Citations

Abstract Early-phase clinical trials of BTK degraders in relapsed/refractory CLL have shown response rates of over 80%, including in patients with BTK mutations that confer resistance to conventional BTK inhibitors (BTKi). The molecular basis of resistance to BTK degraders is unknown and, given the promise of this class of drugs, would hold implications for therapy sequencing and the design of next-generation BTK degraders. To this end we identified five patients at Memorial Sloan Kettering who developed progressive disease while being treated on the phase 1 trials of zelebrudomide (NCT04830137, 4 patients) or bexobrutideg (NCT05131022, 1 patient). In two patients, one treated with zelebrudomide and the other with bexobrutideg, a pre-existing BTK A428D mutation had expanded at progression, rising from <1.5% at the start of treatment to >25%. In both cases, the increase in frequency of BTK A428D coincided with the loss of BTK degradation in peripheral blood B cells. No mutation in cereblon, the ligase utilized by these BTK degraders, was detected. To validate these clinical findings we generated wild-type and BTK A428D knock-in single-cell clones in TMD8 and HBL1 cells. BTK A428D conferred resistance to BTKi, including ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, as well as the clinical-stage BTK degraders zelebrudomide, bexobrutideg, BGB-16673, and AbbVie-1 (Compound 1, WO 2023183811). BTK A428D’s pan-resistance is unique compared to previously studied BTKi resistance mutations which remain susceptible to at least one BTKi and all clinical-stage BTK degraders tested. To understand how BTK A428D confers pan-resistance to BTKi and BTK degraders we conducted surface plasmon resonance studies which demonstrated that BTKi and all four clinical-stage BTK degraders tested are unable to bind BTK A428D. We next solved the crystal structure of apo BTK A428D to 1.8Å, which revealed that the mutant aspartate, which is larger and negatively charged compared to the wild-type alanine, sterically blocks BTKi and degraders from accessing residues in the hinge region of the kinase that are required for drug binding. We next asked why BTK A428D, despite conferring pan-resistance, has only been detected in 1.1% of patients treated with BTK inhibitors. Intriguingly, we noted that in one of our index patients, the frequency of BTK A428D declined and became undetectable after the withdrawal of zelebrudomide, suggesting a fitness defect. To assess this hypothesis, we compared the proliferation rates of five TMD8 wild-type and five BTK A428D single-cell clones; the BTK A428D clones grew more slowly and were consistently outcompeted in mixing studies. In summary, low-frequency BTK A428D mutations can expand under the selection pressure of BTK degraders and confer clinical resistance by preventing drug binding. The mutation, however, is outcompeted in the absence of BTK-targeted therapies. These findings provide rationale for the investigation of combination therapies and the development of next-generation BTK degraders capable of circumventing BTK A428D. Citation Format: Quinlan Sievers, Hao Lu, Allison Cool, Stefan Grajewski, Tim Kong, Mark Noviski, Xiaoli Mi, Emel Ficici, Ratul Mukerji, James Iuliano, Jordan Ye, Mateo Sanchez Garcia de los Rios, Hugo Bousquet, Sarah Whelan, May Tan, Christopher Phelps, Jahan Raman, Ryan Notti, Lizbeth Mendoza Navarrete, Samantha Sekeres, Eria Lamkin, Eduardo Bravo, Mark Ewalt, Prioty Islam, Anthony Mato, Lindsey Roeker, Justin Taylor, Meghan Thompson, Gwenn Hansen, Omar Abdel-Wahab. BTK A428D is a recurrent pan-resistance mutation to BTK degraders in clinical trials [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr PR004.

ImportanceInternal medicine residents’ professional development preferences were discordant with their perceptions of cardiology in a survey circulated a decade ago; no contemporary data exist. This information is important for effective recruitment and retention of a highly talented and diverse future cardiology workforce.ObjectiveTo identify residents’ professional development preferences and cardiology perceptions, in relation to specialty choice, and compare the findings with those from a decade prior.Design, Setting, and ParticipantsThe original survey from the 2010 study was updated and sent to US internal medicine programs. Respondents (ie, internal medicine residents) rated 38 professional development preferences and 20 cardiology perceptions. Data were collected in 2020 and compared with survey results from the prior 2010 study. Multivariable models were created for specialty choice using scaled independent variables dichotomized using the top 2 options; categorical variables were recoded into binary variables for analysis.Main Outcomes and MeasuresMultivariable models were used to determine the association of demographic characterisitcs and survey responses with prospective career choice. Responses were examined by total group, by gender, by self-reported consideration of entering cardiology as a profession, and by comparison with a decade prior both as a group and by gender.ResultsA total of 840 residents (mean [SD] age, 29.24 [2.82] years; 49.8% male; 55.4% White) completed the survey. The survey incorporated a 5-point Likert scale of 1 (not important) to 5 (extremely important) for some of the questions, with additional questions on demographic characteristics. The most important professional development preferences by descending Likert score were as follows: positive role models (4.56), stimulating career (3.81), and family friendly (3.78). The cardiology perception statements with the highest agreement were as follows: interferes with family life during training (3.93) and having met positive role models or having positive views of cardiovascular disease as a topic (3.85). Multivariable analysis yielded a 22-element model predicting cardiology as career choice. Compared with the 2010 survey, the findings of this survey indicated increased importance of work-life balance components for both male and female residents, with a greater change in male residents. Contemporary residents were more likely than their predecessors to agree with negative perceptions of cardiology.Conclusions and RelevanceThis survey study found that both male and female residents place a high value on support for optimal work-life balance; these preferences have intensified over the past decade and factor into career choice. Negative perceptions of cardiology persist and, in some aspects, are worsening. Improving the culture of cardiology may make this specialty a more attractive career choice for all.