Genetic Ancestry Impacts Treatment Outcomes in Acute Lymphoblastic Leukemia

Genetic ancestry influences treatment outcomes for patients with acute lymphoblastic leukemia (ALL) and is independently associated with a poor prognosis, according to a new study.

“There is a strong genetic basis for racial disparities in ALL survival, which is why biology-driven protocols are needed to eradicate these racial disparities,” says Shawn Lee, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

dr. Lee presented these findings at the Society of Hematological Oncology (SOHO) annual meeting.

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dr. Lee noted that the distribution of ALL cases worldwide is highly unbalanced, with most cases in South Asia, Southeast Asia or Africa.

“Despite this, the vast majority of cases with available genomic data actually come from the US and Europe,” said Dr. Lee. “Although they represent only 10% of cases worldwide, they represent about 60% of genomics worldwide. In this age of personalized medicine, it is hard to justify extrapolating this data from European children to children of other ancestral origins.”

With this in mind, Dr. Lee and colleagues collected data from 2,428 children with ALL from studies conducted in the United States, Singapore, Malaysia, and Guatemala.

The researchers performed RNA sequencing to characterize ALL molecular subtypes and genetic ancestors. 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 Caucasian, meaning they had more than 90% European ancestry. There were 520 patients classified as Hispanic. These patients had more 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 descent), 69 classified as Southeast Asian (>70% Southeast Asian descent), and 162 patients with “other” Asian descent. There were 199 patients classified as black, meaning they had more than 70% African ancestry, and 118 patients were classified as “other” American ancestry.

Ancestry and molecular subtype

“We identified striking differences in subtypes between different ancestors,” said Dr. Lee.

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 changes (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).

Results by ancestors

Relapse and survival outcomes differed significantly by genetics, even after the researchers adapted to the treatment protocol.

“We found that ancestors actually influence the results of therapy, even with current, modern treatment,” said Dr. Lee.

Event-free survival (EFS) and overall survival (OS) 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 Caucasian, 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 American ancestry” and highest for Hispanic patients. The 5-year cumulative incidence of relapse was 3.3% for other American, 3.7% for South Asian, 5.6% for Caucasian, 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 the results 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 = 0.044) and OS (HR 3.3; 95% CI 1.1-10.0; P = 0.033).

African ancestry was associated with poor EFS (HR 2.3; 95% CI 1.4-3.8; P = 0.001), poor OS (HR 2.4; 95% CI 1.2-4.7; P = 0.012) and a higher relapse rate (HR 2.7; 95% CI 1.5-5.0; P = .002).

These associations with poor prognosis persisted even after the researchers adjusted for biological subtypes and clinical features.

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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: Society of Hematological Oncology (SOHO) Annual Meeting; September 8-11, 2021.

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