In a first-of-its-kind study, researchers at The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James) found that the youngest (age 18-29 years) Black adolescents and young adult (AYA) patients with acute myeloid leukemia (AML) are 5 times more likely than White young adult patients with AML to die within 30 days of beginning treatment and twice as likely to die within 5 years.
Detailing the study results in the journal Blood Advances, the researchers report a dramatic disparity between Black AYA patients predominantly between the ages of 18 and 29 (2022; https://doi.org/10.1182/bloodadvances.2022007544).
The new study is believed to be the first to compare outcomes, as well as molecular genetic differences, in Black and White AYA patients with AML (ages 18-39 years), which is an especially aggressive blood cancer for which intensive chemotherapy typically is indicated within days of diagnosis. About 20,000 patients are diagnosed with AML in the U.S. every year.
While previous prognostic studies show genetic variations, including changes in structural chromosomes and specific gene mutations, signal the potential for relapse and death, most have focused on White patients with AML, reflecting an underrepresentation of Black patients in clinical trials, as well as biobanking and registry trials. By contrast, the new study examined how disease-specific mutations at presentation are different in Black and White AYA patients with AML.
The new study included 556 White and 89 Black AYA patients with AML, effectively mirroring the proportion of Black individuals in the U.S. population. It utilized banked tissue samples from patients newly diagnosed with AML and treated between 1983 and 2016 in clinical trials run by the National Cancer Center Alliance. Bone marrow and blood cell specimens taken prior to treatment and after achieving remission were collected for cytogenetic and molecular analysis.
The data revealed 11 percent of Black and 2 percent of White AYA patients with AML died within 30 days of initial treatment, while the 5-year survival for Black young adult patients was 32 percent compared to 46 percent for Whites. Early death occurred in 16 percent of Black AYA patients compared to 3 percent of White AYA patients ages 18-29. Median survival was 10.2 years for White AYA patients ages 18-29, but just 1.3 years for the same age Black AYA patients with AML. There were no significant differences in survival rates seen in Black and White AYA patients between the ages of 30 and 39. However, among patients with a typically favorable risk subtype of AML known as core-binding factor AML, the early death rate was 12 percent in Black patients but only 3 percent in White patients, while the 5-year survival rates were 54 percent for all Black AYA patients and 70 percent for all White AYA patients.
Recently, the study's lead author and OSUCCC-James hematologist, Karilyn Larkin, MD, shared additional insights into the study results with Oncology Times.
Growing Outcomes Research
The new study evolved from a group of researchers focused on AML in the Clara D. Bloomfield Center for Leukemia Outcomes Research at The OSUCCC-James. Larkin, who had the pleasure of knowing Bloomfield before she passed away on March 1, 2020, said she "spent her entire career focused on providing a better prognostic awareness for AML patients and treating physicians. And, as part of that group, we are very focused on continuing her legacy and doing outcomes research."
The Bloomfield AML researchers have contributed to a growing body of research on health care inequities and disparities based on race. "We started actually looking within our group of AML patients at how self-identified race as a surrogate for ancestry could impact outcomes, in addition to what we now know about DNA changes," Larkin said.
The new study, in fact, stems in part from research by another member of the Bloomfield research group who previously looked at patients with AML younger than age 65 and noted a disparity in outcomes that appeared to be race-based.
"Our paper is sort of a branch off of that study; however, we decided to look specifically at very young AML patients, the adolescent and young adult population typically not parceled out in AML because it is considered a disease of the elderly, but are presumed to do better overall due to younger age," Larkin noted. "We were able to add a significant number of patients to this group, which allowed us to ask these questions for the first time."
Data collected by the researchers had shown younger patients with AML typically had better outcomes. "And so we wanted to know if, in this otherwise young, healthy population that you would expect to do well, how ancestry influenced outcomes and, importantly, how ancestry might influence the molecular landscape," she stated.
As the data became clear, Larkin was taken aback by "the magnitude of the different outcomes for these very young Black patients compared to White patients, and how they were substantially inferior. Whether you are looking at response rates, the early death rates or the median overall survival rates, the numbers tell a starkly different story for Black and White patients even though they got the exact same kind of therapy."
The findings were given added significance due to the availability of the tissue samples used to identify the molecular signatures and driving factors for AML, Larkin said.
