Associations Between Organizational Support, Burnout, and Professional Fulfillment Among US Physicians During the First Year of the COVID-19 Pandemic.

GOAL: This research aimed to evaluate variations in perceived organizational support among physicians during the first year of the COVID-19 pandemic and the associations between perceived organizational support, physician burnout, and professional fulfillment. METHODS: Between November 20, 2020, and March 23, 2021, 1,162 of 3,671 physicians (31.7%) responded to the study survey by mail, and 6,348 of 90,000 (7.1%) responded to an online version. Burnout was assessed using the Maslach Burnout Inventory, and perceived organizational support was assessed by questions developed and previously tested by the Stanford Medicine WellMD Center. Professional fulfillment was measured using the Stanford Professional Fulfillment Index. PRINCIPAL FINDINGS: Responses to organizational support questions were received from 5,933 physicians. The mean organizational support score (OSS) for male physicians was higher than the mean OSS for female physicians (5.99 vs. 5.41, respectively, on a 0-10 scale, higher score favorable; p < .001). On multivariable analysis controlling for demographic and professional factors, female physicians (odds ratio [OR] 0.66; 95% CI: 0.55-0.78) and physicians with children under 18 years of age (OR 0.72; 95% CI: 0.56-0.91) had lower odds of an OSS in the top quartile (i.e., a high OSS score). Specialty was also associated with perceived OSS in mean-variance analysis, with some specialties (e.g., pathology and dermatology) more likely to perceive significant organizational support relative to the reference specialty (i.e., internal medicine subspecialty) and others (e.g., anesthesiology and emergency medicine) less likely to perceive support. Physicians who worked more hours per week (OR for each additional hour/week 0.99; 95% CI: 0.99-1.00) were less likely to have an OSS in the top quartile. On multivariable analysis, adjusting for personal and professional factors, each one-point increase in OSS was associated with 21% lower odds of burnout (OR 0.79; 95% CI: 0.77-0.81) and 32% higher odds of professional fulfillment (OR 1.32; 95% CI: 1.28-1.36). PRACTICAL APPLICATIONS: Perceived organizational support of physicians during the COVID-19 pandemic was associated with a lower risk of burnout and a higher likelihood of professional fulfillment. Women physicians, physicians with children under 18 years of age, physicians in certain specialties, and physicians working more hours reported lower perceived organizational support. These gaps must be addressed in conjunction with broad efforts to improve organizational support.

Risk of Incident Melanoma Among Individuals With Low-Count Monoclonal B-Cell Lymphocytosis.

PURPOSE: Chronic lymphocytic leukemia (CLL)-phenotype monoclonal B-cell lymphocytosis (MBL) is a premalignant condition that is roughly 500-fold more common than CLL. It is unknown whether the two-fold increased risk of developing melanoma associated with CLL extends to individuals with MBL. METHODS: Using the Mayo Clinic Biobank, we identified participants who were 40 years or older with no previous hematological malignancies, who resided in the 27 counties around Mayo Clinic, and who had available biospecimens for screening. Eight-color flow cytometry was used to screen for MBL. Individuals with MBL were classified as low-count MBL (LC-MBL) or high-count MBL on the basis of clonal B-cell percent. Incident melanomas were identified using International Classification of Diseases codes and confirmed via medical records review. Cox regression models were used to estimate hazard ratios (HRs) and 95% CI. RESULTS: Of the 7,334 participants screened, 1,151 were identified with a CD5-positive MBL, of whom 1,098 had LC-MBL. After a median follow-up of 3.2 years (range, 0-13.5), 131 participants developed melanoma, of whom 36 individuals were positive for MBL. The estimated 5-year cumulative incidence of melanoma was 3.4% and 2.0% among those with and without MBL, respectively. After adjusting for age, sex, and history of previous melanoma, individuals with MBL exhibited a 1.86-fold (95% CI, 1.25 to 2.78) risk of melanoma. This elevated risk persisted when analysis was restricted to those without a history of melanoma (HR, 2.05 [95% CI, 1.30 to 3.23]). Individuals with LC-MBL had a 1.92-fold (95% CI, 1.29 to 2.87) increased risk of developing melanoma overall and a 2.74-fold increased risk (95% CI, 1.50 to 5.03) of melanoma in situ compared with those without MBL. CONCLUSION: LC-MBL is associated with an approximately two-fold increased risk of melanoma overall and a 2.74-fold increased risk of melanoma in situ.

