ISAL 2023 | Chemotherapy-free regimens in Ph+ ALL: where are we now and where are we headed?

So I’m here to talk a little bit about the talk I gave in fact, yesterday, March 22nd in Munich, where there was this acute leukemia number 18 meeting. This is a classic meeting that is held in Germany. And obviously the last few years it changed because of the pandemic. So this was the first gathering again and I must say it was extremely well attended, many speakers from different parts of the world, many from the States, so high standard. And I was asked in a session at the end, in fact, with the last session on [inaudible] treatment strategies in ALL and the title they gave me was, I’m reading, so ‘chemotherapy-free therapy… strategies in ALL, so chemotherapy-free. Well this is something that only a few years ago would have been totally unrealistic, but now it isn’t. It’s something that’s changed completely and clearly my talk for 20 minutes I had was focused on Philadelphia positive ALL because we have to talk about a group of ALL patients where a chemo… and I would add chemo and transplant-free strategy is a realistic option; this is exactly for the Philadelphia positive ALL. So I focused on that, although at the end I did mention in a slide on, let’s say, precision medicine in ALL saying that probably with the new approaches now we will reduce chemotherapy and the number of patients who are going to be transplanted even outside of the Philadelphia positive ALL. But if you talk about really free, then this is a strategy that possibly or probably in fact has a role in the Philadelphia positive.

So what did I do? I mostly spoke of the approach that we took in Italy through the Italian corporate study group for adult hematological patients, which is GIMEMA, and I recall that over the last 20 plus years, in fact, we started the protocol in the year 2000. So this new millennium and right the beginning of the century we started the first protocol for elderly Ph+ ALL patients where we did not give chemotherapy induction, we gave the first tyrosine kinase inhibitor that became available. So the whole story started at the end of last century. In fact, when we started thinking that based on data that had been obtained with imatinib, which was the first TKI in CML and since the most frequent genetic lesion in adult ALL is indeed the Philadelphia chromosome, so the similar mechanism that is a founding genetic lesion in CML. So we thought why don’t we try applying the first TKI also in Philadelphia positive ALL. So we did this first protocol in the elderly patients for the very simple reason that it was a major change to consider not giving chemotherapy to ALL patients. However, since the Philadelphia positive ALL in those days in the era pre-TKI did very, very poorly and since in the elderly most patients just got palliative treatment, it was ethically acceptable to offer a strategy without chemotherapy. And indeed the protocol is written for patients over the age of 60 with no upper age limit and it was approved by all ethical committees. So we did a study and to our surprise, all patients despite age, the oldest patient was 89 entered a complete remission. I’m not saying they got cured. I’m saying they entered a remission. I’ll tell you a story in a minute, in fact, on this point. So if I don’t remember you recall me in the question with that important point here.

So we did a study and it was published in Blood and that was the first of a long story that has gone since then. We did this protocol with the second generation TKI dasatinib, that was for all adult patients 18 years up again, no upper age limit, in others we tested the rotation of inhibitors. We tested ponatinib, so we tested them all. And the last study we published in the New England Journal of Medicine that is in October 2020 was a further step and I think very important step forward because in addition to induction treatment we completed that with consolidation without chemotherapy. So induction was a TKI, targeted treatment and this was followed by this bispecific monoclonal antibody blinatumomab, which is dual.. it targets CD19 on the leukemic B-cells and CD3 active in the host immune system in the patient. So it’s a form of immunotherapy. So it is chemo free induction plus consolidation. And the published study reported the feasibility, the results, the tolerability, the easiness of doing this and virtually all patients went into remission and we had the primary end point, we had 60% of molecular responses which increased further. So here in Munich I gave an update of this which is not published yet, the paper is written but it’s not sent. There’s a long term follow-up because the New England paper, the median follow-up was 18 months. Now we got a follow-up which is well over four years. So it’s more or less a final analysis of the study which is the data that we gathered in an ancillary GIMEMA study where the post consolidation treatment which was left to the centers, was gathered in this GIMEMA study. So we got all the information of what the patient did. To summarize it quickly, what can I say, the data look very good, the disease-free survival at four plus years is still very good I won’t give you exact figures, it’s not published, but it’s a range of 75-80% at four plus years, which is obviously very rewarding for us. About 50% of patients never got chemo, never received systemic even later on in treatment, never got a transplant. So they maintained the disease only on a TKI plus immunotherapy and nothing else.

So that gives already an answer to the fact that clearly it shows that many patients with the Philadelphia positive ALL, which I recall was the worst leukemia you could have, the worst hematological malignancy. The prognosis was dismal before TKIs. So this is a very strong indicator that you can treat a large proportion of patients without systemic chemotherapy and transplant. And we showed that if you have a very early molecular response, you do extremely well, we’ve had no events in these patients. We added further information on genetic profile at diagnosis and the transplant, we are giving data on a transplant. And the transplant seems – I’m not saying not to be useful – but seems to be useful only or mainly in patients with minimal residual disease positivity. So this I think, is a key point. Now the results of this study have opened the way to a new protocol which is ongoing. We already enrolled the first 80 patients or so, which is the first randomized study for Philadelphia positive ALL, and this is a total therapy study. So nothing is left to the individual centers. And here patients will not get systemic chemotherapy and will be transplanted only if they have minimal residual disease positivity or additional unfavorable genetic markers, if not, even if they’re young or have a sibling donor, they will not be transplanted. Going back to my topic, is chemo-free and transplant-free treatment a possibility? And the answer is obviously yes. We’ll have to see for how many patients.

Now I remember what I wanted to say and I’ll tell you this. I showed a slide in Munich of a patient that we treated many years ago… I’ve shown this slide many times… of a gentleman who was diagnosed in 2007, not in Rome, in Verona. And luckily he was tested for this genetic lesion because this opened a very important point: how feasible is all this? It’s feasible if you do the testing, you have to identify the genetic lesion at the first week of diagnosis of acute leukemia. And that is doable in many parts of the world – in some parts of the world, but not doable in a large majority of places around the world. If you can do it, then it’s okay. The other point is that very often in the elderly patients where the disease is more frequent, I forgot to say it increases with age, but most elderly patients, if they are over the age of 70, 75, they’re not tested for this. And if they were tested, they could be controlled with a pill. So it goes to a paradox that it would be a cost saving approach, in fact, if you did it because you would treat them with a pill, you would reduce the hospitalization, etc. So the gentleman in Verona, he was diagnosed with ALL at the age of 89 in 2007, luckily was tested for the genetic profile, he proved to be Philadelphia positive, he had the BCR-ABL, he was given imatinib. He went into remission, he became even MRD negative, was very, very fit, driving a car at the age of 89, he turned 90. Then eventually he relapsed about a year and 8 or 9 months later, we gave him a second generation TKI, he still responded, went into remission. And the bottom line is that he died after two and a half years. So at the age of 89, he lived he turned 90 and 91 and eventually died. And he had two and a half years of a very good quality life despite having an acute lymphoblastic leukemia. Now, if he hadn’t been tested for the BCR-ABL, he would have died in a couple of months. So this is a practical example.