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Intro:

Hello and welcome to the Clinical Care Options’ Oncology Podcast. I’m your host, Sharif Morsalin. Today’s podcast features Dr. Pier Luigi Zinzani from University of Bolonia, and Dr. Max Topp from University of Wurzburg. They will be sharing their insights on the Therapeutic Advances and Practice-Changing Data Emerging from the 2025 EHA and ICML Congresses.

For more information on our presenters, along with a link to the full educational program, please visit the show notes for this episode.

Now, let’s get started and hear what the experts have to say.

Dr. Topp: We got the chance to discuss six very exciting abstract that were presented at EHA and ICML. We do believe that these are either practice changing, or will give us new directions in the way how we will be treating patients in the future with lymphoma and also ALL.

Dr. Zinzani: The first abstract was presented at the last ICML meeting in Lugano a few weeks ago by Dr. Matasar from Memorial Sloan Kettering in New York. He presented the final data of a phase III randomized trial called POLARGO in relapsed/refractory diffuse B-cell lymphoma ineligible for transplant. Is a very simple phase III randomized trial comparing the study arm there is R-GemOx plus polatuzumab for each cycle, versus the control arm, the R-GemOx plus rituximab for each cycle.

The study included more than 120 patients for each arm with the ratio 1:1. The primary endpoint of this study was the overall survival.

This primary part was met because the median overall survival was 19.5 months for the study arm polatuzumab plus R-GemOx versus in more than one year, 12 months for the control arm R-GemOx. The median progression-free survival at the same time was statistically significant in advance of the study arm polatuzumab plus R-GemOx because it was 7.4 months, versus only 2.7 months for the control arm R-GemOx.

In terms of secondary point, the overall response rate was close to 50% for polatuzumab plus R-GemOx versus only 25% for R-GemOx. The CR rate was 40% for Pola-R-GemOx versus only 19% for R-GemOx single agent. In terms of toxicity, the pathological toxicity was quite similar. Of course, in the Pola-R-GemOx studies, there was some peripheral neurological toxicity.

This could be considered a very interesting study concerning the addition of polatuzumab vedotin with the conventional chemo-immunotherapy R-GemOx in this setting of relapsed/refractory patients with diffuse B-cell lymphoma ineligible for transplant.

This advantage is possible to observe not only for the primary endpoint in terms of overall survival, but also in terms of median progression-free survival. At the same time, better overall response rate. Also, CR rate that is close to 40%, as I said before. Without any really difference in terms of toxicity only, of course, the peculiar toxicity related to polatuzumab. It means the neurological toxicity. As you know, is reversible the most part of the patient.

Dr. Topp: I think this is a very interesting abstract, particularly because it shows an OS difference for the experimental arm. Now, we have the abundancy that we have now three phase III trials showing OS difference with the experimental arm. We got the STARGLO. We got also CAR T cells in the ZUMA-7 trial.

Dr. Zinzani: It is quite unbelievable because it is very important. Everybody knows that the FDA, EMA, the drug agency preferred to have this difference when you have a phase III randomized trial. At the same time, I think this data are good. In the new era of chemo free regimen, could be difficult to accept very well this kind of final analysis of the POLARGO study.

At the same time, inside the therapeutic algorithm of relapsed/refractory patient with diffuse B-cell lymphoma, I think there is room also for these new modalities of treatment, in a particular subset of patient, elderly patients ineligible for transplant where the potential competitors could be also, of course, are ineligible for CAR T.

The potential competitor could be polatuzumab-BR or at the same time of tafasitamab plus lenalidomide. It depends patient by patients. We have to evaluate according to the result of these three different trial, and according also the different study population of these three different trials.

Dr. Topp: I agree with that it is really very nice to see that we have these options. As you said completely that we have the younger patients with early relapses. Obviously, those will be CAR T eligible. For the patients who are elderly or do not have access to CAR T-cells, these are potentially very attractive options. It is very exciting in the field.

