Clinical utility of a novel triplex digital PCR assay for clone monitoring in sequential and relapsed pediatric B-cell acute lymphoblastic leukemia patients
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Introduction: Digital PCR studies for clonal disease monitoring in B-ALL patients are currently limited due to the heterogeneous nature of mutations, which limitscost-effective assay designs. Materials and Methods: In the “DETECTOR study”, 70 samples (14 relapse and 56 sequential therapy samples) were tested for 13 mutations in the KRAS, NRAS, NT5C2, PMS2, UHRF1, KMT2D and TP53 genes via a novel triplex digital PCR assay. The results & Discussion: A total of 7 major clones of NRAS [5] and NT5C2 [2] were noted in 6/14 (43%) patients, accounting for50% of very early-early relapses. In addition, 12 minor clones ( PMS2 [4], NRAS [4], NT5C2 [3], and TP53 [1]) were noted in 6/14 (43%) patients. In the 56 sequential therapy samples, 6 major clones were noted ( NRAS [5], KRAS [1]) in 4/14 (28.5%) patients, with 2 increasing in size in maintenance samples, leading to relapse. In addition, therapy-acquired minor clones in NT5C2 [4] and PMS2 [1] emerged in maintenance samples in 4/14 (28.5%) patients, with concordant detection of such clones in unpaired relapse samples, indicating the need for active surveillance during therapy. Overall, digital PCR validated NRAS and NT5C2 major clones in one-third (10/27; 37%) of our patients,driving 50% of very early-early relapses, thereby highlighting its utility for clonal monitoring in LMIC regions.