Recently, several agents were approved by FDA and other health authorities, such as polatuzumab vedotin, selinexor, and tafasitamab, not forgetting the recent approval also of 2 CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel.

This is an evolving field in diffuse large B-cell lymphoma, and we have also a couple of agents that are currently in development with exciting results, such as bispecific antibodies targeting CD3 and CD20, mosunetuzumab being one of them. Others are also on this landscape. Loncastuximab and magrolimab.

So we’ll first review the recently approved agents and discuss some of the data with the agents in development.

Available efficacy and safety data with the antibody-drug conjugate polatuzumab vedotin for DLBCL

DR SALLES: As mentioned, polatuzumab vedotin was approved for relapsed/refractory DLBCL in combination with bendamustine/rituximab. As a background, this is antibody-drug conjugate that linked microtubule inhibitor MMAE to an antibody that recognizes CD79b, which is an antigen expressed in the vast majority of malignant B cells. Like with other ADCs, after binding to the tumor cell the antibodies process into the cell and protease-cleavable peptide is cleaved, and the toxin is delivered into the cell and kills the cell. As a single agent or in combination with rituximab, polatuzumab has demonstrated an interesting activity leading to some combinations.

The study I’m going to discuss was published by Dr Sehn in JCO last year. It’s a randomized study that examines the combination of polatuzumab vedotin with bendamustine/rituximab versus bendamustine/rituximab alone. There was a safety run-in and expansion, but we are going to focus on strict head-to-head comparison of bendamustine/rituximab, shown here, versus pola/bendamustine/rituximab. So primary endpoint was complete response rate, assessed using PET evaluation with Lugano criteria.

As you can see, and when we look at these primary endpoints, there was a marked difference and significant difference regarding both the overall response rate, but also the CR rate, that reached 40% in those patients that received polatuzumab plus BR versus only 18% on those treated with BR. At the time of the cutoff about 7 patients had an ongoing response, and this is reflected on this progression-free survival curve, showing a significant advantage for the patients that received polatuzumab vedotin in combination with BR. As well, and this was more as a surprise, an advantage in terms of overall survival.

Remember these are diffuse large B-cell lymphoma, heavily pretreated, usually means a second or third line of therapy. The median age was over 65. And you can see that those patients that received BR only had a median survival that was less than 5 months, while those that received the triple combination had a median survival of more than 1 year, a significant benefit. And based on this data this drug was approved in this setting.

The drug was also evaluated in the first-line setting for patients with DLBCL in combination with R-CHOP, actually not exactly R-CHOP, because vincristine was omitted to avoid overlapping toxicities of vincristine and polatuzumab vedotin. In fact, we do know that polatuzumab vedotin, like other ADCs with the same kind of toxin, may generate some neurotoxicity.

This trial that led to the administration of 6 to 8 cycles of R-CHP/pola to patients has the results described here, published in Lancet Oncology recently, with 77% of the patient achieving a complete response plus 12% achieving a partial response we make it to 89% of the patients responding. And as you can see, this was very encouraging PFS results, with a 2-year PFS result of 83%, while the trial enrolled also patients with Stage III/IV disease or high IPI, who responded well to this therapy.

On the basis of these results a large international study was launched comparing rituximab-CHOP versus rituximab-CHP plus polatuzumab and CHP/pola versus R-CHOP in randomized patients. These are 875 patients, as described here, with an IPI of 225, previously untreated. And this is an international study with many countries participating: United States, France, and other countries worldwide. And the enrollment has been completed, and we expect that we will see these results in 2021.

The primary objective of this study is actually to evaluate the safety and efficacy of pola-CHP versus R-CHOP in those patients previously untreated. And secondary endpoint includes CR rate, event-free survival rate, as well as safety. And there will be a couple of interesting ancillary analyses within this study.

DR LOVE: What’s the single-agent response rate with polatuzumab? And what kind of tolerability/toxicity issues are known to be associated with the drug?

DR SALLES: So as a single agent, the response rate of polatuzumab is in the range of 40% to 60%. This was a Phase I study that was published. Slightly increased when it’s compared to rituximab, but this was a marginal increase. And this was patients that received the drug for sometimes several months. The main toxicities are either hematologic, with some Grade 3/4 neutropenia, a few thrombocytopenias, a few infections, but very few febrile neutropenias, and neurological toxicity with peripheral neuropathy/sensitive neuropathy of usually Grade 1 and 2, and that is usually reversible. But I would say that the toxicities that we encountered when combined with bendamustine are in the same range, a little bit more hematological toxicity, but the neurological toxicity was moderate not enhancing over Grade 2, and reversible in some patients.

DR LOVE: What do you think you would have seen if you compared single-agent polatuzumab to polatuzumab plus bendamustine?

DR SALLES: I think that’s a very interesting question. I think if we had compared bendamustine/rituximab versus polatuzumab/rituximab we may have had very similar results. I’m not quite convinced that bendamustine adds a lot in this regimen. It may add a little bit of toxicity, slight efficacy, but as you can see from the results in terms of response rate of PFS bendamustine/rituximab as a regimen for salvaging DLBCL leads to rather palliative effect, with less than 1 of the 5 patients responding and median PFS in the range of 4 months.

Mechanism of action of selinexor, the novel selective inhibitor of nuclear export; key efficacy and safety findings from the pivotal Phase II SADAL trial of selinexor for relapsed/refractory (R/R) DLBCL

DR LOVE: So let’s hear about selinexor.

DR SALLES: So let’s move to selinexor, We do know that in cells there is a mechanism which is the ability of the cell to export protein from the nucleus. This is governed by a protein called exportin 1, abbreviated XPO1, and it’s overexpressed in most of malignant lymphoma, including diffuse large B-cell lymphoma.

It’s sometimes mutated, although it’s unclear what is the potential advantage given by mutation.

Selinexor is a first-selective inhibitor of this nuclear export protein, and it inhibits XPO1, and it forces retention of both tumor suppressor proteins and other proteins that are important for tumorigenesis. For instance, when you expose a cell to selinexor you reduce the level of MYC, BCL2, BCL2, you block NF-kB activation, so you control a couple of mechanisms within the cells.

The drug was developed in Phase I and II studies in patients with diffuse large B-cell lymphoma and multiple myeloma, where it has been approved. And the approval of the single agent in patients with diffuse large B-cell lymphoma was based on the results of this Phase II SADAL study. As you can see here on this table, the overall response rate with the single agent was 28%, not markedly different for patients with the GCB subtype or non-GCB subtype. Out of this 28% of patients there were 12% that achieved a complete response and 17% a partial response.