Dr. Zinzani: Absolutely. Is full of option.

Dr. Topp: I would like then maybe to take over and speak about an update that Martin Dreyling presented. I thought this was a very important piece of information. The background is he spoke about mantle cell lymphoma patients, particularly the elderly patients. The ECHO trial established a new standard of care, both in the United States and also in Europe, by actually now showing superiority for bendamustine in combination with rituximab and acalabrutinib.

This is really very nice to see because we have for the younger patients the TRIANGLE trial, which showed also a real benefit in these patients. We do know what they do not do any more high-dose chemotherapy based on the trial that Martin Dreyling presented a couple of years ago.

Back to this trial. Why do I feel this is a very important trial? It is first, a quite a big trial with mantle cell lymphoma. The authors have to be congratulated. With 600 patients aged 65 and above, and stratification between the regions and MIPI and we have seen this data being published in the JCO by Michael Wang.

Martin spoke at ICML about the patient population that we really do fear in mantle cell lymphoma. The higher risk disease population defined as follow: high-risk MIPI Ki-67 by 30% plus, p53 mutation, and of course blastoid subtype.

In this trial, they were well balanced between the experimental arm being the acalabrutinib plus BR, and the placebo arm for both the age, tumor bulkiness, LDH, also between the whole population but also the high-risk population. As you would imagine, the high-risk population, there was a trend of higher LDH tumor bulk and a higher MIPI, but that was to be expected.

It is very important to understand that, in all the risk factors that Martin presented, if it is the MIPI, if it is Ki-67, also 30% or 50%, depending if it is the United States, we quite often have 50% of Ki-67 being important, or 30% or even with patients with blastoid mantle cell lymphoma. There was for all three of these subgroups, a significant benefit in PFS in the primary endpoint of this clinical trial, adding acalabrutinib to the mix in the situation.

I think this is very important that we know that even these very hard-to-treat patients, that adding a BTK inhibitor can make a big difference. The toxicity has been reported by Michael Wang in that situation. The only caveat that I do see is that the p53 was not included. Now, on a post hoc analysis, Martin has tried to pull the patient data, but obviously, there are just a few patients.

It is very difficult to conclude in that situation. You have to understand that quite often p53 is associated with high MIPIs, with high Ki-67, of course, with the blastoid phenotype. I would presumably say that this is also true for p53 patients in this situation.

With that data set, I think we have another piece of a cornerstone how to improve further in mantle cell lymphoma patients.

Dr. Zinzani: I think, Max, another really important issue concerning these new trial by the end of the day will be a new indication in the setting of untreated mantle cell lymphoma. After the TRIANGLE, there is also the ECHO, and we have the complete new front-line for mantle cell lymphoma. With the inclusion, in particular, in this case, our second-generation BTK inhibitor, acalabrutinib.

It was quite interesting also to observe that also in this case, there is a trend in advantage of acalabrutinib arm in terms of overall survival when you skip the patient who died for COVID. This is another important point when you come back to the prior discussion concerning that. At the end of the day, in the last few years, there are several data concerning the positive role of overall survival when you charge the patient with the new generation of treatment. I think this is another important point.

I have a question for you. Which is the real role of, for example, MRD negativization in the setting of this patient when you put this new therapeutic option in the real life? Because as you know now, there are several trial related to the MRD evaluation in terms of to continue the treatment, to stop the treatment, to modify the dose also could be difficult to apply these in the real life.

[00:21:51]

Dr. Topp: I agree. That is a completely different level. This could be a completely new session, that we can speak about the MRD. We saw a glimpse at Lugano that MRD is going to be what we will be working on in the next five years, and how to satisfy therapy, because we are already doing so well. There are subsets. I agree with you, Pier Luigi, where we perhaps can stop therapy because still nevertheless, acalabrutinib, all these drugs still do have side effects like diarrhea and easy bruising.

