Table 1.
Selected next-generation-sequencing-based studies that identified alternative genetic aberrations other than BTK or PLCG2 mutations, acquired or clonally selected during disease progression to ibrutinib resistance.
| Study | Method | Major Findings | Size | Reference |
|---|---|---|---|---|
| DLBCL | WES and transcriptomics | Inactivating mutation of KLHL14, enriched in 29.6% tumors of MYD88L265P-CD79B subtype | 574 (biopsy) | Schmitz [21] Jaewoo [22] |
| MCL | WES, and TDS | 9p21.1–p24.3 loss and/or mutations in components of SWI–SNF chromatin-remodelling complex | 24 (R/R) | Aggarwal [23] |
| WES on IS and IR | CARD11 mutation in 5.5% of cases | 13 | Chenglin [24] | |
| WES on 7 IS, 7 IR | Changes in DNA copy number alteration, broad deletions of 6q, 9p, and chromosome 13 | 37 | Zhang [25] | |
| FL | TDS panel of 140 genes, on pre-ibrutinib treatment | CARD11 (16%) and predicted resistance to ibrutinib (NCT01849263) | 31 (biopsy) | Bartlett [26] |
| WM | WES on ibrutinib progressed tumors | Homozygous loss of chr; 6q and 8q at baseline (33% and 66%), at progression (60% and 80%) in tumor of MYD88L265P | 5 (biopsy) | Jimenez [27] |
| AS-PCR for MYD88 and CXCR4 mutation followed by ibrutinib response | Major response rate; MYD88L265PCXCR4WT (91.2%), MYD88L265PCXCR4WHIM (61.9%); Clinical Trial (NCT01614821) | 63 (biopsy) | Treon [28] | |
| CLL | TDS, for mutations in 29 genes | Mutation in TP53, SF3B1, and CARD11 genes | 11 (paired) | Shamanna [29] |
| WES and SNP 6.0 array profiling | Acquired or increased status of del17p/TP53 mutation in three out of five ibrutinib-resistant cases. | 48 (paired) | Amin [13] | |
| WES and TDS | Chr;8p del with additional driver mutations (EP300, MLL2 and EIF2A) | 5 | Burger [30] | |
| A hybrid capture or SNV for panel with 1200 or 1212 CAG | BTKT316A mutation confer activation of PLCG2 | 1 and 9 | Sharma [31], Kadri [32]. |
Abbreviations: WES, whole exome sequencing; TDS, targeted deep sequencing; SNV, single-nucleotide variations; CLL, chronic lymphocytic leukemia; WM, Waldenstrom macroglobulinemia; MCL mantle cell lymphoma; DLBCL, diffuse large B-cell lymphoma; IS, ibrutinib-sensitive; IR, ibrutinib-resistant; R/R, relapsed/refractory; CAG, cancer-associated genes; AS-PCR, allele-specific polymerase chain reaction.