Citations

Abstract Early-phase clinical trials of Bruton’s tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate clashes with the adenine ring of ATP and the adenine-mimetic moiety of BTK inhibitors and degraders. Combining BTK degraders with venetoclax mitigated the expansion of BTK A428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies.

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.

Background: Journal editors influence the visibility and direction of scientific research and should have adequate gender and geographic representation. Research Question: Are there disparities in gender and institutional country affiliation among editors of highly cited cardiology and cardiovascular disease journals? Methods: In May 2025, we used Scimago Journal Rankings to identify the 50 top-cited cardiology and cardiovascular disease journals worldwide from 2022 to 2024. Due to the large volume of members, general editorial board listings without defined roles were excluded. Editors’ genders and country of institutional affiliation were extracted independently and in duplicate by eight sub-investigators. An additional sub-investigator resolved any discrepancies. Gender was determined using institutional profiles and publicly available pronouns on academic or professional platforms. Country affiliation was based on the editor’s primary institution and categorized by World Bank income classification 2025, which divides countries into high-income (HIC), upper-middle income (UMIC), lower-middle income (LMIC), and low-income countries (LIC). Key journal characteristics, such as country, impact factor, and article processing charges, were also extracted in duplicate. Results: All 50 top-cited cardiology and cardiovascular disease journals identified were based in HICs. A total of 1,762 editors were included. Most editorial positions were held by men (67%), with women accounting for 28%. One editor was identified as non-binary, and the gender of 91 editors (5%) could not be determined based on publicly available information (Table 1). Pronouns were identifiable for all EIC (n=52), out of which 87% were men (n=45) and 13% were women (n=7). Ninety-five percent of editors were affiliated with institutions based in HIC, while only 5% were based in UMIC (n=71), LMIC (n=16), or LIC (n=5). The most represented countries were the US (41%), Italy (8%), and the UK (7%) (Figure 2). All EICs (100%) were affiliated with institutions based in HICs, mainly the US (52%) and the UK (10%) (Figure 3). Conclusion: Editors of top-cited cardiology journals are predominantly men affiliated with HICs. Diverse editorial leadership in academic cardiology journals is needed to reflect global perspectives in research.

Abstract Background Invasive fungal infections have been described throughout the COVID-19 pandemic. Cryptococcal disease after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in several isolated case reports and 1 larger case series. We sought to describe cryptococcal infections following SARS-CoV-2 through establishing a database to investigate underlying risk factors, disease manifestations, and outcomes. Methods We created a crowdsourced call for cases solicited through the Mycoses Study Group Education and Research Consortium, the Centers for Disease Control and Prevention Emerging Infectious Diseases Network, and infectious diseases Twitter groups. Data were collected in a web-based and secure REDCap survey without personal identifiers. Results Sixty-nine cases were identified and submitted by 29 separate institutional sites. Cryptococcosis was diagnosed a median of 22 days (interquartile range, 9–42 days) after SARS-CoV-2 infection. Mortality among those with available follow-up was 72% (26/36) for the immunocompetent group and 48% (15/31) for the immunocompromised group (likelihood ratio, 4.01; P = .045). We observed a correlation between disease manifestation (central nervous system infection, proven/probable disseminated disease, and respiratory) and mortality (P = .002). Conclusions The mortality rate of 59% for patients with cryptococcosis following SARS-CoV-2 is higher than that of modern Cryptococcus cohorts. There was an association between immunocompromised status and cryptococcal disease manifestations as well as mortality. Moreover, our series emphasizes the need for clinical and laboratory assessment of opportunistic infections beyond 30 days when concerning symptoms develop.

In this study, we demonstrate that Raman microscopy combined with computational analysis is a useful approach to discriminating accurately between brain tumor bio-specimens and to identifying structural changes in glioblastoma (GBM) bio-signatures after nordihydroguaiaretic acid (NDGA) administration. NDGA phenolic lignan was selected as a potential therapeutic agent because of its reported beneficial effects in alleviating and inhibiting the formation of multi-organ malignant tumors. The current analysis of NDGA’s impact on GBM human cells demonstrates a reduction in the quantity of altered protein content and of reactive oxygen species (ROS)-damaged phenylalanine; results that correlate with the ROS scavenger and anti-oxidant properties of NDGA. A novel outcome presented here is the use of phenylalanine as a biomarker for differentiating between samples and assessing drug efficacy. Treatment with a low NDGA dose shows a decline in abnormal lipid-protein metabolism, which is inferred by the formation of lipid droplets and a decrease in altered protein content. A very high dose results in cell structural and membrane damage that favors transformed protein overexpression. The information gained through this work is of substantial value for understanding NDGA’s beneficial as well as detrimental bio-effects as a potential therapeutic drug for brain cancer.