If someone is MRD negative, do we actually stop therapy in these patients? Or if we have someone who is MRD positive, do we escalate in the situation? We got license out there in the mixer like a CAR T-cell therapy and almost for the younger patients. Is there going to be a trigger point for that? This is discussion where we go in the future, but I completely agree with that.

Then on the other hand, there is also a subset of patients which actually get away with not using any chemo at all rituximab plus a BTK inhibitor. There is a patient that is completely chemo-free with mantle cell lymphoma. This is a very exciting prospect, but also pinpoints that we have to be very clear on the diagnostics in mantle cell lymphoma.

Dr. Zinzani: Is a real Copernican revolution in the setting of mantle cell lymphoma, not only for frontline and in young patients and elderly patients, but also a second-line, third-line, with the non-covalent BTK inhibitor with the combination of venetoclax plus ibrutinib according to the SYMPATICO venetoclax plus ibrutinib. Also, the [inaudible] glofitamab in the setting of a relapsed/refractory patient.

The CaDAnCe‑101 study presented at the last Lugano meeting by Dr. Scarfo from San Raffaele Hospital in Milan, in Italy. It was involved in this trial. It is a phase I study, and with a new drug. It is a very new interesting track called a BTK degrader.

There are several different BTK degraders so far. This is phase I in relapsed/refractory patient with CLL or was born with lymphocytic lymphoma. Of course, the most part of the patient that we are all aware CLL. Patients received at least two prior lines of systemic treatment including at least one of them with the BTK covalent ibrutinib or acalabrutinib or zanubrutinib.

The primary endpoint was the safety and the MTD because it is a phase I study with some preliminary data in terms of efficacy. We included 66 patients. It is particular because it is a really a high-risk study population because in this study population, we included 65% of patients with deletion 17 and/or p53 mutation. At least 50% of patients had complex karyotype.

The median number of prior systemic treatment was four. Really high-risk heavily pretreated patients.

In terms of toxicity, this BTK degraders, there is fatigue in at least one-third of the patients, but in 90% of the patients is grade 1 or 2. Bruising in at least 30% of the patient, but all grade 1 and 2.

In terms of a peculiar toxicity in the setting of BTK covalent, of course, also in BTK degrader, atrial fibrillation was observed only in two patients out of 66, and both of them are at the grade 1. The safety profile is very good. At the same time, there is a rapid improvement of cytopenia. This is another important point. In this phase I study, there were six different subsets in terms of different doses, and the MTD was 200 milligram for the phase II study. The doses ranged between 50 milligram until 500 milligram.

Another important point is the median time to response was close to three months. This is another important point for our patient.

If we move to efficacy, this is a second endpoint in the setting of a phase I study, but the overall response rate was more than 80%. The CR rate was only roughly 5%. I think it is important. We are talking about CLL patients. The overall response rate in heavily pretreated patient, high-risk patients is close to 80%. In particular, when you stratify some subset of patients, double-exposed patients, the patient who received BTK inhibitor covalent and also BCL-2 inhibitor 95% overall response rate.

For triple exposures, BTK inhibitor covalent, non-covalent, and BCL-2 inhibitor, 75% overall response rate. Patient with deletion 17 and/or p53 mutation, 82% overall response rate, and complex karyotype was 73% overall response rate. Last but not the least, in patient with BTK mutation was 75% of overall response rate.

The progression-free survival at one year was close to 80%. At least 65% of the patients are still on treatment, with a median follow-up of roughly 15 months. I think these are really preliminary phase I data, but could be a very important new strategic drug for the future of CLL. There are also preliminary interesting data, not only in CLL but also in Waldenström disease. At the same time also in marginal zone lymphoma, mantle cell lymphoma, and diffuse B-cell lymphoma.

