Management of Philadelphia Chromosome-like Acute Lymphocytic Leukemia with Combination Therapy
A small subset of children with ALL possess the Philadelphia chromosome (identified over 50 years ago in Philadelphia). Patients with ALL who possess this chromosome are at a higher risk for poor outcomes than children who have ALL without this chromosome.
The Philadelphia chromosome produces a tyrosine kinase protein called BCR-ABL1, and until recently this was considered the highest risk subset of pediatric ALL. Adding medications such as imatinib and dasatinib that specifically inhibit the BCR-ABL1 tyrosine kinase (tyrosine kinase inhibitors or TKIs) to chemotherapy led to dramatic improvements in cure rates for children with Philadelphia chromosome positive ALL.
When a recent study on the genomes of children with high-risk ALL was performed, a new subset, called Philadelphia chromosome-like (Ph-like) ALL was identified. The abnormalities present in leukemia cells of patients with Ph-like ALL are highly similar to those of patients with Philadelphia chromosome positive ALL, but these cases do not contain BCR-ABL1 fusion. Research led by Center for Childhood Cancer Research director Stephen P. Hunger, MD and his collaborators determined that one major subtype of Ph-like ALL had abnormalities in the Abl protein itself or in closely related proteins and showed that, as with Philadelphia chromosome-positive ALL, these abnormalities were very responsive to imatinib or dasatinib.
Dr. Hunger and collaborators are now taking the next step after identifying specific genomic mutations in children with high-risk ALL. A national clinical trial is being launched to screen ALL patients for the Ph-like subset and to characterize the genetic abnormalities present in these cases. If Abl class lesions are present, patients will have the opportunity to enroll in a trial where conventional chemotherapy is augmented with tyrosine kinase inhibitor therapy (dasatinib) to see if this improves cure rates.
Identification of the specific genetic characteristics of ALL subsets has contributed significantly to more options for precision medicine therapies and is anticipated to improve survival rates in children with Ph-like ALL.