Genomic Analysis Reveals That a High-Risk Leukemia Subtype Becomes More Common With Age
More than one-quarter of young adults with the most common form of acute lymphoblastic leukemia have a high-risk subtype with a poor prognosis and may benefit from drugs widely used to treat other types of leukemia that are more common in adults, according to multi-institutional research led by St. Jude Children’s Research Hospital investigators. The study by Roberts et al was published in The New England Journal of Medicine.
Study Details
The research focused on a subtype of ALL known as Philadelphia chromosome–like ALL The present study found the prevalence of Philadelphia chromosome–like ALL increases with age and that the subtype is associated with poor survival. This discovery followed a detailed genomic analysis of 1,725 patients aged 1 to 39 with the most common form of ALL, B-cell ALL.
The investigators also used next-generation sequencing to identify the genetic alterations that give rise to Philadelphia chromosome–like ALL, including some involving genes not previously linked to cancer. The results highlight the genetic diversity of Philadelphia chromosome–like ALL, but also demonstrate that alterations affect a limited number of biologic signaling pathways. Those pathways regulate genes controlling cell growth and proliferation, which are disrupted in cancer.
Tyrosine kinase inhibitors, such as dasatnib (Sprycel) and imatinib (Gleevec) are widely used to treat other types of leukemia that are more common in adults, but have also been used in a small number of patients with Philadelphia chromosome–like ALL. The current study reported the experiences of eight such patients, including seven children who were treated at different medical centers. All had leukemia that persisted despite chemotherapy. Each patient enjoyed a dramatic, immediate benefit when a tyrosine kinase inhibitor was added to the treatment regime. Five patients remain in remission with no detectable cancer, one for more than a year.
“The findings are tremendously exciting and pave the way for clinical trials testing tyrosine kinase inhibitors plus chemotherapy in subsets of children and adolescents with ALL,” said corresponding author Stephen P. Hunger, MD, Professor of Pediatrics at the University of Colorado School of Medicine and the Chair of the COG ALL Committee. A clinical trial designed to identify children who might benefit from this approach is expected to open by early 2015.
Increasingly Common Subtype of B-Cell ALL
Both Philadelphia chromosome–positive and Philadelphia chromosome–like subtypes of ALL share similar patterns of gene expression, but patients with Philadelphia chromosome–like ALL lack the fusion of the BCR and ABL1 genes that is a feature of Philadelphia chromosome–positive ALL.
In this study, Philadelphia chromosome–like ALL comprised 10% of children 1 to 9 years old with standard-risk B-cell ALL. The percentage rose with age and accounted for 27% of B-cell ALL cases among those ages 21 to 39. Work is underway to establish the incidence in older adults.
Regardless of their age, patients with Philadelphia chromosome–like ALL were less likely than other B-cell ALL patients to be alive and cancer-free 5 years after their disease was discovered. Overall survival for children, adolescents and young adults with Philadelphia chromosome–like ALL was 62% compared to 91% for other B-cell ALL patients of the same age. Leukemia-free survival was about 47% for patients with Philadelphia chromosome–like ALL and about 83% for other patients.
Possible Treatment Option Identified
The search for the genetic changes that give rise to Philadelphia chromosome–like ALL included whole genome sequencing of 42 patients plus additional sequencing, including of RNA from the leukemic cells of 136 patients.
Researchers found that 91% of patients with Philadelphia chromosome–like ALL had chromosomal rearrangements or other genetic alterations that activate cytokine receptor or kinase signaling.
"We identified several new subgroups of Philadelphia chromosome–like ALL that were distinguished by the type of cytokine receptor or kinase gene alteration," said Kathryn Roberts, PhD, a St. Jude postdoctoral fellow and the paper’s co–first author along with Yongjin Li, PhD.
Evidence suggests that several of the newly identified Philadelphia chromosome–like ALL subtypes are vulnerable to tyrosine kinase inhibitors and other targeted therapies. For example, about 12% of patients had rearrangements involving the genes ABL1, ABL2, CSF1R, and PDGFRB, which are known to respond to dasatinib and related tyrosine kinase inhibitors.
Numerous other Philadelphia chromosome–like ALL patients had gene rearrangements involving JAK2, EPOR, and other genes that can be targeted by the drug ruxolitinib (Jakafi).
"We showed that Philadelphia chromosome–like ALL is a common disease that spans the age spectrum, and we identified new genomic alterations that converge on a handful of signaling pathways that are vulnerable to treatment with tyrosine kinase inhibitors," said corresponding author Charles Mullighan, MD, MBBS(Hons), a member of the St. Jude Department of Pathology. "The findings lead the way for clinical trials that could help to transform the outlook for patients regardless of age."
Dr. Mullighan is the corresponding author for The New England Journal of Medicine article.
The research was funded in part by the Pediatric Cancer Genome Project, grants from the National Cancer Institute, Stand Up to Cancer, St. Baldrick's Foundation, The Leukemia & Lymphoma Society, Alex's Lemonade Stand Foundation, a grant from the National Institute of General Medical Sciences at the National Institutes of Health, and ALSAC. For full disclosures of the study authors, visit www.nejm.org.
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