ISAL 2023 | Novel combinations being explored in AML using an HMA-venetoclax backbone

So this year I presented the combination therapies using the HMA-ven backbone, the hypomethylating agent-venetoclax backbone. So I presented four different types of combinations which are sort of rationally designed in some ways based on the known resistance mechanisms to venetoclax. The first combination is with the FLT3 inhibitor and the patients who have FLT3-ITD mutations because we know that this mutation confers resistance to BCL2 inhibition mainly through upregulation of other anti-apoptotic family members. So what the preclinical data showed that if you combine the FLT3 inhibitor with BCL2 inhibitor, there is very strong synergy through several mechanisms that we described. And so there was a clinical trial first doing the doublet venetoclax plus gilteritinib in the relapsed/refractory salvage population which was published in JCO last year and that showed very high bone marrow response rate up to 75 to 80%, including responses in patients who failed prior FLT3 inhibitors, and patients who were able to transition towards stem cell transplantation, they had quite long survival. So that looks fairly promising in the salvage setting. However, we want to move this into the frontline setting.

So the data presented at ASH by Nick Short from MD Anderson and Farhad Ravandi showed what we call triplet, which is HMA, venetoclax and gilteritinib in both relapsed/refractory and newly diagnosed patients, and in the newly diagnosed patients who were older and unable to get the intensive chemotherapy, this combination was highly effective and producing the response rate of nearly 100%. And so far the duration looks very appealing and durable. But of course we need longer follow-up. So I think this combination hopefully will be going forward, but we all have to remember that it requires very careful dosing studies with reduction of venetoclax duration to two weeks and also reduction of the doses of gilteritinib down to 80mg daily. Second combination that we discussed was combination with IDH1 inhibitor ivosidenib and again this was triplet in the IDH1-mutated setting. So we demonstrated that this combination actually enhanced the depth of response and prolonged the survival in patients with IDH1 mutation. There were several cohorts based on the dose level based on the disease, but all of them look very promising. And most impressive is that the toxicities were similar to HMA-ven or HMA-ivo combination, so there was no excess toxicity, therapy was very well tolerated. So I think this is another genetic sort of defined combination triplet that we have.

And finally, I presented two immune therapy combinations, one with the anti-CD123 antibody-drug conjugate, which is now called PVEK from ImmunoGen and the second with the anti-CD47 antibody magrolimab. So both were presented at ASH last year and my lab has done pre-clinical studies that showed the synergy between aza-venetoclax and these two new agents. So in the HMA-ven-PVEK study this study was in the relapsed/refractory salvage population and there was quite impressive reduction of the bone marrow blasts. And also in the newly diagnosed patients there were only ten, but the response rate was 50%, but the MRD negative response was 75%. So at least it looks like that we are able to get deeper responses with this triplet. Again, we need more data and the doses had to be modified for it to be safe. And finally, the aza-ven-magrolimab study, which was an MD Anderson investigator-initiated study, included both P53 wild-type and p53 mutated patients and the response rates were 91% in the wild-type patients, but it was also 64% in the mutated patients. And that’s where we really need new therapies because we know that HMA-ven not beneficial in this subset. So this study moved into a randomized Phase III study that is about to start called ENHANCE-3, which will randomize HMA-ven-magrolimab versus HMA-ven. So we’re looking forward to the results of these studies.