Now, because of very many side activities I don’t go that much to the sessions, it’s the usual story. But some points that are emerging very clearly, in general if I had to consider some take-home messages, at least the areas that we follow, I think one is clearly immunotherapy, obviously. We can’t forget that this year the Nobel Prize for Medicine has gone to two colleagues who are working on the immune system and checkpoint inhibitors so immunotherapy inevitably is one of the hot topics and is very important because we’ve been working on immunotherapy, including who is actually speaking, for years or decades with ups and downs and more downs than ups to be very honest. Now is a turning point. We’ve said this many times in the past too but I think it’s probably true this time and the whole story of the CAR T certainly generates a lot of hype and it’s a very hot topic here too.
So that is one of the changing points that is coming here from what is presented and from side meetings that we’re having too which I participate in and I can see the developments. We’re really in the infancy of what we are seeing because so far, as necessary, the CAR T are utilised as a last resort, as we do with any new drug, nothing really new. When we test some new drug we have to go to relapsed resistant patients but in the future the treatments are going to be to use them much earlier. To make a longer story, there’s all this discussion how much do they cost, how feasible is it, and the answer is that they cost an enormous amount of money, let’s be very open. So how feasible is the big question mark. But the point is, as I always say, it depends where you actually can place these new… it’s a drug after all, it’s cellular therapy but it’s a drug; it depends where you place it. So so far it’s been in relapsed ALL, for non-Hodgkin lymphomas, CLL, the data in many diseases, but the future is going to be, as I see it, I’m sure of this, is to include these compounds much earlier. I’ll give you one practical example – two approvals in acute lymphoblastic leukaemia and in diffuse large B-cell lymphoma. So in acute lymphoblastic leukaemia the endpoint of treatment has to be eradication of the disease up front; we don’t wait for relapse, we would like to be sure that patients do not relapse. But if they relapse the rescue is more complicated – it’s costly, it’s toxic and not always effective, or let’s say only in a proportion of patients. The goal of all treatments, including ours, the GIMEMA, the multicentre study we are conducting in Italy, is to induce as high as possible proportion of patients becoming MRD negative, minimal residual disease negative, by molecular test up front. So I’m sure CAR T will move earlier, in fact there have already been discussions for a trial using CAR T for minimal residual disease. So the challenge will be not to use it after but to use it immediately, try to prevent a relapse. If you can show that you can cure a patient then the issue of costs will diminish because you give less treatment. If a patient relapses it means hospitalisations, it means infection complications, antibiotics, anti-fungal treatments, it means a transplant, a second transplant, much more expensive. We can avoid that so that is the challenge. We haven’t discussed it yet here but we’re discussing it inside meetings. No data yet, maybe some but very scanty, but that’s the future of the CAR T.
Immunotherapy is not only CAR T, we are developing NK cells from cord blood, we’ve expanded NK cells from patients so it’s a whole theme. It’s not only CAR T but a whole theme, a whole movement is going in that direction. So that is one very important.
Talking about minimal residual disease in ALL, I’ll just give you one further hint and we have many papers here, this is one for instance. As I told you, patients with acute lymphoblastic leukaemia, whether this is a child, adolescent, young or elderly, should go into minimal residual disease status up front. How do we quantify this? This is mainly done by quantitative PCR which is more sensitive than flow. I know many groups here use flow but it’s less sensitive than quantitative PCR which we consider, the community considers, the standard of monitoring of disease. The problem is that quantitative PCR the laboratory sometimes, in a not small proportion, defines as the final comment as positive not quantifiable which means that you have a small signal but you can’t really be sure that that is disease or not. So we are presenting here in the papers and press a study where we’ve used, let’s say, more advanced technologies which are the so-called digital PCR or next generation sequencing, we have done both in patients or in cases where the response was positive not quantifiable. We present the data showing that, indeed, by using these more advanced technologies we can refine the definition of MRD negativity.
Why is this important? I’ll give you a practical example. In our protocols, both for Philadelphia negative and Philadelphia positive ALL, the primary endpoint is to induce an MRD negativity to an extent that in a Philadelphia negative if a patient is MRD negative by quantitative PCR at two sequential determinations, then we don’t transplant the patient unless there are other prognostic factors. Then the study that we closed recently, it’s about 70% being projected to be alive and possibly cured. So MRD is guiding treatment to an extent that transplant yes, transplant no. So if we can refine the positive not quantified you can understand the practical implication of this which goes to the Philadelphia positive too. Because we don’t present data here but our studies for many years have been induction without chemotherapy, only tyrosine kinase inhibitors and steroids. Now we are using after that, after induction, consolidation with blinatumomab, so a bispecific monoclonal antibody, immunotherapy, going back to the CAR T, that’s a form of immunotherapy before CAR T. The endpoint there is MRD negativity molecularly without chemotherapy. Tyrosine kinase inhibitor and blinatumomab. So, again, this is a challenge but in the old days the only option for a Philadelphia positive ALL patient was a transplant. We’re going to challenge this and probably show, hopefully, that not only many patients can be spared a transplant but hopefully that you can cure some patients without systemic chemotherapy which is a challenge and the data on the MRD are therefore important.
Then, one important point is emerging here. If you think about chronic lymphocytic leukaemia, this is the most frequent leukaemia in the Western world. We grew up with this disease knowing that it was a chronic disease, indolent. We had chlorambucil then chemoimmunotherapy and last year there has been all the hype of the new drugs, obviously, which are mechanism based because they target the B-cell receptor or the BCL2 overexpression. One of the hottest things that are coming from this congress, there are multiple studies being presented, including yesterday and today again, and there will be late breaking, on the activity of the combined use of new drugs with or without an anti-CD20 monoclonal antibody, so without chemotherapy. The data are looking very strong, to an extent that many patients become MRD negative, so really being extremely positive.
