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Pharmacotyping Links Childhood Leukemia Subtypes to Treatment Response

NEW YORK – A research team from the US and Singapore has uncovered treatment response-related "pharmacotypes" within childhood acute lymphoblastic leukemia (ALL), including several associated with patient prognoses and event-free survival.

"Given the marked heterogeneity of somatic genomic profiles of childhood ALL and the incomplete knowledge of their relationships with leukemia drug sensitivity, genomics-centric approaches may have limited utility for precision medicine of ALL," co-senior and corresponding author Jun Yang, a researcher at St. Jude Children's Research Hospital, and his colleagues wrote in Nature Medicine on Thursday, adding that "defining a patient's drug sensitivity phenotype, that is, pharmacotyping, may be an additional useful strategy for treatment individualization."

Starting with samples from 805 children with new pediatric ALL diagnoses, the researchers looked at leukemia cell sensitivity to 18 therapeutic agents applied ex vivo at a range of concentrations, analyzing the drug sensitivity patterns in the context of 23 ALL molecular subtypes found with genomic profiling of somatic alterations and RNA sequences in primary ALL cells, as well as minimal residual disease (MRD) patterns in vivo after treatment in pediatric ALL patients participating in St. Jude trials.

"Taken together, our data point to new subtype-specific therapeutic opportunities in ALL," the authors reported, adding that the findings "have potential clinical relevance because they provide new insights for the design of novel combination therapy, particularly in conjunction with ALL molecular subtyping."

The team's results revealed pharmacotypes that corresponded with known treatment outcomes, while offering new prognostic clues and ALL molecular subtype relationships that may eventually inform treatment selection.

The researchers found that L-asparaginase and glucocorticoid sensitivity tended to coincide with ALL subtypes known for favorable outcomes — drug sensitivities that also tracked with MRD in patients with B-cell ALL. But their results also highlighted half a dozen ALL pharmacotypes that showed ties to specific cytotoxic-, targeted-, or combination treatment response patterns and related event-free survival outcomes after taking MRD into account.

In particular, the team delved into a group of T-cell ALL cases with reduced event-free survival times and higher-than-usual relapse risk that appeared to respond to the targeted treatment dasatinib (Sprycel from Bristol Myers Squibb) in the ex vivo pharmacotyping experiments.

"[S]ensitivity to dasatinib in this T-cell ALL subset revealed a therapeutic vulnerability that could be leveraged to improve survival given their inferior treatment response to conventional cytotoxic chemotherapy that did not include dasatinib," the authors reported. "These findings should be explored prospectively on a large scale in clinical trials."