1. Fuerst, Mark L.

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ORLANDO-African American patients with acute myeloid leukemia (AML) may have more abnormal kidney function than white patients, but this does not necessarily lead to any difference in overall survival, according to a new study (Abstract 381). The results have implications for the design of clinical trials, which typically exclude patients with signs of kidney dysfunction and may disproportionately, and unnecessarily, exclude minority patients.

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Clinical trials often seek to enroll patients who have few health problems other than the one being studied. "Minority patient populations are underrepresented in clinical trials. Clinical trial eligibility criteria are often overly restrictive and biased towards 'fit' patient populations. They potentially discriminate against those with comorbidities, which leads to systematic exclusion of subpopulations," said lead author Abby Statler, PhD, a research associate at the Cleveland Clinic, at a press briefing at the 2019 ASH Annual Meeting.


African Americans tend to have higher rates of comorbidities and chronic conditions and therefore poorer overall health, she noted. As a result, the population of trial participants does not reflect the real-world diversity of the patient population who will ultimately receive the drug.


"It's important that we understand how drugs work in different patient populations in clinical trials, especially those that reflect the patients we will eventually treat with the drug," said Statler. "Designers of clinical trials can use data from studies like ours to inform future eligibility criteria in order to test drugs in more diverse populations."


Study Details

In the study, Statler and colleagues examined the health records from 1,040 AML patients, 939 (90.3%) patients identified as white and 101 (9.7%) patients as African American, who received care at the Cleveland Clinic from 2003 to 2019. Age, AML etiology, and AML risk were balanced between the two groups.


Most patients were treated with intensive, cytarabine-based therapy (83.5%), while others received non-intensive regimens (low-dose cytarabine or hypomethylating agents) (16.5%). African American patients were just as likely as white patients to receive intensive therapy.


African American patients presented with similar frequencies of both overall and specific comorbidities. Liver function laboratory values (AST/ALT/bilirubin) and cardiac test results (QTc/LVEF) at baseline were also similar. However, a greater proportion of African American patients (48.5%) presented with renal dysfunction when compared to whites (36.5%) as measured by creatinine or creatinine clearance (55.4% vs. 47.3%, respectively).


With a median follow-up of 12.73 months, overall survival (OS) for the entire cohort was 14.75 months. Median OS did not differ by race (African Americans, 13.7 months vs. whites, 14.9 months). Overall, the complete response (CR) rate was 44.2 percent, which also did not differ by race (African Americans, 37.6% vs. whites, 44.9%).


When adjusting for other known predictors, in a multivariable analysis, there was no difference in OS between African Americans and whites. Additionally, Statler said there was no association between comorbidities/organ dysfunction and OS, with the exception of liver comorbidities and bilirubin. Clinically insignificant creatinine and creatinine clearance abnormalities were not independently associated with OS. Subgroup analyses by race revealed similar results for African Americans, although there were no differences in OS based upon bilirubin.


"The results suggest that treatments worked just as well in African Americans as whites," said Statler.


With the exception of liver comorbidities, the analysis failed to identify significant evidence of association between response and comorbidities/organ dysfunction, with similar results within the African American subgroup. Although African Americans were less likely to achieve a CR, there was no association between response and creatinine/creatinine clearance abnormalities, regardless of severity, said Statler.


The signs of kidney abnormalities may be benign, as previous studies suggest African Americans have higher creatinine levels than whites. Consequently, this laboratory value may falsely underestimate this subpopulation's kidney function, causing them to fail study enrollment requirements that require normal creatinine or creatinine clearance values, she said.


The study's finding that patients with minor creatinine or creatinine clearance abnormalities showed no differences in overall survival calls into question the necessity of excluding patients with these abnormalities from AML trials, Statler said. The study also bolsters evidence that African American patients may simply have higher baseline creatinine levels than white patients.


"These findings suggest trials might be able to broaden their criteria to include patients with kidney disease without compromising the safety of the participants," said Statler. "In doing so, we might be able to truly improve the number of patients from minority populations who are potentially eligible for trials, but who would have been excluded for that reason alone."


The researchers plan to further examine the data to determine precise kidney function cutoff points for future clinical trial eligibility criteria. In addition to AML, Statler said the study findings could be relevant to designing trials for other cancers, particularly prostate cancer, which disproportionately affects African American men.


They concluded "future trials that broaden the renal function eligibility criterion have the potential to accrue more diverse patient populations, which may reduce recruitment racial disparities and improve the generalizability of the trials' results."


The key findings of the study, said Statler, note that "renal function eligibility criteria may be an important barrier to clinical trial enrollment for African Americans." She recommended liberalized renal function eligibility criteria.


"The implications of the study are to reduce racial disparities in clinical trial enrollment, expand access to investigational products, and improve generalizability of clinical trials' results," said Statler.


Mark L. Fuerst is a contributing writer.