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ALL with Dr. Bijal Shah and Dr. Ibrahim Aldoss

Dr. Shah: Hi, my name is Dr. Bejal Shah from the Moffit Cancer Center. I am joined by my very dear colleague, Dr. Ibrahim Aldoss from the City of Hope. And we are here to talk about ALL, acute lymphoblastic leukemia.

Ibrahim, just as a kind of a starting point, where are we in 2026? I mean, there have been a lot of changes, I think.

Dr. Aldoss: Thank you, Bejal. I mean, we have made significant progress in ALL, especially in B-cell acute lymphoblastic leukemia, where we have seen recent advances in frontline therapy. And these are the results of optimizing frontline chemotherapy backbone, the integration of immune therapy early on, improve risk stratification, the more precise identification of high-risk patients based on the MRD response and the molecular profile of ALL. And actually these advances have contributed to better initial disease control.

Now, progress in relapsed/refractory B-cell has also been particularly notable, I would say, decade, in the last 12-15 years, with several antibody-based and cellular immune therapies approved in recent years.

These include inotuzumab, which is an anti-CD22 antibody-drug conjugate. We have blinatumomab, which is a bispecific T-cell engager. And more recently, we have three actually approved CD19 targeted CAR T-cell therapies approved for patients with relapsed/refractory B‑cell ALL. These are tisa-cel, brexu-cel, and obe-cel as well.

Now, despite these advances, I would say substantial challenges persist. I mean, while real-world data and clinical trials demonstrate significant immune therapy efficacy in relapsed/refractory B-cell ALL, many patients, unfortunately, remain at risk for relapse, although the response early on is high. But besides the efficacy part, there are some treatment-related toxicities we should take into account, including cytokine-release syndrome, ICANS, that we see with CD19-targeted immune therapy. But also, there are some challenges in how to administer these immune therapies.

You have blinatumomab. It requires 28 days' continuous infusion. You have CAR T-cell therapy that require T-cells collection. Then it takes four weeks to manufacture these CAR T-cells, as all the approved CAR T-cell therapies at this time are autologous CAR T-cell therapies.

So with that, there is a critical unmet need for immune therapies, that we need a safer immune therapy that produce more durable remissions and potentially cure, as well as more accessible and easy to administer.

Dr. Shah: That was incredible. You just laid out, I think, extraordinarily, this incredibly abbreviated but comprehensive summary. So I am going to dig in a little bit and maybe provide commentary, if nothing else.

I think in relapsed/refractory ALL, it is wild, right? You know, when we started, we were talking about an expected survival in first relapse now, right, long-term survival of around 5-10% for patients with BALL. You know, this is coming off of the Hyper-CVAD data, this was coming off of the ECOG 2993 data, and we are now in a position where we can say with some degree of certainty that we will probably cure somewhere between 30-50% of patients who relapse after their initial course of chemotherapy. And, wow. I mean, that is a sea change. That is a really big deal.

And so, I think that immunotherapy has played an enormous role in helping us to get there, and I think it also informs how we think about the frontline setting a little bit. But when we talk about relapsed/refractory therapy, integrating blinatumomab or MRD ALL first got us to that 50% benchmark in terms of curability, still depended on a transplant. And I think that that is something we still have to make sure we think about in 2026. We are not able to really say that we are talking about transplant-free therapy yet. But I think a major step forward.

We talk about CAR T-cell immunotherapy, same thing. We have got the five-year data now with brexu-cel. We have got emerging data with obe-cel. But, you know, again, kind of hitting that 50% plateau, despite the fact that these patients are heavily pretreated.

So it really begs the question, or begged the question, since we are really talking about past tense now, why cannot we bring these therapies forward? You know, we have now got blinatumomab incorporated into frontline therapy. We have got, you know, not just for Ph‑negative patients or Philadelphia-negative patients, but also Ph-positive, and seeing extraordinary outcomes.

You know, with ponatinib and blinatumomab what we used to call high-risk ALL, which was Philadelphia-positive, now we can really relegate that to standard-risk for the most part. And it has just been incredible to watch.

