The covalent Bruton's tyrosine kinase inhibitors (BTKi) are highly effective for the treatment of chronic lymphocytic leukemia (CLL). The dominant resistance mechanism observed with the BTKi ibrutinib is the development of BTK Cys481 codon mutations. Whether a similar resistance mutation profile exists for the newer generation, more selective, BTKi zanubrutinib is unknown. From samples referred for diagnostic next generation sequencing in patients with progressive CLL we observed an enrichment in the kinase-dead BTK Leu528Trp mutation in patients treated with zanubrutinib compared to ibrutinib (54% [7/13] vs 4% [1/24], p=0.001). We describe 2 patients with BTK Leu528Trp mutations who showed clinical cross-resistance and progressive enrichment of the BTK Leu528Trp mutation over time when treated with the non-covalent BTK inhibitor pirtobrutinib. Both patients subsequently responded to venetoclax based treatment. In summary we have identified an enrichment of the BTK Leu528Trp mutation arising in patients treated with zanubrutinib which may impart cross-resistance to the non-covalent inhibitor pirtobrutinib and therefore implications for sequencing of these treatments in CLL.
Previous research has shown that social support can have a beneficial impact on coping processes and psychological adjustment in patients with rheumatoid arthritis (RA). The association of individual coping styles and perceived responses from others to one's pain episodes with patients 'distress and disease status over time was investigated. The sample consisted of 42 middle-aged patients with RA who were predominantly White (98%), female (64%), and married (88%). Participants completed surveys and their rheumatologist completed clinical assessments of patient disease status at 2 time points over a 9-month period. Although punishing responses from others (e.g., getting irritated or angry when the patient is in pain) were perceived as relatively infrequent, they were associated with a patient coping style of focusing on and venting of negative emotion as well as elevated negative affect (NA). Findings also indicated that those who perceived punishing responses from close others and coped by venting negative emotions reported increased NA over time and were rated by their rheumatologist as having more severe RA disease status over time. Implications for psychosocial intervention and directions for future research are discussed.
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