Impact of Work on Personal Relationships and Physician Well-being.

OBJECTIVE: To assess the impact of work on personal relationships (IWPR) by specialty and demographic variables in a national sample of physicians, to assess the association between the IWPR and burnout, and to determine the effect of adjusting for IWPR on the risk of burnout associated with being a physician. METHODS: Analysis was conducted of data from a representative sample of US physicians surveyed between November 20, 2020, and March 23, 2021, and from a probability-based sample of other US workers. IWPR and burnout were measured with published assessments. RESULTS: Of the 7360 physicians who responded to the survey, 6271 (85.2%) completed the IWPR assessment. In multivariable analysis, moderate or higher IWPR was associated with female sex (odds ratio [OR], 1.26; 95% CI, 1.11 to 1.43), married vs single (OR, 0.59; 95% CI, 0.48 to 0.71), and emergency medicine (OR, 1.93; 95% CI, 1.43 to 2.60) or physical and rehabilitative medicine (OR, 1.67; 95% CI, 1.12 to 2.50) vs internal medicine subspecialty. Physicians were more likely than workers in other fields (OR, 2.65; 95% CI, 2.33 to 3.02) to endorse the statement "In the past year, my job contributed to me feeling more isolated or detached from the people who are important to me" as at least moderately true. After adjustment for responses to this statement, work hours, and demographic characteristics, being a physician was not associated with the risk of burnout. CONCLUSION: IWPR is associated with burnout. Adjustment for IWPR eliminated the observed difference in burnout between physicians and workers in other fields. Interventions that identify and mitigate work practices that have a negative impact on physicians' personal relationships and interventions that support affected individual physicians are warranted.

The Mayo Leadership Impact Index Adapted for Matrix Leadership Structures: Initial Validity Evidence.

Importance: Physician burnout has reached crisis levels. Supportive leadership is one of the strongest drivers of physician well-being, and monitoring supervisor support is key to developing well-being focused leadership skills. Existing measures of leader support were designed within "direct report" supervision structures limiting their applicability to matrixed leadership reporting structures where direct reports are not the predominant norm. Antecedently, no measure of leadership support is validated specifically for implementation in matrixed leadership structures. Objective: Adapt and validate the Mayo Leadership Impact Index (MLII) for settings with matrixed leadership structures. Design: A psychometric validation study utilizing classical test theory and item response theory. Setting: A tripartite hospital system in the southwestern US. Participants: Physician-respondents to a 2023 cross-sectional survey. Main Outcomes and Measures: After pilot testing, the adapted MLII was examined using a unidimensional graded response model and confirmatory factor analyses. Convergent validity was investigated via correlations with professional fulfillment, perceived autonomy support, self-valuation, and peer connectedness/respect. Divergent validity was tested via correlations with burnout. Results: Of the three candidate revisions of the MLII, the 9-item adaptation was selected for its superior validity/reliability indices. Standardized Cronbach's and Ordinal alpha coefficients were 0.958 and 0.973, respectively. CFA loadings exceeded 0.70 (p < 0.001), and coefficients of variation (R2) exceeded 0.60 for all items. GRM slope parameters indicated "high" to "very high" item discrimination. Items 2, 5, and 8 were the most informative. Positive correlations of the adapted MLII with professional fulfillment, perceived autonomy support, and peer connectedness/respect were observed, supporting convergent validity. Negative correlation with overall burnout supports divergent validity. Conclusions and Relevance: The findings provide evidence of the adapted MLII's validity, reliability, and appropriateness for implementation within matrixed leadership settings. Prior to this study, no leadership support measure had been validated for use among the growing number of healthcare systems with matrixed leadership reporting structures.

