ALL-332: Loss of Heterozygosity in the Short Tandem Repeat (STR) Loci Found in Tum or DNA of De Novo-Diagnosed ALL Patients as a Factor Predicting Poor Outcome

Abstract

Context Loss of heterozygosity (LOH) was described for many malignancies including leukemia. Previously, we noted LOH at STR loci is especially frequent for relapsed ALL patients. LOH established for de novo-diagnosed ALL could be used as a prognostic factor for possible poor clinical outcome. Objective To identify LOH in the blast cells of the patients with ALL at diagnosis and to analyze therapy outcomes relative to patients without LOH. Design This study includes an analysis of the STR profiles of the DNA of tumor cells from a cohort of 47 patients with de novo-diagnosed Ph-negative ALL undergoing treatment according to the “RALL-2016” regimen at the National Research Center for Hematology (Moscow, Russia) and statistical evaluation of LOH as a possible risk factor. Patients with the LOH at the short arm of 12 chromosome (12pLOH) are excluded from risk group because 12p LOH is not associated with worse outcome according to many publications. 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 the buccal swab. STR profiles were assessed by PCR with COrDIS Plus multiplex kit for amplification of 19 polymorphic STR-markers and amelogenin loci (Gordiz Ltd, Russia). 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 pre-treatment. 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 primary endpoint. Results Of the 47 patients, 10 were found with LOH in the certain STR loci (21%). 12p LOH was detected in four patients. OS of patients with other LOH was significantly lower than for patients without LOH (HR=6.02 (95% CI: 1.66–21.78), p=0.0019). Conclusions We have found a statistically significant association of clinical failures with the LOH in STR loci (except 12p LOH) measured at the onset of ALL. Funding This study was supported by Rakfond grant 5/2019