Molecular associations of response to the new generation BTK inhibitor zanubrutinib in marginal zone lymphoma.
Maciej TatarczuchMark WalthamJake ShorttGalina PolekhinaEliza A HawkesShir-Jing HoJudith TrotmanDaniella BrasacchioMelannie CoJessica LiVanitha RamakrishnanKarin DunneStephen Samuel OpatGareth Peter GregoryPublished in: Blood advances (2023)
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. WES was performed on baseline tumor samples obtained from 18 patients. For seven patients, ctDNA was interrogated using a bespoke hybrid-capture next-generation sequencing (NGS) assay for 48 targeted genes. Somatic mutations were correlated with objective response data and survival analysis using Fisher's exact test and Kaplan-Meier (log-rank) method respectively. Baseline WES identified mutations in 33/48 (69%) prioritised genes. NFkB, NOTCH or BCR pathway genes were implicated in samples for 16/18 (89%) patients. KMT2D mutations (n=11) were most common followed by FAT1 (n=9), NOTCH1, NOTCH2, TNFAIP3 (n=5) and MYD88 (n=4). MYD88 or TNFAIP3 mutations correlated with improved PFS (not reached (NR) vs 11.1 months, p: 0.008, HR: 0.09, 95% CI: 0.01-0.52); KMT2D mutations trended to worse PFS (PFS: 13.40 months vs NR, p: 0.05, HR 6.5, 95%CI: 1.00-37.78). Acquired resistance mutations PLCG2 (R665W/R742P) and BTK (C481Y/C481F) were detected in two patients whose disease progressed. A BTK E41K non-catalytic activating mutation was identified prior to treatment in one zanubrutinib-refractory patient. MYD88, TNFAIP3 and KMT2D mutations correlate with PFS in patients with rrMZL treated with zanubrutinib. Detection of acquired BTK and PLCG2 mutations in ctDNA while on therapy is feasible and may herald clinical disease progression. This trial was registered at https://anzctr.org.au/ as ACTRN12619000024145.
Keyphrases
- end stage renal disease
- ejection fraction
- newly diagnosed
- clinical trial
- chronic kidney disease
- circulating tumor
- prognostic factors
- peritoneal dialysis
- tyrosine kinase
- randomized controlled trial
- toll like receptor
- stem cells
- patient reported outcomes
- gene expression
- genome wide
- study protocol
- deep learning
- acute lymphoblastic leukemia
- immune response
- patient reported
- case report
- fatty acid
- dna methylation
- electronic health record
- cell free
- density functional theory
- cancer therapy
- high throughput
- reduced graphene oxide
- big data