Highlights
– Applying contemporary, safety-based eligibility criteria to 190 phase II/III AML trials increased median patient eligibility from 47.9% to 84.2% in a retrospective cohort of 2,226 newly diagnosed patients across eight hospitals.
– Excluding upper age limits, modernization still increased eligibility by a median of 11.5%, indicating that non-age criteria also substantially restrict participation.
– Modernized criteria reduced between-group eligibility disparities for non-Hispanic White versus Asian, Black, and Hispanic patients and improved representation across racial/ethnic groups without worsening safety-risk selection.
Background
Clinical trial eligibility criteria are a necessary element of trial design: they define the population being studied, help ensure participant safety, and improve signal detection by reducing heterogeneity. However, restrictive or poorly justified eligibility rules can impede accrual, slow development timelines, and produce study populations that do not reflect real-world patients. This issue is particularly important in acute myeloid leukemia (AML), a disease that primarily affects older adults and for which newer therapeutics and combinations are being rapidly tested in phase II and III trials.
Concerns about narrow eligibility have prompted professional and regulatory efforts to modernize trial criteria, emphasizing meaningful, safety-based exclusions and arguing against blanket exclusions (for example, arbitrary upper age limits or prior malignancy bans) that disproportionately limit participation for older adults and historically underrepresented groups. Key statements include the American Society of Clinical Oncology–Friends of Cancer Research (ASCO-FOR) joint recommendations to broaden eligibility and the U.S. Food and Drug Administration’s guidance encouraging sponsors to reconsider restrictive criteria that lack a clear safety justification.
Study design
The study by Hantel et al. (2025, Blood) evaluated the potential impact of applying contemporary, safety-focused eligibility criteria across a large set of completed AML trials, then tested those criteria against a real-world population. The investigators first abstracted eligibility requirements from 190 phase II/III AML trials. Using FDA and professional society guidance on modernizing eligibility, they generated an alternative set of safety-based criteria for each trial, aiming to retain appropriate safety protections while removing non–evidence-based exclusions.
They then applied both the original (trial-based) and the proposed safety-based criteria to a retrospective cohort of 2,226 newly diagnosed AML patients treated across eight hospitals. The primary outcome was the proportion of patients who would be eligible under each criteria set. Secondary analyses examined the impact of removing age limits, changes within racial/ethnic subgroups, and which individual eligibility items contributed most to increased eligibility and to reductions in between-group differences.
Key findings
The principal finding was a large, consistent increase in theoretical trial eligibility when trial criteria were modernized to focus on safety. Median eligibility across the cohort rose from 47.9% under the original trial-based criteria to 84.2% under the safety-based criteria (median difference 30.0%; p < 0.001). This represents an absolute, median increase of roughly one-third in the pool of potentially eligible patients.
Age limits explained part but not all of the increase. When upper age limits were excluded from the analysis, the median increase in eligibility remained statistically significant at 11.5% (p < 0.001), indicating that other eligibility elements—comorbidities, laboratory thresholds, prior malignancy, and cardiovascular exclusions—also meaningfully constrained access.
Representation analyses across major racial/ethnic groups showed baseline differences with trial-based criteria and large within-group gains after modernization, but little evidence of differential gains between groups. With original trial criteria, median eligibility proportions by group were: non-Hispanic (NH)-Asian 41.1%, NH-Black 44.0%, NH-White 47.9%, and Hispanic 50.0%. Applying safety-based criteria increased eligibility within each group by 27.9–31.6% (all within-group p < 0.001), and when age limits were excluded the gains were 10.0–11.9% (all p < 0.001). Importantly, the between-group differences after modernization were not statistically significant (between-group p > 0.05), indicating improved equity of theoretical access.
At the trial level, moving from trial-based to safety-based criteria decreased the proportion of trials with significant eligibility differences between NH-White patients and NH-Asian (-11.1%), NH-Black (-4.2%), and Hispanic (-12.1%) patients. In other words, modernized criteria reduced the number of trials where eligibility disproportionately favored white participants.
Which eligibility items mattered most? The investigators identified several criteria whose relaxation both increased overall eligibility and reduced between-group differences: coronary artery disease, congestive heart failure, aspartate aminotransferase (AST) thresholds, upper age limits, and prior malignancy exclusions. Each of these commonly used exclusions often lacked contemporary evidence showing elevated risk specific to trial interventions and therefore appeared amenable to a safety-based reconsideration.
Safety outcomes were not directly measured in the retrospective application (the analysis was theoretical eligibility mapping), so the study does not provide direct evidence that broader criteria are equally safe in practice. The rationale for the redesigns was guided by FDA and professional society frameworks that stress individualized assessment and monitoring rather than categorical bans.
Expert commentary and interpretation
This study offers actionable evidence that modernizing eligibility criteria per established guidance can substantially increase the pool of potentially eligible AML patients and improve racial/ethnic representation without obvious tradeoffs in safety-selection (based on the principle of retaining safety-based exclusions). Several points deserve emphasis for clinicians, trialists, and regulators:
- Magnitude of the effect: A near-doubling of median eligibility in many trials is a striking finding. If reproduced prospectively, such changes could accelerate enrollment, reduce trial timelines, and improve the external validity of AML studies.
- Age is important but not the only barrier: Upper-age limits remain a potent exclusion, particularly in AML where median patient age at diagnosis is high. However, removing age limits alone would not fully remedy limited eligibility. Other commonly used exclusions are modifiable and should be reconsidered.
