So here we are in Nice, South of France, for the 4th International Workshop on Acute Leukemias. And we’re discussing here with three colleagues. I’ll present them in a second. It’s session three: novel treatment strategies in ALL. So a couple of well, one person was from a distance is not here. We have Nicholas Short, Nicolas Boissel, Rob Pieters and myself. I’m Robin Foa.

So where do we start from? Shall we follow the program? Because Nicholas Short spoke a bit about ponatinib combination strategies in ALL. So do you want to sum up briefly what your views on this? And we discuss it, obviously.

Sure. So, you know, we have a number of different TKI options for Philadelphia chromosome Positive ALL now, and so our approach at MD Anderson I know a lot of others are also looking at this is the role of ponatinib. We know that T315I mutations are a common mechanism of resistance that occur with first or second generation TKIs. And so that kind of is the rationale for the use of ponatinib, particularly in the frontline setting. So there have been multiple studies looking at ponatinib-based combinations. So we’ve done a study of hyper-VCAD plus ponatinib, which showed very high rates of complete molecular response, a five year survival rate around 75%, with most patients not needing transplant in first remission, or at least not undergoing transplant and still having very good outcomes. Other groups have looked at looked at steroids plus ponatinib, and also other approaches of chemo plus ponatinib. There’s the PONALFIL study, which looked at chemotherapy plus ponatinib followed by transplant, and that led to very impressive long-term survival. Three year survival rate around 96% with the chemo, ponatinib and transplant regimen.

I think now we’re moving towards chemotherapy-free regimens. So now we have, as you know, so I would agree. So as you know, so we’ll say TKI generally plus blinatumomab. So I know that you and and your group have done dasatinib blinatumomab with with excellent results, we’ve looked at ponatinib plus blinatumomab. The idea that ponatinib is a more potent TKI, and hopefully we’ll overcome any potential T315I mutations that could emerge. We’ve seen very good outcomes with those so far. Very high response rate. Complete molecular response rate of about 85%. The follow up is still relatively short, but the two year survival looks to be 93%. And importantly, we haven’t been transplanting patients on this protocol. So I think we’re very excited about this chemotherapy-free regimen as a potential way to overcome the need for transplant in patients with Ph positive ALL.

Do you have an age limit to that study? I can’t remember.

There’s no age limit, so we treat it up to 80 years, or so.

Is there a lower age limit?

18.

So initially we were concerned. Initially, we were very concerned about eliminating the chemotherapy entirely from patients, you know, from these patients who are younger, so initially we did some chemotherapy-based combinations with them, even with the blinatumomab and then now its full chemotherapy-free 18 and older, because I treat adult patients only, so. You want to add something on this point?

Yes, because the transplant has become a very important question. So what we have decided in the…group is to combine low dose chemotherapy, blinatumomab and ponatinib, and to ask for the indication of allogeneic stem cell transplant and to randomize the transplant in patients with a good MRD response. Because we think that probably, Ig/TCR MRD will add some information when compared to BCR-ABL. Maybe we will use Ig/TCR MRD to assess the response to the patient and patient with excellent response with no detectable MRD after blinatumomab and ponatinib will be randomized to receive allogeneic stem cell transplant or not. So I hope we have an answer to this question.

We hope so, too, from our studies. But I think one point that we should make to whoever follows this online, I think it’s an important point because I mean, you’re younger. But in the old days, the Philadelphia -Positive ALL was the worst condition you can get. Maybe not only in hematology. It was a real disaster. Now, this morning it was said this is a favorable condition. I mean, I’m old enough to remember somebody else, that this was exactly the opposite. So this I think is a message that we should convey very clearly. Paradoxically, this has become a favorable subgroup, but we have to diagnose it quickly. That goes back to what we discussed this morning. I mean, we need the laboratory, and that’s the key point for the mandatory ALL.. all ALL, not only for the Philadelphia. Laboratories, here you have to pick up the BCR-ABL within a few days, a week. Maybe if you have the steroid prephase. Then you start the TKI without going to do which or whatever this is. I mean, if you want to consider chemo free, you need to make a good diagnosis. We need the MRD. You’ve been discussing the MRD, MRD is a key point.

And you can’t cure the patients if the patient has become MRD negative. So I think this is a real revolution. I asked you the age because now we can cure 70 year old 80 year olds, try to cure at least treat them adequately, even if.. our oldest is 89, two 89 patients. And they responded very well. This is unthinkable. But you have to diagnose, and I think it also has consequences for the Children with ALL, so below the age of 18, because now we only transplant 5 to 10% of these cases based upon the MRD.

