Hi I’m Bijal Shah, I’m here with Dr Sabina Chiaretti, Dr Elias Jabbour, Dr Nicolas Boissel at the International Working Group for Acute Leukemias in Nice, France. And it’s my pleasure to talk to all three of you about the evolution of therapy in adult ALL, finally. Sabina, if you can tell me first what’s changing in Philadelphia positive ALL

Well, in Philadelphia positive ALL in this moment, everything is changing because we passed from a moment in which the prognosis was horrible. And it’s not so far time ago to a moment in which we can and we’re realizing and Sapienza, MD Anderson, several groups are realizing an approach in which we’re not using chemotherapy anymore, by dual-targeting leukemic cells from one side using TKIs, second or third generation TKIs plus blinatumomab, specific monoclonal antibodies. And I think that from our study… which was followed from another trial which is currently ongoing with ponatinib plus blinatumomab that the results are quite sound. We have… follow up of 40 months and we showed that the overall survival and disease-free survival is in the range of 80% so the results are quite impressive. Similar results with a shorter follow-up are from the MD Anderson. They are now using a similar approach using both ponatinib and blinatumomab, different schedules in the way of administration. But we seem to go in the same direction.

So Elias, are we at the point now where Ph positive ALL is no longer high-risk?

Well, definitely. It’s not high-risk. I think Ph+ ALL is what CML used to be in 2000 when imatinib came to the market. I think it’s a revolution in this treatment. I think the best disease to have in ALL is a Ph positive. In fact, we’re not doing any more transplant. We went from intensive chemotherapy to transplantation to immune therapy, the target therapy and transplant may be minority, and the next step will be, can you imagine Bijal, like curing…stopping therapy? So we’re now following these patients with the NGS to look for the response sustainablity of the response and slope of the response, and maybe one day be able to offer therapy for, like, three or four years and we’re done. We’re not there yet, but we’re going there. This is very, I mean, I still remember the original trial data, right. It was around 25% long-term survival only in patients who are transplanted with imatinib and chemotherapy. That’s remarkable to see what’s changed.

Dr Boissel, CAR-T cell therapy. We had a nice conversation about that. And one of the challenges with Ph positive ALL, or at least in the past, was the development of central nervous system involvement. Can you speak to the efficacy of CAR-T cell therapy in managing those patients? Is it something where we still need to consolidate with transplant or how are the results looking?

You mean in patients with CNS involvement or, in general?

Isolated CNS involvement using using CAR-T cell therapy.

So I think that we have enough data now to say that CAR-T cells are efficient for patients with CNS infiltration, even if we lack huge data in the field. Because, as you know, many of the patients that were included in the study had to have controlled CNS disease before being treated. But now there are real-world evidence that those patients with a history of CNS relapse or with CNS relapse at the time of apherisis do quite well with CAR-T cells. We know that CAR-T cells are able to cross the blood brain barrier and to control the CNS disease. So in this patient, in our experience, we do not add any therapy to CAR-T cell. And I think that we need more data, but it’s what we do now.

Wonderful, Dr Jabbour, I mean Elias, tell me for non-CNS EMD, I mean, this is one of the things that I had shared during my talk, but I was also surprised by it seemed as though we’re still having some difficulty managing those patients. You had mentioned that maybe antibody therapies could provide some benefit there.

Correct. You know, Bijal, we heard during the presentation, about ino, blina and CAR-T cells, but I don’t think we should pick one or the other. The best approach is how to use them in the optimal fashion. Maybe a combination, sequential approach. We know that ino works well with extramedullary disease. The responses are short-lived. So what we’re doing, what we did in Houston is to embark into a combination of… ino.. Lower the tumor bulk and then add the blina sequentially, and then eventually CAR-T cells. And now we moved another level. So we moved to another level by… receiving the ino-blina together. So we do the four days of ino chemotherapy. On day 5, we start the blina. So we downgrade the tumor, because earlier you see the response happening really early on and add the blina, and take advantage of the maximum combination.

And one thing I would like to hear your opinion on that because I don’t think CAR-T should be offered as they are. And you mentioned you thought maybe CAR-T to go replacing allo-transplant in your conclusion and go for randomized trial, and I’m fine with that. But I think what we can do is for these patients with high-risk, to get the ino-blina, because they’re going to be front-line, no matter what we will do and you hear prior blina – I don’t believe this. So, essentially, ino-blina are here to stay in the frontline. So we either add CAR-T consolidation or CAR-T will be for multiple failure and for a short survival. So I think you get your ino-blina, I mean…for example. You want to call it or call it whatever you want, because people are sensitive to mini-CVD. Mini-CVD ino-blina, add CAR-T consolidation, do a pilot trial and then come back into a randomized trial for high-risk patients. You randomize them to mini-CVD, ino, blina, whatever, followed by either CAR-T or allo-transplant to high-risk patients and prove the point.

You know, I’m going to go further. I would say for high-risk, we don’t need randomized data. And I will tell you this is my honest… I’m coming from a place where I don’t do randomized trial. But just because I know some people next to me are sensitive to this point… but I do think for low and intermediate risk and and again trying to understand how we use these tools as complimentary, right? And not competing. But complementary for the optimal management of acute leukemia is going to be important. And I have to tell you, I was talking to one of your colleagues, Nicholas Short the other day. I’m really impressed by the combination of inotuzumab and blinatumomab for several reasons. Not just because it works and because it’s safe. But, you know, ultimately, if that proves effective in the long term, you heard a question today. Can we add anything to CAR-T cell immunotherapy? Meaning actually during the CAR-T cell immune therapy phase may be part of our lymphodepletion now includes the addition of inotuzumab understanding that its half life may actually again control those patients with higher tumor burden, may give us some ability to optimize immunotherapy, ponatinib and blinatumomab again, highly highly successful therapeutic approach in Philadelphia ALL, but what if it has not as much to do with controlling the ALL, what if all of those other targets that we’re hitting, you know, and this is something that Dr Nitin Jain is going to be studying looking at ponatinib in T-ALL. But is there an immunotherapeutic benefit to some of those targets? Can we start now integrating therapies onto a CAR-T cell backbone to extend our remission duration? These are all fascinating questions to me, but again, building on what you said these are complimentary.