I am also enamored by some of the data you are generating with frontline CAR T. But you hit the nail on the head, right? You know, when you were talking about toxicity, and I do consider administration of the drug as a component of toxicity.

I know it is a strange way to think about it. But if you have got to hospitalize a patient for a month, if the delivery is really cumbersome, right? A patient's got to drive back and forth. And, you know, it creates a conundrum, right? It creates this challenge of delivery. And I think that that is something that we have got to really make sure that we think hard about.

And so, when we talk about bringing novel bispecific antibodies into the frontline setting, whether that is sub-Q Blina, whether that is the new Merck drug, or surovatamig, the new drug from AstraZeneca, I think what the real promise here is we may be able to blend this with therapy and achieve extraordinary outcomes.

But before my run-on sentence goes any longer, what is your take on maybe focusing on some of the bispecifics, how some of these are delivered, right? Because we have now got a few different options.

We have got intravenous blinatumomab, sub-Q Blina, surovatamig, Merck 104.5. I mean, maybe I am asking you to dovetail a little bit on my concept of toxicity. But what is your take on the administration of these?

Dr. Aldoss: No, I completely agree with you, Bijal. I mean, especially as we are moving these agents to the frontline setting, I agree, the convenience for the patient is very, very important. And this is where the field should move.

We have effective therapy in the relapsed/refractory setting. It is how to actually bring it earlier, especially in adults. They tend to have disease that is more chemo refractory, and they tend to develop more toxicity to chemotherapy. So replacing chemotherapy, especially these long regimens with more effective, less toxic immune therapy in the early setting, I think this is where the field should move, and we can shorten the duration of treatment of ALL. So as we are giving it actually to more patients, it makes sense that we have to select agents that are actually easier to administer to the patient.

Continuous infusion, blinatumomab, it can be convenient for some patients, but many patients, they cannot handle the fact that they have to be on continuous IV cancer therapy for 28 days. So keep blinatumomab. I mean, it seems to be very active, but it requires frequent visits to the clinic, and not everybody lives close to the actual treatment center, and that actually adds more burden to the patient and the family as well.

So I agree. I mean, I think coming up with more convenient immune therapy, it is an important thing, and it actually decreases the burden and the toxicity on the patient. And we are very excited with agents like the MK drug, where it is given weekly. We have surovatamig that can be given every other week, and eventually can actually move to the monthly schedule. And I mean, it is a great experience for the patient. Less burden on them and their family as well.

So with that, Bijal, I mean, let me ask you about the emerging bispecific and trispecific antibody strategies in ALL. Of course, now they are in the relapsed/refractory setting. But as you mentioned, the hope is how we can bring them early on for our patient with newly diagnosed ALL.

Dr. Shah: Yes, I mean, I think I loved what you said about replacing elements of the chemotherapy backbone. You know, one of the things that really inspired me to work harder was actually an old, old paper from Nicola Gopoget. She had done one of these American Society of Hematology review papers, where you give your talk at ASH, and then you write a summary of your talk. And she summarized all of the frontline chemotherapy-based approaches for adults with ALL. Hyper-CVAD, ECOG, you name it, you know, Larsen-Linker, all, you know, the German protocols. And you know what? When you look far out, meaning at about five years, they all landed at around 35% in terms of overall survival. Just pause and reflect, right?

When we really talk about taking on patients from age 18-70 or 70, you know, whatever that upper age limit is going to be, we are hitting 35% in terms of our overall survival expectation. And to be honest, if you look at the SEER index, that has not changed in 2026. We can talk about incorporating pegaspargase and talk about trying to intensify chemotherapy, but the reality is with very limiting returns.

The only thing that is really moved the needle has been the incorporation of immunotherapy into this setting. And so, when we talk about replacing the chemo backbone, it is not a matter of if, it is overdue. We have got to find a way to do this, and we have got to find a way to do it right.

