AML in younger Black AYAs molecularly distinct, associated with shorter survival
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Younger Black patients with acute myeloid leukemia had worse outcomes than their white counterparts, including a higher early death rate, numerically lower complete remission rate and shorter OS, according to study results.
The findings, presented at ASH Annual Meeting and Exposition, were specific to adolescent and young adult (AYA) patients with AML aged 18 to 29 years and suggest a need for different treatment intensities or modalities for these patients, as well as systemic changes to reduce health inequities, according to researchers.
“Our study demonstrates there is a different genetic landscape for adolescent and young adults (aged 18-39 years) with AML based on self-identified race, and that Black patients in the youngest half of this age group (aged 18-29 years) have significantly inferior outcomes than white patients of the same age despite completion of the same chemotherapy,” Karilyn T. Larkin, MD, assistant professor of internal medicine in division of hematology at James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer Center, told Healio.
Previous research has shown disease factors such as cytogenetic findings and gene mutations affect AML outcomes, along with patient-related factors such as age and race. In addition, approximately half of patients diagnosed as AYAs may be cured of their disease. Larkin and colleagues pursued the study because the impact of race on outcome and associated disease profiles remained unknown.
The analysis included 655 AYA patients with AML (Black, n = 89; white, n = 566) who underwent treatment between 1986 and 2016 on front-line Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols based on standard-intensity cytarabine/anthracycline induction therapy. Researchers reported no significant differences in clinical features at diagnosis and noted that a comparison of clinical characteristics of AYA patients with AML by race revealed almost identical age and sex.
Larkin and colleagues used targeted sequencing of 81 genes to molecularly analyze 310 patients, and performed integrated genomic profiling and measured residual disease in serial samples of four Black patients who experienced AML relapse.
A greater proportion of white patients had cytogenetically normal disease (42% vs. 18%; P < .001). The abnormal karyotypes in Black patients more frequently contained abnormalities associated with core-binding factor (CBL) AML (39% vs. 25%, P = .01). A higher proportion of white patients had known pathogenic NPM1 variants (29% vs. 9%, P = .01), whereas Black patients had a higher incidence of ZRSR2 pathogenic variants (9% vs. 0.4%, P = .004) and tended to have pathogenic KRAS variants more often (12% vs. 5%).
Researchers found Black AYA patients with AML had a higher early death rate, defined as death within 30 days of diagnosis (11% vs. 2%, P < .001), a trend toward lower complete remission rate (73% vs. 82%) and shorter median OS (1.5 years vs. 3.1 years; P = .002). The disparity in survival was driven “almost exclusively” by patients aged 18 to 29 years, as they found no significant outcomes differences between Black and white patients aged 30 to 39 years, they wrote.
Multivariable analysis of all patients who received intensive chemotherapy showed Black race as an independent predictor of shorter DFS (P = .04), as well as OS (P < .001). The OS differences remained significant when researchers included patients who underwent allogeneic transplantation in first complete remission (P < .001).
Black patients aged 18 to 29 years with any non-CBF AML had much lower rates of 5-year OS than their white counterparts (12% vs. 45%, P < .001), whereas those with CBF-AML tended to have shorter 5-year OS compared with white patients (41% vs. 44%).
Genomic profiling of paired leukemic samples of four Black AYA patients taken at diagnosis and relapse suggested the original dominant leukemic clone persists during treatment with conventional cytotoxic chemotherapy. Measured residual disease detection of NPM1 mutations in patients who had these mutations at the time of morphologic complete remission supported this observation.
“From my very first research training I was drilled the importance of ‘knowing your assumptions,’” Larkin told Healio. “To me, the most compelling aspect of our work is to shine a light on the assumptions we make, as physicians who treat AML, that may be incorrect — namely that we can apply one prognostic score to all patients or expect that genetic mutations alone will predict disease behavior, which is the same in patients regardless of age or ancestry.
“Much of our knowledge of this already-heterogenous disease is based heavily on studies that have not included adequate representation of racial groups to necessarily be generalizable,” she added. “With our data, we now have the imperative to look much more closely, in particular at young Black AML patients, with regard to not only disease biology, but all aspects of treatment and response, including pharmacodynamics and minimal residual disease, but also social determinants of health and access, as well as clinical and biobanking trial enrollment.”
Perspective
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Douglas Tremblay, MD
This study is remarkable given that it utilizes a highly validated and robust data set from Cancer and Leukemia Group B trials and identifies disparities in Black AYA patients. Despite being enriched for some favorable cytogenetic features (eg, CBF), Black AYA patients aged 18 to 29 years have worse outcomes. Although prior investigations have identified disparities in outcomes, this study is unique in its focus on the AYA population and further reinforces the disparities in AML care in United States based on race.
Given that disparities in outcomes seem to be at least partially driven by delays in diagnosis and care, it is important to identify barriers to care for patients with AML and do everything to overcome these challenges.
One next step in this area is to design interventions to address these outcome disparities, both from a medical and socioeconomic standpoint. Providing improved access to care should be explored and studied as a means to narrow the gap in outcomes between white and Black AYA patients with AML.
Icahn School of Medicine at Mount Sinai
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Larkin KT, et al. Abstract 221. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
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