High-risk leukemia subtype becomes more common with age

High-risk leukemia subtype becomes more common with age
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 (ALL) 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.

ALL is the most common childhood cancer. This research focused on the subtype known as Philadelphia chromosome-like ALL (Ph-like ALL). In 2009, scientists from St. Jude Children's Research Hospital in Memphis, Tennessee, working with the Children's Oncology Group (COG), were among the first to describe the Ph-like ALL subtype in children.

The present study, published in The New England Journal of Medicine (2014; doi:10.1056/NEJMoa1403088), found the prevalence of Ph-like ALL increases with age and that the subtype is associated with poor survival. The discovery followed a detailed genomic analysis of 1,725 patients age 1 to 39 years with the most common form of ALL, which involves white blood cells known as B cells and is called B-ALL.

Researchers also used next-generation sequencing to identify the genetic alterations that give rise to Ph-like ALL, including some involving genes not previously linked to cancer. The results highlight the genetic diversity of Ph-like ALL, but also demonstrate that alterations affect a limited number of biological signaling pathways. Those pathways regulate genes controlling cell growth and proliferation, which are disrupted in cancer.

The findings, combined with earlier work from St. Jude and other institutions, laid the foundation for clinical trials to determine whether drugs called tyrosine kinase inhibitors (TKIs) could help improve patient outcomes. A nationwide study meant to answer that question in children is scheduled to begin later this year or early 2015. By targeting enzymes known as kinases, TKIs work more precisely than chemotherapy drugs to kill cancer cells.

"We showed that Ph-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."

TKIs, including drugs such as dasatinib and imatinib, are widely used to treat other types of leukemia that are more common in adults. The drugs have also been used in a small number of patients with Ph-like ALL. This study reports 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 TKI was added to the treatment regime. Five patients remain in remission with no detectable cancer, one for more than a year.

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