You know, that is part of the promise. I think the other part is, you know, you alluded to it, three years of therapy. That is what we are talking about for the average adult coming in with newly diagnosed ALL. I mean, that is, I mean, I do not know, I cannot say unacceptable, right? We are stuck with the paradigms we are stuck with. But, you know, that is not an easy go if you are a young adult trying to go to school or hold your first job. That is certainly not an easy go for someone who is mid-career trying to get promoted. And if you are retired, trying to enjoy that retirement. It does not fit with anything that we would call normal life. And, you know, managing the toxicities and cytopenias in those parts.

So we really have a responsibility to improve survival, but also the practical delivery of therapy for patients with ALL. And I think immunotherapy is the path forward.

You asked a second question, which was, how do we think about some of these novel agents in terms of integrating them onto our chemo backbones? And I think it is something that I also spend a lot of time trying to dissect. And what do I mean by that?

Is delivery of these agents, should we think about it as something that is given commensurate with therapy? And an example of that would be giving blinatumomab and inotuzumab together. Or is it something that we need to think about sequentially, where we give something and then we want to avoid any T-cell toxicity, and so, we would just give the bispecific next. And that is the latter, has been the method that we have been employing. But we are really talking about very, very potent therapies that we are now able to space out. You know, you mentioned surovatamig maybe once a month. I mean, that is huge. You know, your opportunity now, to say, okay, I am going to give my once-a-month therapy.

I feel comfortable integrating an Ino or some other thing here onto this because, look, we do not have to worry as much about, you know, the toxicity with this approach because we are really able to space out our dosing. And it changes a little bit of the dynamic of what we are doing, allows us to compress therapy, allows us to compress therapy with, again, therapeutic benefit without losing folks along the way.

I think it is early to talk about the trispecifics. It is interesting. I think that it is a cool concept, but it is going to be hard to really show that it is this profoundly more active than the bispecifics that we currently have in the mix. And what do I mean by that?

Ibrahim, you are front and center on the surovatamig data. I mean, we are talking about 70-80 percentile complete remission rates. I mean, many of these are MRD-negative. I mean, this is massive. I will pause there and let you, you know, fill in the details. But I have been very impressed with what we have seen so far from, again, these novel bispecifics.

Dr. Aldoss: Yes, no, I agree. I mean, it is it is I mean, the bar is higher and higher to complete well. And can I comment about the surovatamig?

I mean, we are very actually excited and impressed with the data. I mean, in the SYRUS study, which is a Phase I/II dose escalation optimization and expansion trial that tests the surovatamig as a single agent, which is a CD19 T-cell engager that is unique where it has lower affinity CD3 that actually releases less cytokines. And therefore, we are hoping with less CRS and toxicity. And this will actually allow for higher exposure and increasing the dose. But at the same time, it also has a long half-life that can be between 8-12 days. And this is what is supporting the administration every 2-4 weeks.

And what we have seen in the SYRUS study, I mean, very encouraging data early on, even with the lower dose level. We have seen responses in the 40%, including patients who failed prior blinatumomab and CAR T-cell therapy. And as we escalate in the dose, we are not actually seeing dose-dependent increased toxicities, but we are actually seeing dose-dependent improved response, where the response rate with dose level three was as high as 82%.

And these responses, as you mentioned, I mean, the majority are the MRD-negative: patients who failed blinatumomab, CAR T-cells, and as well as some of them are triple-exposure, including inotuzumab as well. And what is unique with responses, that unlike what we see with blinatumomab, where we see actually less response if the patient has high disease burden, if they have extramedullary disease. We have in patients with high disease burden, patients with extramedullary disease that they respond to single-agent surovatamig.

So this is where all the excitement of surovatamig comes in: the high MRD response rate, even in heavily pretreated patients, as well as actually the safety profile for the drug. I mean, we only have seen grade one and two CRS and ICANS with one grade 3 CRS and one grade 3 ICANS. So this is why we have all this excitement.

And we think this is maybe actually a more powerful drug compared to blinatumomab. It is maybe as comparable as to CAR T-cell therapy, but it is available off the shelf. You do not need to make the CAR T-cells, the drug, to give it later after four weeks.

