Studies’ Results Support Liberalization of Some Eligibility Criteria for Acute Myeloid Leukemia Clinical Trials

Overly restrictive exclusions may lead to racial disparities and unrealistic outcomes

Two related Cleveland Clinic studies examining acute myeloid leukemia (AML) outcomes in various patient populations bolster the case for easing some restrictions on clinical trial enrollment. Loosening select eligibility criteria would increase access for patients who potentially could clinically benefit, in addition to producing less racially biased and more generalizable results, the researchers contend.

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Investigators from Cleveland Clinic’s Department of Hematology and Medical Oncology and their collaborators presented data from the two studies at the American Society of Hematology’s (ASH) 2019 annual meeting.

The aim of both studies was to gain a better understanding of the ways in which clinical trial eligibility criteria influence enrollment and outcomes. The first study analyzed how comorbidities and organ dysfunction criteria commonly used to determine clinical trial eligibility impact outcomes in AML patients receiving induction chemotherapy. The second study examined whether racial disparities in AML clinical trial enrollment are associated with comorbidities and/or organ dysfunction.

“The results of these studies point to several important conclusions,” says research scientist and first author Abby Statler, PhD, MPH, MA, of Cleveland Clinic Cancer Center’s Biostatistics Department. “The first is that if we are able to liberalize comorbidity eligibility criteria, we may reduce racial disparities in clinical trial enrollment. The second is that if we are able to offer clinical trials to a broader patient population, and specifically those patients with minor organ dysfunction, then we can expand access to investigation products. Finally, if we are able to enroll patients who are similar to those we treat on a regular basis, clinical trials’ outcomes may be more achievable by the general population.”

Earlier studies raise issues

There are valid reasons to put rigorous clinical trial eligibility criteria in place: for patient safety; to maximize the chances of detecting statistically significant and clinically meaningful effects of the drug being tested; and to accurately evaluate the cause or source of any adverse events.

Sponsors of clinical trials also design eligibility criteria that maximize the likelihood of positive treatment effects and minimize the possibility of adverse events, each of which may improve their drug’s chances of earning regulatory approval.

But one concern is that exclusions may be so rigid that they omit patients with conditions that may not meaningfully affect the trial’s efficacy and adverse event outcomes, and who might actually benefit from the drug if they were included. Another concern is that the safety results of highly restrictive clinical trials might not be generalizable because they don’t reflect clinical outcomes among real-world patients.

Dr. Statler explains that the research presented at ASH was prompted by earlier studies demonstrating that specific eligibility criteria might discriminate against certain patient populations.

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In 2017, her team published a study showing that RCTs involving hematologic malignancies that exclude patients with organ dysfunction do not reflect expected toxicities or adverse events reported on the trials. Additional studies from early 2019 found that approximately 60% of clinical trial exclusions pertain to comorbidities or performance status, indicating that many patients are excluded from enrollment because they present with comorbidities or organ dysfunction.

“One of the challenges is understanding if those eligibility criteria are indeed appropriate and whether we should be modifying them so that we can accrue more diverse patient populations,” she says. “Our earlier work demonstrated that eligibility criteria relevant to comorbidities and organ dysfunction might actually be unjustified. [In follow-up research] we wanted to understand, among AML patients, the potential impact of comorbidities on clinical trial enrollment, and compare outcomes among those patients with and without the comorbidities or organ dysfunction that have commonly been used in clinical trial eligibility criteria.”

Details of the new research

The first new study analyzed a cohort of 1,082 AML patients, the majority (88.1%) of whom presented with at least one comorbidity and/or clinically insignificant liver or renal abnormality that could have caused their exclusion from clinical trials. Dr. Statler and her colleagues found that survival, response and dose modification outcomes after chemotherapy did not significantly differ between patients with and without comorbid conditions or organ dysfunction.

“We looked at several different comorbidities — those relevant to neurological, renal, endocrine, gastrointestinal, cancer, myocardial and vascular conditions — and found that they were not significantly associated with overall survival,” or OS, says Dr. Statler. “The only comorbidity that was significantly associated with OS was chronic liver disease.”

The findings show that eligibility criteria that broadly exclude patients with comorbidities may not be appropriate, because these comorbidities are unlikely to affect survival outcomes in the trials, Dr. Statler says. Furthermore, there was no significant difference in the OS of patients with mild liver or kidney dysfunction, indicating that mild organ function abnormalities should not be a reason for exclusion.

“If we are able to broaden eligibility criteria and include patients who are more analogous to the real-world patient population, we may improve clinical trial enrollment and generalizability of clinical trials’ results,” she says. Regarding AML clinical trials, “we now have data to support the recommendation that we should liberalize specific eligibility criteria relevant to comorbidities and liver/kidney dysfunction, so that we can study investigational products in a broader patient population, reflective of people who will ultimately receive the drug once it is approved and on the market.”

Probing potential racial disparities

The second new study analyzed the associations between clinical outcomes (overall survival and response) and the presence of comorbidities/organ dysfunction in a cohort of 1,040 AML patients, 90.3% of whom identified as white and 9.7% as African-American.

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Minorities are under-represented in clinical trials in general, and the proportion of African-Americans participating in cancer clinical trials has recently declined.

“Our study aimed to understand whether specific comorbidity eligibility criteria are discriminating against certain minority patient populations because of their higher rates of comorbidities,” says Dr. Statler. “The second goal was to understand if clinical outcomes are different in patients with and without specific comorbidities and organ dysfunction.”

The study found significantly higher rates of kidney disease at baseline in African-American patients compared to whites. However, among all included patients, kidney disease was not independently associated with response or overall survival. Similar outcomes were reported for neurological, endocrine, gastrointestinal, cancer, myocardial and vascular conditions. Across all conditions studied, chronic liver disease was the only comorbidity associated with response and overall survival.

Consequently, the authors concluded that renal function eligibility criteria may be an important barrier to clinical trial enrollment of African-American patients, because renal disease is more common in this group.

“These findings indicate that eligibility criteria relative to kidney dysfunction may be appropriately liberalized without undue risk [in AML clinical trials], which may result in an increase in the accrual of patients from hard-to-reach minority patient populations” Dr. Statler says.