Jana Hoffmann1, Manuela Krumbholz2, Helia Pimentel Gutiérrez1, Marion Fillies1, Annabell Szymansky1, Kirsten Bleckmann3, Udo Zur Stadt4, Rolf Köhler5, Roland P Kuiper6, Martin Horstmann7,8, Arend von Stackelberg1, Cornelia Eckert1, Markus Metzler2. 1. Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany. 2. Pediatric Oncology/Hematology, University Hospital Erlangen, Erlangen, Germany. 3. Department of Pediatrics, University of Schleswig-Holstein, Kiel, Germany. 4. Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 5. Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany. 6. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. 7. Research Institute Children's Cancer Center, Hamburg, Germany. 8. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Abstract
BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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. CONCLUSIONS: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.
Authors: Roland P Kuiper; Patricia G Hoogeveen; Reno Bladergroen; Freerk van Dijk; Edwin Sonneveld; Frank N van Leeuwen; Judith Boer; Irina Sergeeva; Harma Feitsma; Monique L den Boer; Vincent H J van der Velden Journal: Br J Haematol Date: 2021-08-01 Impact factor: 8.615
Authors: Neetha Nanoth Vellichirammal; Nagendra K Chaturvedi; Shantaram S Joshi; Donald W Coulter; Chittibabu Guda Journal: Cancer Lett Date: 2020-11-25 Impact factor: 9.756