ASH 2024 | An individualized sequential alloSCT approach in patients with R/R AML or HR-MDS with active disease

First of all, we know that current salvage therapies are unfortunately not curative in the vast majority of relapsed refractory acute myeloid leukemia patients, and the only way to cure them is to bridge them to an allotransplant. However, we lose some of those patients due to inefficacy of the salvage therapies or their toxicity. So our aim of the study was actually to offer those patients a different approach, is that we do everything at once. So we give a salvage therapy, a bridging therapy, which is a 10-day regimen consisting of venetoclax, hypomethylating agents, low-dose cytarabine, actinomycin D, and the possibility to add an additional drug based on the cancer acute myeloid leukemia genomics. And after those 10 days, the patients directly proceed to a standard conditioning regimen and an infusion of the donor stem cells. So as a sequential allogeneic stem cell transplantation approach is based on that. 

We’ve enrolled 48 patients with relapsed refractory acute myeloid leukemia or high-risk MDS cases. 85 percent of those patients were with acute myeloid leukemia and 15 were with MDS. So the median age of those patients was 58 years old with a slight male predominance. The median ECOG evaluation was one. Based on the acute myeloid leukemia genomics, we saw that 85% of those patients were actually stratified to the adverse ELN 2022 risk group. So these were poor risk patients. Half of those patients were actually post-venetoclax already, so they had failed venetoclax-based therapy. A third of those patients were already relapsed post an allotransplant. Around 30% had TP53 mutations and around 35% had adverse cytogenetics. So a tough group to treat. The patients were pre-treated with a median of one prior therapy line. However, 40% of those patients had actually received two or more prior therapy lines. So again, 48 patients, really poor prognosis, and really a lack of optimal therapies to try to salvage them. 

So they all received a 10-day preconditioning regimen, which as I’ve said consisted of hypomethylating agents, venetoclax, low-dose cytarabine, actinomycin D, and half of those patients received a fifth drug, whether that was a purine-analog cladribine or gilteritinib, trametinib, ponatinib, dasatinib, based on the targetable mutations which we had identified in the patient’s cancerous cells. After that, all patients proceeded to a standard conditioning regimen, which was either myeloablative conditioning that was used in 15% of the patients, and the vast majority of patients received a reduced intensity conditioning, 85% of those. 

What we saw that the response rates were actually very high, 93% of all transplanted patients of those 48 patients achieved a response. So 93% complete remission or complete remission within incomplete platelet recovery rate, and only 7% had a leukemia regrowth after the stem cell transplant. However, what we also saw that the therapy was actually intensive and toxic. 30% of patients had to be transferred to the ICU and the early mortality rate was 17%, so quite high. The median overall survival for the whole group was 8.1 months and 37% survived more than two years. In terms of relapse-free survival, the median relapse-free survival was 9.5 months, and 40% of patients were relapse-free at the two-year mark. 

So overall, an alternative approach to those patients rather than conventionally trying to achieve a response and then perform an allo-transplant. Our approach was different, and it produced a high response rate, 93%, but unfortunately, the treatment is limited by its intensity and of course toxicity and early mortality. So this is something we will have to look on how to optimally manage that toxicity part.

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