SOHO 2020 | Advances and challenges in AML treatment

In 2020, we have a lot of progress that’s occurring in the treatment of acute myeloid leukemia. We’ve had eight drugs approved by the US FDA in the last three years, and these include targeted therapies such as FLT3 inhibitors, midostaurin, and gilteritinib, IDH inhibitors, including IDH1 inhibitor ivosidenib, and IDH2 inhibitor enasidenib, as well as immune treatments, antibody-drug conjugates, gemtuzumab ozogamicin that targets CD33 antigen on the surface of the AML cells and very important, and probably one of the most important breakthroughs BCL-2 inhibitor venetoclax that seems to work across majority of the subsets of acute myeloid leukemia, especially when combined with hypomethylating agents, such as azacitidine, decitabine, and new and better tolerated and more effective formulations of intensive chemotherapy, such as CPX-351 and Hedgehog inhibitor glasdegib. There has been dramatic progress. Eight new drugs, and a lot of these were approved either as single-agent, especially for the targeted therapies, or in combinations with azacitidine or induction chemotherapy.

Now, the challenge that emerges is that even though many of these treatments take, for example, azacitidine/venetoclax have improved the historical. With azacitidine alone, we saw response rates of about 25 to 28%, CR CRI median overall survival of about eight to ten months and a three-year survival of about 15%. With azacitidine/venetoclax we’re seeing CR CRI rates of about 70%, median overall survival of 15 to 18 months, as well as a three-year survival of about 35 to 40%. This is definitely better than azacitidine alone, but in the end of the day, 35, 40% at three years is not curative. And the main areas of development in acute myeloid leukemia at this time are how we can optimally combine these azacitidine/venetoclax with other treatments such as with FLT3 inhibitors in FLT3 mutated AML with IDH inhibitors in IDH mutated AML, with some of the immune drugs, such as cusatuzumab CD70 monoclonal antibody, or with IMGN CD123 antibody-drug conjugate, or with TP53 directed therapies such as APR and magrolimab.

At our institution at this time, our major focus by far is the development of these targeted triplets for FLT3, IDH1, IDH2, TP53, and immune agents building on the backbone of the HMA venetoclax. And the hope is that these triplets of HMA venetoclax plus the additional drug used in appropriate personalized setting, targeting a particular mutation or antigen will really further improve that 35, 40% to three-year survival to hopefully 60, 70%. At which time I think one of the big questions that’s going to emerge is whether this is truly a regimen we should only be using in the older AML patients not fit for intensive chemo, or are the results now emerging and looking very comparable. And could we start considering using HMA venetoclax plus the third drug in a particular targeted group, maybe even in younger fitter patients? I think that question still is very open, but I think a lot of these ongoing Phase I/II triplet studies will help us get more information.

A second area of major unmet need in acute myeloid leukemia now is MRD-directed therapies. We are getting better and better at getting patients into an initial remission, whether that be with HMA venetoclax, or with induction chemotherapy or induction chemotherapy plus a FLT3 inhibitor or gemtuzumab or IDH inhibitor, in spite of the high remission rates with these approaches, anywhere between 70 to 90%, we still see that about 20 to 30% of patients will have minimal residual disease positive, usually analyze in the United States by flow cytometry, but can also be picked up by deep, next generation sequencing. And what we now know based on a number of big publications is that anybody who is MRD positive, whether it’s after induction based anthracycline cytarabine based approaches, or whether it’s after HMA venetoclax will have a inferior outcome. And now there is a lot of effort trying to develop drugs that will target eradicate MRD.

And with that, hopefully improve the duration and the depth of remissions and some of these drugs that are being evaluated in the MRD setting are immune agents, because we do know that when the patient is in a marrow remission and there’s only minimal residual disease, the immune system will kick back, becomes active again. And that could be an optimal time to harness the T-cells or immune system. And approaches such as bi-specific antibodies, antibody-drug conjugates, immune checkpoints, and others are being extensively evaluated in the minimal residual disease eradication setting. We don’t yet have a clear winner or path, but I expect to see in the next two years, a lot of intense MRD-directed and or maintenance directed approaches is being used in acute myeloid leukemia trials. And hopefully, some of these will lead to breakthroughs for eradication of MRD. The third major area of clinical research in development for acute myeloid leukemia is developing treatments for TP53 adverse cytogenetic, and high-risk acute myeloid leukemia.

There are three major drugs that we’re excited about in this space. One of them is the CD47 antibody magrolimab, that has shown a high response rate CR CRI rates are 70 to 75% for azacitidine with magrolimab in TP53 AML, which is better than the 50 to 55% CR CRI rates, we have seen with azacitidine/venetoclax and the durability and duration of responses at this early time point does seem better than azacitidine/venetoclax. And we’re looking for updated data that will be available later this year, early next year. A second drug that is quite exciting specifically for TP53 AML is an agent called APR. This is a drug that blocks the folding of the TP53 protein. Our data mainly in MDS has shown that azacitidine with APR gives very high response rates, CR CRI rates of about 80% double of the 40 to 50% we were getting with azacitidine alone.

And the response has seemed to be quite durable, a Phase III study looking azacitidine/APR versus azacitidine in the newly diagnosed TP53 mutation MDS has been completed and we are eagerly waiting for the responses. And we think that this drug will have applicability not only in MDS, but also in TP53 AML based on some of the early data showing high responses and improve survival. And the third one is a agent called cusatuzumab, which is a CD70 monoclonal antibody. And this drug in combination, again with azacitidine has shown high, early response rates. This is not a TP53 focus treatment per se, but we believe that it may be a mutationally agnostic and that it may work well, even in TP53 adverse cytogenetics where some of the molecular or BCL-2 therapies may not be as good.

In summary, I think the three main areas that we are quite excited about and to look out for in the next one to two years are development of triplets of azacitidine/venetoclax with FLT3 or IDH inhibitors or immune antibodies or immune checkpoint treatments. Second is strategies to eradicate MRD and or maintenance to improve the depth and durability of remissions. And number three are new agents that will have efficacy in the high-risk AML subsets, including TP53, adverse cytogenetics, secondary therapy related acute myeloid leukemia. And we hope that this progress we’re seeing in acute myeloid leukemia will not only continue, but be accelerated in the next two to three years. Thank you very much for listening.