iwAL 2019 | The evolving landscape of ALL therapy and the impact of MRD

Dieter Hoelzer:
We had a remarkable session today on adult acute lymphoblastic leukemia, with a lot of new therapeutic options. Just to set the scene. We cure now about 60% of adult ALL and in adolescents we already achieve 70 to 80% cure, five years and longer. However, we would like to reduce the intensity of the chemotherapy. We would like to reduce the stem cell transplantation, and we also focus on elderly patients. So we discussed more or less all these topics. The first one was how oncogenetics can improve the classification in ALL.

Oliver Ottmann:
Yes. I thought that was actually a topic that pervaded several of the talks. Some very elegant presentations which actually I think bring us to the new level of diagnostics. In a way we are taking the same pattern as from chemotherapy where we combined agents, and with the MRD now we combine MRD with other oncogenetic profiles, and actually some very simple old-fashioned things like white blood count, which actually are reappearing as a discriminator.

Dieter Hoelzer:
We discussed today actually in every talk, minimal residual disease. In acute lymphoblastic leukemia, we are in the lucky situation that 95% have their individual markers, but I think that in nearly every new therapy MRD is guiding the avenue.

Oliver Ottmann:
Absolutely and what does strike me is that in areas like Ph-positive ALL, we still don’t have a common uniform approach to MRD. We recently had a meeting with Heike Pfeifer from the Frankfurt Group, who’s been working since 2007 on standardizing the MRD analysis in Ph-positive ALL. So lagging behind, but I think that despite all the improvements, standardization still is the major avenue that we have to pursue.

Dieter Hoelzer:
I think that is one. The other is we have a really good prediction. If an adult ALL patient is MRD-negative, the probability to be cured is 70%. However, we have also 30% they achieve a molecular remission, but despite this they relapse. Now the question is, do you think that next-generation sequencing or digital droplet PCR, going to a deeper sensitivity, could improve it or it’s more a hope?

Oliver Ottmann:
Well, I personally am convinced that more sensitivity is going to improve things. But what strikes me is that we always try to extrapolate from maybe two or three early time points onto what will happen over several years. I mean, actually data that I showed was that we have relapses over the course of the first, second and third year of treatment.

Oliver Ottmann:
What I’m wondering, whether or not this approach of having only early analysis is really appropriate, or if we shouldn’t do it like the CML community do, who over time, throughout treatment actually serially measure MRD, and also act in small increments. Looking at the cost, I think that actually MRD is not so expensive, that in view of the treatment options it really makes a dent.

Dieter Hoelzer:
So what you mean is we should follow longer minimal residual disease, you showed it clearly that in Philadelphia-positive ALL, which are 25% of our patients, and 50% of all older patients, a constant follow up of MRD is necessary.

Oliver Ottmann:
Yes.

Dieter Hoelzer:
It might well be with our very promising new immunotherapies that there is same case. We have to go for longer periods.

Oliver Ottmann:
I agree. I think the lack of therapies that we had before was also the reason why it wasn’t widely adopted. After transplant, it has been accepted more widely. There was, TKI, donor lymphocyte infusions, whatever. But I think only now are we actually in a position to act on an MRD signal prior to transplant. And so, hopefully this will promote a more stringent serial analysis.

Dieter Hoelzer:
We discussed in several presentations the role of stem cell transplantation. This is after chemotherapy, so far, our curative approach. However, still we have a 20% treatment related mortality. It even increases in the older patients. So clearly the wishes to substitute allotransplant, also it’s curative by any other therapy like the immunotherapies. But there is a kind of hope. So what do you think is the situation reality?

Oliver Ottmann:
Well everyone wants to get rid of transplant. When it comes down to making the decision, it is the tried and trusted curative option. We do tend to ignore all the grafters as hosts and the long-term morbidity issues, which are improving nowadays. I think that what we have to do to get rid of transplant is actually to use all of our newer agents in the frontline setting.

Oliver Ottmann:
And with frontline I mean, MRD-positive as a trigger is fine, but I think we have to move them up even earlier because that’s where all of the prior treatment have really made an impact, and not later on. Then I think we will have a realistic option, together with the MRD and the other risk predictors to fine tune treatment to an extent that we will actually start seeing a drop in transplant.

Dieter Hoelzer:
It’s also interested, in transplant, we had the strict age limits, 50 years, 60 years. Now, as in your study, patients above 65 or elderly patients are transplanted with reasonable good results? So it’s even not out in the elderly patients.

Oliver Ottmann:
I mean, we had results of 61% long-term survival with a median age of 61, although in that trial there were very few haplo transplants, and although many people would still consider them a little bit premature, the Chinese are using them all the time, and with the posttransplant cyclophosphamide, the patients, the elderly patients that I’ve seen actually go through it almost with ease. I don’t want to make it sound trivial but I do see a huge improvement over the conventional conditioning regimens and immunosuppressive regimens.

