BTK R665W

For example, BTK C481S mutation is well known as a resistant mutation to covalent BTK inhibitors and several mutations of BTK (such as T474I and L528W mutation) have recently been reported in relapsed or refractory CLL patients with acquired resistance to pirtobrutinib, a non-covalent BTK inhibitor...ONO-7018 and tirabrutinib were orally administered to the mice twice a day... ONO-7018 would provide novel therapeutic strategies to overcome the BTK inhibitor acquired resistance and enhance the antitumor effect of BTK inhibitors in clinic. Phase 1 study of ONO-7018 (NCT05515406) is currently ongoing.

We used duplex sequencing, a technology that enables detection of mutations at ultra-low allelic frequencies, to identify mutations in five genes associated with drug resistance in CLL and followed their evolution in two patients who received multiple targeted therapies and ultimately developed disease progression on pirtobrutinib...In patient R001, multiple known resistance mutations in both BTK and PLCG2 appeared following progression on zanubrutinib (BTK p.L528W, p.C481S, PLCG2 S707F, L845F, R665W, and D993H). In contrast, patient R002 developed multiple BTK mutations following acalabrutinib treatment including known resistance mutations p.C481R, p.T474I and p.C481S...For example, BTK p.L528W in patient R001 increased in frequency more than 1000-fold (from CCF 0.02% to 35%), and p.T474I in patient R002 increased in CCF from 0.03% to 4.2% (more than 100-fold). Our data illuminates the evolutionary dynamics of resistant clones over the patients' disease course and under selective pressure from different targeted treatments.

Novel, non-C481 BTK mutations have been described, including BTK L528W, which has been reported in patients treated with ibrutinib, zanubrutinib, and pirtobrutinib (Maddocks, JAMA Oncol. This is the largest dataset characterizing the incidence and patterns of BTK and PLCG2 mutations in patients with CLL treated with ibrutinib. BTK C481 mutations are the most frequently occurring mutations. PLCG2 mutations occur across the gene at a low incidence per locus (<5%).

73 patients had only one BTKi (ibrutinib (IBR), 64; acalabrutinib (ACA), 9). 12 pts had multiple BTKis, 8 with two drugs with IBR first followed by ACA (Nf3, 37.5%), vecabrutinib (Nf1, 12.5%), and PIR (Nf4, 50.0%); and 4 with three or more drugs... Our retrospective report summarizes mutations detected during BTKi treatment and shows that BTK L528W can occur during both covalent and non-covalent BTK inhibitor therapy. Four of six patients who progressed on PIR had T474 mutations. In addition, our results may suggest that activating mutations in RAS/RAF/MAPK pathway are related to BTKi resistance.

Multiple mechanisms are involved in resistance to the BCL2 inhibitor venetoclax, including point mutations that impair drug binding, the upregulation of BCL2-related anti-apoptotic family members, and microenvironmental alterations. Recently, immune checkpoint inhibitors and CAR-T cells have been tested for CLL treatment, obtaining conflicting results. Potential refractoriness biomarkers to immunotherapy were identified, including abnormal levels of circulating IL-10 and IL-6 and the reduced presence of CD27CD45RO CD8 T cells.

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.

An exploratory analysis of the ibrutinib-treated rrMZL study showed mutations in genes regulating NF-kB signalling pathway: TNFAIP3 ( A20 ) and MYD88 predicted response, whereas KMT2D ( MLL2 ) and CARD11 were associated with primary resistance. Conclusion Mutations in genes associated with the NFkB pathway present at baseline are predictive of response to zanubrutinib in rrMZL patients. Detection of acquired BTK and PLCy2 mutations on therapy is feasible and may herald clinical disease progression.