Relation between Genomic DNA Breakpoints in MLL Gene and Treatment Outcome in Infants with Acute Leukemia

• Main Authors: GA Tsaur, C Meyer, TO Riger, AM Kustanovich, EV Fleischman, YuV Ol’shanskaya, AM Popov, OI Sokova, EA Matveeva, OV Nikulina, AE Drui, OR Arakaev, OV Streneva, SA Rumyantsev, EV Shorikov, AG Solodovnikov, LI Savel’ev, R Marschalek, LG Fechina
• Format: Article
• Language: Russian
• Published: Practical Medicine Publishing House 2016-01-01
• Series: Kliničeskaâ onkogematologiâ
• Subjects: acute leukemia; infants; 11q23/MLL rearrangements; MLL-Baby; treatment outcome
• Online Access: http://bloodjournal.ru/en/relation-between-genomic-dna-breakpoints-in-mll-gene-and-treatment-outcome-in-infants-with-acute-leukemia/

Aim. To evaluate the relation between genomic DNA breakpoints in MLL and translocation partner genes (TPG) and clinical parameters of infant AL. Methods. 68 infants (29 boys and 39 girls with median age of 4.8 mo) with MLL-rearranged acute lymphoblastic leukemia (ALL) (n = 46), acute myeloid leukemia (AML) (n = 20) and mixed phenotype acute leukemia (MPAL) (n = 2) were included in the current study. Results. 5-year EFS was significantly lower in patients with breakpoints in intron 11 (n = 29) in comparison to patients with breakpoint localized from intron 7 to exon 11 (n = 17) (0.16 ± 0.07 vs 0.38 ± 0.14, p = 0.039). While cumulative incidence of relapse was remarkably higher in the first group of patients (0.74 ± 0.09 vs 0.52 ± 0.17, p = 0.045). Although in Cox regression model including breakpoint location in intron 11 together with age, immunophenotype, initial white blood cell count, initial CNS involvement, type of MLL rearrangements, absolute blast number at day 8 of dexamethasone profase, minimal residual disease (MRD) at time point 4 (TP4) of MLL-Baby protocol, the only significant covariate was the presence of MRD at TP4 (HR 5.994, 95% CI 2.209–16.263, p < 0.001). In 22 AML patients there was not any correlation between breakpoint location and treatment outcome. Conclusion. Breakpoints in intron 11 of MLL gene led to significantly worse outcome in infants with ALL, treated by MLL-Baby protocol, although this parameter was overcome by MRD-positivity at TP4. The latter was the only independent covariate in multivariate analysis. Our data provide additional information of molecular genetic features of MLL-rearranged infant AL.