Precision medicine treatment in older AML: Results of Beat AML master trial
Dr Amy Burd - Leukemia and Lymphoma Society, White Plains, USA
The Beat AML master trial is a study that started in November 2016 and the concept of the trial started with we know now that AML is a heterogeneous disease and it’s driven by the serial acquisition of mutations that lead to inter-patient heterogeneity, both in biology and clinical response. With increasing evidence of efficacy in targeted therapies we had hypothesised could we improve patient outcomes by matching patients to the appropriate therapy. We created this Beat AML master trial which is an umbrella study that requires screening upon entry into the study and has a primary endpoint of achieving a treatment decision within seven days.
The study is designed for newly diagnosed AML patients that are 60 years and older. The concept of how the trial is set up is that patients consent upon suspicion of AML and then three diagnostic assays are utilised in making a treatment decision, that’s local cytogenetics, next gen sequencing from Foundation Medicine and a PCR based FLT3 assay from Invivoscribe.
All three assays are utilised in making a treatment decision and all three assays must be completed within the seven days. The treatment decision is done centrally by Dr John Byrd or one of the other principals of the study. Once a treatment decision has been made patients are either assigned a molecular group where they receive a targeted agent or combination of agents or the marker negative group where they receive a broad acting agent or a combination of agents. By having the marker negative group it allows all patients who want to participate in this trial an opportunity to receive a novel therapy.
Why did you choose seven days?
There is some literature that has shown that delaying treatment by up to eight days did not change the overall survival. So building on that hypothesis we made the decision to delay treatment by up to seven days to complete the genomic testing that was needed to make a precision medicine approach to targeting AML.
What did you find?
We found that after screening patients we had 395 newly diagnosed AML patients. The majority of those patients did go on to the assigned therapy; for the patients that did not go on to the assigned therapy the majority did go on to either standard of care, we had 10% that went on to palliative care and 7% went on to an alternative clinical trial. From that we determined that we could achieve the primary endpoint of the study with 94.7% of the patients were able to make the treatment decision within the seven days. We showed that there is a superior overall survival for patients that were treated on the Beat AML study, any one of the eleven sub-studies that we had, that had a median of 12.8 months compared to patients that were treated with standard of care that had a median of 3.9 months.
What were the main conclusions? Why is this clinically relevant?
We demonstrated that delaying treatment by up to seven days is both feasible and safe for patients in this older AML patient population. We also demonstrated that patients that go on to the assigned therapy had a lower early death rate and a superior overall survival compared to patients who elected to take standard of care.
The study has the potential in how we’ve designed this umbrella study to improve both short- and long-term outcomes for patients of AML and also has set the stage for how clinical trials in a precision medicine approach can be done in blood cancers in the future.
Were co-morbidities a factor due to the patient population?
Our eligibility criteria for the study was just to be newly diagnosed with AML and be 60 years and older. So many of the patients were very sick and had a lot of comorbidities but we kept the eligibility criteria very broad to enrol the majority of AML patients that we could.
Can this genetic and cytogenetic information be used for counselling and to guide treatment decisions for both the patient and the clinician?
Yes, we feel like we’re on the road to changing the paradigm for how AML is treated and that a precision medicine approach to targeting and treating AML is definitely in the future and that this is one of the many studies that is going to prove that that’s how AML should be treated.
What are the next steps?
Our next steps are we really created a platform in designing the study that allows us to test compounds rather quickly and determine whether they’re going to work in a targeted way for the patients. So we’re continuing to advance and test more drugs and add that into our pipeline but also move into novel-novel combinations in the future where we can bring two investigational agents together in the hopes that we can create a more durable response for AML and possibly a cure.