Question: : What is the validity and reliability of a well-being centered leadership measure adapted for use in healthcare systems with matrixed, multiform reporting structures? Findings: : Classical test theory and item response theory analyses of cross-sectional survey data from 158 physician-respondents supported the adapted measure's construct validity. All reliability coefficients were strong. Leadership ratings positively correlated with professional fulfillment, autonomy support, self-valuation, and peer connectedness/respect, and negatively correlated with burnout. Meaning: : Findings support the adapted measure's validity and reliability. This study is the first to demonstrate a valid empirical measure of well-being centered leadership behaviors in settings with multiform, matrixed leadership structures.

Characteristics and Habits of Psychiatrists and Neurologists With High Occupational Well-Being: A Mixed Methods Study.

Objective: To identify the characteristics that distinguish occupationally well outliers (OWO), a subset of academic psychiatrists and neurologists with consistently high professional fulfillment and low burnout, from their counterparts with lower levels of occupational well-being. Participants and Methods: Participants included faculty physicians practicing psychiatry and neurology in academic medical centers affiliated with the Professional Well-being Academic Consortium. In this prospective, longitudinal study, a mixed qualitative and quantitative approach was used. Quantitative measures were administered to physicians in a longitudinal occupational well-being survey sponsored by the academic organizations where they work. Four organizations participated in the qualitative study. Psychiatrists and neurologists at these organizations who competed survey measures at 2 consecutive time points between 2019 and 2021 were invited to participate in an interview. Results: Of 410 (213 psychiatrists and 197 neurologists) who completed professional fulfillment and burnout measures at 2 time points, 84 (20.5%) met OWO criteria. Occupationally well outliers psychiatrists and neurologists had more favorable scores on hypothesized determinants of well-being (values alignment, perceived gratitude, supportive leadership, peer support, and control of schedule). Ultimately, 31 psychiatrists (25% of 124 invited) and 33 neurologists (18.5% of 178 invited) agreed to participate in an interview. Qualitatively, OWO physicians differed from all others in 3 thematic domains: development of life grounded in priorities, ability to shape day-to-day work context, and professional relationships that provide joy and support. Conclusion: A multilevel approach is necessary to promote optimal occupational well-being, targeting individual-level factors, organizational-level factors, and broader system-level factors.

A qualitative study of strategies to improve occupational well-being in physical medicine and rehabilitation physicians.

BACKGROUND: Physiatry is a specialty with high rates of burnout. Although organizational strategies to combat burnout are key, it is also important to understand strategies that individual physiatrists can use to address burnout. OBJECTIVE: To identify changes that resulted in improvement of occupational well-being of physiatrists over a 6- to 9-month period. DESIGN: We employed two quantitative surveys spaced 6 to 9 months apart to identify physiatrists who experienced meaningful improvement in occupational burnout and/or professional fulfillment between the two survey timepoints. These physiatrists were subsequently recruited to participate in a qualitative study using semi-structured interviews to identify changes that respondents felt contributed to improvements in burnout and professional fulfillment. SETTING: Online surveys and interviews. PARTICIPANTS: Physiatrists in the American Academy of Physical Medicine and Rehabilitation (AAPM&R) Membership Masterfile. MAIN OUTCOME MEASURE: Burnout and professional fulfillment were assessed using the Stanford Professional Fulfillment Index. RESULTS: One hundred twelve physiatrists responded to the baseline and follow-up surveys. Of these, 35 were eligible for interviews based on improvements in the Stanford Professional Fulfillment Index, and 23 (64%) agreed to participate. Themes from the qualitative interviews highlighted the importance of personal lifestyle choices, approaches to improve professional satisfaction, and strategies to foster work-life harmony. Personal lifestyle strategies included investing in wellness and mental health. Efforts to improve professional satisfaction included decreasing work intensity, prioritizing meaningful aspects of work, and building relationships with colleagues. Fostering work-life harmony also included making trade-offs in both domains, setting boundaries at work, setting expectations at home, and overcoming personal challenges. CONCLUSION: Our findings illustrate that, in addition to organizational strategies demonstrated to be effective, there are actions that individual physiatrists can take to recover from burnout and foster professional fulfillment.