The median progression-free survival was short, only 2.6 months, but the median overall survival for the whole patient cohort was 9 months. And in fact, if we looked at responding patients, the median overall survival was not reached. And even for patients with stable disease the median overall survival was about 1 year and a half. So there is apparently control of the disease that can be prolonged in some patients, even if they don’t reach a complete response.

However, there are a couple of side effects with this drug, and the most common Grade 3/4 AEs consistent of cytopenia, either thrombocytopenia in 1 out of 2 patients, neutropenia in 1 out of 4 patients, and anemia, as well as fatigue, hyponatremia, and nausea, and substantial numbers of Grade 2 side effect in the GI tract. So when you start to treat patients with this oral agent, which is given in the schedule of twice a week, 60 mg 2 days a week, you have to envision to immediately install supportive measures for the patient. Regarding cytopenias, you can correct the cytopenia with growth factor or transfusion, and you may have to dose reduce the administration of the drug to a lower dose, 40 mg twice a week, or eventually 60 mg only once a week.

You may have to fight against anorexia and weight loss, and it has been recently shown that olanzapine can have favorable effect for these patients. And obviously you need to administer to patients agents against nausea and vomiting such as 5HT3 antagonists, NK1 receptors. You may also improve tolerability with steroids or sodium intake.

So it’s not a drug very easy to administer to patients, but as you can see limited number of patients, but a substantial can benefit in terms of disease control, response, and prolonging overall survival. It has been approved as a third-line regimen for these patients.

DR LOVE: Could you talk a little bit more about the mechanism of action? And does this have anything to do with p53?

DR SALLES: Yeah, the mechanism of action is really blocking 1 of the essential mechanisms that is used in the cell. As we know, the RNA is transcribed in the nucleus, but also outside, but a couple of proteins traffic between the cytoplasm and the nucleus. And this exportin controls this export. And when you block that there are a couple of proteins that maintain segregated within the nucleus. p53 traffic within the cell is also influenced by exportin, and it’s also blocked by selinexor. So we rather think that all the proteins, such as Myc and other transcription factors are the key targets of selinexor.

DR LOVE: So of course we’ve been hearing about selinexor in myeloma, and initially there were a lot of concerns, and oncologists in practice were saying it’s very hard to use, just as you were talking about, the GI problems. And then more recently I’ve been starting to hear that now they’re kind of like seeing it better tolerated, particularly when they give it once a week, I think with bortezomib. I’m just curious about your own experience and whether or not by,

I see here that they go once a week after a while. Does that make a difference?

DR SALLES: This is clearly a drug that is not easy to manage, and the side effects are sometimes very severe for patients. We have weight loss. We have anorexia. So you have to take preventive measures. The advantage of olanzapine is that some of the side effects are probably linked to the fact that selinexor actually crosses the blood-brain barrier and has some central effect. And using olanzapine may prevent some of this effect. So you have to add that. And my personal experience has been limited in this trial.

I should say that one of the patients that I treated had really to stop after 6 to 8 weeks. But I have met colleagues that have treated patients for more than 1 year with dose adaptation, with these preventive measures, clearly indicating that there might be a small proportion of patients that have a long-term benefit of this drug. And because after chemo, after immune therapies and all the other agents we are going to discuss, sometimes are blocked. It’s good to have this agent. Obviously there is also some future developments of these agents in combination with either some chemotherapy or immunotherapy regimen that are currently being explored.

Emerging data with tafasitamab and biologic rationale for combining it with lenalidomide for DLBCL; benefits and risks of tafasitamab/lenalidomide for patients with R/R DLBCL

DR LOVE: Let’s talk about tafasitamab.

DR SALLES: So tafasitamab is an antibody directed against CD19. CD19 is an antigen expressed in most B cells, the vast majority of normal and malignant B cells. This is an antibody that has been modified in its Fc-constant portion to increase the immune involvement of NK cells, macrophages, and T cells to kill B cells. There might be some direct effect of cytotoxicity, but the majority of these in vitro effects that are observed enhance antibody-dependent cytotoxicity or enhance antibody-dependent phagocytosis.

Based on this mechanism of action and on the early results of the administration of this drug as a single agent that demonstrated some good signals in patients with DLBCL and follicular lymphoma, a combination rationale was developed, which is to combine this antibody plus lenalidomide. We do know that lenalidomide has a direct cytotoxicity effect on tumor cells, but that it increases the number of NK cells. It activates NK cells and has other effects on the microenvironment.

So there was a rationale to combine lenalidomide plus tafasitamab in order to improve the efficacy of this combination. The clinical trial that assessed this combination was called L-MIND. It’s a clinical trial that was developed in patients with relapsed or refractory DLBCL. The median age of the patients was 70 years, and a couple of patients had advanced-stage disease.

The primary endpoint was actually the overall response rate. And what was seen in this trial was that the overall response rate in this population was 60%, with 42.5% of the patients achieving a CR. This result was confirmed in the vast majority of patients using PET evaluation which was not mandatory in the study. But very interestingly what was also seen was that the median PFS achieved with this combination was of 12 months. This is a noncytotoxic combination, and despite the frequent administration of tafasitamab at the initial loading phase of this combination, this is quite well tolerated.

But also quite surprisingly and markedly interesting was the duration of response that was seen in those 40% of patients that achieve a complete response.

As depicted on this curve, you can see that at 2 years the vast majority of the patients that actually had achieved a CR were maintaining this response, where the patients in PR had relapsed in a few months. This led to an overall survival that is depicted here, and the median overall survival recently updated at 2 years.

If we look at the baseline characteristics of the patients and the efficacy of the drug, you can see that the drug was efficient across different types of patients, maybe more efficient in patients with low-intermediate risk on the International Prognostic Index and maybe less efficient in those with high IPI, despite the fact that this was 50% of those that responded. But whether the patients were refractory to the previous regimen or not didn’t influence the response rate, and we have the same number of patients that responded at 12 months. This was also true given the number of lines of therapy. There were slightly more patients responding and maintaining response that were on the non-GCB subtype of DLBCL, although this was not significant.

If we look at the side effects by the treatment phase,

During 1 year there was a combination of the antibody plus lenalidomide initiated at 25 mg per day during 21 days out of 28, and tafasitamab administered every 2 weeks after the first cycle. But after 1 year lenalidomide was dropped, and patients that responded or benefitted from therapy were continuing on tafasitamab alone given every 2 weeks.

