High sensitivity and clonal stability of the genomic fusion as single marker for response monitoring in ETV6-RUNX1-positive acute lymphoblastic leukemia.

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Assessment of minimal residual disease (MRD) is an integral component for response monitoring and treatment stratification in acute lymphoblastic leukemia (ALL). We aimed to evaluate the genomic ETV6-RUNX1 fusion sites as a single marker for MRD quantification. In a representative, uniformly treated cohort of pediatric relapsed ALL patients (n=52), ETV6-RUNX1 fusion sites were compared to the current gold standard, immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements. Primer/probe sets designed to ETV6-RUNX1 fusions achieved significantly more frequent a sensitivity and a quantitative range of at least 10-4 compared to the gold standard with 100% and 73%versus 76% and 47%, respectively. The breakpoint sequence was identical at diagnosis and relapse in all tested cases. There was a high degree of concordance between quantitative MRD results assessed using ETV6-RUNX1 and the highest Ig/TCR marker (Spearman's 0.899, P<.01) with differences>½ log-step in only 6% of patients. A high proportion of ETV6-RUNX1-positive ALL relapses (40%) in our cohort showed a poor response to induction treatment at relapse, and therefore had an indication for hematopoietic stem cell transplantation, demonstrating the need of accurate identification of this subgroup. ETV6-RUNX1 fusion sites are highly sensitive and reliable MRD markers. Our data confirm that they are unaffected by clonal evolution and selection during front-line and second-line chemotherapy in contrast to Ig/TCR rearrangements, which require several markers per patient to compensate for the observed loss of target clones. In future studies, the genomic ETV6-RUNX1 fusion can be used as single MRD marker.