Using pharmacogenomics to guide induction may reduce racial disparities in pediatric AML
Key takeaways:
- Researchers reported similar induction therapy outcomes regardless of race.
- Black patients more frequently had low ACS10 scores, making them candidates for intensified therapy.
Outcomes among children with acute myeloid leukemia treated with high-dose cytarabine-based regimens did not vary by race, according to study results presented at ASH Annual Meeting and Exposition.
The findings suggest clinicians should consider therapy intensification and differences in pharmacogenomics between Black patients and white patients — including ACS10 scores, derived from a combination of 10 single nucleotide polymorphisms involved in cytarabine metabolism — when tailoring induction therapy regimens.
Doing so may result in better outcomes for Black patients and reduce racial disparities in AML, according to researcher Jeffrey E. Rubnitz, MD, PhD, pediatric hematologist/oncologist at St. Jude Children’s Research Hospital.
“At St. Jude, we’re not seeing any difference in outcomes between patients who are Black and white, and we believe that at least part of the reason is that most of our patients received higher doses of cytarabine during induction therapy than in most trials in the literature,” Rubnitz told Healio. “In the literature, most patients received lower doses of cytarabine and — because Black individuals in general don’t activate cytarabine as well as white patients — Black patients tend to do worse. In our trials, where we give higher doses of cytarabine, we saw no difference between Black and white patients.”
Background
Prior studies revealed racial disparities in outcomes in AML, with Black children, adolescents and young adults achieving shorter EFS and OS than non-Hispanic white patients.
“We saw [these reports] and ... without looking at our data, our impression was that was not true here,” Rubnitz said. “Just thinking about our patients, it didn’t seem like there was really a difference.”
Methods
Rubnitz and colleagues analyzed data from 445 children (80.6% white, 19.3% Black) with newly diagnosed AML treated on one of two earlier trials — AML02 and AML08.
Trial participants received initial therapy with one of three regimens: high-dose cytarabine, daunorubicin and etoposide (HDAC); low-dose cytarabine, daunorubicin and etoposide (LDAC); or clofarabine and cytarabine (Clo/AraC).
Researchers assessed outcomes by race based on induction regimen, as well as ACS10 scores.
Results
Results showed no significant difference between Black patients and white patients in complete remission rates after two courses of therapy (92.6% vs. 95%) or minimal residual disease negativity after one course (55.8% vs. 55.4%).
Black patients and white patients achieved similar 5-year rates of EFS (58.3% vs. 58.2%) and OS (63.8% vs. 69.4%), as well as nearly identical cumulative incidence of relapse (26% vs. 26.1%) and treatment-related mortality (7% vs. 6.8%).
Researchers observed a higher prevalence of core binding factor (CBF) leukemia among Black patients than white patients (30% vs. 19%; P = .04); however, EFS did not differ by race among those with or without CBF AML.
“We were pleased with the results, but ... we needed to look further to really try to figure out why our results were different than [those in] the literature,” Rubnitz said.
Investigators hypothesized that ACS10 scores may provide some answers.
In prior research, they identified an association between low ACS10 scores and poorer outcomes among patients treated with low-dose cytarabine-based induction.
In the analysis presented at ASH, they observed a significant difference in distribution of ACS10 scores by race, with more than twice as many Black patients as white patients having low scores (73% vs. 30%; P < .001).
Analyses that accounted for all treatment regimens showed similar EFS for both races among those with low or high ACS10 scores.
However, Black patients who received the Clo/Ara-C induction regimen achieved significantly longer EFS (P = .01) and OS (P = .04) than those who received LDAC induction.
This observation may — at least indirectly — explain the outcome disparities reported in earlier published literature, Rubnitz said.
"Low-dose cytarabine is really considered standard for the first course of therapy,” Rubnitz said. “Among patients treated on the low-dose cytarabine arm of the AML02 trial, the outcomes were worse for Black than white patients, and worse for patients with low [ACS10] scores.”
A multivariable model that adjusted for risk group, age and leukocyte count identified Clo/Ara-C as the optimal treatment option for Black patients with low ACS10 scores (HR for EFS = 0.2; P = .03).
Next steps
The key question now is whether standard therapy should change.
Rubnitz said he would not shift to high-dose cytarabine-based induction for all patients; however, he would recommend evaluating high-dose cytarabine-based induction for patients with low ACS10 scores in a clinical trial setting.
"I don’t know if this explains everything, but I think it’s at least part of the answer,” Rubnitz said.
Further research could provide additional valuable insights, he added.
“We talk about AML as if it’s one disease but, genetically, there are around 15 different subtypes,” Rubnitz said. “We don’t know within genetic subgroups whether ACS10 score is important. ... It would take a lot of patients, but it would be interesting to find out.”
Perspective
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Lamba JK, et al. Abstract 386. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.