As you can see, for those patients that received the combination of tafasitamab/lenalidomide there was a substantial proportion of patients, about half of them, with Grade 3 or 4 neutropenia, and there were a few patients also with thrombocytopenia or anemia. Those were easily corrected with growth factor. The other side effects were essentially of Grade 1 and 2 were reminiscent of those that we see with lenalidomide, including a few patients that had Grade 3 rashes, something we know with lenalidomide, or other symptoms. There were less than 10% of the patients that experience febrile neutropenia.

This was during the combination phase, but when tafasitamab was continuing as a single agent in patients that responded after 1 year you can see that the number of patients experiencing side effects was markedly diminished. A few patients, about 15%, experiencing neutropenia, Grade 1 to 2 diarrhea, or other minor side effects.

So based on these results the L-MIND regimen, the combination of tafasitamab plus len for 1 year, continued with tafa alone, was approved for FDA for patients in first or second relapse with DLBCL. Other combinations are currently being evaluated, such as the combination of tafasitamab plus bendamustine or the combination in the first-line treatment of DLBCL with rituximab-CHOP.

DR LOVE: Could I just ask how we know whether tafasitamab is adding anything to lenalidomide alone?

DR SALLES: Yes. If we compare the results of tafasitamab/lenalidomide compared to lenalidomide alone, obviously numerically these are different numbers. But the company did actually a study where they retrieved data from the real world observed with lenalidomide given in the community despite the fact that this was not yet approved in this indication. And based on this study, which is called REMIND, there was a significant difference in terms of overall response rate or complete response rate. If I recall well, the overall response rate was in the range of 25% to 30% for lenalidomide alone versus, as I mentioned, 60% for the combination. And the complete response rate was only 12% versus here 40%. And the progression-free survival, with limitation of this nonrandomized comparison, but still was clearly markedly improved with the combination. And actually the REMIND study for the control arm of lenalidomide alone reproduced the early results achieved by lenalidomide as a single agent in DLBCL.

DR LOVE: And I kind of think like somewhere I’ve seen something where rituximab’s been added, like R-squared/tafasitamab. Is that being done?

DR SALLES: So we do know 2 things. First of all, in diffuse large B-cell lymphoma the combination of rituximab and lenalidomide has been also evaluated, has never been published in large series. But there is also a signal of efficacy, although again, reported data with this combination shows lower response rate, I will say, from R-squared as compared to tafa/len in DLBCL.

Given these results what has been evaluated now in another study is the combination of R-squared plus tafasitamab in patients with follicular lymphoma, because R-squared has been approved in patients with follicular lymphoma.

DR LOVE: Yeah. That makes sense. There’s another question about this drug. It kind of reminds me, again, myeloma, where you have an antibody-drug conjugate, belantamab

Of course you have CAR T anti-BCMA strategy, and people are asking there can you do one after the other. What about here? Do we know whether or not you can use CAR T after this, and it still has the same impact?

DR SALLES: So this is an important question. Tafasitamab and CAR T target the same antigen, which is CD19. We don’t know exactly what is the best sequence of these 2 agents. So far, it hasn’t been reported a loss of antigen after tafasitamab exposure in malignant B-cell, whether it’s CLL in the early studies or diffuse large B-cell or follicular. But the data are scarce, only a handful of patients, and we need to continue to evaluate that. However, we do know that after CAR T there may be relapse of patients that have lost CD19 expression, and they may not be a candidate for tafasitamab alone.

But I think the question whether prior exposure to tafasitamab will diminish or not the activity of CAR T is not fully solved. There are theoretical arguments for that, but so far it hasn’t been observed. But we’re obviously at the beginning of the development of this drug, and we should look further into this. It’s probably safe to say that having an interval washout period between tafasitamab and CAR T will keep patients on the safe side. And given the length of manufacturing of CAR Ts, 2, 3, 4 weeks, I think it’s a good idea not to use tafasitamab during that time.

Role of chimeric antigen receptor (CAR) T-cell therapies in the management of DLBCL

DR LOVE: Let’s talk about CAR T now.

DR SALLES: So before we discuss other new agents that are being developed I will just say a few words on the CAR T field. As you know, there have been 2 drugs that have been approved, 2 compounds, axi-cel (axicabtagene ciloleucel called axi-cel) and tisagenlecleucel (called tisa-cel). They differ in their factors, in the costimulatory domain that provides a signal to proliferate the B cells. And as you can see from this graph there were also differences in overall response rate, or CR rate, in the trials, although there were differences in the trials. A third drug is currently in development. It’s liso-cel, and we hope to see this drug approved in the near future.

And as you can see, the results are in line with the results observed with the previous drugs, although it’s possible that this later drug is associated with less Grade 3/4 cytokine release syndrome, the cytokine storm that occur after CAR T-cell administration, and less neurotoxicity than the number of neurotoxic events observed with axi-cel. Although again, it’s not a head-to-head comparison, and this has to be taken with caution.

Having said that, it was interesting to see last year published the use of axicabtagene ciloleucel in the real world, and a large consortium assembled more than 300 patients. And what was interesting and published in JCO recently, was the fact that the results from clinical trials were reproducible both in terms of safety, with the number of Grade 3/4 neurotoxicity being in the range of 30%, and 3/4 CRS being in the range of 15% to 20%. But also the response rate and at the preliminary, the PFS.

But this study also showed, unfortunately, that we do see that patients that have a performance status higher than 2, or patients with elevated LDH, do not have the same substantial benefit as compared to the patients with a good performance status or with normal LDH, clearly mentioning ways to either improve upon the existing CAR T cell or combining CAR T cell with other agents, and also the need to continue the development of new agents in the field.

DR LOVE: What do we know right now about the comparative efficacy and toxicity of these 3 products? There was a presentation at ASH that used some kind of indirect comparison, and it kind of seemed like they came to the conclusion that liso-cel had maybe a better safety and comparable efficacy versus axi-cel and versus tis. What are your thoughts about that work, and also in general your impression about whether or not you can differentiate these 3 products yet?

DR SALLES: Yes. There haven’t been head-to-head comparison, but we started to collect data from registries regarding the efficacy of the commercial CAR T and can compare then to the results of liso-cel. It seems that the response rate and CR rate with axi-cel appears to be slightly higher in younger patients maybe with aggressive disease, and that is usually the choice of centers when these patients are young and have aggressive disease. But it’s also apparent that axi-cel has a little bit more toxicity, such as CRS of Grade 3/4, and neurotoxicity. So when we are dealing with patients that are older than 60 or 70, where we may be worried about these side effects, particularly the neurological events, several investigators and centers may prefer to use tisa-cel in the current setting.