And you know, Bijal, I mean, some of those relapse can be very proliferative, very difficult to maintain, can have some control to be able to collect the T-cells, then actually give the CAR T-cells after four weeks. Many times we lose this patient while we are trying to make the CAR T-cells. So this is why we are very excited.

And the same thing we are seeing actually with other actually bispecifics, including the CN-201 drug, which is similar to Cervatimic, but it is given once a week. And again, data is still early, maybe patient not as heavily as pretreated as Cervatimic. But the data is also very encouraging.

And it has the same structural concept, longer half-life, lower affinity, where you see actually less CRS. We have not seen, at least the investigators, they have not seen any ICANS in their study. But the study is still early on, still accruing patients as well.

So, I mean, with the high response rate, where we feel that planetumumab has really actually moved the needle in frontline therapy for ALL, if we have a more powerful drug than planetumumab, more convenient to give, are we able to actually improve furthermore? And which make it also harder to kind of look at trispecific. How is this will improve outcomes compared to some successful drug like Cervatimic?

So I like the CN-201 drug as well. And that comes to one of the questions, Bijal. I mean, now people ask, I mean, we have all these CD19 target therapy.

I mean, it is getting very crowded in relapsed/refractory setting. And of course, Cervatimic, the MK drug. Initially, I mean, the goal is to get them approved in the relapsed/refractory setting with eventually the plan to bring them early on.

With all these drugs, the planetumumab, the three CD19 cortisotherapy, the emerging CD19 bispecific, where do you see this emerging CD19 bispecific in the relapsed/refractory setting? I mean, let us say that Cervatimic tomorrow gets approved. So how to select for someone who is CAR-naive between Cervatimic and cortisotherapy for relapsed patients?

Dr. Shah: I love, I love the question. And I think it is really, really important to help, you know, navigate that space. Number one, I see these therapies as complementary.

I think that, you know, and again, this, the work that you have done, Ibrahim, contributes to this data set. Right? Giving blinitumumab in your trial prior to cortisotherapy as a consolidation for older adults worked.

Even though both the patients were MRD-negative, it worked. And it builds on this idea that we may be getting some, for lack of a better term, tumor vaccination with our bispecifics. And so you have your patient with bad ALL.

You want to give them the bispecific. And maybe you have a go, no-go decision. Right?

They are doing well. They achieve early MRD negativity, which, by the way, most of the patients on the SURRO trial, you know, were MRD-negative after the first cycle. But, you know, you see something that says, okay, you know, I am concerned maybe you are not MRD-negative at 10 to the minus 6.

I have essentially done my tumor vaccination. Right? I have given my blinitumumab, or I am sorry, my novel bispecific.

And now I am going to consolidate with a CAR and kind of let the immune system take over. And it, again, allows us to punctuate the therapy. Still requires some organization in terms of keeping the patient there for a month.

I am not going to say that CAR T is a button you can push. But, you know, perhaps allows us to think about these novel therapies synergistically. And that is why I was saying, right, these longer half-lives, the ability to space out therapy, you know, really drive the T-cells, you know, to behave in a way that is complementary to what we are trying to achieve with CAR T may allow us to, you know, get over that hump.

But I have a feeling what you were really asking me was not how I am going to combine bites and CARs. I have a feeling what you were asking me is what does it mean for CD19 loss? And for those patients who are otherwise CD19 refractory, right?

Because we cannot really talk about relapsed/refractory BALL without talking about prior CD19 exposure, now that Blinn is really recommended frontline for everyone. And that is a hard one. And I really try to go back to the molecular biology as much as I can.

You know, you had mentioned when you introduced kind of where we are in 2026, this idea of being able to understand high-risk genotypes, not just MRD. I think about the p53s and what that might mean in terms of novel therapy approaches for those, you know, patient subgroups. We are still a long way off.

I mean, you know, we saw the epinetopops data, you know, in AML, which almost got us there. I mean, there is been a lot of almost in p53 AML, but I think lots of opportunities to try and figure out how we can continue to develop that strategy. Again, a molecular strategy in ALL that even perhaps one day we could combine with immunotherapies.

