Table 1.
Summary of identified biomarkers of treatment refractoriness to CLL.
| Biomarker | Prevalence before Treatment | Prevalence at Progression | Mechanism of Resistance | Predictive Value | References |
|---|---|---|---|---|---|
| Unmutated IGHV gene | ~40% | 70–80% | Increased BCR signaling capacity | Poor response to CIT | [24,25,26] |
| Del(17p) | 5% | ~30% | Genomic instability, survival advantage, and reduced DNA damage response | Poor response to CIT, BTKi, and BCL2i | [24,25,27,28,29,30] |
| TP53 mutations | 7% | 30–40% | Genomic instability, survival advantage, and reduced DNA damage response | Poor response to CIT, BTKi, and BCL2i | [24,25,27,28,29,30] |
| BIRC3 mutations | 2–6% | ~8% | Upregulation of non-canonical NF-κB signaling pathway | Poor response to CIT | [24,31,32,33,34,35,36] |
| NOTCH1 mutations | 8–10% | 30% | Transcriptional activation of cell survival and proliferation and reduced expression of CD20 | Poor response to CIT and anti-CD20 mAbs | [24,25,27,37,38,39] |
| BTK point mutations of C481: C481S/R/Y/G | N/A | ~50% | Reduced affinity for covalent BTKi | Poor response to covalent BTKi | [40] |
| BTK point mutations of the tyrosine kinase domain: L528W, V416L, T474I, M437R, A428D | N/A | ~16% | Binding impairment of non-covalent BTKi | Poor response to covalent and non-covalent BTKi | [41] |
| PLCG2 mutations: R665W, L845G, C849R, D993H | N/A | 13% | Constitutively active PLCγ2 | Poor response to BTKi | [42,43] |
| BCL2 mutations: G101V, D103Y, F104I | N/A | ~15% | Binding impairment of BCL2is | Poor response to BCL2i | [44] |
| Upregulation of MCL-1 and/or BCL-xL | N/A | N/A | Enhanced apoptosis evasion | Poor response to BCL2i | [45,46] |
| High serum [IL-10] | N/A | N/A | Reduced T cell response through IL-10R stimulation | Poor response to PD-1/PD-L1 immune checkpoint inhibitors | [47] |
| Low serum [IL-6] | N/A | N/A | CAR-T cell exhaustion due to defective IL-6R stimulation | Poor response to CAR-T cells | [48] |
| Low levels of CD27+CD45RO− CD8+ T cells | N/A | N/A | Reduced population of active CAR-T cells | Poor response to CAR-T cells | [48] |
Abbreviations: IGHV, immunoglobulin heavy variable; del(17p), deletion of the short arm of chromosome 17; BCR, B cell receptor; CIT, chemoimmunotherapy; BTK, Bruton tyrosine kinase; BTKi, BTK inhibitors; BCL2, B cell lymphoma 2; BCL2i, BCL2 inhibitors; PLCG2, phospholipase-C-gamma-2; PLCγ2, phospholipase-C-γ-2; IL-10, Interleukin-10; IL-10R, IL-10 receptor; IL-6, Interleukin-6; IL-6R, IL-6 receptor; CAR, chimeric antigen receptor; mAbs, monoclonal antibodies.