If we look at liso-cel, as mentioned, it seems that this is probably the easiest to administer CAR T right now. It has been given in some trials on an outpatient basis, and it has been developed also in non-academic centers. So the clinical results in terms of efficacy are clearly aligned with those of axi-cel, and maybe a little bit better, but again, no head-to-head comparison as compared to tisa-cel. But clearly the safety is improved compared to axi-cel. Actually in real life the data of tisagenlecleucel in terms of safety tends to be closer to the one of liso-cel than the one to axi-cel. So we will have 3 products, and we’ll see better evaluation of efficacy and safety in the future.

DR LOVE: Another important variable in this situation is how long it takes to prepare the product. Again, how would you compare the 3 in terms of time for preparation?

DR SALLES: The time to preparation of CAR T-cell is clearly an issue, and the production of axi-cel has been emphasized to be rapid, less than 3 weeks in some cases, while the production of tisagenlecleucel usually took 4 to 5 weeks, and liso-cel may sit somewhere in the middle. I think it’s important because we do treat patients with aggressive disease, and in need of a rapid intervention. This led a couple of investigators to choose some bridging therapy. We don’t know if bridging therapy may or may not affect the efficacy of CAR T.

But it’s true also that we need the time for approval with insurance and time from leukapheresis. So overall when you see a patient that is a good indication for CAR T you will be usually having to maintain the patient for 4 to 6 weeks before he receives the drug in real life.

Therapeutic algorithm for patients with DLBCL

DR LOVE: So let’s talk about this algorithm you have. This looks really interesting.

DR SALLES: Well in this algorithm what I have tried to represent is the pathway of patients with relapsed or refractory DLBCL, just mentioning that we have to keep in mind that while we cure 60% of the patients with R-CHOP a few patients, 10% to 15%, are refractory, 20% to 30% relapse. If we consider this population of patients of relapsed/refractory DLBCL we do know that about half of the patients may be eligible for autologous stem cell transplant based on age and comorbidities.

But unfortunately only 50% of them will finally make it to transplant because they respond to salvage, and about 40% to 50% of those are finally cured because we do observe relapse after transplant. So overall about a quarter or a third of the patients that are transplant eligible are cured by transplant. And if we cumulate the number of patients that are not eligible to transplant, that do not respond to salvage, that relapse after transplant, about 30% of the patients that are in this group that needs additional therapy.

So what are these therapies? We used to have chemoimmunotherapy, which was essentially palliative in these patients, and we have got a couple of agents that are now approved, even second line, such as tafasitamab/lenalidomide, or currently in third line such as CAR T-cell, pola/BR, or selinexor. And we know that CAR T cells are currently compared to autologous stem cell transplant in 3 large, randomized trials and may move, in the near future, in second line if these trials are positive, and that sometimes you can get approval for polatuzumab early in line. But this is clearly, in 3, 4 years, major enrichment of the ability to treat patients that have relapse with DLBCL and that are not eligible or have failed the transplant path.

And in addition to that, what we will discuss, are a couple of investigational agents that are currently being developed.

DR LOVE: I’m just kind of curious. I know there are trials comparing CAR T to transplant, any thoughts? Any predictions about what they’re going to show?

DR SALLES: I think the comparison of CAR T versus transplant is very important.

What we do know is that, and this has been confirmed now, is that the patients that achieve a CR with CAR T clearly benefit from CAR T on the longer way, and patients that achieve a CR, 70% to 80% are still alive after 3 to 4 years. This is data of ZUMA-1 and the early trials.

Unfortunately, if we take the whole number of patients that have received CAR T, it’s only about 40% of them that are on this curve because of failure in about more than half of the patients. So how does it compare to autotransplant I think we will learn in the near future, I hope.

What I should say is that despite the side effects associated with CAR T, such as CRS and neurotoxicity, I think overall it’s a treatment that is well tolerated, and patients recover quality of life and performance status faster than after autologous stem cell transplant. So I think there may be a tradeoff here, and we’ll see whether it really improves the outcome of patients. We hope so, but we have to wait until we see the results of the trials.

DR LOVE: I think maybe it was an initial impression that CAR T was at least as difficult on a patient as transplant. But I think as time has gone on at least my impression has been that CAR T may be less difficult than transplant and that maybe you could use it in older, more frail patients than transplant.

DR SALLES: That’s for sure. Initially because we were impressed by the CRS and the neurotoxicity we felt that only young, fit patients can receive CAR T, but we gained more and more experience showing that we can treat patients that we found not eligible for autologous stem cell transplant because autologous stem cell transplant has these particular toxicities, which are organ toxicities linked to the administration of high dose of chemotherapy and also a time of neutropenia, profound neutropenia, which is at least 10 days or more. Here we do have cytopenias with CAR T, but usually less frequent, less prolonged. We have also infections, but usually less severe. And clearly we can administer CAR T to patients that are up to 80, 85 years of age in many centers, obviously selected patients, but patients of this age can tolerate CAR T that you may not envision them to tolerate autologous stem cell transplant.

Biologic rationale for the investigation of the novel bispecific antibody mosunetuzumab; activity and tolerability of mosunetuzumab in DLBCL

DR LOVE: So let’s continue.

DR SALLES: So this brings us to the field of investigational agents, and I will discuss a few of them. The first one which I will discuss is a bispecific antibody, mosunetuzumab, which basically is an antibody that has 2 binding sites. One of these binding sites is CD3 on the T cells, and the other one is binding site to CD20 on malignant B cells. So when the antibody is infused it basically brings the T-cell in the vicinity of the malignant B-cell, and it increases the activation of T cells leading to increase in cytotoxic potential.

There are several of these antibodies in development, and mosunetuzumab, as I discussed, is one of them. And what I will discuss here are the results presented by Dr Steve Schuster at ASH in 2019. Mosunetuzumab, when examined in patients with aggressive diffuse large B-cell lymphoma, as you can see, was associated with an overall response rate of 37% and a CR rate of 20%. So this response was observed at different doses, so they were more frequent in patients that received a dose higher than 2.8 mg and up to 40 mg. There hasn’t been right now, at least published, a maximum-tolerated dose, and the Phase I trial with typical dosing has been continued for some time, and we are looking to final results of this trial in the near future. But clearly these were encouraging results, and these were shown and reproduced by other antibodies.

