Dr Eytan Stein, MD, from the department of medicine at Memorial Sloan Kettering Cancer Center, New York, NY, has presented in the past on IDH2-mutant AML and continued this work with some recent research presented at the ASH Annual Meeting and Exposition in December 2018. Abstract 287 featured the activity of enasidenib in previously untreated IDH2-mutant AML – results from the BEAT AML Master Trial. In a podcast for the Journal of Clinical Pathways website, Dr Stein shed further light on his findings. What follows is an edited and condensed excerpt of Dr Stein’s comments.
Treating Older Adults With AML
Treating older patient populations with AML continues to be an area of unmet need. There are really two reasons that older patients with AML have issues when it comes to being treated. One of the issues has to do with the biology of the disease and the second issue has to do with the treatments that we have available. Most patients with AML are older; the median age of patients who have this disease is around 68 years old. And in those older patients, it is much more common to have what are known as unfavorable risk markers—that is, either unfavorable cytogenetics or unfavorable molecular genetics which makes their disease more resistant to treatment, specifically to induction-type chemotherapy.
In addition, the patient factors are that the treatments that we have or that we have had up to very, very recently, like induction chemotherapy, can cause fairly significant morbidity and mortality. What is known as the induction mortality rate—that is death within 30 days of receiving traditional induction chemotherapy with drugs like daunorubicin and cytarabine—ranges between 5% and 10%, depending on the study. When you combine these things, that means these patients have high-risk disease, they can be very resistant to chemotherapy, and that even when you give them chemotherapy, all sorts of bad things can happen because of the toxicity of the chemotherapy. That is really what makes the disease difficult to treat in an older adult.
The ways to get around that issue are twofold. One way would be to come up with therapies that are more potent or better so that they can overcome the unfavorable biology of the disease. The second way would be to come up with therapies that are less toxic, because if you can do that, then you may not lose as many patients while you’re giving them treatment.
Beat AML Study
The rationale behind the Beat AML study was to come up with therapies that are more effective, more targeted, and less toxic so that we can improve the overall survival of patients with AML who are older than the 60 years of age and do not do particularly well for the reasons I mentioned.
We do this by taking a precision medicine approach: looking for specific genetic abnormalities that are driving and causing these patients acute myeloid leukemia, and then using targeted therapies, either alone or in combination with standard-of-care therapies like hypomethylating agents, to improve the outcomes of these patients with less toxicity.
Using a precision medicine approach makes a lot of sense. We know that AML almost always has at least one and sometimes multiple driver mutations, so if you target them you can potentially improve the outcome of these patients. However, until recently, there was this thought that a patient had to be treated as soon as they presented to the hospital with AML, and it often can take days or a week before the genetic results are available that dictate what therapy to use. The primary goal of the Beat AML Master trial was to test the hypothesis that we can get genetic results back on these patients’ leukemia samples within 7 days and that we can then act on those results quickly enough to not negatively impact the outcome of the patients.
The trial includes patients with AML older than the age of 60. Participants receive a bone marrow biopsy to determine if they are positive for IDH2 mutation, and if they are, they are assigned to the IDH2-mutant arm. Treatment for that arm consists of single-agent enasidenib, which is the only IDH2 inhibitor approved for relapsed and refractory AML. It is not yet approved for newly-diagnosed AML. Patients receive up to five cycles of the IDH2 inhibitor enasidenib. It is an oral medication taken once daily, and it is very well tolerated.
If patients achieve a complete remission, or a complete remission with incomplete blood count recovery by the end of the fifth cycle, they are then allowed to continue on the monotherapy. Patients who do not achieve a complete remission go on to combination therapy with enasidenib and the standard-of-care medicine azacitidine.
Monotherapy Treatment Results
At the 2018 ASH Annual Meeting, our presentation of the study findings really focused primarily on the monotherapy group. We do not have a lot of data yet on the combination therapy group. In short, patients in the monotherapy arm do very, very well. As of the meeting date, we treated 27 patients on the IDH2 mutant arm. The drug has been remarkably safe. The biggest side effect we have seen is what is called differentiation syndrome, which occurs with differentiation agents like enasidenib that cause immature leukemia cells to mature to normal white blood cells. When that happens, patients can get fluid accumulation in the lungs or in the legs, and that has been the most pronounced adverse event that we have seen. It has been easily managed with steroids.
In terms of responses, the overall response rate for these patients has been 44%, so nearly half of the patients have had a response. If you break up the responses by the best response category, 37% of the patients have had a complete remission, and 7.4% of the patients have had a complete remission with incomplete blood count recovery.
What we are showing here—and I think what is really exciting—is that with a single-agent oral medication that you take at home with really minimal toxicity, you can induce a remission in nearly half of patients (44%). That is really remarkable.
In patients who have IDH mutations with co-occurring mutations in genes in the RAS pathway, only one out of six of those patients responded to enasidenib on this trial. We have not done this yet, but you can imagine that if you modified the trial to come up with a different strategy for that patient group, you would potentially even boost that response rate even higher.
What this trial has also allowed us to do is to understand who might not respond so that those patients who were getting precision medicine on this arm of the trial can potentially be rolled into or treated on an arm yet to be developed where they will have a greater chance of response.
Future Directions
There are two important points to take away from this. One is that, for patients with newly-diagnosed AML older than the age of 60 who have an IDH2 mutation, the preliminary results would suggest that this is a very effective drug, and it is a drug that in certain patients should definitely be considered as potentially even front-line therapy. The patient population I am thinking of is patients who might not be able to receive induction chemotherapy because they have medical problems that would keep that from being a good approach.
Overall, the message is that precision medicine in the treatment of AML is feasible, and these precision medicine trials that we are doing not only are good for the patients who respond but also really teach us what the next trial should be. In this way, the trial does not just end when this trial is over, but it allows us to build upon the results that we presented at the meeting.
The only way these trials are able to work is that patients get referred in to have the trials done. It is really important for the treatment of AML that all patients, if possible, enter a clinical trial. Although there is a lot of excitement with what is going on in AML in terms of new drug approvals and in terms of better therapies, the sad truth is that AML is still a terrible disease, and most patients still do not do very well. In order to make real progress, patients need to go on clinical studies.
Specifically for the Beat AML trial, I would encourage any practicing clinician to go to www.clinicaltrials.gov and search for the Beat AML trial, or go to the website of the Leukemia and Lymphoma Society to look and see where there might be a site in the country that is participating and refer patients for potential participation.