You know, we have got the minin inhibitors now making really considerable progress in the MLL rearrange space. And I could go on and on, but I would say a testament to this sort of therapeutic idea is what we have done with bispecifics and TKIs in the context of pH positive disease. What we are actively doing and learning with now CAR T and TKIs.

And so I think where I hope we land, right, in the next five years, very low dose chemotherapy to prepare someone to receive a bispecific. And maybe we will not even need it. Again, where we are at with bispecifics is going to be so active that we may not even need anything more than a little bit of steroid before integrating the, you know, a bispecific without having to worry about toxicity.

Thinking about what that means in terms of immune stimulation, maybe delivering that with some kind of a TKI component, and then following up with a CAR. And then for those patients that relapse, despite our 19 directed strategies, thinking about what we can do with other immune directed approaches, maybe not targeting 19, but with some of these molecular tools, or maybe even building those again into that bipartite approach. So long winded way of saying the more tools we have, the better off we are.

I do not think that we should worry about competition. We are going to have to, we are going to sort out, you know, which one we are going to use. In terms of, you know, between the different bispecifics, this is where all of the companies that we work with are going to be mad.

One of them is going to be, one of them is going to win. I cannot tell you which one, but one of them is going to win. One of them is going to be the easiest and safest to deliver.

And that is going to ultimately be what kind of lands in clinical practice. So I cannot say it any differently than that. So I will stop.

And now I will try and ask you.

Dr. Aldoss: Thank you, John. I really enjoy listening to you. I agree with you.

I mean, everything you mentioned, I mean, I think this is where the field is moving. It is the only thing, I mean, we live in kind of time where finance, insurance may not approve. You give like two, three novel drugs, like sequentially, you have to fail one before you move to the other one.

At least when we talk about the relapsed/refractory setting. So the question I have, Bijal, someone with relapse leukemia. I mean, like when do you decide that I want to give CAR T-cell therapy?

Again, now everybody actually going to have some exposure to Blenatumab in frontline therapy. So I mean, it will be very difficult to have a patient that did not have Blenatumab exposure before. So I think the bigger question is between this emerging CD19 bispecific antibodies and between CD19 CAR T-cell therapy.

And as we made actually progress in CD19 bispecific, we are making progress even in CD19 CAR T-cell therapy. I mean, with the recent approval of Obacil. I mean, where, you know, previous CAR T-cells used to have a lot of toxicity, although manageable.

Obacil, you have less grade 3 ICANS compared to the other ones, which make it, made it actually easier to kind of offer it to trial for older patients, even for younger patients. I mean, many practices, they move completely from kind of older CAR to more recent, to more newer CAR for that reason. But now you have the CAR, you have the bispecific, and it is also an active bispecific.

Where do you see that you would favor maybe bispecific over CAR versus CAR over bispecific relapse disease?

Dr. Shah: Yes, I mean, and I was kind of hinting that a little bit. So I think the good news is most of us are going to be following our patients fairly closely, right? So they are receiving chemotherapy plus or minus, not plus or minus, chemotherapy with Blenatumab now is kind of the standard.

And, you know, I really put a lot of thought into how to reframe our NCCN guidelines to address MRD. And we created this concept of persistent or rising MRD as a criteria to move directly to salvage approaches. So, you know, starting at that very early stage of saying, you know what, I am two or three cycles in.

Maybe I have already integrated my Blenatumab and I have not cleared MRD. You know, I think at that point in time, the warning bells are sounding. You know, you need to really think hard about what you are going to do and how you are going to move.

And being able to move, again, from an insurance standpoint or a coverage standpoint, being able to move now to novel approaches is not protected, right? You know, it is now built into the guidelines so that it is accessible. So I think that is the first piece.

And now if I am talking about integration in the MRD setting, you got a little bit of time, right? You got time to collect. You got time to administer.

You got time to do things. And I think that there is really tremendous opportunity for integration of CAR, whether that is Brexu, whether that is OB. You know, it is funny.

We do spend a lot of time talking about toxicity with these two different CARs. But to your point, it is gotten to the point where even with grade 3 toxicity, we are still talking about, you know, an average of 10 to 12 days of hospital stay, right? It is gotten to be very, very easy to deliver both products.

