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SOHO 2020 | Next questions in AML
Amer Zeidan, MBBS, Yale University and Yale Cancer Center, New Haven, CT, explores the next questions in acute myeloid leukemia (AML) treatment and management, including the recent approval of CC-486, an orally available azacitidine, approved for maintenance therapy in AML. Furthermore, Dr Zeidan outlines the significance of new clinical trial endpoints for efficacy, including evaluating minimal residual disease (MRD) as a potential surrogate endpoint, as well as the growing importance of immune therapies for this indication. This interview was recorded via an online conference call with The Video Journal of Hematological Oncology (VJHemOncal
Transcript (edited for clarity)
One of my presentations in this meeting is focusing on the next questions for acute myeloid leukemia. There has been a tremendous improvement in the field over the last three years. Since 2017, we had nine drugs approved specifically for acute myeloid leukemia indications in the US. The last one to be approved, which was really a few days ago, is the oral version of azacitidine or CC-486, which was specifically approved for older patients who undergo intensive treatment, whether induction plus/minus consolidation and cannot continue on those therapies or not proceeding to bone marrow transplantation...
One of my presentations in this meeting is focusing on the next questions for acute myeloid leukemia. There has been a tremendous improvement in the field over the last three years. Since 2017, we had nine drugs approved specifically for acute myeloid leukemia indications in the US. The last one to be approved, which was really a few days ago, is the oral version of azacitidine or CC-486, which was specifically approved for older patients who undergo intensive treatment, whether induction plus/minus consolidation and cannot continue on those therapies or not proceeding to bone marrow transplantation. The use of maintenance oral azacitidine compared to placebo has been shown to prolong overall survival in this patient population. And therefore has been approved by the FDA for use in the USA. So I think between these nine agents that are approved, there is still I think a lot to be done in trying to and further improve the outcomes of our patients.
I think one important aspect is increasing the rate of treatment of patients with acute myeloid leukemia. So we actually, we and others have done population-based studies looking at the rates of treatment of patients in the US and when you look at patients who are 65 years and older, and that’s the bulk of MDS patients strictly because the median age at diagnosis is 68. So it’s a disease of older people, really. Many of the patients who are 65 years or older are not being treated, almost as many as 40% don’t receive any kind of therapy. And this is data as recent as 2015. So basically almost 10 years after the introduction of hypomethylating agents, which were specifically approved for this patient population. Of course the use of hypomethylating agents by themselves have been suboptimal, the median overall survival is in the range of seven to eight months.
So clearly I think that was one of the reasons why many of the patients were not being treated because the outcomes with hypomethylating agents as single agents were not particularly great. So I think we are going a direction where more older patients are going to be treated, and hopefully that will improve the outcomes. There is increasing availability of oral agents and several of those oral agents have been approved as oral therapies, such as getting treatment for FLT3 mutated refractory, relapsed AML with the FLT3 mutation or the IDH inhibitors. I think the next cycle of studies are going to focus on different combinations. How do you actually combine two drugs and potentially three drugs? Now we have as a sight in Veneto class, also as a platform, a lot of the upcoming trials are going to add other agents to this tablet basically. All these agents that were approved are potentially being combined and going to be looked at.
I think another important aspect that will be becoming more and more commonly used in the studies is the adaptation of new clinical trial endpoints for efficacy. Traditionally computer response has been the most commonly used endpoint. The complete response with income and complete country covering has become used frequently in the past. But now that we have more active agents, I think there is a lot of interest in looking at MRD, negative CR or measurable residual disease and the durability, because there are multiple studies that show that when you are an MRD negative, why not everybody is cured? However, that correlates with significantly prolonged survival. So it potentially could serve as a surrogate endpoint in many of the new and upcoming trials. We have actually also some data suggesting that if they use, for example, of myeloablative conditioning for patients who have measurable residual disease seem to improve their outcomes while they use of non-myeloablative conditioning in those patients don’t seem to be particularly helpful.
So we are already seeing some data that suggest some action on MRD at level of the patients could potentially improve outcomes of patients. I think we are going to a situation where we are going to follow the multiple myeloma paradigm in which therapies are being introduced, moving away from intensive chemotherapy to more targeted therapies. More use of oral agents, tablets and triplets, the more stringent endpoints such as MRD negative, CR outpatient therapy. We are seeing more and more outpatient therapy for older patients with acute myeloid leukemia and the concept of total therapy and sequencing. So it’s not only the use of, basically of one clinical trial looking at one agent, but trying to understand what is the best sequencing and how we can optimize the survival of our patients using the best sequencing.
And also the, as mentioned earlier, the use of maintenance strategies, which have been a main part of the treatment of patients with multiple myeloma and other hematologic malignancies. And now they have finally, we have a drug. The oral azacitidine, in which approves, improves survival for patients post intensive treatment, but also looking at other maintenance strategies for patients who have positivity and post allogenic bone marrow transplantation. In terms of the number of agents that are being tested. There is a large number of new agents that are being tested in this space, including targeted agents, such as novel FLT3 inhibitors, novel IDH inhibitors. But I think also importantly, other immune therapies, as such as bi-specific T-cell engagers, antibody-drug conjugates, CAR T-cells. I think all of those are taking the management of AML into a new place where we are going to have better outcomes. So I think the future is definitely looking better and better over time, and eventually I think we are going to see the overall survival of patients with AML continue to improve with time.