A Qualitative Study of Strategies to Improve Occupational Well-being in Physical Medicine and Rehabilitation Physicians.

BACKGROUND: Physiatry is a specialty with high rates of burnout. Although organizational strategies to combat burnout are key, it is also important to understand strategies that individual physiatrists can use to address burnout. OBJECTIVE: The aim of the study is to identify changes that resulted in improvement of occupational well-being of physiatrists over a 6- to 9-mo period. DESIGN: We employed two quantitative surveys spaced 6-9 mos apart to identify physiatrists who experienced meaningful improvement in occupational burnout and/or professional fulfillment between the two survey time points. These physiatrists were subsequently recruited to participate in a qualitative study using semistructured interviews to identify changes that respondents felt contributed to improvements in burnout and professional fulfillment. SETTING: Online surveys and interviews. PARTICIPANTS: Physiatrists in the American Academy of Physical Medicine and Rehabilitation (AAPM&R) Membership Masterfile. MAIN OUTCOME MEASURE: Burnout and professional fulfillment were assessed using the Stanford Professional Fulfillment Index. RESULTS: One hundred twelve physiatrists responded to the baseline and follow-up surveys. Of these, 35 were eligible for interviews based on improvements in the Stanford Professional Fulfillment Index, and 23 (64%) agreed to participate. Themes from the qualitative interviews highlighted the importance of personal lifestyle choices, approaches to improve professional satisfaction, and strategies to foster work-life harmony. Personal lifestyle strategies included investing in wellness and mental health. Efforts to improve professional satisfaction included decreasing work intensity, prioritizing meaningful aspects of work, and building relationships with colleagues. Fostering work-life harmony also included making trade-offs in both domains, setting boundaries at work, setting expectations at home, and overcoming personal challenges. CONCLUSIONS: Our findings illustrate that in addition to organizational strategies demonstrated to be effective, there are actions that individual physiatrists can take to recover from burnout and foster professional fulfillment.

Artificial Intelligence Electrocardiography to Predict Atrial Fibrillation in Patients With Chronic Lymphocytic Leukemia.

Background: The use of an artificial intelligence electrocardiography (AI-ECG) algorithm has demonstrated its reliability in predicting the risk of atrial fibrillation (AF) within the general population. Objectives: This study aimed to determine the effectiveness of the AI-ECG score in identifying patients with chronic lymphocytic leukemia (CLL) who are at high risk of developing AF. Methods: We estimated the probability of AF based on AI-ECG among patients with CLL extracted from the Mayo Clinic CLL database. Additionally, we computed the Mayo Clinic CLL AF risk score and determined its ability to predict AF. Results: Among 754 newly diagnosed patients with CLL, 71.4% were male (median age = 69 years). The median baseline AI-ECG score was 0.02 (range = 0-0.93), with a value ≥0.1 indicating high risk. Over a median follow-up of 5.8 years, the estimated 10-year cumulative risk of AF was 26.1%. Patients with an AI-ECG score of ≥0.1 had a significantly higher risk of AF (HR: 3.9; 95% CI: 2.6-5.7; P < 0.001). This heightened risk remained significant (HR: 2.5; 95% CI: 1.6-3.9; P < 0.001) even after adjusting for the Mayo CLL AF risk score, heart failure, chronic kidney disease, and CLL therapy. In a second cohort of CLL patients treated with a Bruton tyrosine kinase inhibitor (n = 220), a pretreatment AI-ECG score ≥0.1 showed a nonsignificant increase in the risk of AF (HR: 1.7; 95% CI: 0.8-3.6; P = 0.19). Conclusions: An AI-ECG algorithm, in conjunction with the Mayo CLL AF risk score, can predict the risk of AF in patients with newly diagnosed CLL. Additional studies are needed to determine the role of AI-ECG in predicting AF risk in CLL patients treated with a Bruton tyrosine kinase inhibitor.