And now the question that I think we are all struggling with is, okay, which one is the better one to give? Which one is the easier one to give? Which one is the more effective one to give?

And I think that those are the questions that are going to continue to track us and may again have more to do with reimbursement based on time of hospitalization and hospitalization required. So I think the CAR for MRD, you know, early MRD is probably where I am going. But, you know, we have to acknowledge that somewhere between 5 and 10 percent of ALL will be refractory, you know, or those patients will simply be unfit.

And that is a higher percentage of patients, probably upwards of 15 percent of patients will just be unfit to receive standard doses of chemo immunotherapy and Blenatumumab. And with that, we really need an alternative strategy, an alternative approach. And I think integration of bi-specifics, the novel bi-specifics for this patient group makes tremendous sense.

Right now we are limited, right? The trials are third-line plus. And I think it is going to take us a little bit of time to move some of these novel bi-specifics forward.

But, you know, trying to think about how we move novel bi-specifics into that second-line setting for or even the frontline setting, if you think about it that way, maybe someone's MRD-negative, but they are just unfit for therapy. You know, how do we integrate this so that we can improve outcomes? And again, using MRD adapted approach, if they are failing to clear it early, we have got our cars as a backup.

We are still going to be stuck with 19 relapses, 19 negative relapses. And I think that is always going to be a challenge when we talk about, you know, again, these particular genotypes. We are going to find out that ALL really emerges, you know, well before, you know, that, you know, LMPP step in hematopoiesis, right?

You know, lipocyte, monocyte, progenitor population. We are going to find out that, you know, we are probably seeing some of these ALLs emerge from stem cells that have a myeloid component to them. We are already seeing that in DEX4 rearranged ALL.

We are seeing that in some of the B53s, and I could go on and on. But, you know, I think if we do not acknowledge that, if we continue to try to operate agnostic of the genomic sort of counterpart, then we are also doing ourselves a disservice. So we have to figure out how to integrate those pieces when we talk about, you know, our approaches.

And, you know, to your point, maybe that is the place where you say, okay, you know, I need to think about antigens beyond the classical B cell antigens 19 and 22 and so on. But I want to ask you a hard question because you have been asking me hard ones. So I want to ask you, what is the role for allogeneic transplant in 2026?

Dr. Aldoss: Yes, I think for transplant-naive adults who relapse, I mean, we still recommend transplant. I mean, now, when I have an adult who relapse and they are not fit for transplant or they do not have a donor, which is unusual nowadays, but at least some, you have some adults who relapse, they are transplant-naive, due to psychosocial issues, maybe frailty, some chronic disease, they are not eligible for transplant. I tend to go with salvage therapy that provide actually the most durable remissions.

And as of now, what we know, I mean, we think CAR T-cell therapy is the way to go to kind of try to cure these patients without subsequent transplant consolidation. But I think the field is evolving. I mean, we are trying to see who really can be cured without transplant consolidation.

We have seen some data, so just maybe patients who relapse after transplant and they receive CAR T-cell therapy, they could have durable remission and potentially cure without transplant. We have seen patients with pH-positive ALL who receive TKI maintenance afterward. They have durable remission.

Are they cured? I do not think we know. I mean, it is not like someone who had transplant, then you try to kind of stimulate the GBL effect to take over and prevent relapse.

For someone who is transplant naïve, the question TKI and pH-positive ALL, would it just kind of delay the relapse or truly actually cure the patient? So, I mean, I think there is still significant room for transplant for transplant naïve. For someone who relapse after transplant, I mean, typically second transplant is difficult to do.

Many of us will try to optimize actually the sitting before we give the salvage therapy to improve the chances of cure, like try to reduce the disease before lymphodepletion so we can have a better chance with CAR T-cell therapy in curing the patient, or at least extend the durability of remission. Now, with this emerging by specific antibodies, I mean, the truth we do not know. I mean, data is still there.

