|The following article features coverage from the 2021 Annual Meeting of the Society of Hematologic Oncology (SOHO). Click here to read more of Cancer Therapy Advisor’s conference coverage.|
Genetic ancestry influences treatment outcomes for patients with acute lymphoblastic leukemia (ALL) and is independently associated with poor prognosis, according to a new study.
“There is a strong genetic basis for racial differences in ALL survival, and, therefore, biology-driven protocols are needed to eradicate these racial disparities,” said Shawn Lee, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.
Dr Lee presented these findings at the Annual Meeting of the Society of Hematologic Oncology (SOHO).
Dr Lee noted that the distribution of ALL cases globally is heavily imbalanced, with most cases in South Asia, Southeast Asia, or Africa.
“Despite this, the large majority of cases with available genomic data actually come from the US and Europe,” Dr Lee said. “Even though they represent only 10% of cases worldwide, they represent about 60% of genomics globally. In this era of personalized medicine, it is hard to justify extrapolating this data from European children to children of other ancestral descent.”
With this in mind, Dr Lee and colleagues analyzed data from 2428 children with ALL from trials conducted in the United States, Singapore, Malaysia, and Guatemala.
The researchers performed RNA sequencing to characterize ALL molecular subtypes and genetic ancestry. They then looked at associations between genetic ancestry and subtypes as well as associations between genetic ancestry, subtypes, and outcomes.
Most patients in the cohort (n=1128) were classified as White, meaning they had greater than 90% European ancestry. There were 520 patients classified as Hispanic. These patients had greater than 10% Native American ancestry, and their Native American ancestry had to be greater than their African ancestry.
There were 232 patients classified as East Asian (>90% East Asian ancestry), 69 classified as Southeast Asian (>70% Southeast Asian ancestry), and 162 patients with “other” Asian ancestry. There were 199 patients classified as Black, meaning they had greater than 70% African ancestry, and 118 patients were classified as having “other” US ancestry.
Ancestry and Molecular Subtype
“We identified striking differences of subtypes across various ancestries,” Dr Lee said.
Native American ancestry was positively associated with CRLF2 rearrangements (P <.001), TCF3-PBX1 fusions (P =.003), and B-ALL (P <.001) but associated with protection against hyperdiploid ALL (P =.001), T-ALL (P <.001), and ETV6-RUNX1 fusions (P <.001).
African ancestry was positively associated with TCF3-PBX1 fusions (P <.001), MEF2D rearrangements (P =.019), and T-ALL (P =.002) but negatively associated with DUX4 rearrangements (P =.025) and hyperdiploid ALL (P <.001).
East Asian ancestry was positively associated with ZNF384 (P <.001) and DUX4 rearrangements (P <.001), TCF3-PBX1 fusions (P =.029), and PAX5 alterations (P =.019). It was negatively associated with T-ALL (P <.001), CRLF2 rearrangements (P =.052), and BCR-ABL1-like ALL (P =.004).
Southeast Asian ancestry was positively associated with DUX4 rearrangements (P =.040) and negatively associated with hyperdiploid ALL (P =.026).
Outcomes by Ancestry
Relapse and survival outcomes differed significantly by genetic ancestry, even after the researchers adjusted for treatment protocol.
“We found that ancestry actually influences outcomes of therapy even with current, modern-day treatment,” Dr Lee said.
Event-free survival (EFS) and overall survival (OS) rates were best for South Asian patients and worst for Hispanic patients. The 5-year EFS rates were 94.6% for South Asian, 91% for White, 88% for other US, 86% for East Asian, 81.7% for other Asian, 80.7% for Black, and 72.1% for Hispanic patients (P =.017).
The 5-year OS rates were 98.2% for South Asian, 95.5% for White, 95% for other US, 94.7% for East Asian, 90.1% for other Asian, 89% for Black, and 82.3% for Hispanic patients (P =.050).
The relapse rate was lowest for patients with “other US ancestry” and highest for Hispanic patients. The 5-year cumulative incidence of any relapse was 3.3% for other US, 3.7% for South Asian, 5.6% for White, 12.4% for East Asian, 14.6% for Black, 14.7% for other Asian, and 22.8% for Hispanic patients (P =.015).
The researchers also found that outcomes were influenced by the percentage of genetic ancestry as a continuous variable.
Native American ancestry was associated with poor EFS (hazard ratio [HR], 2.5; 95% CI, 1.0-5.9; P =.044) and OS (HR, 3.3; 95% CI, 1.1-10.0; P =.033).
African ancestry was associated with poor EFS (HR, 2.3; 95% CI, 1.4-3.8; P =.001), poor OS (HR, 2.4; 95% CI, 1.2-4.7; P =.012), and a greater likelihood of relapse (HR, 2.7; 95% CI, 1.5-5.0; P =.002).
These associations with poor prognosis remained even after the researchers adjusted for biological subtypes and clinical features.
Read more of Cancer Therapy Advisor’s coverage of SOHO 2021 by visiting the conference page.
Lee S, Antillon F, Pei D, et al. The impact of genetic ancestry on the biology and prognosis of childhood acute lymphoblastic leukemia. Paper presented at: Annual Meeting of the Society of Hematologic Oncology (SOHO); September 8-11, 2021.