Novel genomic predictors of relapse in childhood B-cell acute lymphoblastic leukemia discovered

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 the risk of relapse in children with standard-risk B-cell acute lymphoblastic leukemia (SR B-ALL), the most common childhood cancer. Identifying 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 Journal of Clinical Oncology.

Standard-risk ALL has an excellent prognosis, with remission rates exceeding 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. SR-B ALL represents a larger group of patients and accounts 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 SR-B ALL.

ALL, as the most common childhood cancer, is a great success story with over 90% of children cured. But there is still a population of children whose disease is not fully cured, and we do not fully understand why this is the case. This study focused on that poorly understood group of cases where we know less about the characteristics that influence the risk of treatment not working and the disease coming back.”

Charles Mullighan, MBBS (Hons), MSc, MD, St. Jude Comprehensive Cancer Center, Deputy Director and Member of the Department of Pathology, Co-Senior Author

Identification of genetic variations that modulate risk

Genomic profiling identifies specific genetic alterations associated with cancer susceptibility, risk of recurrence, and how tumors respond to therapy. These studies allow scientists and clinicians to predict how patients are likely to respond to therapy, providing insights that shape the treatment of childhood ALL. The results of this collaborative study demonstrate the importance of genomic profiling in accurately determining a patient’s risk in B-ALL, in conjunction with traditional criteria.

“We plan to reduce conventional therapies in the future for children with ALL because we know that many patients can be cured with less therapy,” explained co-senior author Mignon Loh, MD, leader of the Seattle Children’s Cancer and Blood Disorders Center, chair emeritus of the COG ALL Committee, director of the Seattle Children’s Ben Towne Center for Childhood Cancer Research, 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 these children, and because of the special design of the study, this project allowed us to do just that.”

Scientists conducted genome and transcriptome sequencing on SR B-ALL samples that relapsed and samples that remained in complete remission in a ratio of one:two. They found that ALL subtypes, genetic alterations, and patterns of aneuploidy (extra or missing chromosomes) were associated with the risk of relapse and time to relapse. Some B-ALL subtypes, such as hyperdiploid and ETV6::RUNX1 ALL had a low frequency of relapse, but others, including PAX5-changed, TCF3/4::HLF, similar to ETV6::RUNX1 and BCR::ABL1-like were associated with an increased risk of relapse. Notably, the specific type of genetic alterations within these B-ALL subtypes further influenced the risk of relapse. This work demonstrated that genetic variations and cancer subtypes influence the risk of relapse in SR B-ALL, and patients classified as standard risk may have tumors with high-risk features.

“Whole genome sequencing was important to accurately and comprehensively identify these changes, and they could not have all been identified without it,” Mullighan explained. “Children with SR ALL should have the genome of their tumor cells sequenced after initial diagnosis to identify whether their tumor cells have these high-risk features, so that the initial intensity of therapy can be increased.”

“In addition to conventional therapies, this information can also be used to develop and explore new and personalized treatment strategies,” Loh added.

Authors and funding

The study’s co-authors are Ti-Cheng Chang and Wenan Chen of St. Jude.

The study’s other authors are Mary Shago, University of Toronto; Karen Rabin, Baylor College of Medicine; Elizabeth Raetz, William Carroll, Perlmutter Cancer Center; Anne Angiolillo, Children’s National Medical Center; Michael Borowitz, John Hopkins University; Michael Burke, Medical College of Wisconsin; Andrew Carroll, University of Alabama at Birmingham; I-Ming Chen, Richard Harvey; University of New Mexico, Albuquerque; Nyla Heerema, The Ohio State University; Jeremy Wang, University of North Carolina at Chapel Hill; Eric Larsen, Maine Children’s Cancer Program; Leonard Mattano, HARP Pharma Consulting; Kelly Maloney, University of Colorado; Nilsa Ramirez, Nationwide Children’s Hospital and The Ohio State University; Wanda Salzer, Uniformed Services University; Cheryl Willman, Mayo Clinic; Naomi Winick, University of Texas Southwestern Medical Center; Brent Wood, University of Southern California; Stephen Hunger, Children’s Hospital of Philadelphia and University of Pennsylvania; and Chunxu Qu, Zhongshan Chen, Dale Hedges, Abdelrahman Elsayed, Stanley Pounds, Meenakshi Devidas, Cheng Cheng, Pradyuamma Baviskar, Ilaria Iacobucci, Sima Jeha, Ching-Hon Pui and Gang Wu, St.

The study was supported by the National Institutes of Health (R35 CA197695 and CA21765), the Cancer Moonshot (HHSN261201500003I), and ALSAC, St. Jude’s cancer awareness and fundraising organization.