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COSTEM 2021 | The role of alloHSCT in patients with Ph+ ALL

Robin Foà, MD, Sapienza University of Rome, Rome, Italy, shares his views on the role of allogeneic hematopoietic stem cell transplantation (alloHSCT) in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Prof. Foà describes how prior to the introduction of tyrosine kinase inhibitors (TKIs), alloHSCT was the only treatment option for this largely elderly patient population with a poor prognosis. Prof. Foà also discusses the GIMEMA LAL1509 Protocol (EudraCT 2010-019119-39) evaluating induction therapy with dasatinib and steroids followed by chemotherapy and/or alloHSCT alone in patients who do not reach a sustained molecular response post-induction, reporting that it demonstrated that long-term survival could be achieved using a chemotherapy-free induction. More recently, the Phase II GIMEMA LAL2116 trial (EudraCT 2016-001083-11) assessed the efficacy and safety of dasatinib induction therapy followed by consolidation with blinatumomab, a bispecific monoclonal antibody. Prof. Foà discusses the findings of this trial, reporting that 60% of patients had a molecular response at the end of the second cycle of blinatumomab, with molecular responses increasing after each subsequent cycle and an acceptable safety profile. Finally, Prof. Foà comments on the role of measurable residual disease (MRD) in the management of these patients. This interview took place at the 6th Congress on Controversies in Stem Cell Transplantation and Cellular Therapies (COSTEM), which took place virtually.

Transcript (edited for clarity)

This is a very, how can I say, a very timely controversy as it is in the COSTEM program, so we’re talking about controversy in hematology. This is a very interesting point because for a long, long time, allogeneic transplant has been considered the only option in attempt to cure Ph-positive ALL patients. So, now we are at a point where we are considering in many congress and meetings and in this debate, if a transplant can be avoided in Philadelphia-positive ALL...

This is a very, how can I say, a very timely controversy as it is in the COSTEM program, so we’re talking about controversy in hematology. This is a very interesting point because for a long, long time, allogeneic transplant has been considered the only option in attempt to cure Ph-positive ALL patients. So, now we are at a point where we are considering in many congress and meetings and in this debate, if a transplant can be avoided in Philadelphia-positive ALL. So, I think we should put this point into context.

And first of all, I think it’s very important to remind ourselves that before the event of the tyrosine kinase inhibitors, which means the targeted form of treatment, the prognosis of Philadelphia-positive ALL was really extremely unfavorable. I always tell our students of postdoc or interns that it used to be the worst hematological malignancy and possibly the worst cancer, because in the old days, when I worked for a long time in hematology before the TKIs, there was very little offer to these patients and they did very poorly. All the long-term studies showed roughly about 10-15% of patients who had a long-term outcome. And these were largely patients who managed to go to an allogeneic transplant. And I should add that even in a pediatric age transplant was really the only way to try to cure patients. So, this was before the TKIs. Then when the TKIs came on the scene, the whole management of Ph-positive ALL has changed and the prognosis has changed too. So, this is why we are questioning whether transplant should still be offered to all patients who can actually do it.

Now, I think I am here to defend the possibility that transplant can be avoided and may be substantial, be provocative a lot, I don’t know, we don’t exactly know patients with Philadelphia-positive ALL. As you know, these are debates and obviously there’s no 100% answer to this. If not, it would not be a debate. So, each of us obviously defends one position and sometimes it’s a bit artificial because we may both think in the same way. Here it’s a very typical example because the two good opponents are myself and Alexandra Rambaldi. So interestingly, we are running the same protocols in Italy, so we have exactly the same view on the topic. So, it is a bit artificial.

Now, why have I been asked to cover the hypothesis transplant can be avoided in patients with Philadelphia. We’re talking about adult patients. Now, I think we it’s important remind our young audience that Philadelphia-positive ALL is the most frequent genetic subgroup in adult ALL and old papers stated that it accounts for about 25-30% of cases. But what is important is it increases with age. So in a young adult, I don’t know, 18-25, we have the data and we in fact published it some time ago the incidence is not that high, it might be 15-18%. It consistently increases with age to an extent that in the fifties or sixties or more, it’s about one out of two B-lineage ALL carrying the Philadelphia chromosome [inaudible]. So, it is highly frequent in the elderly population. Though that is very important because we know that in the elderly, obviously the transplant is less doable.

Then, where are we with the new forms of treatment? I said, the TKIs have revolutionized our approach to Philadelphia-positive ALL. And in Italy, through the GIMEMA study groups for the last, I would say more than 15 years, all patients with adult Philadelphia-positive ALL wouldn’t have to be identified within one week from diagnosis of ALL. It’s during the week of the steroid pre-phase. All these patients are induced into remission only with the TKI and steroids with no systemic chemotherapy. And I don’t have time to go through the data, but this has been very rewarding because virtually all patient going to remission and toxicity is very limited.

Now, what I wanted to lead into our last study, which was published in England Journal of Hematology a few month back, where we, in addition to giving a TKI at induction which was dasatinib, we consolidated patient with a bispecific monoclonal antibody blinatumomab. So, it was an induction and consolidation with a targeted treatment, the dasatinib and immunotherapy blinatumomab. And this led to virtually remission of patients and to high proportion of molecular responses. An additional blinatumomab led to 60% of MRD responses, molecular MRD responses, after two cycles of blina which increased about 80% after subsequent three cycle of blina. It was allowed to go up to 80%- erm- five cycles. So, this was extremely important. Toxicity was very limited. And this, obviously, in a follow-up information we showed that about half of these patients continued without any chemotherapy and without transplant. And many patients are doing very well. Some patients went to transplant.

So, I’m not saying that transplant can be avoided, I’m them saying that certainly we know now that patients can have a long-term remission without transplantation. And I will also add that in the study, already in NEW England paper, we put some data and then we added more information recent publication in Blood, that this approach led to a very marked activation of the host immune system of the patients, the activation of T-cells and NK-cells. Now, this may play an additional role in controlling the disease.

So, putting all this together clearly shows or indicates, doesn’t demonstrate, but strongly suggests that many patients can be spared transplant. And we are not the only ones to hypothesize this. MD Anderson recently has published that there’s no difference occurred between transplant and non-transplanted patient. And this was also now in our data so far, there’s no difference.

And to conclude the story, in the current new protocol which opened recently, patients who have a good genetic profile and diagnosis, and I don’t have time to go into detail, but it’s in our previous papers, and obtain a sustained molecular response, even if they have a sibling donor, will not be transplant. They will be actually monitored by MRD. Clearly we need a very precise MRD approach, which is done by quantitative PCR, and we are also doing digital droplet PCR, which is more sensitive. So, this indicates that a proportion of patients probably can be spared and in the ongoing GIMEMA trial, we hope to demonstrate this. And then Rambaldi will obviously say that situation is that we need a longer follow-up phase to show this, which is true. But I think we are quite convinced that a good proportion of patients will be spared transplant for many reasons, age and the data I just told you about.

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