But we said for 40 years that the adult ALL had to learn from us, but I think now it’s the other way around. It’s not only replacing the transplant, it’s also replacing the intensive chemotherapy we use at the moment, and that should be changed in the coming years, I think. It’s a very important point. I mean, I started as a pediatrician so many years back, I find it amazing. Despite the data, you still give intensive chemo in kids. I know they put up with a much better than adults, but there can be side effects on the long run. So that’s something that it’ll change, I’m sure. Any other comments on this part here? I think we should definitely move on. The second and let’s go to Nicolas, we have two Nicholas – progressing treatment in adolescents, young adults. I mean, that has been another key point. I think, in management of ALL. If we talk about the changes in ALL, one has been the manner of young patients.

Because in the old days, again to do a bit of history, what happened if you were the adolescent was a question. If you were 17 were you treated in a pediatric department or an adult? So when the pediatric got a pediatric protocol and if you were in an adult, you got an adult. And that made a difference because it all started by retrospectively analyzing young adolescents treated in the pediatric, came back that if you’re in a pediatric… and do you want to make a comment on that? That’s what you covered here.

It’s an important question, and this story started about 20 years ago, and, by comparing the outcome of patients age 15 to 20 years old, treated either according or in pediatric or in adult trials. And at that time it was obvious that just the treatment or the care pathway or journey of the patients were a very important prognostic factor. And, so many groups have extended either pediatric approaches or pediatric-like approaches, and I think that the question that is still pending say is how old, until which age we can extend this this kind of practice. And I think it’s of course, really protocol-dependent and intensity dependent because, in our experience, but we tried to extend up to 60 years old. We found that in patients older than 45 clearly older than 55, it was not reasonable to have this asparaginase and delayed intensification and so on. But we know from other studies that very intensive study that if you try to apply this protocol in patients older than 30 it’s also not reasonable. So for each protocol, or each schedule, then you may have an upper age limit to apply these trials.

And what has become obvious also because of short-term and long-term toxicity, is that probably will reach like a ceiling in terms of dose intensity. And these AYA patients, that now if we want to move forward, we will have to combine either with small molecules. We know that in this AYA population, we have a high amount of patients with Ph-like ALL, so activating mutation for signaling pathway. Some of them may be targeted, and there are some prospective trials with tyrosine kinase inhibitors or JAK inhibitors, for those with CRLF2 rearrangement and JAK-STAT pathway activation. But of course, the more reasonable, is to implement the immunotherapy that have been approved in the relapsed/refractory setting, antibody drug conjugates, inotuzumab or bispecific antibodies like blinatumomab frontline, according to MRD response for all patients, or for inotuzumab for instance, in patients that are not eligible for allogeneic transplant. We know that there is a question about, hepatic safety in these patients that receive inotuzumab. So there are a lot of trials now that are addressing this question of inotuzumab in patients with a good MRD response that are not eligible to allogeneic stem cell transplant, and that will be randomized to receive inotuzumab either in consolidation or delayed intensification.

You know, they said, it’s interesting again because, as you said, these data go back about 20 years, and now it’s all changed, the approach. Because the young adults are treated very intensive, but even less young are treated more intensively than we used to do 20 years ago and this is based on these studies. So I think it had a broader consequence than only, let’s say, from up to 30 which is obvious. But even later we’re treating… and again the laboratory plays now a role, because you mentioned the abnormalities, et cetera.

Thanks. Okay. And the third one was on an old drug. Asparaginase, which is still possibly the most effective single drug in ALL, maybe. I don’t know.

I think together with dexamethasone…

That’s another new one that’s extremely new. Has it been approved? I don’t think.

My talk was mainly on asparaginase and had basically two important messages, the first one was, if you truncate the asparaginase, you do not give the planned dose of asparaginase.

That you’ll with ALL then have a worse outcome. So you should try to replace as much as possible if you have to stop the first line drug, which is PEG-asparaginase. And the second message was to use therapeutic drug monitoring for asparaginase because you can pick up those patients that inactivate the drug in a silent way. So without clinical signs, inactivated drug, and then you can pick it up with a drug monitoring and replace the PEG-asparaginase with Erwiniase.. And the second thing is we can use therapeutic drug monitoring is to lower the dose that we need because we see that many, many patients have far too high drug levels, which is not necessary. And, well, there is more and more evidence that is related to some important side effects. So this may also be helpful for the adult population.