Dieter Hoelzer:
Two other topics raised today, which are the real great promise in ALL is the immunotherapies and several new generations of tyrosine-kinase inhibitors. Can you comment first on the last one, because we have now many of those?

Oliver Ottmann:
Actually, I think it is very encouraging and interesting that the kinase inhibitors are now also being applied in the non-Philadelphia positive population or a part of it, like the Philadelphia-like or BCR-ABL-like population, where Ponatinib seems to have considerable promise.

Oliver Ottmann:
I think we will follow the same pattern, we will combine it with immunotherapy, be it a bispecific antibody or an immunoconjugate, and we will benefit from the experience that we have had in the Ph-positive. So I think that in a couple of years we will probably get rid of a large part of chemotherapy in a substantial fraction of the patients by early introduction of immunotherapy.

Dieter Hoelzer:
But just to say, I mean, okay, one of the intention is to reduce the chemotherapy, but we have to realize 90% of the children are cured still with a simple combination chemotherapy.

Oliver Ottmann:
Yes.

Dieter Hoelzer:
You know, that’s a point. It’s also cheap compared to anything what’s coming up. So we have to think very carefully where we substitute chemo being successful, with the limitation that it doesn’t work in this intensity in elderly patients, to be replaced by the other one. But I just want to come back to the Philadelphia-positive. There were only 10% surviving 15 years ago, 10%. In all the international studies, it was the worst subgroup. Now with the tyrosine-kinase inhibitor and a transplant, the cure rate is 60% in all the studies. This is a real great achievement. So moving away, it’s a risk.

Oliver Ottmann:
Yeah. No, absolutely. I mean, when I started working on Ph-positive ALL, everybody thought I was crazy because it was ridiculous. It was a waste of time. It was dismal. Now it is a paradigm actually for successful targeted therapy. But coming back to the pediatricians who actually are using the same regimens that we have, TKI, plus chemotherapy, are even better than we are in terms of their cure rates, which makes it more difficult for them, because they have more to lose by reducing the toxicity. So they’re the victim of their own success in a way.

Dieter Hoelzer:
Yes. But if we argue with age, I mean the adults are not elderly children.

Oliver Ottmann:
No.

Dieter Hoelzer:
We have different genetic markers and I think this beautiful concept of curing 90% in children works just in children. As older you are, you will less tolerate the chemotherapy. So we are now in a new era where we explore the new drugs that we will just discuss as next point, the immunotherapy, where we start in the elderly patients to avoid any deaths with intensive chemo, reduce the transplant, and explore the new avenues with immunotherapies.

Oliver Ottmann:
Yeah. It’s almost a reversal of what we did before where we learned from the pediatric doctors and the children’s study and now it’s almost the opposite.

Dieter Hoelzer:
I guess, we have to show it in the elderly where there’s much room for improvement, and generally considered in the US and everywhere to improve the elderly is a medical need. We will do it, most likely with the immunotherapies. Then we go back to the adults, and finally the pediatrician will adopt the things which are safe.

Oliver Ottmann:
Yeah. Speaking of the US, and having a chat with some of our US colleagues, they actually have a huge problem by the general availability of these immunoconjugates and immuno-oncology drugs because everybody can use them as they like. Patients are no longer entered into clinical trials. And so, I think in Europe we’re probably even better placed with our trial discipline to achieve exactly the data that you’re referring to.

Dieter Hoelzer:
I think what we heard today, the results was a bispecific antibody Panitumumab with the CD 22 Inotuzumab, we did not discuss intensively CAR T. We are moving to a new era, and the important thing is to find out what is the best place in frontline therapy. This can only be done in prospective trials, whether I doubt that one immunotherapy is sufficient therapy to cure. We mostly need a combination of two approaches, a little bit of chemo and then the immunotherapy. But we need prospective trial to see whether CAR-T cells is first, or Inotuzumab, or Panitumumab.

Oliver Ottmann:
Yeah. In that context I think that the transnational and international trials are really of huge value, like the EWALL trials, European Working Group for Adult ALL, because we don’t have the patient numbers otherwise. But it’s not only the numbers and being able to conduct the trial, I think this constant scientific exchange between and among colleagues from different countries is a huge benefit to promote the field.

Dieter Hoelzer:
So we have now what’s absolutely needed and which is done in controlled trial to bring the immunotherapies in the frontline, are ready to have combination, and then to compare the real promising CAR T-cells and Panitumumab, and Inotuzumab side by side. If we have this study is finished, we will have a picture, which is so far not a guarantee that everything is solved.

Oliver Ottmann:
No, absolutely. But I think it’s scientifically extremely exciting, and I think exciting for the patients as well.

Dieter Hoelzer:
Yeah. I think this is probably at the end, the message in acute lymphoblastic leukemia, which is a very rare disease, you know? It has shown in children that you can cure the disease just with chemotherapy, but now we have all the new options, which are not available in this extent in the other diseases. So as you said, it’s a very exciting time. In the next meetings I think we have the comparison, and we will know what the frontline setting is, and then I have no prediction what the cure rate will be.