ALL-258: Loss of Heterozygosity in STR Loci Found in Tumor DNA of De Nονο-Diagnosed ALL Patients as a Factor Predicting Poor Outcomes for B-ALL but Not T-ALL Patients

Abstract

Context: Loss of heterozygosity (LOH) in some STR loci established for de novo-diagnosed ALL could be used as a prognostic factor for possible poor clinical outcomes. Objective: To identify LOH in the blast cells of patients with B- and T-ALL at diagnosis and to analyze therapy outcomes according to LOH status. Design: This study includes an analysis of the STR profiles in the DNA of tumor cells for a cohort of 87 patients with de novo-diagnosed Ph-negative ALL (40 B-ALL, 44 T-ALL, 3 biphenotypic ALL) and a statistical evaluation of LOH as a possible risk factor for B- and T-ALL. All patients were treated according to the “RALL-2016” regimen at the National Research Center for Hematology (Moscow, Russia). Setting: DNA was isolated from patient bone marrow samples taken at diagnosis. Control DNA samples were taken from the blood of patients in complete remission and/or from a buccal swab. STR profiles were assessed by PCR with the COrDIS Plus multiplex kit (Gordiz Ltd, Russia). LOH in tumor DNA was verified by chromosomal microarray (CMA CytoScanHD). Patients: Inclusion criteria: de novo-diagnosed Ph-negative ALL patients, 18-55 years old, intermediate-risk group without MLL translocation t(4;11)(q21;q23), and treatment by RALL-2016 protocol. Exclusion criteria: patients older than 55 years, MLL translocation t(4;11)(q21;q23), and pretreatment. Main Outcome Measures: A multivariate survival analysis was used to assess the independent impact of the LOH as a risk factor. Overall survival (OS) was chosen as the primary endpoint. Results: Of the 87 patients, 21 were characterized with LOH in certain STR loci (24%). The most common was 9p LOH (12 patients). 12p LOH was detected in 8 patients. According to OS analysis, LOH 12p seems to be a marker of a favorable prognosis. For B-ALL patients, LOH (excepting 12p LOH) was an independent risk factor (OS hazard ratio 3.89, log-rank P-value 0.0395). For T-ALL patients, the OS hazard ratio was 0.59 (log-rank P-value 0.62). Conclusions: We have found a statistically significant association of clinical failures with the LOH in STR loci measured at the onset of B-ALL but not T-ALL. Funding: This study was supported by Rakfond grant 5/2019