What was also interesting in this study is that response rates were seen also in patients that were refractory to previous exposure to anti-CD20 antibodies and also patients that had failed autologous stem cell transplant, and even more surprising in a few patients that had failed CAR T-cell. And in this graph we have a few patients that have been treated with CAR T, that failed CAR T, but the administration of bispecific antibodies have really either restored the activity of CAR T or brought these patients from a partial response to a complete response, or rescued some patients.

As I mentioned, this is the first of these bispecific antibodies, and recently during the meeting of the American Society of Hematology, in December 2020, we have seen updated results from a few of these antibodies that are presented here, mosunetuzumab, odronextamab, glofitamab, and epcoritamab. They may differ in the structure, in the number of recognition domains for CD20 antigens. So these are not head-to-head comparisons, and you can see that mosunetuzumab is the one with the largest experience, and 20 to 30 patients treated with the other antibodies.

But if we look overall at these results, we do see that the overall response rate is in the range of 40% to 70%, and the complete response rate in the range from 20% to 50%, making it a very encouraging drug in this field. Also because you don’t have the waiting time like we have with CAR T. While preliminary results indicate that some of these responses are prolonged to 1, 2 years, we are still missing long-term follow up of these results to know whether patients that have achieved a complete response with this drug have a prolonged maintained complete response, and whether this result will compare to CAR T in terms of median or long-term efficacy.

DR LOVE: So a couple of follow up questions about these bispecifics. First of all, to what extent — and I think about blinatumomab, I know it’s not exactly the same, but this is a bispecific, what do we see in terms of CRS and neurotoxicity? Do you see that with these bispecifics?

DR SALLES: Yes. The CD3/CD20 bispecifics all have in common to illicit some cytokine release syndrome in some patients. We call that cytokine release syndrome, we should remember, when rituximab, the anti-CD20 antibody was developed we had infusion-related reactions also. And this happened also with obinutuzumab. But let’s put it like that. A few patients may have fever, may have low blood pressure. And in a very small number of patients there was more CRS that was observed, with organ failure and so on.

This led to the different companies and the development of these drugs, to adapt some step-up dosing, with the first dose which was comprising a limited amount of the drug, wait a few days, 8 days, 15 days, until a higher dose was administered. For some drugs there was a requirement of having patients staying overnight with the first administration or with the second administration. Another schedule that first proposed was to administer obinutuzumab before the bispecific antibody to limit the number of circulating B cells and blunt the CRS effect.

So there are a couple of effects, and right now although there is better management of these Grade 1/2 side effects, there is probably a need for a majority of patients to stay overnight after their first administration, although the companies are working to try to avoid that by preventive measures, by administration of steroids for some of them, or offering patients to go slowly into the administration of these drugs.

In terms of neurotoxicity, I’m not convinced that what we see is comparable with CAR T-cell. We see a few patients having headache or having a little bit of confusion. Whether it’s really a neurotoxic event or just the fact that the patient had had fever or other side effects. I think I’m not sure, and we haven’t seen anything like seizures or severe side effects that we have seen with some of the CAR T-cell initial trials.

DR LOVE: It’s interesting you bring up the issue of infusion reactions to rituximab and obinutuzumab. I never really thought about it, but do visualize those as cytokine release?

DR SALLES: Yes. In fact there are cytokine release, and this was published at the early onset of these drugs, that immediately after the administration of rituximab there is an activation of the complement pathway. There is a liberation of TNF and IL-6 and so on. So it’s still a cytokine story. It’s just that with CAR T-cell we call that cytokine release syndrome, but in fact it’s a, I would say related, side effect of T-cell activation in the peripheral blood on the site of tumors.

DR LOVE: One of the issues with blinatumomab is it requires 24-hour infusions. What about these products?

DR SALLES: These products are full-length antibody administered over several hours and only 1 infusion every week, every 2 weeks, or every 3 weeks, depending on the schedule, the step-up dosing. But there is no requirement of long-term infusions, and we haven’t seen with these CD3/CD20s the neurological events that we have seen with blinatumomab, which is probably leading to the targeting of the CD19 antigen.

DR LOVE: What do we know at this point about duration of response?

DR SALLES: As mentioned, the results with bispecific antibodies are preliminary. We do know that some patients that have had a CR, had a prolonged CR for 1 to 2 years. But I think we are missing solid data in this field, and we need to have longer follow up to really determine if the responding patients and endure a prolonged response comparable as those that we see for patients treated with CAR T cells.

When we look, however, at patients with follicular lymphoma, I should say that the patients treated with some of these compounds, now we have 12, 18, or 24 months of follow up, seems to have kind of prolonged response. So it’s encouraging for follicular, and we will see whether it stands for diffuse large B.

DR LOVE: Interesting.

Efficacy of the antibody-drug conjugate loncastuximab tesirine and the anti-CD47 antibody magrolimab; role of venetoclax-based therapy for DLBCL

DR LOVE: Why don’t we continue?

DR SALLES: So on this table I just present a few drugs that are either recently approved or in development. I mentioned, and we already discussed, CD19 tafasitamab in combination with lenalidomide. I will discuss a new antibody-drug conjugate, which is loncastuximab. We discussed the results of polatuzumab vedotin. We discussed the bispecific antibodies. Venetoclax has brought some hope in diffuse large B-cell lymphoma, but unfortunately as a single agent the overall response rate and CR rate were limited. And we do know that selinexor has been approved. We discussed it. But the checkpoint inhibitors by themselves have very limited efficacy. Magrolimab has been developed, and we will discuss some results for this drug.

DR LOVE: Could you comment a little bit about venetoclax and whether biologically there’s a reason — I don’t know sometimes you see studies of BCL2 levels, et cetera, to think that it would work in this disease? And also I’ve seen early trials combining it like with R/chemo. What do you think about that?

DR SALLES: Well venetoclax is an attractive drug in the field of lymphoid malignancies because we know that many of these malignancies express BCL2. However, while they may express a protein some of them may not be dependent anymore on the expression of these antiapoptotic proteins. So inhibiting BCL2 may not be sufficient to provoke the death of the tumor cell. So it has thought because this was shown in an experimental model, that combining venetoclax with chemotherapy may increase the activity of chemotherapy. And that led to several trials investigating different combinations, either with bendamustine or even with R-CHOP in the first-line setting.