- Equity implications: The safety-based approach yielded similar proportional gains across racial/ethnic groups and reduced the number of trials with significant between-group eligibility disparities. This suggests that modernized criteria can be a tool to improve representation—an important goal given the variable incidence and outcomes of AML across populations.
- Operational and safety safeguards: Modernizing criteria does not imply removing safety monitoring. Instead, it favors individualized risk assessment, closer monitoring, staged dose-escalation strategies, and clear mitigation plans for patients with comorbidities. Prospective studies are needed to demonstrate that these approaches do not increase adverse events or dilute efficacy signals.
These conclusions align with the ASCO–Friends of Cancer Research joint recommendations and FDA guidance urging sponsors to justify exclusions and adopt evidence-based thresholds. Notably, the ASCO-FOR report (Kim et al., J Clin Oncol, 2017) argued for inclusion of patients with controlled comorbidities and for reconsidering arbitrary laboratory cutoffs. Likewise, the FDA guidance (2020) recommends limiting eligibility barriers that lack a plausible safety rationale and encourages enrollment practices that increase diversity.
Limitations and generalizability
Several limitations should guide interpretation. First, the analysis is retrospective and theoretical: it maps criteria to an existing cohort rather than testing outcomes when patients with broader eligibility actually receive investigational therapies. As such, the study cannot directly assess how expanded eligibility would affect adverse events, tolerability, or treatment efficacy.
Second, the cohort comprised patients from eight hospitals—likely including academic centers and large community programs—and may not perfectly represent all practice settings or international populations. Third, the safety-based alternative criteria were constructed by investigators using existing guidance; different reasonable interpretations could yield different eligibility sets. Finally, the study examined phase II/III AML trials broadly; specific agents (e.g., intensive chemotherapy, targeted inhibitors, or combinations with cardiotoxic potential) may still warrant tailored exclusions.
Practical implications and next steps
For sponsors and investigators designing AML trials, this work provides a strong empirical rationale to:
- Reassess the justification for each exclusion criterion. Require a specific, evidence-based rationale tied to the investigational agent or regimen rather than defaulting to conservative rules from earlier eras.
- Eliminate arbitrary upper-age limits and instead specify functional or physiologic criteria (performance status, organ function thresholds) that predict tolerance to therapy.
- Relax historical laboratory cutoffs when evidence shows minimal additional safety risk and adopt monitoring strategies (more frequent labs, predefined dose modifications) to manage risk.
- Include patients with controlled comorbidities, prior malignancies, or stable cardiovascular disease when mechanistic or prior-experience data do not indicate increased risk.
- Collect and report enrollment demographics and reasons for ineligibility prospectively to assess the real-world impact of eligibility modernization.
Regulators and funders can support these changes by encouraging justification of exclusion criteria in trial protocols, incentivizing representative enrollment, and sponsoring prospective studies that test safety and efficacy under broader eligibility rules.
Conclusion
The study by Hantel et al. provides compelling, empiric support for modernizing AML clinical trial eligibility to focus on safety-based, evidence-driven exclusions. Applied retrospectively to a large trial set and real-world cohort, such modernization markedly increased theoretical eligibility and reduced representational disparities across racial and ethnic groups. While prospective validation of safety and efficacy under broadened eligibility is needed, the findings align with regulatory and professional guidance and should prompt sponsors and investigators to critically reexamine exclusion rules that lack a clear justification.
Funding and clinicaltrials.gov
The primary article and authorship include multi-institutional contributors; specific funding sources and trial registration details should be consulted in the original publication: Hantel A, Wang Y, Cronin A, et al. Impact of Modernizing Eligibility Criteria on Enrollment and Representation in Acute Myeloid Leukemia Clinical Trials. Blood. 2025 Oct 16:blood.2025030741. doi: 10.1182/blood.2025030741. Epub ahead of print. PMID: 41100728.
References
1. Hantel A, Wang Y, Cronin A, Khan I, Abraham IE, Eisfeld AK, Patel AA, Stock WA, Monick S, Walsh TP, Gallagher E, Luskin MR, Avila Rodriguez AM, Galvez C, Doukas PG, Altman JK, Burkart M, Erra A, Zia M, Larson ML, Dave A, Tsai SB, Aleem A, Raptis NI, Lathan CS, Uno H, DeAngelo DJ, Abel GA. Impact of Modernizing Eligibility Criteria on Enrollment and Representation in Acute Myeloid Leukemia Clinical Trials. Blood. 2025 Oct 16:blood.2025030741. doi: 10.1182/blood.2025030741. Epub ahead of print. PMID: 41100728.
2. Kim ES, Bruinooge SS, Roberts S, Ison G, Lin NU, Gore L, Bunn PA Jr, Ellis LM, Gore I, Kurzrock R, et al. Broadening eligibility criteria to make clinical trials more representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement. J Clin Oncol. 2017;35(33):3737–3744.
3. U.S. Food and Drug Administration. Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry. 2020. Available at: https://www.fda.gov/ (accessed [date]).
Thumbnail image prompt (for designers)
Photorealistic scene of a diverse group of adult patients (older and middle-aged, varied racial/ethnic backgrounds) seated in a hospital corridor, talking with a hematologist who points to a clipboard labeled ‘Clinical Trial Eligibility.’ Include medical charts, soft clinical lighting, and a subtle overlay of data visualization (bar chart) in the background to evoke analytics and policy. Convey inclusivity and a pragmatic, evidence-driven mood.