So what can come out from this meeting is a suggestion or indication that maybe chemoimmunotherapy, putting quote-unquote, could be “dead” in CLL. We don’t know but that is what will come out of this. I personally don’t think this will be the case because I think many things but, one, I think is extremely important. The world is very vast, it’s something I’m very close to. We were talking about CAR T before, even blinatumomab, new drugs, combinations, how feasible is all this? There’s an issue of accessibility and, to be very practical, of sustainability of all this. So I travel a lot, we do education programmes around the world, at this for EHA, for a very long time. The world is very vast, real life is very different. So if here comes out the message, which is probably true, that you can control disease very well and much better without chemoimmunotherapy, how applicable is this on a worldwide scale? Miles away, years, who’s paying for it, to be very practical? So this we have to be very careful not to extrapolate too much and we have to keep our feet down on the ground on earth and say what can we do in real life. This is extremely important.
So did come very strongly out of here, this is valid for the US, maybe for central Europe, maybe for Japan and some other places but the world is much vaster – think of India, think of China, small countries. That is a key point – how much can this be done there? So we have to be very careful to say it’s finished. But it goes back also to the fact that biology can guide treatment decisions – some patients with CLL with a very good biological profile can be managed very well with chemoimmunotherapy, we have to keep this in mind.
Talking about real life, which I brought up, we have another presentation here on real life in Italy with ibrutinib and CLL in a so-called named patient programme to see whether the data from real life are similar or not from trials because trials are sometimes slightly biased and you don’t know. The data luckily look very good but there’s one point that I think we should keep in mind, that there is a degree of withdrawal from protocol. So many patients on long term ibrutinib stop treatment for many reasons which could be toxicity but could be other reasons too. So this is something to keep in mind because if you stop treatment, and this is normally continuous treatment, this can obviously be a problem if you’re going in this direction. So this is something we have to keep in mind.
These are some of the most important and there are others, obviously. We’ve done studies, I can bring you another example, for instance, we did a study on chronic myeloid leukaemia in children. Chronic myeloid leukaemia is obviously very important in adults but it occurs in children too very rare; we coordinate the study in Italy, we are the reference centre. There’s a lot of interest in CML in adults to identify which patients can stop treatment because a tyrosine kinase inhibitor forever is always a problem of compliance, maybe some toxicity. There are many studies, and we are involved in that too, which patients can stop treatment in adults, maybe the immune system can be triggered, there are many aspects. If that is for the adults, just imagine for a child – much more important because an inhibitor in a child can interfere in the growth of a child, so there are many issues. So I’m presenting data here on the intermittent use of imatinib in children to try to reduce the dosing and the time on treatment which is something that’s going in adults. I must say, maybe with ibrutinib in CLL the issue of reducing dose or giving intermittent treatment.
So these are some of the aspects, I can continue to give you others but these are some of the important points that are emerging here. One thing I would like to say, that I am old enough to remember how haematology has gone and is changing. It’s always more based on rapid and precise diagnostic work up once you define a treatment to stratify patients based on biology, different categories. Then there’s a whole issue of giving always less systemic chemo, it’s always more targeted treatment or pathways, whatever. This is developing at an extraordinary pace; we already know that in haematology we can control acute promyelocytic leukaemia without systemic chemo, that’s an acute leukaemia. Chronic myeloid leukaemia obviously, Philadelphia positive ALL, we are controlling many patients without chemotherapy and more is developing. CLL now with a new drug, it’s not genetic, it’s two pathways but it’s not chemotherapy.
So that is a real challenge and with whole genome sequencing and new alterations we’re finding, the whole area of targeting treatment, of intelligent treatment, is becoming really obvious to me. But then it goes again back to the sustainability of this, can we all do it, that’s the big question mark.
What about AML?
AML, let’s say that AML, apart from acute promyelocytic leukaemia, has been a bit not very exciting for many years, to an extent that I always joke about this, that excitement is with Mylotarg which has been around for masses of years but poorly, now it’s even come back but that’s not the change. But there are some changes, the data with the FL3 inhibitors have certainly started to shed light on the possibility and now new targets that are certainly being developed as treatment on abnormalities. So I think we are seeing at last an opening, a bit of light at the end of the tunnel in AML. I know this is not in a clinic, it’s not presented, but I know there are developments of these bispecific monoclonal antibodies, BiTE for ALL, the blinatumomab anti-CD3, anti-CD19, is obviously the most important. But that’s a technology so I know the development of BiTEs against AML, that’s still in an early phase but I’m sure in the next two years we’ll hear a lot about it.
So at last we are seeing an opening. We have the usual problem in the clinic but for ALL we have many options. If a patient relapses you have anti-CD22, you have the BiTE, so you have many options. For AML it’s a big problem so now, at last, we are starting to see some hope.
The other thing I may just say very quickly that there’s obviously the issue of transplant and obviously we’re always transplanting. We hope, everybody hopes, to reduce the transplants but transplant has certainly been a life-saving approach for many patients. But transplant is a tough issue, I’m talking about allogeneic transplant, obviously, not autologous. It’s not easy to do, there are toxicities which doesn’t mean necessarily live or die but you can also live with a poor quality of life. So with all these immunotherapy strategies that we discussed and targeted treatment, I’m convinced, I’m hopeful, that we’re going to reduce the number of patients that we need to transplant, which we’re already doing in acute lymphoblastic leukaemia. CML was a great transplanted disease and now we are exceptionally transplanting a CML patient that has dropped down because of tyrosine kinase inhibitor. CLL we used to transplant more and it’s going down with the new drugs. With the development of the CAR T and other immunotherapy drugs that are going earlier, that will be an important challenge to reduce the transplants. So that is good news, although it’s the beginning, but we’re going in that direction.