Minor kidney dysfunction should not preclude African Americans with AML from enrolling on clinical trials
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ORLANDO — Although abnormal kidney function appeared more common among African American patients with acute myeloid leukemia than their white counterparts, minor dysfunction did not appear associated with poorer OS among this group, according to study results presented at ASH Annual Meeting and Exposition.
Thus, renal function eligibility criteria for clinical trials may unnecessarily exclude minority patients from participation and should be eliminated, according to study researchers.
“We do not suggest removing all kidney dysfunction criteria, but we recommend removing exclusion criteria relevant to minor kidney dysfunction because, as our results suggest, those who have mild kidney abnormalities have similar clinical outcomes to those without such abnormalities,” Abby Statler, PhD, MPH, MA, research associate at Cleveland Clinic Taussig Cancer Institute, told Healio.
Minorities are underrepresented in clinical trial patient populations, but the relationship between comorbidity/organ dysfunction exclusion criteria and minority recruitment to AML clinical trials had not been well-understood, Statler said.
“Although several national initiatives have been devised to increase the diversity of clinical trial patient populations, many comprehensive cancer centers struggle to accrue minorities onto interventional studies,” she said. “Overly restrictive eligibility criteria may be an important barrier to clinical trial enrollment among minority patients, as these criteria are biased toward ‘fit’ patient populations, potentially discriminating against patients who present with comorbidities. This may, indeed, be the case for African Americans, as this subpopulation has higher rates of comorbidities and reports poorer overall health compared with whites.”
Clinical trials typically exclude patients with comorbidities to ensure a homogenous trial population, and to not put patients at increased risk.
“Patients with comorbidities may be more prone to adverse reactions, given their concomitant conditions,” Statler said. “This, however, limits the generalizability of the clinical trials’ results, as the intervention is not tested in a diverse array of patients, many of whom will likely receive the investigational product once it is approved and on the market.”
Statler and colleagues evaluated data on 1,040 patients with AML who received chemotherapy at Cleveland Clinic between 2003 and 2019. Most of the patients (n = 939; 90.3%) were white and 101 (9.7%) identified as African American.
Although age and AML etiology and risk appeared comparable between white and African American patients, the latter group appeared more likely to have Medicaid (11.9% vs. 5.1%) and less likely to have private insurance (16.8% vs. 34.6%; P < .001 for both) than whites.
Most patients (n = 868; 83.5%) underwent intensive, cytarabine-based therapy — including an equal proportion of white and African American patients (83.6% vs. 82.2%) — whereas 172 (16.5%) underwent nonintensive therapy with low-dose cytarabine or hypomethylating agents.
Researchers defined organ dysfunction among the patients using the Common Terminology for Adverse Events criteria ( grade 1).
Overall, the prevalence of most comorbidities appeared similar between white and African American patients, as did liver function laboratory values and cardiac tests results. However, a greater proportion of African Americans had renal dysfunction as indicated by abnormal creatinine levels (48.5% vs. 36.5%; P = .01) and creatinine clearance by Cockcroft-Gault (55.4% vs. 47.3%; P = .01).
After median follow-up of 12.73 months (interquartile range, 4.59-43.05), median OS for the study population was 14.75 months (range, 0.03-189.25).
Median OS was 13.7 months among African American patients and 14.9 months among white patients, which did not represent a significant difference.
Complete response rate was 44.2% overall and also did not differ significantly between whites (44.9%) and African Americans (37.6%).
Results of a multivariable analysis showed no difference in OS between white and African American patients (HR = 1.2). Researchers also observed no association between comorbidities and OS, with the exception of liver comorbidities (HR = 2.03; P = .002) and bilirubin levels greater than 1.5 times the upper limit of normal (HR = 1.69; P = .01).
Levels of creatinine 1.5 times the upper limit of normal (HR = 0.99) and abnormal creatinine clearance (84 ml/min to 60 ml/min vs. normal; HR = 0.96) did not appear associated with OS.
However, as the abnormality became more severe, survival differences began to emerge, Statler said during her presentation. OS appeared negatively impacted by creatinine levels 1.5 times to 3 times the upper limit of normal (P = .01) and levels higher than 3 times the upper limit of normal (P = .02).
Researchers did not observe any associations between comorbidities and likelihood of responding to therapy, with the expectation of liver comorbidities (OR = 0.17; P = .01).
African American patients appeared less likely to achieve complete response (OR = 0.56; P = .05), but researchers did not observe an association between response and kidney dysfunction measures.
“These findings suggest trials might be able to broaden their criteria to include patients with kidney disease without compromising the safety of the participants,” Statler said in a press release. “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.”
Researchers next seek to validate these findings in a nationally representative AML patient population, Statler told Healio.
“Additionally, studying the impact of liberalized renal dysfunction eligibility criteria on minority recruitment rates will help elucidate if these design modifications improve the diversity among AML clinical trial patient populations,” she said. – by Alexandra Todak
Reference:
Statler A, et al. Abstract 381. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Statler reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
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Ann F. Mohrbacher, MD
The premise of this study by Statler and colleagues was whether racial disparities in trial enrollment exist because of race or because of some organ dysfunction or comorbidity that prevents the patient from being allowed on the trial. Eligibility criteria of every trial is very specific, especially when it comes to organ function. The common cutoff for kidney function is a creatinine level of 1.5 mg/dL. Because African American patients are underrepresented in trials, the researchers sought to evaluate whether they could not enroll because of specific medical criteria.
The data showed that about 85% of both Caucasian and African American patients received relatively intense treatments, and OS also appeared equivalent. There was a slight difference in bilirubin levels, but researchers observed the most striking differences in creatinine. About 19% of African American patients had a creatinine level above 1.5 mg/dL — meaning they would not have made a trial cutoff — compared with 10% of white patients. In other settings, the differences might be even more vast. This is not a trivial number of patients being excluded from clinical trials.
Researchers also showed that those with kidney dysfunction had similar survival outcomes, although I’m sure those with major kidney dysfunction did not receive high-dose intensive treatments. This implies these patients are being excluded for an unimportant reason.
But, trials cross many different boundaries, in many different countries, so how could this be changed? It would require a formal review process by the FDA to reassess these limits that have been around for 25 years and that might not make any sense; they come from a time when almost everyone on trials was white. They might consider a different formula for calculating kidney dysfunction that normalizes for race, because there is a slight difference between African Americans and Caucasians in what is considered normal function.
We have to be mindful that some of our ideas of “normal” are based only on white populations. Kidney function shouldn’t exclude you from receiving appropriate treatment, and we should liberalize those criteria from trials so we don’t exclude these patients.
These data also imply that we think some patients might have intrinsic biologic differences in response on trials; we want to have participation, but there is sometimes an assumption that their biologic response would be different, although it isn’t necessarily. You won’t know that unless you include these patients on clinical trials.
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