Impact of Targeted Agents on Survival of Chronic Lymphocytic Leukemia Patients Fit for Fludarabine, Cyclophosphamide, and Rituximab (FCR) Relative to Age- and Sex-Matched Population.

To assess the impact of first-line treatment with targeted agents (TAs) or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT) on overall survival (OS) compared to age- and sex-matched individuals in the general population, we conducted an aggregated analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and CLL13 trials. The restricted mean survival time (RMST), an alternative measure in outcome analyses capturing OS changes over the entire history of the disease, was used to minimize biases associated with the short follow-up time of trials. Patients treated with TAs demonstrated a higher 5-year RMST (58.1 months; 95% CI: 57.4 to 58.8) compared to those treated with CIT (5-year RMST, 56.9 months; 95% CI: 56.7-58.2). Furthermore, the OS comparison of treatment groups with the AGMGP suggests that TAs may mitigate the impact of CLL on OS during the first five years post-treatment initiation. In summary, the 5-year RMST difference was -0.4 months (95% CI: -0.8 to 0.2; p = 0.10) when comparing CLL patients treated with TAs to the Italian age- and gender-matched general population (AGMGP). A similar trend was observed when CLL patients treated with TAs were compared to the US AGMGP (5-year RMST difference, 0.3 months; 95% CI: -0.1 to 0.9; p = 0.12). In contrast, CLL patients treated with FCR exhibited sustained OS differences when compared to both the Italian cohort (5-year RMST difference: -1.6 months; 95% CI: -2.4 to -0.9; p < 0.0001) and the US AGMGP cohort (5-year RMST difference: -0.9 months; 95% CI: -1.7 to -0.2; p = 0.015). Although these results support TAs as the preferred first-line treatment for younger CLL patients, it is crucial to acknowledge that variations in patient selection criteria and clinical profiles across clinical trials necessitate a cautious interpretation of these findings that should be viewed as directional and hypothesis-generating. A longer follow-up is needed to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP.

Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis.

ABSTRACT: High-count monoclonal B-cell lymphocytosis (HCMBL) is a precursor condition to chronic lymphocytic leukemia (CLL). We have shown that among individuals with HCMBL, the CLL-International Prognostic Index (CLL-IPI) is prognostic for time-to-first therapy (TTFT). Little is known about the prognostic impact of somatically mutated genes among individuals with HCMBL. We sequenced DNA from 371 individuals with HCMBL using a targeted sequencing panel of 59 recurrently mutated genes in CLL to identify high-impact mutations. We compared the sequencing results with that of our treatment-naïve CLL cohort (N = 855) and used Cox regression to estimate hazard ratios and 95% confidence intervals (CIs) for associations with TTFT. The frequencies of any mutated genes were lower in HCMBL (52%) than CLL (70%). At 10 years, 37% of individuals with HCMBL with any mutated gene had progressed requiring treatment compared with 10% among individuals with HCMBL with no mutations; this led to 5.4-fold shorter TTFT (95% CI, 2.6-11.0) among HCMBL with any mutated gene vs none, independent of CLL-IPI. When considering individuals with low risk of progression according to CLL-IPI, those with HCMBL with any mutations had 4.3-fold shorter TTFT (95% CI, 1.6-11.8) vs those with none. Finally, when considering both CLL-IPI and any mutated gene status, we observed individuals with HCMBL who were high risk for both prognostic factors had worse prognosis than patients with low-risk CLL (ie, 5-year progression rate of 32% vs 21%, respectively). Among HCMBL, the frequency of somatically mutated genes at diagnosis is lower than that of CLL. Accounting for both the number of mutated genes and CLL-IPI can identify individuals with HCMBL with more aggressive clinical course.

Prediction of outcomes for high-count monoclonal B lymphocytosis using an epigenetic and immunogenetic signature.

