How AML Clinical Trial Design Is Evolving for a Mutation-Driven Era
As AML therapies advance to include mutation-specific drugs, clinical trial design must also evolve.
Acute myeloid leukemia (AML) is no longer referred to as a single disease. Increasingly, it’s understood as a collection of genetically defined subtypes, each with unique treatment opportunities and challenges. This deeper understanding is reshaping expectations for clinical trial design and execution, requiring integrated biomarker workflows, flexible protocols and earlier use of real world evidence to stay competitive.
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In particular, advances around two genetic alterations in AML (the KMT2A rearrangement and NPM1 mutation) are fueling momentum for targeted, specific therapies. The shift toward mutation-driven research began nearly a decade ago with the introduction of FLT3 inhibitors, but with menin inhibitors now progressing through the pipeline and additional targets emerging, this evolution has solidified into a defining trend.
Today, more than half of AML patients have an identifiable target, marking a new phase in trial design—one that demands even greater precision, adaptability and collaboration from the outset. Translating these therapies into meaningful patient outcomes requires reimagining how AML trials are designed, optimized and operationalized from the outset.
Designing Combination Regimens in Mutation-Driven AML Trials
The arrival of menin inhibitors brings new potential for treating more patients with targeted therapies—directed at genetic aberrations that interact with HOXA9-MEIS, including KMT2A rearrangement, MN1 or NUP98 fusions, NPM1 mutation and UBTF internal tandem duplications.
While menin inhibitor monotherapy has shown clear clinical benefit, high rates of resistance remain a challenge. Introducing these agents earlier in treatment and combining them with standard regimens may improve long-term outcomes but also adds layers of complexity to trial design and execution.
"Success with menin inhibitors hinges on strategic integration—how these molecules fit into a broader therapeutic plan determines trial feasibility and patient safety. Combination timing, dose sequencing and safety management are what make or break feasibility in real-world settings," explains Chris Keuker, MD, Executive Medical Director in Oncology at Syneos Health.
Why Biomarker Testing Is a Bottleneck in AML Trial Enrollment
AML is a very aggressive disease, making rapid identification of eligible patients critical. "In AML, you often have a very short window to identify eligible patients and start treatment. If your testing infrastructure isn’t fast or integrated into the site’s workflow, you lose them," says Liat Vidal, MD, Executive Medical Director in Oncology at Syneos Health.
Yet many AML programs still face delays due to lack of real-time testing infrastructure, unclear sample requirements or fragmented workflows. For menin inhibitor trials targeting KMT2A or NPM1, every day between diagnosis of relapse and enrollment counts.
Dr. Vidal notes that AML patients may present with therapy-resistant disease or evolving mutational profiles at relapse, emphasizing the importance of repeat genetic testing—via cytogenetics, fluorescence in situ hybridization and mutation analysis or next-generation sequencing—before selecting therapy within or outside a trial.
Sponsors need to be planning upfront for diagnostic testing availability, from confirming local lab capabilities to building centralized testing partnerships for implementing a companion test. Integrating biomarker workflows into feasibility planning and not after protocol finalization helps to avoid costly enrollment gaps.
Building for Operational Agility
Mutation-driven trials introduce layers of complexity that demand tight cross-functional alignment. From protocol setup through execution, sponsors must account for the realities of global site operations, regulatory variability and fluctuating patient access.
"In mutation-driven AML trials, operational delays can result in missed windows for enrollment or suboptimal patient outcomes. Sponsors need to plan for variability in site capabilities, regulatory response times and access to diagnostics across regions from day one," says Dr. Vidal.
Early engagement with clinical operations, data management and regulatory partners helps streamline workflows and ensures nothing is missed in the transition from protocol to operations. This agility is especially important in studies with adaptive designs or mid-trial amendments, which are becoming more common in AML clinical development.
Designing AML Trials With the End in Mind
Today’s trial designs must anticipate the evolving expectations of regulators, payers and clinicians responding to the rise of targeted therapies. In AML, as patients are increasingly segmented by mutation status, smaller, more molecularly defined populations are raising the bar for evidence. Beyond response rate, sponsors now face mounting pressure to demonstrate durable, real-world value, from survival and quality-of-life gains to performance against emerging competitors.
“With mutation-targeted therapies, the bar is higher,” says Dr. Keuker. “You’re dealing with smaller populations, faster-moving disease and more scrutiny around how results translate into real-world care. That means aligning trial endpoints—and evidence strategy—upfront to reflect those access realities.”
Design teams must work cohesively from day one—bringing together medical affairs, commercial strategy and data science—to ensure the endpoints chosen not only meet regulatory thresholds but also support payer review, market adoption and real-world use.
A Strategic Imperative for AML Sponsors
AML sponsors operating in a highly competitive landscape must move fast—but not at the expense of precision. Designing around mutation-specific treatment strategies requires upfront integration of scientific, operational and regulatory perspectives. Mutation-driven AML trials are already reshaping the field. The question for sponsors is whether their studies are built to keep pace.
Ready to accelerate your mutation-driven AML strategy? Connect with our oncology experts to explore faster, innovative trial execution.
Contributors
Chris Keuker, MD | Executive Medical Director, Oncology
Daniel Mazzolenis, MD | Senior Vice President, Medical Management
Liat Vidal, MD | Executive Medical Director, Oncology
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