SOHO 2021 | Unmet needs and key challenges in the treatment of ALL

With regards to unmet needs, I think there are still several. The first major unmet need is, what we do for relapse. Meaning, how do we prevent relapse and how do we manage relapse? And so, those are two very big, broad questions but they’re very relevant for adult patients with ALL. If you look at the SEER data, we’re still showing only about 38% of adult patients, so this is those over the age of 20, as a whole, I mean as a population, are showing extended survival. And again, that’s largely driven by relapse.

We are starting to integrate novel agents into our frontline protocols. We are waiting on the readout from ECOG 1910, which is blinatumomab plus multi-agent chemo immunotherapy. We are still accruing to a frontline trial with inotuzumab and multi-agent chemotherapy. And I think we’re also trying to understand, in elderly patients where aggressive chemo may not be an option, how we can better use inotuzumab and blinatumomab in those groups. And so, there is a frontline trial now of inotuzumab followed by blinatumomab consolidation for this group.

We’re in the process in 2021 of really integrating these very effective of relapse agents into the frontline setting, but with the principal goal of preventing those relapse, and changing that benchmark that I just described. I think the next question is also extremely relevant, how do we manage those relapses? And this is going to become even more important as we integrate these novel agents into our frontline protocols. So what do we do next?

So now, we’ve given blina and inotuzumab in a frontline regimen. What do we have left to manage disease, particularly if those antigens CD19 or CD22 are still present? And I do think CAR T fills a very, very important gap here. So for patients who are refractory, for patients who relapse with these therapies, particularly if the relapses are early, we need to be able to move them to highly effective therapies.

CAR T-cell therapy as we presented at ASCO with the ZUMA-2 data, and also now published in BLOOD in The Lancet, is showing very high response rates, and those response rates do appear to be durable. A fundamental question is, what do you do with that response? And this relates, I think, to another major unmet medical need, which is… Sorry. This relates to another major unresolved question in ALL, what is the role of transplant and how do we think critically about avoiding allogeneic transplant? And I know that’s a bloated sort of statement. I’m not suggest that we move away from allogeneic bone marrow transplant. I think it’s necessary for many patients. But I think we have to acknowledge in that same breath that transplant carries with it, considerable, considerable morbidity and mortality. And that morbidity in some cases may be lifelong when we talk about chronic graft versus host, and it’s not a small thing.

You know, when we project out five years from the transplant, we’re stuck at around 60-65% long term survival, and that’s assuming that we delivered the transplant as consolidation in the first remission setting. And assuming that we went in without any detectable minimal residual disease. And assuming that we’re doing a perfect transplant, meaning in terms of how well we matched it, ideally a sibling match. And that’s assuming that the transplant as a whole was well-tolerated. I’m sorry, well tolerated in the sense that the patient is young.

And so, when we start adding additional variables, right, comorbidities, age, presence of MRD going into the transplant, poorly matched donors, so on and so on, we quickly come to a wall, right? Now our benefit is not going to be that high. If we talk about applying this in the relapse refractory setting, we also run into a similar wall. And so, we have to start finding creative ways to figure out how to get past this transplant crutch. And I’m hopeful that CAR T will facilitate that.

Now, hopeful is a very important and very keyword here. We don’t have data. We don’t. We have some attempts to try and answer that question, whether that be landmark analyses, whether that be censoring for transplant to gauge whether there’s an impact on durability of remission. But these analyses are far from perfect. And I think ultimately we’re going to have to formally ask the question, very specifically, does transplant benefit patients who achieve a remission from CAR T-cell immunotherapy in the relapse refractory setting?

And we’re also going to have to ask even harder questions. Is that something we pursue in a patient who’s already had a prior allogeneic stem cell transplant? So lots of things to kind of sink one’s teeth into, but that would be a very quick and dirty summary of how I perceive unresolved, or unmet needs right now, for adults with ALL.