Acute lymphoblastic leukemia (ALL), a cancer affecting the blood and bone marrow, presents a significant variance in survival rates between children and adults. While children have a long-term survival rate exceeding 85%, adults experience much lower rates, ranging between 50-75%. Researchers at St. Jude Children’s Research Hospital conducted an extensive study to uncover the biological reasons behind these differences. Their findings, published in the Journal of Clinical Oncology, offer a detailed understanding of B-cell acute lymphoblastic leukemia (B-ALL), the most prevalent form of ALL.
Biological and Pharmacological Insights
“Our study provides a pharmacological and biological explanation of why the survival rate of ALL becomes progressively worse as age increases,” said Jun J. Yang, corresponding author and a member of St. Jude's Departments of Pharmacy and Pharmaceutical Sciences and Oncology.
ALL leads to the overproduction of immature lymphocytes, a type of white blood cell, in the blood and bone marrow. Despite longstanding observations of age-related differences in B-ALL outcomes, the underlying causes remained unclear. “ALL is one of few cancers that can occur throughout development, but in adults it is significantly more lethal,” explained Yang. “Many of us have assumed that adult ALL may be differentially resistant to standard treatments, but it had never been tested comprehensively until our study.”
Drug Sensitivity Across Age Groups
The study assessed 767 children and 309 adults diagnosed with B-ALL, focusing on the leukemia cells' sensitivity to 21 drugs. Using RNA sequencing, the researchers identified 23 molecular subtypes of ALL. Satoshi Yoshimura, co-first author from St. Jude's Department of Pharmacy and Pharmaceutical Sciences, noted, “Seven of the 21 drugs showed drastic differences in their ability to kill leukemia cells between children and adults. For example, pediatric ALL samples are generally more sensitive to asparaginase, mercaptopurine, and prednisolone compared to adult samples.”
The team found that the effectiveness of these drugs correlates with the molecular subtypes of B-ALL. “For the majority of cytotoxic drugs with differential activity between adults and children, it’s largely explained by the age-related differences in the underlying genomic abnormalities of their cancer,” added Yang.
Pharmacogenomics and Age in B-ALL
The molecular subtype did not account for all differences in drug sensitivity between children and adults. For example, the DUX4 gene rearrangement occurs in both childhood and adult ALL, but adult cases are more drug-resistant due to the activation of a specific set of genes with age.
The study also found that some children exhibited "adult-like" ALL based on their gene expression profiles, leading to more treatment resistance and poorer outcomes. This indicates the necessity of considering both age and individual genomics when predicting treatment responses. “There’s a lot of heterogeneity within each age group,” said Yang. “You cannot simply divide patients into older or younger than 18 and offer therapy on the basis of legal age of majority; you have to look at their underlying molecular characteristics and pharmacogenomic features.”
Tailoring Treatment for Patients with B-ALL
The findings advocate for tailored treatment strategies for both children and adults with B-ALL. “This is the first time that such a large amount of pharmacogenomic data has been generated in a single effort looking at both children and adults,” stated Zhenhua Li, co-first author from St. Jude's Department of Pharmacy and Pharmaceutical Sciences. “This gives us an opportunity to fairly compare them.”
Publication Details
Satoshi Yoshimura et al., Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia. JCO 0, JCO.24.00500
DOI:10.1200/JCO.24.00500
Biological and Pharmacological Insights
“Our study provides a pharmacological and biological explanation of why the survival rate of ALL becomes progressively worse as age increases,” said Jun J. Yang, corresponding author and a member of St. Jude's Departments of Pharmacy and Pharmaceutical Sciences and Oncology.
ALL leads to the overproduction of immature lymphocytes, a type of white blood cell, in the blood and bone marrow. Despite longstanding observations of age-related differences in B-ALL outcomes, the underlying causes remained unclear. “ALL is one of few cancers that can occur throughout development, but in adults it is significantly more lethal,” explained Yang. “Many of us have assumed that adult ALL may be differentially resistant to standard treatments, but it had never been tested comprehensively until our study.”
Drug Sensitivity Across Age Groups
The study assessed 767 children and 309 adults diagnosed with B-ALL, focusing on the leukemia cells' sensitivity to 21 drugs. Using RNA sequencing, the researchers identified 23 molecular subtypes of ALL. Satoshi Yoshimura, co-first author from St. Jude's Department of Pharmacy and Pharmaceutical Sciences, noted, “Seven of the 21 drugs showed drastic differences in their ability to kill leukemia cells between children and adults. For example, pediatric ALL samples are generally more sensitive to asparaginase, mercaptopurine, and prednisolone compared to adult samples.”
The team found that the effectiveness of these drugs correlates with the molecular subtypes of B-ALL. “For the majority of cytotoxic drugs with differential activity between adults and children, it’s largely explained by the age-related differences in the underlying genomic abnormalities of their cancer,” added Yang.
Pharmacogenomics and Age in B-ALL
The molecular subtype did not account for all differences in drug sensitivity between children and adults. For example, the DUX4 gene rearrangement occurs in both childhood and adult ALL, but adult cases are more drug-resistant due to the activation of a specific set of genes with age.
The study also found that some children exhibited "adult-like" ALL based on their gene expression profiles, leading to more treatment resistance and poorer outcomes. This indicates the necessity of considering both age and individual genomics when predicting treatment responses. “There’s a lot of heterogeneity within each age group,” said Yang. “You cannot simply divide patients into older or younger than 18 and offer therapy on the basis of legal age of majority; you have to look at their underlying molecular characteristics and pharmacogenomic features.”
Tailoring Treatment for Patients with B-ALL
The findings advocate for tailored treatment strategies for both children and adults with B-ALL. “This is the first time that such a large amount of pharmacogenomic data has been generated in a single effort looking at both children and adults,” stated Zhenhua Li, co-first author from St. Jude's Department of Pharmacy and Pharmaceutical Sciences. “This gives us an opportunity to fairly compare them.”
Publication Details
Satoshi Yoshimura et al., Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia. JCO 0, JCO.24.00500
DOI:10.1200/JCO.24.00500