Circulating Tumor DNA-Based MRD Assessment in Patients with CLL Treated with Obinutuzumab, Acalabrutinib, and Venetoclax.

PURPOSE: With the advent of highly efficacious time-limited combination treatments of targeted agents in chronic lymphocytic leukemia (CLL), minimal residual disease (MRD) assessment has gained importance as a measure for therapeutic success and as a surrogate for progression-free survival. The currently most widely used method is multicolor flow cytometry, which detects circulating CLL cells in the peripheral blood. However, it seems to be less sensitive for the detection of MRD in the lymph node compartment. PATIENTS AND METHODS: To evaluate whether a cell-free approach can overcome this limitation, we performed serial assessments of circulating tumor DNA (ctDNA) in patients with CLL treated with obinutuzumab, acalabrutinib, and venetoclax in the phase II CLL2-BAAG trial. Patient-specific variability, diversity, joining (VDJ) rearrangements as well as somatic driver mutations were tracked before, during and after treatment by digital droplet PCR in blood plasma. Furthermore, these were systematically compared to matched flow cytometry data. RESULTS: In the 381 sample pairs, ctDNA and flow cytometry yielded highly concordant results. However, clone-specific ctDNA was detected in 44 of 152 samples (29%) that were assessed as undetectable MRD (uMRD) by flow cytometry (defined as less than one CLL cell in 10,000 normal leukocytes). 29 ctDNA-negative samples showed detectable MRD >10-4 by flow cytometry. Also, somatic driver mutations were detected with a similar sensitivity compared with patient-specific VDJ rearrangements in plasma. In patients with predominantly nodal residual disease, ctDNA compared favorably with 4-color flow cytometry and seemed to more accurately reflect the entire disease burden across compartments. CONCLUSIONS: On the basis of these findings, ctDNA-based MRD assessment appears to be a promising method to complement cell-based MRD approaches like flow cytometry that focus on circulating CLL cells in the peripheral blood.

Establishing realistic exposure estimates of solitary bee larvae via pollen for use in risk assessment.

Bees foraging in agricultural habitats can be exposed to plant protection products. To limit the risk of adverse events, a robust risk assessment is needed, which requires reliable estimates for the expected exposure. The exposure pathways to developing solitary bees in particular are not well described and, in the currently proposed form, rely on limited information. To build a scaling model predicting the amount of protein developing solitary bees need based on adult body weight, we used published data on the volume of pollen solitary bees provide for their offspring. This model was tested against and ultimately updated with additional literature data on bee weight and protein content of emerged bees. We rescaled this model, based on the known pollen protein content of bee-visited flowers, to predict the expected amount of pollen a generalist solitary bee would likely provide based on its adult body weight, and tested these predictions in the field. We found overall agreement between the models' predictions and the measured values in the field, but additional data are needed to confirm these initial results. Our study suggests that scaling models in the bee risk assessment could complement existing risk assessment approaches and facilitate the further development of accurate risk characterization for solitary bees; ultimately the models will help to protect them during their foraging activity in agricultural settings. Integr Environ Assess Manag 2022;18:308-313. © 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).