How do CLL patients with downstream treatment-resistant mutations such as PLCG2 respond to pirtobrutinib?  

Although BTK/PLCG2 mutations are present in patients with CLL relapsing on covalent BTK inhibitors, more than one-third of them DO NOT harbor such mutations even after high-sensitivity analyses. Additional genetic mechanisms, in particular aberrant activation of the BcR and NF-κB pathways, may...

In the BRUIN trial, among 222 patients with PLCG2 mutation data available, 18 had mutations and 204 did not. The overall response rate (ORR) was numerically lower in those with PLCG2 mutation (56% vs 84%) (Mato et al., PMID 37407001).The ORR was numerically higher in those with BTK C481 mutation com...

There is limited data in this regard. PLCG2 mutation leads to a lower response rate to pirtobrutinib.

It has been described by Wang and colleagues how mutations that occur outside the C481 residue and PLCG2 downstream mutations are associated with resistance to both covalent (irreversible) and non-covalent (reversible) BTK inhibitors. This work is based on genomic analyses conducted on patients trea...