ABSTRACT: Monoclonal B-cell lymphocytosis (MBL) progresses to chronic lymphocytic leukemia (CLL) requiring therapy at 1% to 5% per year. Improved prediction of progression would greatly benefit individuals with MBL. Patients with CLL separate into 3 distinct epigenetic subtypes (epitypes) with high prognostic significance, and recently the intermediate epitype has been shown to be enriched for high-risk immunoglobulin lambda variable (IGLV) 3-21 rearrangements, impacting outcomes for these patients. Here, we employed this combined strategy to generate the epigenetic and light chain immunoglobulin (ELCLV3-21) signature to classify 219 individuals with MBL. The ELCLV3-21 high-risk signature distinguished MBL individuals with a high probability of progression (39.9% and 71.1% at 5 and 10 years, respectively). ELCLV3-21 improved the accuracy of predicting time to therapy for individuals with MBL compared with other established prognostic indicators, including the CLL international prognostic index (c-statistic, 0.767 vs 0.668, respectively). Comparing ELCLV3-21 risk groups in MBL vs a cohort of 226 patients with CLL revealed ELCLV3-21 high-risk individuals with MBL had significantly shorter time to therapy (P = .003) and reduced overall survival (P = .03) compared with ELCLV3-21 low-risk individuals with CLL. These results highlight the power of the ELCLV3-21 approach to identify individuals with a higher likelihood of adverse clinical outcome and may provide a more accurate approach to classify individuals with small B-cell clones.

Vacation Days Taken, Work During Vacation, and Burnout Among US Physicians.

Importance: Vacation has been shown to be an important restorative activity in the general population; less is known about physicians' vacation behaviors and their association with burnout and professional fulfillment. Objective: To examine the number of vacation days taken per year and the magnitude of physician work while on vacation and their association with physician burnout and professional fulfillment, by individual and organizational characteristics. Design, Setting, and Participants: This cross-sectional survey of US physicians was conducted between November 20, 2020, and March 23, 2021. Data analysis was performed from March to July 2023. Main Outcomes and Measures: Burnout was measured using the Maslach Burnout Index, and professional fulfillment was measured using the Stanford Professional Fulfillment Index. Number of vacation days taken in the last year, time spent working on patient care and other professional tasks per typical vacation day (ie, work on vacation), electronic health record (EHR) inbox coverage while on vacation, barriers to taking vacation, and standard demographics were collected. Results: Among 3024 respondents, 1790 of 3004 (59.6%), took 15 or fewer days of vacation in the last year, with 597 of 3004 (19.9%) taking 5 or fewer days. The majority, 2104 respondents (70.4%), performed patient care-related tasks on vacation, with 988 of 2988 (33.1%) working 30 minutes or more on a typical vacation day. Less than one-half of physicians (1468 of 2991 physicians [49.1%]) reported having full EHR inbox coverage while on vacation. On multivariable analysis adjusting for personal and professional factors, concern about finding someone to cover clinical responsibilities (odds ratio [OR], 0.48 [95% CI, 0.35-0.65] for quite a bit; OR, 0.30 [95% CI, 0.21-0.43] for very much) and financial concerns (OR, 0.49 [95% CI, 0.36-0.66] for quite a bit; OR, 0.38 [95% CI, 0.27-0.54] for very much) were associated with decreased likelihood of taking more than 3 weeks of vacation per year. Taking more than 3 weeks of vacation per year (OR, 0.66 [95% CI, 0.45-0.98] for 16-20 days; OR, 0.59 [95% CI, 0.40-0.86] for >20 days vs none) and having full EHR inbox coverage while on vacation (OR, 0.74; 95% CI, 0.63-0.88) were associated with lower rates of burnout on multivariable analysis, whereas spending 30 minutes or longer per vacation day on patient-related work (OR, 1.58; 95% CI, 1.22-2.04 for 30-60 minutes; OR, 1.97; 95% CI, 1.41-2.77 for 60-90 minutes; OR, 1.92; 95% CI, 1.36-2.73 for >90 minutes) was associated with higher rates of burnout. Conclusions and Relevance: In this cross-sectional study of 3024 physicians, the number of vacation days taken and performing patient-related work while on vacation were associated with physician burnout. System-level efforts to ensure physicians take adequate vacation and have coverage for clinical responsibilities, including EHR inbox, may reduce physician burnout.

