High-Risk Subtype Associated With Poor Outcomes in Patients With ALL

A high-risk subtype of acute lymphoblastic leukemia (ALL) first identified in children appears to be highly prevalent in adults with ALL and is associated with a poor outcome, according to a study published in the Journal of Clinical Oncology. The new findings may have significant clinical implications since these patients may benefit from treatment already currently available.

Philadelphia chromosome (Ph)–like ALL is a high-risk subtype of childhood ALL and it is characterized by kinase-activating alterations. Researchers at St. Jude Children’s Research used gene expression profiling to identify cases of Ph-like ALL. The incidence among adults with ALL peaked at 27.9% in young adults between the ages of 21 and 39 years old. It remained 20% or more in patients between 40 and 86 years old.  

“Our 2014 findings that the prevalence of Ph-like ALL increased with age and was particularly common in young adults generated tremendous interest because adult ALL is difficult to treat,” said study investigator Charles Mullighan, MD, MBBS, who is with St. Jude Hospital in Memphis. “In this study, we determined that the prevalence remains high across the age spectrum of adults with ALL.”

The study included 798 adults, who were between the ages of 21 and 86 when their cancer was diagnosed.  The team found that 194 patients (approximately 25%) had the high-risk subtype Ph-like ALL. Many patients had genetic changes that suggest they may be treatable with dasatinib, imatinib, and ruxolitinib. These tyrosine kinase inhibitors are already widely used to treat other types of leukemia.

Dr. Mullighan said the findings provide a compelling reason to identify those patients with Ph-like ALL and move forward with clinical trials of these targeted therapies in combination with current chemotherapeutic regimens. These latest findings also highlight the importance of centralized comprehensive genomic sequencing for leukemia patients, according to the authors.

Tyrosine kinase inhibitors are designed to block different cytokine receptor signaling pathways. Dasatinib works by inhibiting ABL1 proteins, while ruxolitinib targets the JAK2 protein. This new comprehensive sequencing showed that Ph-like ALL in adults is the most genetically diverse subtype of leukemia that has been described to date.

Study co-author Kathryn Roberts, PhD, a St. Jude staff scientist, said cumulatively more than 50 different chromosomal rearrangements involving 15 different kinases and cytokine receptors have been identified. In this study, the team identified 11 chromosomal rearrangements that are new to Ph-like ALL.

ALL is less common in adults than in children. However, adults are far less likely to survive. Adults make up about 40% of the estimated 6,590 new cases of ALL identified annually in the US. At St. Jude, about 94% of pediatric ALL patients are alive 5 years after diagnosis. In this study, adults with Ph-like ALL had a 5-year survival rate of 23.8% compared to 52.4% for adults with other ALL subtypes.