I mean, I have patients who are, who has been on the Sorvatimic more than a year and a half, and she is still in remission, and I did not do transplant because she is frail. Now, if we follow her for another year, will she stay in remission or not? So, I think we need to accumulate more data before we start recommending not to transplant these patients.

So, as of now, I would say, Bijal, whenever the patient is fit and transplant naïve, whatever therapy the patient into remission, we still recommend transplant in the sitting. But it is highly debatable. We have been in a lot of meetings, Bijal, and people, they have different ideas.

Patient treated in remission sitting, this is likely curative. You still need to do transplant. It is the challenge if you relapse after CAR T-cell therapy, one of those novel by specific antibodies, options will be limited.

Especially, as you kind of mentioned, if you relapse with CD19, negative disease, because patients, already they get exposed to Blenatoma, but now you give them either one of the emerging by specific or CD19 CAR T-cell therapy. So, so much pressure on CD19. And I worry about actually risk of relapse with CD19 negative disease, where options will be significantly limited.

Dr. Shah: Absolutely. I mean, now sub-Q Blen is moving frontline, right? So, we will have the OUDEX trial that will open hopefully the next month or so across the U.S. and Europe. But that is going to be a big deal, right? With the sub-Q Blen, the PK that they are talking about achieving means that the patients who progress will likely be progressing without CD19. And I think that that is going to really change for all the discussion we are talking about.

It is still a chemo backbone. I still do not know if it is the perfect solution. It is still lots of therapy.

But it is still, you know, I think the closest we have to the ECOG-1910 design for trying to advance, you know, the sub-Q Blen up forward. But it, you know, again, with that approach, we may really be under the wire here a little bit, right? I mean, we are going to have to find alternative approaches and ways of trying to get these patients back into remission.

But I love what you said. And, again, I just want to quote you because I am going to get in trouble when this call is over with our transplanters. One, I want to say unequivocally that I agree with you.

Transplant for all-comers with newly diagnosed ALL is not where we are anymore. I think that we have such effective therapies for first relapse that we need to think hard about who is getting transplant in the frontline setting. I will still transplant the P53s and, again, the mixed phenotypes and these others.

But by and large, we really have to thoughtfully, you know, step back from our ECOG-2993 experience and say, okay, well, maybe with CAR-T, maybe with serovotimig, maybe with MK-1045 and sub-Q Blen and so on and so on. What we are really saying is transplant is relegated to first relapse. And, you know, given the fact that these therapies work so well, the novel bispecifics, you know, even in that post-CAR, post-Blen setting, you also got to wonder maybe what we are really saying is outside, you know, again, you know, those high-risk genotypes, maybe even for, you know, second relapse.

And I am not saying I am not willing to commit to that just yet, but I think that that may be where we are realistically headed. And that is certainly where we are in other lymphoid neoplasms like large B-cell lymphoma and others. We are really waiting to third-line plus because our agents just keep getting better and better.

I really appreciate that. We did not really talk a lot about CRS or ICANs with the different approaches, you know, only because we have about 10 more minutes for this, just to kind of balance out what we have said in terms of how excited we are in terms of the activity. I do not know if you wanted to comment a little bit.

You mentioned a little bit with Sero that you are seeing low rates of CRS and ICANs and maybe even lower with MK-1045. But I do not know if you wanted to sort of comment on what we are seeing across these novel agents.

Dr. Aldoss: Yes, I mean, with MK-1045, I mean, what they have seen, they have seen no ICANs at all. Although they have seen maybe around 40 plus percent grade, all grade CRS and maybe grade 3 was around 3%, if I am not mistaken. So we are about to make, again, we are seeing grade 1 and 2 CRS, but grade 3, I think there are only one case.

ICANs, grade 3 was only one case, but we have seen grade 1 and 2 ICANs. Usually they are reversible. I mean, in general, by specific antibodies, I mean, ICAN CRS are manageable.

Maybe sub-tubulinar, we are seeing more ICANs, grade 3 and higher, but it is also reported as manageable with treatment. CAR T-cell therapy, I mean, it was more challenging with the older CAR T-cells because it can take longer time for the ICANs, grade 3 and 4 to resolve. And again, we are getting better and better with the CRS management.

