Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab

Abstract

To advance the use of circulating tumor DNA (ctDNA) applications, their broad clinical validity must be tested in different treatment settings, including targeted therapies. Utilizing the prespecified longitudinal systematic collection of plasma samples in the phase 1/2a LYM1002 trial (NCT02329847), we tested the clinical validity of ctDNA for baseline mutation profiling, residual tumor load quantification, and acquisition of resistance mutations in patients with lymphoma treated with ibrutinib plus nivolumab. Inclusion criterion for this ancillary biological study was the availability of blood collected at baseline and cycle 3 day 1. Overall, 172 ctDNA samples from 67 patients were analyzed using LyV4.0 ctDNA CAncer Personalized Profiling by deep Sequencing assay. Among baseline variants in ctDNA, only TP53 mutations (detected in 25.4% of patients) were associated with shorter progression-free survival; clones harboring baseline TP53 mutations did not disappear during treatment. Molecular response, defined as a >2-log reduction in ctDNA levels after 2 cycles of therapy (28 days), was achieved by 28.6% of patients with relapsed diffuse large B-cell lymphoma who had ≥1 baseline variant and was associated with best response and improved progression-free survival. Clonal evolution occurred frequently during treatment, and 10.3% new mutations were identified after 2 treatment cycles in nonresponders. PLCG2 was the topmost among genes that acquired new mutations. No patients acquired C481S BTK mutations implicated in resistance to ibrutinib in CLL. Collectively, our results provide the proof of concept that ctDNA is useful for noninvasive monitoring of lymphoma treated with targeted agents in the clinical trial setting.

A two‐part, single‐arm, multicentre, phase I study of zanubrutinib, a selective Bruton tyrosine kinase inhibitor, in Chinese patients with relapsed/refractory B‐cell malignancies

“…Mutations in TP53 and CARD11 are associated with worse responses to ibrutinib in FL patients. 19,20 In the current study, among zanubrutinib-progressive FL patients, 57.1% carried TP53 mutations and 42.8% carried BCL10/ CARD11 mutations, a rate higher than the 9.5% BCL10, 16% CARD11 and approximately 25% TP53 mutation rates previously reported in recurrent FL patients, 19,21 and suggests that TP53 and CARD11/BCL10 mutations may contribute to resistance to BTK inhibitors in FL patients. Five patients had mutational status available in pre-treatment samples using a different NGS panel.…”

Circulating versus cellular tumor DNA for the detection of BTK resistant CLL clones

“…Another limitation might be the WTB-PCR itself as it is a single mutation method with a maximum sensitivity of 1:2000 per ml plasma while multiple mutation assays like CAPP-seq NGS or PhasED-seq can reach a sensitivity up to 2.5:100.000 [ 8 , 9 , 22 ]. However, these NGS methods are costly and not yet available in daily routine.…”

“…Recently, detection of circulating tumor DNA (ctDNA) has also been evaluated for hematological malignancies either as initial biomarker, response monitoring or for early detection of relapse [8] , [9] , [10] , [11] .…”

Increasing tissue requirements in lymphoma trials may exclude patients with high-risk disease or worse prognosis

“…Finally, liquid biopsy or peripheral blood circulating tumor DNA (ctDNA) can potentially be utilized to expedite some of the biological analyses. 23 , 24 , 25 , 26 , 27 , 28 Recently, ctDNA has been efficiently utilized for molecular characterization of DLBCL; this strategy can compensate some of the tissue needs of clinical trials. 29 ctDNA can potentially be used as a surrogate for tumor burden and prognosis in lymphoma.…”