But we’ve seen the real-world data with the CAR-Ts, and true, the best outcome is seen in MRD negative setting. So people are concerned about B-cell expansion correct and all things. And, you know, the data is fascinating where you get the best outcome when you have no disease. So if I want to go back to the financial questions because I hear from colleagues in Europe, well, it’s expensive and when you get…all things. But if we invest into a product, it will be best to invest up front and put my money up front and have the best… Theoretically, we MD Anderson show the way. But if if we want the drug to be accessible for a lot of patients, and not only in clinical trials, I think unfortunately, we have to go step by step and we have to demonstrate the benefit of inotuzumab frontline. We have to demonstrate the benefit of blinatumomab frontline. There are a lot of Phase III studies that are ongoing. And I think, of course, the way is to decrease the toxicity also in AYA patients, because we know that we’ve reached… in terms of toxicity, in the elderly, it’s known for years, but in AYA it’s also the case. I think that we have reached the maximum in terms of intensity in terms of asparaginase, for instance. And now if you want to go back and de-escalate, we have to go step by step. I agree on the direction. But if we want to make the drug accessible for everybody, then we have to respect.

I agree with randomized trial 100%. But my question is right now what do we compare to? Because let’s say you want to embark into a trial, blina-chemotherapy, that together we work on it versus chemotherapy. So okay, when you go for randomized trial, it will take it 3, 4, 5 years to get to the end point. But then we know that ino-blina is better than a hyper-CVAD blina alone. So we need to have If we have really an optimal regimen we can compare to, by all means but the treatment is evolving so rapidly that we cannot pick a winner to go for the randomized trial.

In principle, I think we totally agree. I mean, you’re completely right. Unfortunately, at least for Europe, and most likely, Nicolas understands better than you my point, we unfortunately have to respect some rules. And we have to prove, despite we believe that sometimes it does not make sense. So can we be brave? I mean, we’re here. We’re again. I’m sitting in front of three luminaries in ALL. Can we be brave and propose randomized designs that do just that?

You can still use the… You can still use PATHEMA, GIMEMA, whatever, but it’s randomized against something that’s radical that brings ino and blina frontline without the chemotherapy or with minimal chemotherapy that brings CAR-T cell therapy into that frontline setting. And now, with randomized data, begin to answer that question. And I would be hopeful in that scenario that if there is an advantage in longevity, I do believe there’s an advantage in quality of life, having treated many CAR-T cell patients, cutting back the chemotherapy and not having the consequences of, I could go on and on. But the point being that to me is a randomized design. And I wonder, with the regulators scoff, would they say, listen, here’s the data from MD Anderson. Here are the frontline data. You can do this and then we change the world. In the US when you have a system where you can force the drug company to give you the drug if you go for randomized trial, a cooperative, you can go to sit up and you can get the drugs. It’s not the same in Europe and the US.

But instead of like right now, we’ve got trials sponsored by pharmaceuticals with the drug approved because they don’t have interest to… they don’t see bigger than their own drug. So if company A has product A, I want to fund A randomized to standard of care and then B will be competing with me..

Instead, if a government or health authorities force company A and B to donate the drug to a randomized trial and do the best sequence or the best optimal regimen in a randomized way, that will solve the question, because otherwise when I get to randomized trial, by the time you get the results, it will be obsolete, outdated because something else is coming. This is my concern right now in ALL.

You really think that something else is coming after the 95%?

I think it’s beyond the point. But unfortunately for certain things we are really forced.. Can I refer to one question of yours because you were speaking about CAR-T and immunity and so on. And I don’t know about ponatinib. We’re studying the effect of ponatinib on T-regs and NK cells. So hopefully with the new trial… we will see something more. But with the… study, What we showed was that we know from several studies that for sure that dasatinib somehow up-regulates the immune system. So for sure, it’s not only the target effect on the… cell, but also on the immune system,

Absolutely. And this is something that is very important also for in light of CAR-T later. Exactly. So there was initially some data, you know, looking at…inhibition, looking at that impact on B-cell receptor signaling. But now we also know LCK inhibition and and these things can impact T-cell proliferation. But the reason I specified and monocytes right, it was very focused on T-cells. And obviously we have the entire tumor microenvironment to contend with, and we may find that it’s not just a short period of T-cell rest, but actually, there are many other changes that are happening in the tumor microenvironment to provoke and extend the benefit of CAR-T cell therapy and bispecific antibody therapy on the line. So very exciting. To your point about 95% survival at what cost. And that’s still my question is, you know, I love ponatinib blinatumomab. I’ve been doing it, actually, after the very first presentation that, you and and Nicholas Short gave. We’ve been using ponatinib blinatumomab at our institution. But I would also love it even more if it was just one cycle or two cycles and I could stop and this is really what I’m coming to that there is. There

We went from transplant to lifetime treatment..

I’m very aggressive. Yes, because I think that, you know, we can, we’re all inspired by our patients to do better and and to make it easier. And as you pointed out, I want this to be CML on the other hand, we must be ethical. So we need time to confirm our results.

Thank you.