ASH 2024 | Long-term survival and relapse patterns in FLT3-mutated AML treated with frontline triplet therapy

So the standard of care for patients who are younger and fit for intensive chemotherapy who have FLT3 mutated AML is intensive chemotherapy in combination with a FLT3 inhibitor, either a midostaurin or a quizartinib. Now for older patients who are not suitable candidates for intensive chemotherapy, the standard of care is azacitidine plus venetoclax, irrespective of whether or not they have a FLT3 mutation. However, we know that the patients who have FLT3 mutated AML treated with azacitidine venetoclax have poor outcomes, and these are largely driven by the FLT3 mutation, which is generally present at the time of relapse. And in fact, in the VIALE-A study, which is the study that led to the approval of venetoclax in this setting, the median survival for patients with FLT3-ITD mutated AML was only 9.9 months. So we’ve reported very good outcomes with patients treated with a triplet regimen of azacitidine, venetoclax, and gilteritinib. In a 30-patient prospective study, we reported an 18-month overall survival of 72%. In this particular analysis, we pooled data from a number of different triplet regimens, so a hypomethylating agent, venetoclax, and a FLT3 inhibitor. And we wanted to report, first of all, the long-term outcomes for patients treated with these regimens, but also look at patterns of relapse with this particular triplet regimen. So we pulled together across a number of studies, patients who were treated, who had FLT3 mutated AML, who were older and were treated with a hypomethylating agent, venetoclax, and a FLT3 inhibitor. Generally speaking, it was with gilteritinib, and most of the patients were FLT3-ITD mutated, although we also did have some TKD mutated patients as well. So overall, we see very high rates of response with this regimen. Actually, 99% of patients achieved at least a marrow remission. 82% of patients achieved a full complete remission. And this translates to excellent outcomes. So we look at the outcomes of patients with FLT3 ITD mutated AML. We have a three-year overall survival rate of 45%. If we look at patients with FLT3-TKD mutated AML, we have a three-year overall survival of 76%. We compare that with data from VIALE-A with just the azacitidine venetoclax without a FLT3 inhibitor. There, the 2-year overall survival for FLT3-ITD mutated patients was only 20%, and it was around 40% for patients with TKD mutated disease. So we think we’re seeing much better survival with this triplet regimen. We also looked for different predictors for outcomes. We did not see an impact of, for example, NPM1 co-mutation status, ELN risk, or interestingly, or the impact of stem cell transplant. What we did find was that patients who have a baseline RAS pathway mutation did have significantly worse outcomes, as has been described previously with both azacitidine venetoclax as well as FLT3 inhibitors. We also looked at the patterns of relapse in these patients. We found that about two-thirds of patients lose the FLT3 mutation at the time of relapse, emphasizing the potency of using FLT3 inhibitors in this setting. About a quarter of patients who relapse have new RAS pathway mutations. Again, this is known as a mechanism of resistance to both the azacitidine venetoclax component as well as FLT3 inhibitors. And also, once patients do relapse after this regimen, their outcomes are very poor, particularly if they still have the FLT3 mutation at the time of relapse. So overall we’re very encouraged by these data. We’re happy to present long-term follow-up with these triplet regimens, which we believe will be more and more widely used in community academic practices.

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