Acquired resistance mutations PLCG2 (R665W/R742P) and BTK (C481Y/C481F) were detected in two patients whose disease progressed. KMT2D mutations (n=11) were most common followed by FAT1 (n=9), NOTCH1, NOTCH2, TNFAIP3 (n=5) and MYD88 (n=4). NFkB, NOTCH or BCR pathway genes were implicated in samples for 16/18 (89%) patients. Baseline WES identified mutations in 33/48 (69%) prioritised genes. Somatic mutations were correlated with objective response data and survival analysis using Fisher's exact test and Kaplan-Meier (log-rank) method respectively. For seven patients, ctDNA was interrogated using a bespoke hybrid-capture next-generation sequencing (NGS) assay for 48 targeted genes. WES was performed on baseline tumor samples obtained from 18 patients. Utilising tissue whole exome sequencing (WES) and circulating tumor cell-free DNA (ctDNA), this Australasian Leukaemia & Lymphoma Group (ALLG) translational study sought to characterise primary and acquired molecular determinants of response and resistance of MZL to zanubrutinib for patients treated on the MAGNOLIA clinical trial.
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