Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia

Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia
Cytogenetic analysis and minimal residual disease (MRD) assessment are used to personalize treatment in current protocols for acute lymphoblastic leukemia (ALL). MRD status is currently assigned using cut-off limits in treatment protocols. This study assessed MRD as a continuous variable using PCR-based MRD assessment (Ig/TCR rearrangements) and correlated results with somatic genetic changes.
3,113 consecutive patients with ALL treated in the MRC UKALL2003 protocol (2003 to 2011) were eligible and 2,542 were analysed. Patients were classified into four mutually exclusive cytogenetic genetic groups: good risk: ETV6-RUNX1, high hyperdiploidy (51 to 65 chromosomes); high risk: KMT2A (MLL) fusions, near haploidy, low hypodiploidy ( 40 chromosomes), iAMP21, and TCF3-HLF; intermediate risk: TCF3-PBX1 and all other patient-cases with B-ALL; and patients with T-ALL. MRD at end of induction was assessed as a continuous variable with a minimum detection level of 1x10e-5.
MRD results were highly dependent on genetic risk groups with ETV6-RUNX1 but also TCF3-PBX1 showing rapid MRD-clearance (in 36% and 43% respectively). Patients with iAMP21 on the other hand had a high rate of recurrence even in those with negative MRDs. T-ALL patients more frequently had not reportable results which renders the Ig/TCR PCR-based technique less reliable for this patient group. In T-ALL, outcomes were associated with MRD-negativity or frank positivity (>=5%) but not intermediate results.
This is a post hoc analysis of MRD results and treatment was not based on these findings. The impact of continuous MRD assessment was therefore not assessed on possible treatment modifications.
As previously known, PCR-based high-sensitive MRD-assessment is a powerful tool and results differ between different cytogenetic groups. The inclusion of iAMP21 as a high-risk somatic change per se was supported.