And there have been some signals that eventually some patients with diffuse large B-cell lymphomas that overexpress BCL2 may benefit from the combination of venetoclax with R-CHOP. However, when we use this combination we increase the toxicity of R-CHOP, in particular the hematological toxicity. So for this reason we have a good Phase II study which was recently published showing the results of the combination of venetoclax with R-CHOP, with a signal that may lead us to think that a subpopulation of patients with DLBCL may benefit from this combination. However, given the side effects, the further development of this combination is still under reflection I will say.

DR LOVE: Any thoughts about using like venetoclax maintenance instead of combining it?

DR SALLES: I think in the field of DLBCL we don’t see single agent activity that’s really encouraging to use maintenance venetoclax after chemo. And in general in DLBCL there is a general feeling that none of the drugs that have been evaluated in the maintenance setting have proven efficacy and there is very little attraction for maintenance trial, at least in the first line.

DR LOVE: Okay. Well let’s continue.

DR SALLES: So I’d just like to give a few words regarding a new antibody that is in development and that may be available for patients in the near future, which is loncastuximab tesirine. This is a new antibody-drug conjugate targeting the CD19 antigen and has an original toxin which is called PBD, or the PBD family. There have been now an extensive trial with more than 100 patients treated with DLBCL. And as you can see on this table, the overall response rate for all of these patients is over 40%. I think the last results were about 48%. And a little bit less than a quarter of these patients achieved a complete response.

So it’s a drug that has efficacy. It’s rather rapid efficacy. It’s sustained in some patients. Patients that achieve a complete response or partial response appear to continue to benefit with this response for a couple of months. However, prolonged administration of this drug appears to sometimes be difficult. There is a little bit of edema, weight gain, a little bit of liver toxicity, and hematological toxicity.

So it’s an interesting drug. There may be comparison to be assessed in the near future of this drug with other agents, and this is enriching the field of new agents in diffuse large B-cell lymphoma. How this drug, which is an antibody-drug conjugate, will fit with polatuzumab, which is already approved. We don’t know. But this has a different toxin and a different mode of actions, different antigens that are being recognized, so these are not directly overlapping agents.

Just to conclude with a few words with magrolimab, which is an antibody developed to block signal which is called the “don’t eat me” signal. Don’t eat me signal is a protein, CD47, which is expressed on tumor cells and that blocks macrophage phagocytosis. So the idea was to administer this antibody in order to lower macrophages to perform this phagocytosis. The study, although that was initiated and published now years ago, was the combination of this antibody magrolimab plus rituximab, and there was an interesting response rate. As you can see, an overall response rate of 40% with a CR rate of one third of the patients, lasting in the majority of patients.

Further results have been presented in meetings, and maybe because patients have benefitted from CAR T-cell and other agents these results were not necessarily further enriching the early signals. But I believe this is still a drug which is interesting and it’s worth exploring in different combinations in the field of diffuse large B-cell lymphoma while its further developed in patients with follicular lymphoma and in patients with other hematological malignancies.

To conclude the field of relapsed/refractory DLBCL, we now have different agents, different modes of action, different toxicity profiles. For most of these agents outpatient management is feasible. The question will be how do we sequence these agents between themselves. How do we sequence them with CAR T therapy? There is a feeling that we may want to avoid using bendamustine before leukapheresis for CAR T. How to sequence tafasitamab versus CAR T is a question we have already discussed. And how to bring this noncytotoxic agent as a combination for second-line or third-line treatment of patients is interesting.

What we are missing right now is predictive markers of activity. We do know also that some combinations are under development, and we for sure need to push for clinical trials to better evaluate these agents and better define their role in the management of patients with DLBCL.

Case: A man in his late 60s with DLBCL receives polatuzumab vedotin in combination with bendamustine/rituximab (B/R) after disease progression on 3 lines of therapy, including autologous stem cell transplant and CAR T-cell therapy

DR LOVE: So let’s hear about your cases.

DR SALLES: So I would like to present to you the case of this 67 years old man who has no previous medical history that was diagnosed with diffuse large B-cell lymphoma several years ago, in August 2016. This patient had extensive disease, Stage III, high LDH, and while the performance status was favorable, it still had an age-adjusted IPI of 2. This was a patient with characteristics of the tumor showing germinal center origin result, double-hit or triple-hit characteristics, but still a high proliferation index.

The patient then had received R-CHOP for 6 cycles, had achieved a CR. But as you can see, about 1 and a half years later had relapse and was treated with R-ICE, autologous stem cell transplant, and reached a new CR, the usual pathway for patients with DLBCL.

But less than 1 year after, the patient had relapse. He got benefit from axicabtagene ciloleucel, but had a partial response at month 1 and progressed at month 3.

And the question we ask for this patient is what are the available options for this patient that has received 3 lines of therapy, including transplant and CAR T. There were different options that we could discuss, bendamustine/rituximab in combination with polatuzumab. It’s feasible. And we do know that there is a hematological toxicity for this combination, but it’s feasible. Tafasitamab plus lenalidomide was just going to be approved, and there was just the thought that we need to confirm CD19 persistence, and at that time selinexor was not approved.

What we had done for this patient was to check whether CD19 was still present in the tumor. And as you can see, based on this histological slide, while the patient still expressed CD20, CD19 expression was lost, so he wasn’t a good candidate with tafasitamab/lenalidomide combination. And this is unfortunately what we see in about 30% of the patients that relapse after CAR T.

In fact, this patient was treated with 6 cycles of R/benda/pola. Bendamustine was reduced at cycle 3, withdrawn at cycle 6. So the patient had achieved a CR, but unfortunately recently relapsed.

But I would say it’s in line with what we’ve observed with this regimen, giving a 1-year benefit for this patient.

DR LOVE: So a couple questions about the case here. First of all, I’m just kind curious. I see he required a dose reduction for benda/polatuzumab. Why was that?

DR SALLES: Well we dose reduced bendamustine because of cytopenias. I mean the patient was 70 years old. He was in good shape, but he experience febrile neutropenia after cycle 2, and we decided to dose reduce benda to 70 mg/m2 instead of 90 mg. And then at cycle 6 he was still tired, and we decided to do polatuzumab vedotin plus rituximab alone. Again, I think that when we look at the efficacy of the combination of R/bendamustine plus polatuzumab there is a general feeling, based on the activity of polatuzumab, that this is the main drug of this combination and that the bendamustine adds little to this combination.

DR LOVE: So he had it looks like a pretty good response there with 11 months. What was his quality of life like during that time?