Dr. Topp: I agree. This was a real highlight. Particularly, also having a new drug class being now really hitting the rim, the forefront. Particularly, I was very surprised by the efficacy of the triple-exposed patients. That is really breathtaking with that high efficacy rate and the duration of response, on the other hand, the tox profile. It just speaks for itself that I think that this drug will move up the ladder quite quickly. Will not be in third line or fourth line. It is going to be something to look out for.

Dr. Zinzani: The next step could be also the combination.

Dr. Topp: Exactly. When you add venetoclax in the mix or something like that, that would be very exciting, or with immunotherapy or so. It is also something we have spoken about last years using CAR T cells in CLL, and it has been a disappointment to my opinion. 25%, 30% is not good enough for something like that. This obviously is a drug that can be applied to all the CLL patients, particularly also the elderly patient population, which are not really eligible for CAR T cell therapy This is really very exciting.

Dr. Zinzani: Also, I think the of future CAR T in the setting of CLL patient could be to move as soon as possible from the right to the left in the second-line. Because we are discussing every time concerning the sequential treatment for our patients to stabilize, to control the disease for 15 years, 20 years, and more.

The real problem is that there are at least 20% to 25% of the patients with CLL with an age range between 40 to 50. What to do? Potentially, after the front-line treatment, we have to allow stem cell transplantation for each patient to try to cure this patient.

At the same time, another opportunity to try to cure could be CAR T cell if there is this possibility to use, why not in second line, where we can increase also the duration of the response, and potentially we can cure a small subset of patients. I think this could be another important issue for the future about the therapeutic algorithm for CLL patients to try to discuss also what to do in really young patients, because it could be difficult to stabilize to control the disease for 40 years.

Dr. Topp: I agree with that. I think also, you did not speak about it, but MRD testing would be also a very important tool here because it is so established. We have seen that now with other trials in frontline, where there is the approach of using MRD to tailor the therapy. This is another angle of technology that will help us here to actually who to take to which therapy.

In younger patient, if they have a very swift response and become MRD negative, then, well, you maybe can withhold transplant. If you have a patient who is a slow responder, particularly in the second-line, and does not clear MRD within a certain time frame, that is a candidate that we have to expose something like that.

Dr. Zinzani: Again, MRD is everywhere.

Dr. Topp: I will like to talk about the use of tafasitamab in the situation of the first or second salvage or follicular lymphoma. The data was reported the first at the late-breaking abstract at ASH last year. The full publication is not yet out there, so we have to watch the abstracts.

It has already been now approved in United States. I think it has a positive opinion also in Europe. We will see this drug very soon moving into the space in our guidelines. This trial also is a big trial, international trial in many countries the inMIND phase III, double-blind, placebo control. This is very important

There were more than 400 patients being selected 1:1 randomization. Primary endpoint was the PFS. Also, talking about key secondary endpoints PET negativity, and secondary PFS by investigator, and OS. There was some updates on this here looking at particular questions. For example, what about the previous therapies these patients have because when we treat a follicular lymphoma patient, there are bendamustine, R-CHOP. In some areas, regions, we use R² or even just rituximab monotherapy, which is not a bad idea actually in follicular lymphoma.

They also spoke about the PFS by baseline risk factors and prior therapies. They also address the question in these updates on histology transformation.

Of course, also which is very important considering what happens to CD19, talking about CAR T cell therapy as the next line of therapy in a patient who is relapsing, particularly when we know the good liso-cel data that we have with CAR T cell therapy. These are very important questions.

Dr. Zinzani: That is an important presentation. It is true because in the setting of follicular lymphoma, now we are talking from the second-line. Also, in this case, there is a revolution because this is a chemo-free regimen, inMIND. There are also, as you know and everybody knows, the fantastic data concerning epcoritamab plus R² or also the mosunetuzumab plus lenalidomide. The future in the indolent disease such as follicular lymphoma could be really free for every conventional chemotherapy.

We are waiting for the second attack to the front-line. There are four different phase III randomized trials. Chemo-free versus the conventional chemotherapy. Probably in the next two, three years, the most part of them will be positive.

