Is the Blexi‑Ven Combo Safe and Effective? | Jenny O'Nions, MD

My name is Jenny An-Ians. I'm one of the Hematology Consultants at University College London Hospitals in the UK. So I'm here today to talk about a poster presentation we've got for the ALE 1002 study, which is a global multi-centre phase 1b dose finding study of Bleximenib, which is a menin inhibitor, in combination with chemotherapy agents, either intensive or less intensive. And the cohort we're talking about is Bleximenib in combination with Venetoclax in patients who've got relapsed refractory AML that harbour either a KMT2A rearrangement or a mutated NPM1. So menin is something called a nuclear scaffold protein and what that means is it's part of a big complex of proteins that helps regulate gene expression. And what have key part of that is the interaction between menin and KMT2A and that controls gene expression programmes in the cell. When you have a KMT2A rearrangement or an NPM1 mutation, as is seen in a lot of AMLs, then that protein is altered and it leads to a kind of unregulated gene expression that contributes to the development of AML. What Bleximenib does is it's an inhibitor of that interaction between KMT2A and the menin protein and by disrupting that interaction you can hopefully restore normal gene expression and help treat leukaemia. So Bleximenib has been shown to be safe and tolerable as a single drug in patients who've got relapsed refractory leukaemias that have a KMT2A rearrangement or NPM1 mutation. And what we were talking about in our study is investigating whether we can improve the outcomes for patients with Bleximenib by adding in other agents, particularly in this case Venetoclax. So it makes an all oral doublet treatment for patients. So in the cohort we're talking about in ALE1002 we treated 15 patients with Bleximenib at doses of either 50 or 100mg twice daily of Bleximenib with Venetoclax. And in terms of safety we found it's quite tolerable combination. So there were no discontinuations, no patients had to stop their treatment. We didn't have big dose modifications or dose delays. It kind of supports it as a tolerable combination. Importantly, there were no significant safety signals in terms of differentiation syndrome. Now that's something that is seen in the menin inhibitors and you'll hear about that a lot as people present their work about it. As you stop or disrupt the kind of abnormal gene expression that's happening in leukaemia, the cells can mature very quickly and turn into kind of hopefully healthy cells again. But if that happens too fast you can have a syndrome called differentiation syndrome that can be life threatening. So avoiding that as much as possible is definitely a plus. So although these are very small numbers that we looked at, you know, 13 to 15 patients, we didn't see any signal of differentiation syndrome in these patients which is encouraging. The other safety issue that has been seen with some menin inhibitors is in terms of how the heart conducts its kind of electrical pathways, so something called QTC prolongation. And that is seen, you'll see it in the revuminib studies being presented. But to date we haven't seen any significant safety signal of that with the blexamenib-phenotoclax combination which is also quite encouraging. The most side effects seen in the study are cytopenias, so neutropenia, anaemia, thrombocytopenia. And there were some gastrointestinal side effects as well but nothing of a significant grade called grade 3 or above. So again, it supports it as quite a tolerable oral regimen. The response rates were really encouraging. Overall response rates are 69%, again small numbers so it needs further exploration. But the CR rates when we looked at a combination of patients who achieved a complete remission was 38.5% which again in this very difficult to treat relapsed refractory population is encouraging. And it actually is quite comparable to the response rates that were reported for the triplet combination of blexamenib-phenotoclaxonase acytogen that was reported at the EHA conference in Milan earlier this year. So again, needs further investigation but encouraging start. It's also important to notice that we saw responses across a broad range of patients including those who'd already received venetoclax-based treatments in their previous lines of therapy before joining us on this study. And we also saw responses in those patients who also had a concurrent flit 3 ITD mutation which can be quite difficult to treat. Four of our patients made it to allogeneic stem cell transplant so supports a kind of proof of concept that you can use this doublet to bridge patients to a potentially curative treatment which is what we all want in the end. So I think overall this cohort is very small, it's 13 patients in terms of the efficacy data but it's encouraging and supports its further investigation in larger, hopefully ideally randomized studies as an all-or combination that may benefit patients.