Vitamin A may reduce the risk of pancreatitis during ALL treatment

Details of this potential dietary solution to prevent a life-threatening adverse event were published on March 15, 2023 in Science Translational Medicine. The research team was led by Sohail Husain, MD, chief of pediatric gastroenterology, hepatology, and nutrition at Stanford University and Anil Goud Jegga, DVM, MRes, computational biologist at Cincinnati Children’s Hospital Medical Center. .

For people with ALL, treatment with the enzyme asparaginase helps starve cancer cells by reducing the amount of asparagine circulating in the blood, which cancer cells need but cannot make on their own. The drug, often used in combination with other chemotherapy, is given by injection into a vein, muscle or under the skin.

However, an estimated 2-10% of asparaginase users develop inflammation of the pancreas in response to asparaginase treatment. For a third of these people, the symptoms can be severe.

Jegga and his colleagues developed predictive analytics using more than 100 million data points encompassing gene expression data, small molecule data, and electronic health records to better understand the mechanisms behind origin of asparaginase-associated pancreatitis (AAP) and identify potential interventions to prevent or ameliorate AAP.

First, they analyzed massive amounts of gene expression data to reveal that gene activity associated with asparaginase or pancreatitis could be reversed by retinoids (vitamin A and its analogues). The team found further supporting evidence by “mining” millions of electronic health records from the TriNetX database and the US Federal Drug Administration’s adverse event reporting system.

This work of processing figures and predictive analysis included the use of AERSExploit software developed at Cincinnati Children’s by Mayur Sarangdhar, PhD, MRes and colleagues. The research team also studied data from mouse experiments and compared plasma samples from people with ALL who developed pancreatitis and those who did not.

Ultimately, the team established two sets of “real-world” human experiences. They found that only 1.4% of patients treated with asparaginase developed pancreatitis when they also took vitamin A, compared with 3.4% of patients who did not take it. Concomitant use of vitamin A was correlated with a 60% reduction in the risk of AAP. Lower amounts of dietary vitamin A were correlated with increased risk and severity of AAP.

“This study demonstrates the potential of mining ‘real world’ data to identify modifiers of therapy to improve patient outcomes. In cases where a primary drug induces toxicity but is critical to therapy, such as asparaginase, therapy modifiers, such as vitamin A and its analogs, may be of immediate relevance for patients on asparaginase who are ‘at risk’ of AAP,” says Sarangdhar, co-first author of the study.

According to Jegga: “Our study highlights the power of integrating and analyzing heterogeneous data in translational research. By leveraging existing ‘omics and patient-centric’ data and a systems approach, we were able to identify new insights into AAP development and potential interventions to prevent or mitigate this side effect.”

Next steps

In some ways, the lessons learned from this study could be immediately applied to patient care. However, more clinical research is needed to determine how much vitamin A is needed to protect ALL patients against pancreatitis; and whether a protective level can be achieved through diet or via supplements. In fact, target vitamin levels may need to vary based on individual differences in metabolism.