ASH 2025 | Phase Ib study of bleximenib plus venetoclax in AML with KMT2A or NPM1 alterations

Bleximenib itself is a potent and oral inhibitor of menin and it’s one of four menin inhibitors that are in quite advanced stages of development, and there are a number of abstracts pertaining to those at ASH this year. There are a number that are in earlier stages of development so this field is going to continue to grow, and there’s been a lot of excitement and enthusiasm about this class of drugs over the last couple of years. So menin itself is a nuclear scaffold protein. So it interacts with a number of transcription factors and chromatin regulators, and its interaction with KMT2A forms part of a large transcriptional complex. This is altered when you have KMT2A rearrangements or NPM1 mutations and that leads to epigenetic dysregulation and transcriptional programs being dysregulated, that ultimately leads to the leukemogenesis. So what the menin inhibitors do is they block this interaction and ultimately restore normal gene transcription. 

So the four in development are revumenib, ziftomenib, enzomenib and bleximenib, and I’m going to talk about bleximenib in particular. All of those agents have been shown to have activity in monotherapy and all are being investigated in combination with existing chemotherapeutic agents, both intensive and less intensive in the relapsed/refractory and newly diagnosed settings. And the hope of this is that we hope that we can improve on this monotherapy efficacy that’s reported and improve the outcomes for a broader range of patients. So there’s a lot of ongoing efforts to improve outcomes through novel combinations of drugs, and triplet therapies are another big theme of ASH this year. The menin inhibitors are being used in triplet therapy combined with venetoclax and azacitidine or other HMAs and bleximenib outcomes as a triplet therapy were reported at EHA last year, and that’s part of this study ALE1002 which I’m going to talk a bit more about, which is a phase 1b multi-centre dose finding study which is combining bleximenib with other intensive and non-intensive, or should I say less intensive, chemotherapeutic agents. 

So we presented data from cohort A1 of ALE1002, which is where we investigated the safety and efficacy of bleximenib in combination with venetoclax in relapsed/refractory patients with AML that had either a KMT2A rearrangement or an NPM1 mutation. And there are 15 patients treated in our cohort. In terms of safety, encouraging that there was no reported cases of differentiation syndrome, which is obviously a class effect to the menin inhibitors and can be potentially life-threatening, although we have improved our ability to manage this and recognise it over time. Prolonged QTc is another side effect of some menin inhibitors, particularly revumenib, and is being monitored very closely in the other menin inhibitor trials. So in our cohort, we only had one case reported, which was unrelated to bleximenib, so in the very small numbers of patients treated to date, this doesn’t seem to be a significant safety signal. The main treatment emergent adverse events that we saw with the doublet combination of bleximenib and venetoclax is hematologic, so cytopenias, which are very commonly seen in many AML therapy trials, but also with the other menin inhibitors as well. There were some gastrointestinal effects reported, mainly nausea, but no grade three adverse events or above in this kind of category. So the tolerability of this kind of all oral doublet is supported by the fact that no patients had to discontinue treatment and there were no significant dose reductions or delays in our cohort of patients. 

We then looked at the outcomes of patients treated with either 50 milligrams twice daily or 100 milligrams twice daily of bleximenib and venetoclax and 13 patients with both KMT2A-rearranged or NPM1-mutated relapsed/refractory AML received this treatment. And really quite encouraging overall response rates of 69% and a composite CR, so that’s CR/CRh/CRi of 38%. And this compares quite favourably with the outcomes from the triplet combination therapy that was presented at EHA this year, and that reported the outcomes of 90 patients treated with 100 milligrams of Bleximenib twice daily, and venetoclax, so that’s the recommended phase two dose, and they had a composite CR rate of 40%. And just to note the slight difference in the fact that in the doublet combination we explored two dose levels of 50 and 100. In terms of the kind of tolerability compared to the triplet there were slightly higher A grades in the triplet therapy reported than we saw in the doublet, but again these are much bigger numbers 90 versus 15 so just have to bear that in mind. 

Another encouraging element of the doublet I’d like to highlight is that the median response or median time to response was 22 days, so these responses are happening relatively quickly and we were seeing responses across the board, so patients who had concurrent FLT3-ITDs and patients who had received venetoclax as a prior therapy before enlisting on this study were still showing responses. In addition, four patients actually went to allogeneic stem cell transplant in this cohort. So although, again, very small numbers of patients, it does show perhaps a proof of concept that this doublet therapy can be used as a bridge to potentially curative treatment for relapsed patients in allogeneic stem cell transplant. 

So in essence these are very small numbers of patients it’s a small cohort but this is almost like a proof of concept, if you like, that an oral doublet of venetoclax plus menin inhibitor, in this case bleximenib, may be a very useful treatment for patients with relapsed AML and it really requires further study in a much larger number of patients and then ideally in a randomised setting.

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