"We found that these very young [Black] patients actually present with very different DNA changes and that they are substantially more likely to have core-binding factor AML compared to White patients, and they have different types of mutations," she explained. "With the identification of different molecular drivers, it raises the question of biologic differences that might impact outcomes, but the differences alone cannot explain all of the disparity that we are seeing."
Raising Important Questions
Core-binding factor AML is supposed to be a "favorable risk" disease state in which patients do better with chemotherapy, especially those who are very young, and irrespective of race, Larkin noted.
"But what we found was that very young Black patients with this favorable risk type of disease actually do very poorly, and worse than I would expect as a physician who treats this disease and does allogeneic stem cell transplants (allo-SCT)," she said, adding, "Normally, we don't offer transplants to patients who are 'favorable risk' because they tend not to need it. Our study is unfortunately not able to answer whether allo-SCT could improve outcomes, but the simple fact that outcomes without allo-SCT are so poor certainly starts to raise these questions."
While very young Black patients potentially having inferior outcomes compared to White patients with AML was expected, Larkin did not anticipate that the differences would be so vast. "I was surprised to see how these patients don't do anywhere near as well as I would expect and, in fact, would counsel patients until we looked at our data. And that's one of the things that we aim to improve on," she said.
"A lot of our prognostic tools and scoring systems are based on data from clinical studies that have more homogenous ethnic and ancestral profiles," Larkin added. "This research project has been humbling in a way; it has caused me to step back and think about how I am practicing in real time and about how I counsel patients."
It is important to remember that, while the study did not seek to determine the existence of structural racism and how it may influence outcomes in AML outcome, it does not ignore the fact that it is certainly a component.
"What our study says is: Here are outcomes that are distinctly different and now there are numerous facets that need to be investigated to find out what kind of contribution each area may have and, most importantly, how can we make these outcomes better?" Larkin said.
"Our paper focuses on what we are able to say with certainty, namely the differences in molecular findings that we have. By design we can say, 'Because these are different drivers in these patients who have very different outcomes with the same, complete therapies, maybe that is one reason for the differences in outcomes.' I think it is part of the reason, but I don't think it is the whole reason."
Measuring Clinical Implications
The outcomes from the new study have many different clinical implications, beginning with the knowledge that differences exist in the molecular signatures between Black and White AYA patients with AML, said Larkin, who also emphasized the need for patients with different ethnicities to be enrolled in clinical trials that can lead to guidelines for prognosis.
"If we can have all of our patients represented in the prognostic tools we use, then we'll be able to better understand their needs and give them the best recommendations. I know it's made me want to renew my effort and strategy toward talking to patients about trials and their value in AML," she said.
Meanwhile, like many areas of cancer care, AML researchers and physicians are recognizing the importance of monitoring patients for minimal residual disease, which Larkin believes is another major clinical implication in the results of the new study.
"Monitoring for MRD allows us to try to understand which patients might not have done as well with therapy and have a higher risk for relapse. And one of the things we showed is that, at least in a handful of patients, we could detect disease when we thought they were in remission.
"We're doing all of this years after the fact, of course, but the outcomes are suggesting that these AML patients don't get to the very deep remission that we would like them to," she continued. "Any young Black patients really should have this MRD monitoring. They should be watched closely so that, if they are going to be more resistant to therapy, we pick up on it sooner and maybe understand that better. I think that any Black patient should see a transplant physician and be considered for different strategies of relapse mitigation therapy and be ready to change course if adequate responses are not seen."
Looking ahead, Larkin admits she has "a laundry list of things I would like to do" in terms of further research, but for now the most pressing is to validate the outcomes from the retrospective study with prospective clinical trials.
"Therapies for leukemia have actually changed quite a bit in the last 5 years. We have more targeted therapies and oral agents, for example, and so we are wondering if all of this is still true. What was the contemporary is very important," she said.
Being able to better capture the data they are missing and understanding what is happening now, in addition to a complete response rate, should enable researchers to better understand how much social or cultural biases factor into patient outcomes, Larkin added.
"I also believe that some of the dedicated analyses of the types of mutations and the associations of mutations and outcomes need to be done for AML patients, especially the Black race and ancestry, because we might find things that we didn't know before," she concluded.
Chuck Holt is a contributing writer.