Importance of Low- and Moderate-Grade Adverse Events in Patients' Treatment Experience and Treatment Discontinuation: An Analysis of the E1912 Trial.

PURPOSE: Despite defined grades of 1 to 5 for adverse events (AEs) on the basis of Common Terminology Criteria for Adverse Events criteria, mild (G1) and moderate (G2) AEs are often not reported in phase III trials. This under-reporting may inhibit our ability to understand patient toxicity burden. We analyze the relationship between the grades of AEs experienced with patient side-effect bother and treatment discontinuation. METHODS: We analyzed a phase III Eastern Cooperative Oncology Group-American College of Radiology Imaging Network trial with comprehensive AE data. The Likert response Functional Assessment of Cancer Therapy-GP5 item, "I am bothered by side effects of treatment" was used to define side-effect bother. Bayesian mixed models were used to assess the impact of G1 and G2 AE counts on patient side-effect bother and treatment discontinuation. AEs were further analyzed on the basis of symptomatology (symptomatic or asymptomatic). The results are given as odds ratios (ORs) and 95% credible interval (CrI). RESULTS: Each additional G1 and G2 AEs experienced during a treatment cycle increased the odds of increased self-reported patient side-effect bother by 13% (95% CrI, 1.06 to 1.21) and 35% (95% CrI, 1.19 to 1.54), respectively. Furthermore, only AEs defined as symptomatic were associated with increased side-effect bother, with asymptomatic AEs showing no association regardless of grade. Count of G2 AEs increased the odds of treatment discontinuation by 59% (95% CrI, 1.32 to 1.95), with symptomatic G2 AEs showing a stronger association (OR, 1.75; 95% CrI, 1.28 to 2.39) relative to asymptomatic G2 AEs (OR, 1.45; 95% CrI, 1.12 to 1.89). CONCLUSION: Low- and moderate-grade AEs are related to increased odds of increased patient side-effect bother and treatment discontinuation, with symptomatic AEs demonstrating greater magnitude of association than asymptomatic. Our findings suggest that limiting AE capture to grade 3+ misses important contributors to treatment side-effect bother and discontinuation.

Ibrutinib-based therapy reinvigorates CD8+ T cells compared to chemoimmunotherapy: immune monitoring from the E1912 trial.

ABSTRACT: Bruton tyrosine kinase inhibitors (BTKis) that target B-cell receptor signaling have led to a paradigm shift in chronic lymphocytic leukemia (CLL) treatment. BTKis have been shown to reduce abnormally high CLL-associated T-cell counts and the expression of immune checkpoint receptors concomitantly with tumor reduction. However, the impact of BTKi therapy on T-cell function has not been fully characterized. Here, we performed longitudinal immunophenotypic and functional analysis of pretreatment and on-treatment (6 and 12 months) peripheral blood samples from patients in the phase 3 E1912 trial comparing ibrutinib-rituximab with fludarabine, cyclophosphamide, and rituximab (FCR). Intriguingly, we report that despite reduced overall T-cell counts; higher numbers of T cells, including effector CD8+ subsets at baseline and at the 6-month time point, associated with no infections; and favorable progression-free survival in the ibrutinib-rituximab arm. Assays demonstrated enhanced anti-CLL T-cell killing function during ibrutinib-rituximab treatment, including a switch from predominantly CD4+ T-cell:CLL immune synapses at baseline to increased CD8+ lytic synapses on-therapy. Conversely, in the FCR arm, higher T-cell numbers correlated with adverse clinical responses and showed no functional improvement. We further demonstrate the potential of exploiting rejuvenated T-cell cytotoxicity during ibrutinib-rituximab treatment, using the bispecific antibody glofitamab, supporting combination immunotherapy approaches.