Scientists at St. Jude Children’s Research Hospital, Seattle Children’s, and the Children’s Oncology Group (COG) have identified novel genetic variations that influence relapse risk in children with standard-risk B-cell acute lymphoblastic leukemia (SR-B-ALL), the most common childhood cancer. The identification of genomic predictors of relapse in SR-B-ALL provides a basis for improved diagnosis, precise tailoring of treatment intensity, and potentially the development of new treatment approaches. The study was published today in the journal Journal of Clinical Oncology.
Standard-risk ALL has an excellent prognosis, with remission rates greater than 90%. However, approximately 15% of patients who achieve remission later experience a relapse. Previous studies examining genomic alterations to predict relapse risk have focused primarily on high-risk ALL subgroups. Standard-risk B-type ALL represents a larger group of patients, accounting for approximately half of children with ALL who relapse. This study is one of the first to systematically examine large-scale genetic factors that influence relapse risk in standard-risk B-type ALL.
“Acute lymphoblastic leukemia (ALL), the most common childhood cancer, is a great success story, with more than 90% of children cured. But there remains a population of children whose disease is not fully cured, and we don’t fully understand why that is,” said co-senior author Charles Mullighan, MBBS (Hons), MSc, MD, deputy director of the St. Jude Comprehensive Cancer Center and a member of the Department of Pathology. “This study focused on that poorly understood group of cases, for which we know the least about the characteristics that influence the risk that treatment will not work and the disease will come back.”
Identification of genetic variations that modulate risk
Genomic profiling identifies specific genetic alterations associated with cancer susceptibility, risk of relapse, and tumor response to treatments. These studies allow scientists and physicians to predict patients’ likely response to therapy, providing information that determines treatment for childhood acute lymphoblastic leukemia. The results of this collaborative study demonstrate the importance of genomic profiling to accurately determine risk for patients with B-cell acute lymphoblastic leukemia, alongside traditional criteria.
“We’re planning to scale back conventional therapies in the future for children with ALL because we know that many patients can be cured with less therapy,” said co-senior author Mignon Loh, MD, director of the Seattle Children’s Cancer and Blood Disorders Center, chair emeritus of the COG ALL Committee, director of the Ben Towne Center for Childhood Cancer Research at Seattle Children’s, and chief of the Division of Pediatric Hematology, Oncology, Bone Marrow Transplantation and Cellular Therapy at Seattle Children’s. “We want to make sure that we accurately identify those children, and because of the special design of the study, this project allowed us to do just that.”
The scientists performed genome and transcriptome sequencing on both SR B-cell ALL samples that relapsed and samples that remained in complete remission in a one:two ratio. They found that ALL subtypes, genetic alterations, and aneuploidy patterns (extra or missing chromosomes) were associated with relapse risk and time to relapse. Some B-cell ALL subtypes, such as hyperdiploid and ETV6::RUNX1 ALL had a low relapse rate, but others, including PAX5-altered, Similar to TCF3/4::HLF, ETV6::RUNX1 and Similar to BCR::ABL1 They were associated with an increased risk of relapse. Of note, the specific type of genetic changes within those B-ALL subtypes further influenced relapse risk. This work demonstrated that genetic variations and cancer subtypes influence relapse risk in SR B-ALL, and patients classified as standard risk may have tumors with high-risk features.
“WGS was important to accurately and comprehensively identify these changes, and not all of them would have been identified without it,” Mullighan said. “Children with SR ALL should have their tumor cells sequenced at the time of initial diagnosis to identify whether their tumor cells have these high-risk features so that the intensity of initial therapy can be increased.”
“Beyond conventional therapies, this information could also be used to develop and explore novel and personalized treatment strategies,” Loh added.