Finally, we can conclude that we can try to cure the most part of a patient with follicular lymphoma without any cytotoxic therapy. What do you think about this really close future for our patient with follicular lymphoma?

Dr. Topp: I am completely excited about this situation. It is a dream to see chemotherapy being abolished. I always like this a lot because we most likely will have a bispecific targeting CD20 in the frontline, hopefully, without chemotherapy. As you said, a couple of trials exploring true chemo-free range, and then if the patient relapses, we can have here another approach. In terms of are we adding CD19 to the mix as a targeted agent? Something like that.

We have got CD20, CD19 sequentially being targeted in that situation. We can then proudly speak to our patients, say, "We got here something which is chemo-free," and this is a dream. That is basically where we grew up with chemotherapy. We added rituximab where we thought this was magic. Now, this is the time of the magic bullet.

Dr. Zinzani: Sometimes you have to pay attention because when you start with the patient, I think it is important to have a vision concerning the sequential treatment of this patient because sometimes, you can close some doors if you use a monoclonal antibody before instead of another one. You have to avoid the role of bendamustine in terms of potential utility of CAR T cell.

Another important point, during the presentation of Laurie Sehn the last ASH meeting, but also training here in Lugano, and EHA concerning inMIND, is that, one of the secondary point, the complete metabolic response was not so different when you compare INMIND versus R². R² is quite active because was 50% of CR, complete metabolic response, for inMIND for the study arm. Tafasitamab plus R² versus R² was 40%.

Dr. Zinzani: Now, we move to peripheral T-cell lymphoma. T-cell lymphoma representing more than 12% of all non-Hodgkin lymphoma. The result in terms of in particular, relapsed/refractory patient, quite poor. At the last Lugano meeting, Dr. Song, presented the final data of the second part of the phase I study using a new drug is SHR2554 is a EZH2 inhibitor. Is a new pathway for the setting of peripheral T-cell lymphoma patients.

Of course, this was a phase I study. In the first part, they reached the MTD was 350 milligram is an oral formulation until progression. In the setting of a relapsed/refractory peripheral T-cell lymphoma, including NOS and angioimmunoblastic, and anaplastic ALK-positive, and also ALK-negative.

In terms of age, they included patients between 18 and 70 years. At least the patient had to receive two prior line of systemic treatment, including conventional chemotherapy and one of the new agents such as pralatrexate or chidamide, that is quite common in China.

The primary endpoint of this phase I study was overall response rate, according to the Independent Central Review, on the basis of the Lugano criteria 2014. They included 67 patients, 55% were angioimmunoblastic, more than 20% NOS peripheral T-cell lymphoma NOS, and at least 15% anaplastic, ALK-positive and ALK-negative.

All these patient receives at least two prior line of treatment. The CR rate, this is very important, was 33%. The overall response rate was close to 65%.

According to the histology, the overall response rate was 70% for angioimmunoblastic, close to 60% for NOS, and roughly 50% for anaplastic. The median duration of response, this is another important point, is 19 months. The time to response is less than two months.

This is the preliminary data phase I only less than 70 patients, but are really important in the issue of relapsed/refractory patients with peripheral T-cell lymphoma. Also, we have to remember two important points. The median progression-free for survival was 10 months, and the median overall survival was not reached.

Last but not the least, the safety profile. No histopathological toxicity, only pathological toxicity grade 3 or more than 3 is neutropenia in at least 20% of the patients, 22% for [inaudible]. This data really impressive for this setting of real unmet medical need for our patient.

Dr. Topp: I agree this is really a space where we are very underserved currently.

Dr. Zinzani: Finally, after the conventional treatment, in Europe, there are for second-line, third-line bendamustine, or there are gemcitabine, where the overall response rate is less than 30%. The same situation in the United States with pralatrexate and belinostat, but no really good result.