DR SALLES: As mentioned, there was some toxicity associated with the administration of rituximab/bendamustine/pola, febrile neutropenia after cycle 2, some tiredness. He didn’t develop other infections. I think we may have had to delay 1 cycle and finally were able to administer the end of treatment. So it’s quality of life like we see with, I would say, a mild chemo regimen. The patient did not develop significant neuropathy. He had a little bit of numbness when he started on the trial. This may have a little bit increased during the treatment, but wasn’t major at the end, didn’t impair his quality of life. But we were cautious about that. And I should mention in some patients you may want eventually to monitor more carefully the neurological toxicity and potentially dose-reduce polatuzumab vedotin if it happens.

DR LOVE: So I’m curious also, he was treated with CAR T, axi-cel, I’m curious how he did with that. Did he have cytokine release? Any neurologic problems? How did he tolerate the therapy?

DR SALLES: So if I recall this patient, I think this patient had virtually no neurologic toxicity. I think we monitored this patient daily, as we usually do. The treatment was administered in an inpatient setting. And he didn’t have any confusion or symptoms, and no modification of the handwriting. He did experience cytokine release syndrome of Grade 1 or 2, had a fever for 1 or 2 days. We decided to intervene with tocilizumab, and I think he may have received 2 doses of tocilizumab, and things resolved after 3, 4 days, so the patient was discharged at day 12 or so after the administration of CAR T.

DR LOVE: What do we know at this point about the correlation, if any, between cytokine release, neurotoxicity, and benefit?

DR SALLES: We don’t know whether the occurrence of CRS, of neurotoxicity, is associated with a different response rate. However, what we know is that patients with higher tumor bulk have more risk of cytokine release syndrome, and that neurotoxicity usually occurs in more than two thirds of the patients in patients that have already CRS. So the patients with a higher tumor burden are also patients that seem to be less benefitting of CAR T, although there are some good responses, even for patients with huge tumors. So I think there is no direct correlation regarding the efficacy, but this is a group of patients that is more difficult to manage. And there are some data suggesting that the patients with very severe CRS or neurotoxicity, they have rather less favorable outcome.

DR LOVE: So you mentioned the fact about the CD19 presence in tafasitamab use.

Is that a standard part of starting tafasitamab, to check CD19 levels?

DR SALLES: So in patients with diffuse large B-cell lymphoma CD19 is virtually always expressed. And in patients that have failed chemotherapy there is no reason to think that CD19 has been lost. In this particular case we have patients that have been exposed to CAR T, and obviously we do know one of the mechanisms of tumor escape after CAR T is the loss of CD19. And so if you want to use tafasitamab after CAR T, I think it will be a good practice to check for CD19 expression. But if you want to use it in second line, as it is marketed now, you don’t have to check for CD19, and you can assume that the expression of the antigen is here.

Sequencing of tafasitamab/lenalidomide, polatuzumab vedotin/BR and selinexor for patients with R/R DLBCL

DR LOVE: Could you talk a little bit about how you sequence these 3 new therapies, tafasitamab/lenalidomide, pola/BR, and selinexor? I know the approval separates it out a little bit because tafasitamab/lenalidomide’s approved second line, the other 2 third line. But putting aside that, how do you think through which patient to start which thing on first and second?

DR SALLES: So the sequencing of treatment in patients with relapsed DLBCL that are nontransplant eligible depends a little bit on the history, the comorbidities, the age, and also patient wishes. I think right now the option of tafasitamab/lenalidomide is an option that is approved in second line. The trial included patients that were mostly relapsing patients rather than primary refractory patients. So we have limited indications regarding primary-refractory patients. But I will say that given the tolerability of this regimen it’s probably a good option to be tried in second line.

If you think that you would like to use CAR T rapidly for the patient it may not be the preferred option, and maintaining the patient with either classical chemo or polatuzumab vedotin combination may be an option. The response we observed with this regimen is in the range of 3 months, so it’s not a very rapid response, but it’s a good response.

The use of R/benda/pola is clearly something that is practical. Again, it’s a chemo-based regimen with 2 cytotoxic agents, one systemic the other one targeted. The side effects are those that you may expect, but are usually quite tolerable. And this is not approved in second line, but you can get it. Also you can use R/gem/ox also in second line or other kind of salvage combination, R-ICE or R-ICE with limited dose intensity or other cytotoxic agent. Obviously, R/benda/pola is one of the best cytotoxic regimens developed so far, so if you want to offer a cytotoxic regimen in second or third line to your patient, I think it’s a good option.

There is a tendency not to use bendamustine before the CAR T pathway because it’s an agent that depletes T cells, so it’s not fully proven either. And sometimes R/benda/pola or R/pola are good bridging agents for patients that are waiting for CAR T manufacturing after leukapheresis.

At the present time, given the response rate in the range of 30% and the median PFS of less than 3 months with selinexor, this drug is rather thought about in third line of therapy or after having failed immune-based intervention, such as tafa/len or R/benda/pola or other regimen. And as a single agent we don’t see this drug moving upward in the earlier management of patients, although it’s an oral agent. But I think it’s again, a drug that can be useful in some patients.

Response to bispecific antibodies in patients with DLBCL

DR LOVE: So I’m curious about bispecifics. What do we know about response to bispecifics, or the CD3/CD20 bispecifics after CAR T?

DR SALLES: It is interesting that the data that were presented at ASH 1 year and a half ago with mosunetuzumab by Dr Steve Schuster indicated that a number of patients that had failed CAR T responded to bispecific antibody. And since that, this has generated quite a lot of enthusiasm by CAR T centers to propose to patients that had failed CAR T to enter into a clinical trial with bispecific.

And there is a general impression that some patients that had failed CAR T can be salvaged with bispecific. Whether the bispecific is able to increase the proliferation of CAR T or whether it just stimulates the remaining normal T cells that are in the patient is unknown. But based on these results there will be trials that will investigate more specifically bispecifics early on after CAR T in patients that do not achieve a CR or in patients that despite achieving a CR have a higher risk of relapse based on their initial characteristics.

The precaution that we have to take is that some patients with CAR T experience CRS, and we have to wait until full CRS resolution before to administer bispecific. So I’m not aware of reports of reappearance of CRS after bispecific administration. But some patients experience prolonged cytopenia after CAR T, and it may be a little bit difficult to fit bispecific immediately, although the hematological toxicity of bispecifics is rather limited.

DR LOVE: I would imagine there might be patients who are considered not in good enough shape to take CAR T but maybe in good enough shape to take a bispecific. So in a patient like that you have these other options that you’ve been talking about, these new approvals, tafasitamab/lenalidomide, pola/BR, and selinexor. If you had one of these bispecifics available, based on the data we have right now, would you want to use it right now? Or do you think we need more data?

