Pharmacotyping provides a precision medicine blueprint for acute lymphoblastic leukemia treatment

Acute lymphoblastic leukemia (ALL), a cancer of white blood cells called lymphocytes, is the most common pediatric cancer. Approximately 98% of children with ALL experience remission within weeks of starting treatment and about 90% of those children are eventually cured. These levels of success are due to advances in ALL treatment. Chemotherapy is tailored based on clinical features, leukemia genomics, and the degree of minimal residual disease (the presence of microscopic levels of cancer cells remaining after the initial treatment).

In a report published in Nature Medicine, St. Jude scientists examined how ALL cells respond to different therapeutics in the context of their genomic features. This is the most comprehensive study to date describing variations in drug response across genetic ALL subtypes.

“Compared to traditional cancer genomics research, our work starts with defining the drug-response phenotype of each patient,” explained corresponding author Jun J. Yang, PhD, Department of Pharmacy and Pharmaceutical Sciences. “We then look into genomics to search for the biological basis for the inter-patient variability in leukemia drug sensitivity.”

The team determined the sensitivity of leukemia cells to 18 different chemotherapy drugs in patients whose ALL cells represented 23 molecular subtypes defined by leukemia genomics. The results revealed wide variability and distinct patterns of drug sensitivity across ALL subtypes.

The disease subtypes with the most favorable prognoses were particularly sensitive to the chemotherapeutic drugs asparaginase and glucocorticoids. Surprisingly, some ALL subtypes share genomic similarities but show different patterns of drug sensitivities. The team also found that patients could be grouped based on their distinct drug-sensitivity profiles, which were associated with prognosis, even after accounting for known risk factors.

Pharmacogenomics is the study of how genetic attributes affect drug response; pharmacotyping is defining a patient’s drug response phenotype (characteristics resulting from the interaction of genomics and environment). The study’s findings highlight the importance of understanding ALL pharmacotypes for survival outcomes.

ALL is a heterogeneous disease; there are many phenotypic differences between genomic subtypes, such as clinical features and prognoses. This work demonstrates that drug sensitivity can also vary between subtypes.

“This work is a big step in the right direction to individualize ALL therapy to spare children the side effects of drugs that will not work against their cancer, as well as to steer them to novel therapies to which their cancer will likely respond,” Yang said. “It is functional precision medicine; it’s not just about sequencing leukemia mutations but also about knowing what drug to use for which mutations.”