But the drug is still very much used in the Philadelphia negative. Obviously we’re not talking about the Philadelphia positive.. yeah

And the Philadelphia positive population in children is only 4%. 96 other are, Philadelphia negative. So, yeah. And of course, we randomize, for instance, inotuzumab we randomize blinatumomab in the frontline treatment. So let’s say in four or five years from now we will know better whether we can use this drug to replace intensive components of the chemotherapy. I hope so. Yeah.

Any other comments you would like to make because then maybe we can conclude, or

If I could be a little contrary. And as you may know, that we don’t use asparaginase, really…

I didn’t want to say it-

Well, you know, we do in the T cell ALL, I mean, I think maybe it may work a little bit better, but it’s certainly it’s a very it’s very effective drug, without a doubt. I think ultimately the question is, and it’s very important that all of these tweaks are being made in terms of optimizing the dose of asparaginase, and who can receive it.

I think the big question going forward is going to be will we need the asparaginase and the toxicities that are potentially associated with it as we move to integrate the inotuzumab and blinatumomab? So we’re using, you know, uh, non asparaginase, hyper-CVAD backbone, but introducing the inotuzumab and the blinatumomab into that, and I think ultimately the question is will we be able to get similar, even better outcomes to asparaginase-based regimens. I agree that you know there’s some data out there retrospectively suggesting that all other things being equal that the asparaginase-based regimen may be superior to the, quote on quote adult regimen. But if we introduce all these other agents, do we need the asparaginase? And I think that’s an open question.

And that doesn’t account only for asparaginase. It also accounts for the anthracyclines.

Do we need all of those drugs? Exactly

So these are even more.. How intensive chemotherapy do we need if we use all of these other agents? I think

I think that’s an important point. And we can probably almost finish with this because I think whoever will listen to us, I think that’s a very important point that for the Philadelphia positive ALL, many times we spoke today of chemo-free strategies, maybe not for all, but for many or chemo and even transplant-free, probably or possibly. For many, this is a total revolution. This will probably extend to the Philadelphia negative B-lineage, at least, because we have drugs there. Nobody mentioned anti-CD20. But I mean we have anti-CD20 drugs. Obviously, we have other antibodies, so I think this is going to be a key point to reduce chemotherapy. Definitely. And the elderly, I mean, we forgot. We didn’t forget. We mentioned it in the room.

I mean, the median age is increasing.

It’s true. But the advantage to the Philadelphia positive ALL, you have a targeted agent. You have the TKIs, which is not the case. And I like very much your approach. Actually, last week I visited with our queen MD Anderson to learn from the chemo-free regimen. But for the Philadelphia negative, you still use a lot of hyper-CVAD together with blina and ino, which is very good. But you have to realize that as long as we don’t have a targetable genetic lesion, we are not sure whether you can only go with blina and ino. And you know, for that we..

I will just add quickly to Dr Foa’s point, and that’s a very important question. Our plan is to slowly move down the age that we’re using. So right now we’re kind of doing these low dose chemotherapy, inotuzumab blinatumomab in the older patients, but can we push that and right now it’s kind of 60 and older. What about 50 and older, 40 and older as we see..

Reduce chemo..

Yeah, and move it up in the age range because obviously, everybody’s apprehensive about going to starting, treating a 20 year old patient with, you know, very low intensity chemotherapy. And I know blina, but maybe in the future, maybe that’s what we will do. I mean, we’ll have to see and one other big difference is at the moment we have a five year survival in childhood ALL of 94%

And, well, personally, I believe we can reduce the chemotherapy a lot. The problem is, will the parents, accept this? take the risk..

I don’t know if you heard at the end the Dr.. from MD Anderson asked, Do you think we can stop TKI in the Philadelphia positive ALL?

I mean, we would all love that. The answer is no so far. Who would ever stop, it is an acute leukemia is not a CML.. You can retreat. There’s no problem… But the hope one day will be if you have, I don’t know, 2, 3, 4, 5 years molecular negativity. If your molecular testing is becoming more sophisticated as it is, maybe this can be at an endpoint. The final point I would like to make, because I think we have to stop.

All this, but it’s something I’m always very close to me because we have events in many parts of the world is the fact that all this is laboratory driven.

How doable is it? I mean, I’m very concerned of that. I mean, all the session have been MRD-oriented sessions. Apart from diagnostic, addition, genetic abnormalities. This is not doable. So I think one other point is that I think this should be made available. Maybe the cooperative groups, it hasn’t been done in every center but regional, to offer the best diagnostic work-up and follow-up, which translate into curves that have changed dramatically over the years, not only in children but now in others, too. So this is a major point.