Charles Mullighan, MD, MBBS
A recent study published in the Journal of Clinical Oncology1
has found that Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) accounts for over 20% of all adult patients with ALL and is correlated with poor outcomes.
The study evaluated the prevalence and genomic landscape of Ph-like ALL in this patient population with the intention of driving future clinical trials toward common targetable rearrangements in this subgroup.
“It’s basic genomic research but it has enormous translational implications,” said Charles Mullighan, MD, MBBS, a corresponding author of the report, in an interview with OncLive. “If one can identify these patients, they are excellent candidates for the addition of tyrosine kinase inhibitor (TKI) therapy.”
Researchers examined samples from 798 patients with B-cell ALL between the ages of 21 and 86. Gene-expression profiling was performed on the samples and patients were classified according to a coefficient (0-1) based on analysis of a 15-gene quantitative reverse transcriptase polymerase chain reaction low-density array. Patients with a coefficient of 0.5 to 1 were classified as having Ph-like ALL. In the study, 194 patients (24.3%) were found to have Ph-like ALL.
BCR-ABL1–rearranged ALL was identified in 23.2% of the patients and MLL-rearranged ALL was identifed in 15.4%.
The patient population was divided into 3 groups based on age: young adult patients (aged 21-39; n = 344), adult patients (aged 40-59; n = 304), and older adult patients (aged 60-86; n = 150). The prevalence of Ph-like ALL was greatest among young adult patients at 27.9%. Adult patients had a frequency of Ph-like ALL of 20.4% and older adult patients, 24%.
Patients with non–Ph-like ALL had better survival rates than patients with Ph-like ALL with a 5-year event-free survival (EFS) rate of 49.3% (95% CI, 42.8-56.2) versus 22.5% (95% CI, 14.9-29.3; P <.001). The 5-year overall survival (OS) rate for patients with non– Ph-like ALL was 52.4% (95% CI, 45.4-59.9) versus 28.8% (95% CI, 16-32.4; P
Survival disparities between patients with Ph-like ALL and non–Ph-like ALL were increased in younger patients. The 5-year EFS rate for young adult patients with Ph-like ALL was 24.1% (95% CI, 12.6-34.1) versus 60.5% (95% CI, 51.2-71.4; P
<.001). For adult patients with Ph-like ALL the 5-year EFS was 21.4% (95% CI, 7.6-32.5) versus 38.7% (95% CI, 27.6-50.0; P
= .0021) for non– Ph-like ALL. Five-year OS for young adults with Ph-like ALL was 25.4% (95% CI, 14.8-37.5) versus 64.2% (95% CI, 53.1-73.3; P
<.001). OS for adult patients with Ph-like ALL was 27% (95% CI, 13.3-42.7) versus 44.9% (95% CI, 33.5-55.7; P
The survival differences for older adult patients with Ph-like ALL were lower than older adults with non–Ph-like ALL, but these differences were not statistically significant. Older adult patients with Ph-like ALL had a 3-year EFS of 8% (95% CI, 0.5-21.6) and a 3-year OS of 13.5% (95% CI, 2.3-34.3) versus 33.3% (95% CI, 15.8-52.2; P
= .047) and 37.9% (95% CI, 19.2-56.6; P
= .64), respectively, for older adult patients with non–Ph-like ALL. The authors noted that the smaller group of older adult patients could have affected the significance of these findings.
Ph-positive ALL has been studied in depth in pediatric and adult patients, as this well-known subtype was associated with a poor outcome. However, the rate of Ph-like ALL—which Mullighan notes has a similar gene expression profile to Ph-positive ALL but lacks BCR-ABL1—in older patients was previously unknown.
“It had been known for many years that the frequency of Ph-positive leukemia, BCR-ABL–positive ALL, rises with increasing age. There are some data suggesting that the frequency of Ph-like ALL may not continually increase throughout age, so we were very interested in doing a comprehensive study with a large number of patients to define the prevalence of Ph-like ALL across the age spectrum of adulthood, and also to identify the underlying genetic lesions and see how they compare to those we had described in children and young adults,” said Mullighan, co-leader of the Hematological Malignancies Program at St. Jude Children’s Research Hospital.
The prevalence of Ph-like ALL across various age groups and the association with a worse outcome stimulates the need for more clinical trials to study ways to treat this subpopulation. To that end, the researchers explored the genetic landscape of adult patients with Ph-like ALL to find mutations and pathways that could be targeted with available therapies.