DR SALLES: I think that based on the actual data bispecifics are very appealing agents in second line of therapy, even before CAR T. And I think how they will fit, how we will sequence all these agents, numerous questions here, but I think they have a response rate which is very encouraging. And when they will be approved they will enter as another option in second or third line of therapy, depending on the approval and on the drugs.

Although we have to remember that the median time to response with some of the bispecifics is also in the range of 2, 3 months, so you may need to combine those with a cytotoxic agent to have some immediate benefit. And we don’t know exactly how this combination works now. So yes, it’s definitely a good probability to use these drugs early on in patients, before CAR T, but this won’t solve maybe the issue of patients with very active disease for whom we need rapid intervention.

DR LOVE: But just backtracking then, you’re saying the typical response is only 2 or 3 months?

DR SALLES: Yes. It takes some time to respond with bispecifics.

DR LOVE: Oh, to start the response.

DR SALLES: Yeah.

DR LOVE: I get it. I get it.

DR SALLES: You usually don’t have a response after 2 weeks or 4 weeks —

DR LOVE: Right.

DR SALLES: — exist in some patients, and maybe with some more than others, but with some of the bispecific antibodies the median time to response — so again, I mean we are working with essentially data from presentation or abstract while looking forward to see the full manuscript. But I think based on the experience, some patients have a slow response to these drugs.

Case: A woman in her mid-70s receives tafasitamab and lenalidomide after experiencing disease relapse on R-CHOP for Stage IV DLBCL

DR LOVE: Let’s hear about your second case, the 75-year-old woman.

DR SALLES: That’s a patient that I would imagine could get on track right now because the approval of the drug. But this would be a 75 years old patient with minimal past medical history, DLBCL that was quite extensive, classified as non-GCB. This patient had received 6 cycles of R-CHOP, well tolerated, was in response in February 2020, but just recently had recurrence of the disease. This patient typically had different options, but she wasn’t keen on receiving R/benda or R/gem/ox, and she wanted to start on a non-chemo approach.

And because this was a relapsed patient occurring a few months after the first achievement of complete remission she was offered to start on tafa/len. And she’s currently responding to this regimen, as you can see on this current PET/CT. This is the experience that we have with some of the patients treated with tafa/len, and we do know that these patients that achieve a CR have a prolonged CR. Whether this will last longer we don’t know.

In this patient we dose-reduced len, given a rash. We had to suspend the drug for a few days, but we restarted at 20 mg instead of 25 mg.

DR LOVE: In general with the tafa/len combination, is it the len that’s causing the tolerability issues?

DR SALLES: I think clearly the combination with len increases the side effects such as rashes and cytopenias. And when you get rid of len at 1 year the tolerability of tafasitamab is virtually excellent. I have had patients treated in the trial up to 4 years with this agent without any side effects.

DR LOVE: That’s great.

Case: A man in his early 70s presents with DLBCL with C-MYC and Bcl-2 translocation

DR LOVE: Let’s hear about your third case, the 73-year-old man.

DR SALLES: This case illustrates the difficulties of managing patients that had several lines of treatment and relapse and substantial medical history, like this man, who had a history of smoking, COPD, high blood pressure, had an MI 3 years ago, was stented and was on antiplatelet agents.

This was a patient with follicular lymphoma, initially with a high tumor burden that received 6 cycles of R/benda, but unfortunately this is the few patients that did not benefit much from this regimen because he progressed 3 months later. And the biopsy that was performed at the time of progression showed that the follicular lymphoma actually transformed to a large cell lymphoma with MYC and BCL2 translocation, which is now called in the WHO classification, high-grade B-cell lymphoma.

Given this new diagnosis, and the patient was not formerly exposed to doses of R-EPOCH or anthracycline, we decided to administer dose-adjusted R-EPOCH, but the patient had stable disease. We proposed the patient to go to another regimen, which was R/gem/ox, which was not efficient. We discussed CAR T eligibility, but based on his past medical history and the risk of using CAR T in this patient, he wasn’t found to be fit. Benda was already administered and was not very tempting to use R/bend/pola. Whether tafa/len may work in such a patient was a little bit unclear. And I think that could be a patient that may eventually benefit from selinexor, and this is an option to consider in those patients where few options remain.

Selinexor was proposed to this patient. And I just want to go with you over the management of selinexor in this patient. The drug was started at 60 mg twice a week with prophylaxis of nausea/vomiting with antiemetic agent. Unfortunately, at the end of the first cycle the patient experience Grade 3 thrombocytopenia, and we dose reduced the patient to 60 mg once a week. Despite the loss of weight, 8 pounds, we put the patient on steroids, used olanzapine at night, but the patient was able to stay on drug for a few months, until unfortunately he progressed and went to hospice.

DR LOVE: So what do we know about the response to transformed disease of all these entities you’ve been talking about? CAR T? Bispecifics? Selinexor? Taf/len? What do we know about responsiveness in a transformed patient?

DR SALLES: I think overall with the vast majority of these newly developed agents we do see the patients with transformed disease don’t have a very different response rate as compared to patients with de novo DLBCL. This is probably related to the fact that these patients have different mechanisms of action. We do know that part of the difficulty of managing patients with transformed disease is linked to the fact that these patients have been already exposed to chemotherapy, and repeating chemotherapy may be difficult in terms of toxicity and mechanism of resistance.

But here because we have a different mode of action, whether it’s CAR T or benda/pola, tafa/len, or selinexor, most of these agents will be working in patients that have been previously diagnosed with follicular lymphoma or other indolent diseases that have transformed.

DR LOVE: What about checkpoint inhibitors in transformed disease?

DR SALLES: I think that the checkpoint inhibitors in patients with diffuse large B-cell lymphoma, whether transformed or not, were not working well. There was some early signal that eventually checkpoint may have some interest in patients with Richter’s transformation from CLL, but that hasn’t been, I would say, fully confirmed in a larger set of patients.

DR LOVE: Anything you want to add?

DR SALLES: Well, I think we are learning a lot on the biology of diffuse large B-cell lymphoma, and we have been looking for years for targeted agents that could be combined with R-CHOP. But what we see right now is that a couple of immune-based interventions, agnostic of the biology of diffuse large B-cell lymphoma, are providing good responses in these patients. And this is probably one of the ways we want to further develop in the future for the benefit of our patients.