With this pathway, EZH2 inhibitor in this trial, but also the same data we can observe with valemetostat, or in other pathway with golidocitinib. This is JAK1 inhibitor. We can increase the overall response more than 60%. Also, the CR rate 30%. This is the first step to move as soon as possible on the right to the left, and also to try to combine. This could be a really important point for our patient with this very bad disease.

Dr. Topp: Particularly also with really very good toxicity profile. That is basically dosing for us, so much easier to think about innovative ways of combining it with this situation. The majority of drugs that we have seen in the past going through, exploring T-cell lymphoma, or actually had horrendous toxicity. Now, we have potentially something to work with for our patients. Finally, we make a difference in T-cell lymphoma.

Dr. Zinzani: Yeah. We hope.

Dr. Topp: We hope. I would also like to jump now to the next abstract as reporting about a new bispecific antibody, CD3, CD19 in acute lymphoblastic lymphoma. It was presented by Aldoss from City of Hope. The compound is AZD0486. It basically was inpatient with two prior lines of therapy, full-blown relapse of acute lymphoblastic leukemia.

This drug has been also explored in follicular lymphoma and also aggressive lymphoma. This is now really working on the toughest B-cell lymphoma that we have. That is B-ALL. It is a classical phase I/II trial. There is a three-part. It reported on the dose-finding portion. In a couple of dose-limiting steps up to DL5, that was the design.

At this meeting, at EHA, 31 patients were reported, in this clinical trial, heavily pretreated. The majority of them exposed to either blinatumomab or CAR T cells, or even double-exposed. The wording of the protocol was in regard of CD19 expression, have evidence of CD19.

I think very liberal in the situation. As expected, there were cytokine release syndrome being something to work with. There were double steps included into the protocol.

To be said that at the DL3[?] group, 83% had a response in that situation, a CR with MRD negativity. If you are looking at the numbers in the patients which were blinatumomab-exposed, 64%, complete responses. Also, the CAR exposed 63%. This is really a very active compound situation. For the first time, we have now the sequence of a bispecific on bispecific targeting CD19. That was the biggest loss that we were seeing that the CD19 we lose it.

Now, this data shows you that you actually do maintain CD19. I think the data is there, that the CD19 exons that are targeted between the different antibody constructs are different to the blinatumomab and the CAR T-cells. I think that is the thing. What about the toxicity?

We saw infections. This was to be expected in this patient group, grade 3, the majority of patients, for neutropenia, an increase of ALTs and the heme.

The most important thing, ICANS was only seen in one out of 31 patients. The development of blinatumomab in that space showed one out of eight patients. Now, we have one out of 31 patients, a grade 3 or grade 4 for neurotoxicity. This track is moving forward into the phase II part. I think this is also something very exciting. I think this can be moving up the ladder very quickly in this hard-to-treat population of ALL.

Dr. Zinzani: Impressive. We open the door of bispecific in the setting of acute lymphoblastic leukemia. I know that probably we already started with the same single agent in CLL.

Dr. Topp: I think that it is probably the better target in CLL and in CD20 because it is dim expression in CLL. CD19, you have a lot of expression of that.

Dr. Zinzani: This could be another real important opportunities for our patients.

Dr. Topp: Absolutely. I think I would like to wrap up. We have a lot of excitement for our field. More than ever, I believe. We have really four confirmatory phase III trials with great data that is coming up there. We have two exciting compounds.

Dr. Zinzani: We are lucky to be in this situation. I think it is important for us. It is absolutely important for our patients that we can increase the response. We can reduce the role of chemotherapy. We have a different target for our different patient situation.

Dr. Topp: We got a vision. That is it. Thank you for being patient with us. I hope you can share the excitement that we have for our patients and these new opportunities.

Thank you, Drs. Topp and Zinzani for a great discussion and for sharing your expertise with us. And many thanks to you, our listeners, for joining us today. Be sure to check back for more episodes on important oncology topics!