And the truth, I mean, as you know, Bijal, with the ROCA real-world data, I mean, the majority of patients were treated for CAR, they are treated in an MRD setting. And that maybe explains why we are not seeing many grade 3 CRS, but ICANs at least with PRXEL cell remain high, grade 3, but it is manageable. And now we have OB cell where we see actually less grade 3 ICANs and CRS.

So I think we are getting better in managing CRS and ICANs. And we are having actually a newer CD19 immune therapy that produce less actually high-grade CRS and ICANs. So I think ICANs and CRS less a problem nowadays compared to before.

And typically it happened early on. That usually beyond the first, second week, it is not something you keep seeing afterward. So this is why I think the primary focus should be efficacy.

I mean, toxicity is important, no question. But since it is manageable, we are seeing less. I think the primary kind of focus should be efficacy.

I think second will be convenience. I mean, what happened after the initial phase, you achieve remission, patient are not going to transplant. I mean, how frequent they need to come to the clinic or to the hospital to receive treatment.

I put it at the same actually, the same kind of area where you mentioned that this is part of the toxicity, the burden of the treatment, how to administer it. I mean, I think this is a nice way to put it, Bijal. I do not know if you have any other thoughts about toxicity.

Dr. Shah: Yes, I wanted to ask what you thought about cytopenias and in particular infection. You know, and we have seen that really stand out with CAR T-cell immunotherapy. And so, you know, you hit the nail on the head, right?

In terms of CRS and ICANs and kind of what we have seen and how we have gotten better at picking the right patient, but also even in the right patient, managing those toxicities much more effectively when they do occur. But, and it is a big but, we are still stuck on the back end, right? You know, it is about a 15%, you know, overall mortality after non relapse mortality after CAR T, almost half or more a reflection of infection with CAR T and kind of speaking to hypogamma globulinemia, you know, all the pieces that come with that.

And so I do not know if you had any thoughts, particularly now, as we talk about maybe moving by specifics earlier in that space, you know, in terms of what we can expect in terms of keeping patients safe. Maybe it is something we also need to approach with the same, I mean, diligence may not be the best word, but, you know, thinking about antibody levels and, you know, prophylaxis with acyclovir or Bactrim or something along those lines.

Dr. Aldoss: Yes, I mean, I would say cytopenia is more a problem, prolonged cytopenia after CAR compared to by specifics, at least from my experience with surovatamig, although we have reported, as you are aware, prolonged thrombocytopenia. But I do not think it is purely related to the drug because, I mean, what happened, we are able to actually continue the drug with thrombocytopenia and the patient recover the platelet while they are receiving the target dose of surovatamig. And that was not very common.

Well, we see it more common after OBCell and Prixacell and T-Cell. And that eventually, actually, many of the patients eventually recover their counts, but it can be prolonged, can last, as you know, eight weeks, sometimes even longer. And you can see infections in that setting.

My experience with the bi-specific antibodies, I mean, I am not sure if we are seeing more infection than what you expect for any salvage therapy. And they tend, the majority of patients, they tend to recover their counts at the time of end of the first cycle, and they tend not to drop the counts with continuing therapy. Now, hypogammaglobinemia, I think it is always comes to question with bi-specific antibody, with CAR-T-cell therapy, and there is a debate if it is needed, if you need to replace IVIG or not.

But I tend to do. I mean, these patients, especially if they are heavily pre-treated, advanced disease, they have been neutropenic for a long time. I mean, we try as much as possible to optimize their immune system to reduce the risk of infections.

And as we move it to kind of frontline therapy, I mean, this patient will be kind of treatment-naive initially. We may not encounter as many infections as in my CAR-T-cell study. Although we saw some prolonged cytopenia, was not as much as what we have seen in the relapsed/refractory setting.

And I can share with you, infection was not a problem. I cannot think of any patient who experienced infection. They have grade 1 CRS, but actually isolating bacterial infection, fungal infection, I cannot think of any patient.

So maybe as we move it to the frontline therapy, this will be less of concern.

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