NEW YORK – Baylor College of Medicine researchers are studying biomarkers associated with chemotherapy toxicity to guide treatment and potentially improve survival outcomes for Latino children with acute lymphoblastic leukemia.
The research project will analyze genomic sequencing data and clinical factors from leukemia patients treated at Texas Children's Cancer Center to identify any potential genetic or clinical biomarkers associated with methotrexate chemotherapy toxicity among Latino patients. Last month, The Cancer Prevention and Research Institute of Texas (CPRIT) awarded a $1.39 million grant to the project.
The effort is led by Brooke Bernhardt and Austin Brown, both assistant professors in the department of pediatrics, section of hematology-oncology, at Baylor College of Medicine.
"At Texas Children's, we have a very diverse patient population and we have unfortunately seen disparities in toxicity and in survival, particularly in pediatric leukemia," Bernhardt said. "This study really builds upon what we've started investigating to try and figure out the extent to which there are more toxicities and whether that changes outcomes. Instead of pinning risk only on Latino ethnicity, [we will study] if there is a genetic rationale that clusters in the Latino population that may be also present in other patients that puts these patients at higher risk of toxicity."
Bernhardt, who is also director of pharmacy at Texas Children's Global HOPE (Hematology/Oncology Pediatric Excellence), said previous research from Baylor and Texas Children's has found Latino leukemia patients are more likely to experience toxicity when treated with methotrexate. A study published in January by Texas Children's researchers, including Bernhardt and Brown, found that of 351 patients treated with high-dose methotrexate, 35 experienced neurotoxicity, and 71 percent of those were Latino. The study suggested that serum creatinine elevation greater than 50 percent after methotrexate infusion may indicate an increased risk for neurotoxicity among Latino children.
These neurotoxicities can include seizures or stroke-like symptoms, and patients who receive high-dose methotrexate may also experience kidney or liver toxicities. These side effects often cause dose interruptions or reductions so a patient can recover, Bernhardt said.
Oncologists can often catch side effects from methotrexate shortly after infusion by measuring serum creatinine, which is a biomarker of renal function, allowing them to add supportive care, Bernhardt said. But the researchers hope to identify a biomarker that can be tested prior to treatment to guide therapy.
To that end, they aim to evaluate several factors that may affect toxicity, including genomic biomarkers, in a larger population. The first part of the study will analyze SNP array data from about 2,000 patients whose blood samples were collected and banked by Texas Children's. This first analysis will be used as a discovery population, Brown said. The investigators will continue analyzing samples prospectively through Baylor's Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, an ongoing effort to collect genomic, clinical, and biological data from more than 1,000 Hispanic pediatric leukemia patients across Texas and California. REDIAL patients also undergo whole-genome sequencing.
"For many years now at Texas Children's Hospital, we've been collecting peripheral blood samples or buccal saliva samples on patients once they reach remission, and we banked these samples with the intent of using them for future research," Brown said. "More recently with the prospective REDIAL initiative, we're doing a better job of systematically collecting these samples, which are often serial samples from individuals over time across all the sites."
The goal is to implement new biomarker-guided treatment regimens for patients who may be at higher risk of methotrexate toxicity. Because methotrexate is a commonly used treatment for leukemia, the researchers aren't seeking to remove it but rather optimize it by changing dosage or infusion times, or adding supportive care for high-risk patients, Bernhardt said.
"We already do this for a [chemotherapy] drug called mercaptopurine where we need to look at a patient's genetic propensity to metabolize that drug by testing for an enzyme called thiopurine methyltransferase," Bernhardt explained. "Every patient with leukemia gets tested for that particular enzyme upfront [at Texas Children's]. We already do that across leukemia treatment, so it's not an unusual thing to consider that we'll also have to do that with methotrexate to fine-tune the treatment."
The ability to fine-tune methotrexate treatment may also improve survival outcomes for Latino leukemia patients by reducing dose interruptions, Bernhardt noted. Historically, Hispanic and Latino patients with acute lymphoblastic leukemia have had worse survival rates compared to non-Hispanic white patients. A 2016 study found 79 percent of Hispanic children with acute lymphoblastic leukemia lived for 10 years compared to 91 percent of white children.
"Latino and non-Latino Black children typically fare worse than their non-Latino white counterparts in terms of various outcomes, such as incidence, relapse, and survival, and this is true even with more contemporary therapy," Brown said. "This is something we've known for many years and it hasn't gone away as there's been continued improvements in the treatment of childhood ALL."