ASH 2024 | The evolving treatment paradigm for unfit patients with AML

So the treatment paradigm of patients who are actually unfit for standard intensive chemotherapy in acute myeloid leukemia field has changed dramatically. I mean from the times when we only had low-dose cytarabine and hypomethylating agents, now we have the possibility to offer those patients effective and safe regimens. Of course the most important of those is venetoclax and azacitidine, which was a landmark trial, a Phase III randomized control trial, which proved that additional venetoclax to standard azacitidine, a doublet, is actually producing high response rates, up to 70%, and offering prolonged survival of about 15 months at median. We also know that some genomic subgroups are actually, seem to do much better with venetoclax, such as IDH2 mutated patients, and of course those who harbor TP53 mutations, unfortunately, are doing the worst. Nevertheless, currently this is the standard of care for unfit, frail, newly diagnosed acute myeloid leukemia patients, and it’s a genomically agnostic, so this works for all genomic subgroups. Importantly that after the AGILE trial, we now have another important treatment algorithm and option for our patients, especially those who have an IDH1 mutation, because now we can offer them the already approved therapy of ivosidenib and azacitidine doublet. So the response rates and the survival with ivosidenib and azacitidine for IDH1-mutated AML patients is really looking very promising. And the remissions are durable. And importantly, it’s a safe therapy, which produces less myelotoxicity in comparison to venetoclax-azacitidine. And this is something very important for our frail patients when we have a lower risk of having them, of developing a febrile neutropenia or a sepsis or a fungal infection. So this is something a very important part of thinking about and choosing the optimal therapy in those patients. Thirdly, we also have the possibility to offer those patients a smoothened receptor blocking agent, which is glasdegib in combination with low-dose cytarabine. That therapy is, of course, much less discussed and offered, but still, this is also an approved therapy, which we also have in our backbone. In terms of investigational therapies, I would like to mention the FLT3 inhibitors and their role in the unfit patient population. Currently, we don’t have any FLT3 inhibitor approved for unfit frontline patients. However, the recent data and the data from the Phase II trials are actually very encouraging. We see that the addition of FLT3 inhibitors, especially second generation FLT3 inhibitors such as gilteritinib are actually looking very promising in terms of very high efficacy when we add them to standard backbone of venetoclax-azacitidine, so a triplet regimen. Of course, the toxicity is also of highest importance because the combination, the triplets, at least with gilteritinib, seem to be quite myelosuppressive, and this is something to be concerned of, especially when we’re talking about unfit, frail patients. Again, menin inhibitors are really changing the treatment paradigm, and they’re moving strongly in the unfit frontline AML field as well. Early Phase I data are actually suggesting that the response rates are very high, up to almost 100% CR, CRp rates when we add a menin inhibitor, for example, revumenib, to standard HMA venetoclax backbone. And again, menin inhibitors seem to be less myelosuppressive in comparison to second-generation FLT3 inhibitors. So this is also important that patients with NPM1 mutations and KMT2A rearrangements could be potentially treated with a triplet when we have a more mature data. I would also like to highlight that a lot of data and a lot of trials are actually trying to address the possibility of finding an optimal backbone to venetoclax. So we know that HMAs is the standard of backbone to venetoclax. However, the data from the Phase II trials are actually showing that the possibility to use an alternative backbone with cladribine, low-dose cytarabine and venetoclax, alternated with HMA and venetoclax, so a treatment of an alternating manner, can actually produce very high response rates and durable remissions again in those less fit patients.

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