ETV6/RUNX1-Postitive Childhood Acute Lymphoblastic Leukemia (ALL): Do Additional Aberrations Influence Treatment Response and Outcome?

Abstract

ETV6/RUNX1 rearrangement, being the most common genetic abnormality in childhood ALL, is combined with controversial prognostic behavior and frequent late relapses, indicating the need for identification of additional prognostic markers. In our study, we examined the relation between ETV6/RUNX1 and presenting clinical/biological features, co-existing subclones/secondary aberrations, early response to treatment (MRD) and their impact on outcome in a pediatric cohort of 133 ALL pts , treated in one Center over a 12-year period.Data from 133 newly diagnosed ALL pts(83 males) with a median age of 5.1 yrs(range 1.2-16.7), have been retrospectively recorded and analyzed. Pts were consecutively diagnosed and homogeneously treated on BFM based protocols during the years 2000-2011. FISH evaluation using commercial probe sets was performed for the detection of ETV6-RUNX1, E2A-PBX1, BCR-ABL fusion genes, MLL gene rearrangements as well as ETV6, RUNX1, CDKN2A/2B and other gene duplications, deletions or amplifications.Twenty seven pts (27/133, 20.3%) were tested positive for the t(12;21)(p13;q22) translocation(16 males), with a median age of 3.9 yrs(range 2.0-16.7). Immunophenotype revealed 22/27 common (81.5%) and 5/32 pre-B cases (18.5%). All pts were characterized as GPR and treated in the IR Arm. 8/27 (29.6%) were positive for the ETV6/RUNX1 fusion gene only with no secondary aberrations. 19/27 ETV6/RUNX1-positive pts (70.4%) harbored additional structural or numerical genetic abnormalities while 8 of those pts showed presence of subclones with multiple patterns of additional ETV6 and RUNX1 aberrations. The most common abnormalities were del12p13(37%), 3-6x21q22(22.2%), del9p21(18.5%), +21(14.8%), and 2-3xETV6/RUNX1(18.5%).On day 15, 13/27 ETV6/RUNX1+ pts (48.1%) presented with FCM-MRD(d15) values≥10-3 while the corresponding percent among IR ETV6/RUNX1- pts was 46.9%. Out the 8 pts with sole t(12;21)(p13;q22) translocation, only 25%(2/8 pts) presented with MRD(d15)>10-3 while among the 19 pts with additional aberrations, the corresponding percent was 52.6% (10/19). Interestingly, referring only to ETV6/RUXN1+ pts with subclones, the percent reflecting MRD(d15)>0.1% rises to 87.5% (7/8 pts). Among the 14 pts with no MRD(d15) detection only 1/14 appeared with clonal heterogeneity.3/27 pts (11.1%) relapsed, in a median time of 30.3 months (median follow-up time 64 months). Common features of all relapses were sub-clonal diversity at diagnosis, del(9p21) and MRD(d15) positivity. 5-year RFS for the ETV6/RUNX1+ subgroup was 86.4%±7.4 vs 87.7%±3.5 for ETV6/RUNX1- pts. The presence of the ETV6/RUNX1 fusion gene as a favorable genetic marker did not seem to have a statistically significant impact on the probability of relapse (p=0.906). The 5-year RFS for those with MRD≥0.1% was limited to 67.3% ±16.0, while the corresponding rate for MRD- pts reached 100%.ETV6/RUNX1+ childhood ALL is characterized by extreme heterogeneity and the prognostic value of the fusion itself varies, depending on coexisting clinical and biological features. In our series, the presence of additional genetic aberrations/subclones (such as del9p21 or ETV6/RUNX1 duplication) and impaired FCM-MRD clearance, influences patient outcome. Longer follow-up is needed in order to further validate these initial results. FISH and FCM data may help establish new prognostic markers to predict relapse and refine risk stratification. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.