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ESH ALL 2021 | Post-allogeneic transplant interventions in ALL

David Marks, MBBS, PhD, FRACP, FRCPath, University Hospitals Bristol NHS Foundation Trust, Bristol, UK, discusses post-allogeneic stem cell transplantation interventions to prevent and treat relapse in patients with acute lymphoblastic leukemia (ALL), including withdrawal of immunosuppression, donor lymphocyte infusions, CAR T-cell therapy, and second transplant. Firstly, Prof. Marks describes the withdrawal of immunosuppression in the hope of enhancing a graft-versus leukemia effect. However, evidence indicates that this is not an effective strategy since it does not result in durable disease control. Another possible strategy is donor lymphocyte infusions (DLI). In the UKALL14 trial, results showed that around half of the patients responded to DLI, but long-term control was disappointing. Additionally, Prof. Marks explains the therapy of choice for post-transplant relapse, CAR T-cell therapy, which is currently only approved for the treatment of children and young adults up to the age of 25 years. The last therapeutic option discussed for patients relapsing after allogeneic transplant is a second transplant, though there is limited data in patients with ALL. This interview took place during the 2021 European School of Hematology (ESH) 2nd Translational Research Conference on Acute Lymphoblastic Leukemia.

Transcript (edited for clarity)

My talk will be essentially about the post-transplant interventions to both prevent and treat relapse. It will focus on the use of donor lymphocyte infusions, a bit about tyrosine kinase inhibitors. I’ll touch on CAR T-cells, and of course, mention second transplant.

To look at them in more detail. If you have a person who’s about to relapse, you have early evidence of relapse at say the molecular level, the first thing you would do is withdraw their immune suppression in the hope of enhancing a graft versus leukemia effect...

My talk will be essentially about the post-transplant interventions to both prevent and treat relapse. It will focus on the use of donor lymphocyte infusions, a bit about tyrosine kinase inhibitors. I’ll touch on CAR T-cells, and of course, mention second transplant.

To look at them in more detail. If you have a person who’s about to relapse, you have early evidence of relapse at say the molecular level, the first thing you would do is withdraw their immune suppression in the hope of enhancing a graft versus leukemia effect. The overall evidence is that this is not an effective strategy. You may get graft versus host disease. You may get some response in the ALL, but it doesn’t result in durable control.

The next strategy worth considering is giving donor lymphocyte infusions. And we have a bit of data from, that from our recently concluded trial, UKALL14. We did about 250 reduced intensity transplants and for the patients who had molecular relapse, we gave them donor lymphocyte infusions. And what we found out in moderate numbers of patients is that about half of them responded. But again, it was disappointing in terms of long-term control. We had very few long-term survivors. And this is not really new, we’ve never really felt that donor lymphocyte infusions produced durable control.

The therapy of choice for post-allograft relapse is CAR T-cells. So if you’re under the age of 26, we have a licensed product, tisagenlecleucel that can produce good survival at two years, around 50% disease-free survival. That, unfortunately, leaves people over the age of 26, who do not have a licensed product. There’s a number of trials, there are trials of Autolus, of Kite, of Celgene. And hopefully, those trials will result in CAR T-cells coming to the market for that group. There’s some data from the University of Pennsylvania showing efficacy, and there was also more toxicity necessitating fractionating the dose.

Another thing to mention is of Philadelphia positive disease using tyrosine kinase inhibitors. And they can be very effective therapy. If you institute a TKI at the point of molecular relapse, or of course, given prophylactically, these are both effective therapies and there was a German group study showing that.

I think the other thing to mention is second transplants. So this is not something that our group have done very much of, because we don’t really see good evidence for it. Some people are doing it now. They will use targeted therapies post-transplant and try and get the person back into molecular remission, then do a second transplant. But there really is a paucity of data showing that you can do this and cure patients. In particular, the GIMEMA group, they haven’t published these data, but in quite large numbers of patients, they have less than 5% survival. However, with the advent of targeted therapies, it’s certainly something to consider.

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