Classifying risk groups based on genetics in children with ALL

This study examined genetic changes in children with acute lymphoblastic leukemia (ALL). Researchers concluded that chromosomal abnormalities and specific gene deletions can reliably predict treatment outcomes.

ALL is a cancer of the blood and bone marrow. It is the most common type of childhood cancer. Using predictors of treatment success is important to help select treatment approaches for patients. Children with medium- or high-risk ALL usually receive more anticancer drugs and/or higher doses of anticancer drugs than children with standard-risk ALL. Factors such as age at diagnosis, white blood cell counts, and early treatment response are commonly used to classify risk groups. Certain genetic changes in ALL can also make it more difficult to treat. Fluorescent in situ hybridization is a test that can highlight abnormalities in the chromosomes (structures at the nucleus of most living cells that carry genetic information), such as damaged or missing parts. Changes on chromosomes as well as changes to specific genes may be useful to help predict ALL outcomes.

The aim of this study was to use specific genetic changes to classify ALL patients into risk groups.

809 children with ALL were tested for genetic changes. This was repeated for 742 patients in a later trial. All patients were treated with induction therapy (standard chemotherapy aimed to induce remission). High-risk patients (based on standard classification) received more intensive chemotherapy during induction.

43% of patients had no gene deletions. 30% of patients had 1 specific deletion of a gene. 18% of patients showed 2 specific gene deletions, and 10% showed 3 or more. The most common gene deletions involved the genes CDNK2A/B and ETV6, occurring in 20 to 25% of cases. Deletions of the genes IKZF1 or PAX5 occurred in about 15% of patients. The remaining gene deletions (PAR1, BTG1, EBF1, and RB1) were less common, each observed in less than 10% of cases.

With the exception of ETV6, each deletion was associated with a poorer outcome compared to no gene deletions. Based on this, patients were allocated to a risk group. 61% were good-risk, 29% were intermediate-risk, and 10% were poor-risk. 80% of good-risk patients did not experience a treatment-related event such as progression, death, or discontinuation of treatment over 10 years. This was 67% for intermediate-risk patients and 49% for poor-risk patients.

After taking into account gene deletions as well as genetic changes on a chromosomal level, 72% of patients were classified as good-risk and 28% of patients were poor-risk. 10-year event-free survival was 82% for good-risk patients and 51% for poor-risk patients. The 10-year relapse rate was also higher for poor-risk patients (44%) compared to good-risk patients (15%).

Similar results were observed with the group of patients in the later trial. 5-year event-free survival was lower for poor-risk patients in the later trial (79%) compared to good-risk patients (94%). Only 4% of good-risk patients relapsed over 5 years. It was 17% for poor-risk patients.

Minimal residual disease (small number of leukemia cancer cells that remain after treatment) was associated with worse outcomes in both risk groups. However, genetic good-risk patients with detectable minimal residual disease on Day 29 of treatment had a 5-year event-free survival over 90%. The influence of treatment regime was less clear.

Researchers concluded that chromosomal abnormalities and specific gene deletions can reliably predict treatment outcomes. Genetic risk groups may help in appropriate treatment selection for children with ALL.

Other genetic abnormalities not tested in this study may contribute to ALL outcomes.