Credit: St Jude Children’s
Research Hospital
New research indicates that Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) becomes more common with age and is associated with poor prognosis.
The study also showed that Ph-like ALL is characterized by genomic alterations that might make patients receptive to treatment with tyrosine kinase inhibitors (TKIs).
Initial tests in a small number of patients seem to support this theory, but trials are needed to verify and expand upon these results, according to researchers.
Charles Mullighan, MD, MBBS, of the St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported the results in The New England Journal of Medicine.
Age and prognosis
The researchers performed genomic profiling of 1725 patients with precursor B-cell ALL, detailed genomic analyses of 154 patients with Ph-like ALL, and transcriptome sequencing for 160 patients with non-Ph-like ALL.
The team found the prevalence of Ph-like ALL increased significantly with age, from 10% among children with standard-risk B-ALL (ages 1 to 9) and 13% among those with high-risk ALL (ages 10 to 15) to 21% among adolescents (ages 16 to 20) and 27% among young adults with ALL (ages 21 to 39).
Regardless of their age, patients with Ph-like ALL were less likely than other B-ALL patients to be alive and leukemia-free 5 years after diagnosis.
Overall survival for children, adolescents, and young adults with Ph-like ALL was 62%, compared to 91% for other B-ALL patients of the same age. Leukemia-free survival was about 47% for patients with Ph-like ALL and about 83% for other patients.
Genomic alterations and TKI treatment
The researchers found that 91% of patients with Ph-like ALL had chromosomal rearrangements or other genetic alterations that activate cytokine receptor or kinase signaling.
“We identified several new subgroups of Ph-like ALL that were distinguished by the type of cytokine receptor or kinase gene alteration,” said Kathryn Roberts, PhD, also of St Jude Children’s Research Hospital.
Evidence suggests that several of these subtypes would be vulnerable to TKIs 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 TKIs.
Other Ph-like ALL patients had gene rearrangements involving JAK2, EPOR, and other genes that can be targeted by the drug ruxolitinib.
To determine if TKIs are effective in these patients, the researchers administered TKIs to 12 patients with Ph-ALL. Follow-up is not sufficient for all of the patients, but 5 achieved remission following TKI treatment (alone, with chemotherapy, or followed by transplant), and 1 patient has been in remission for more than a year.
“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,” Dr Mullighan said. “The findings lead the way for clinical trials that could help to transform the outlook for patients, regardless of age.”
A study testing TKI therapy in children with Ph-like ALL is scheduled to begin later this year or early in 2015.
