Shanafelt, Tait D

This survey study examines whether disparities in risk of burnout and low satisfaction with work-life integration by sex are similar among physicians compared with US workers in other fields.

Background: Monoclonal B-cell lymphocytosis (MBL) is a common premalignant condition that can be classified into chronic lymphocytic leukemia (CLL)-type (CD5, CD23, and CD20 co-expression), and non-CLL-type (CD5-negative) based on flow cytometry immunophenotypes. CLL-type MBL is relatively well characterized with increased risk of hematologic (especially lymphoid) malignancies, serious infections, and decreased response to vaccinations. However, the prevalence, genetic predispositions, and clinical consequences of non-CLL-type MBL remain to be fully elucidated. Herein, we report findings in non-CLL-type MBL in a large screening cohort. Methods: We screened 10,330 individuals (40 years or older with no prior history of hematologic cancers) for MBL with highly sensitive flow cytometry, in the Mayo Clinic Biobank, with patients recruited from primary care-based clinics. Individuals were genotyped by Regeneron Genetics. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Among those individuals residing in the 27 counties surrounding Rochester, Minnesota, we identified incident hematologic malignancies and melanomas using ICD codes and the Rochester Epidemiology Project, a population based medical records linkage system. All diagnoses were manually reviewed for confirmation. Cox regression was used to calculate hazard ratios (HR) and 95% CIs, adjusted for age and sex. Results: We identified 1,736 individuals with MBL and 8,341 individuals without MBL. Among those with MBL, 246 (14.2%) had non-CLL-type MBL as the major clone. The median age of non-CLL-type MBL was 77 years (range, 47-95). The prevalence of non-CLL-type MBL significantly increased with age, with 0.5% prevalence among those between 40 to 59 years of age, 2.3% prevalence among those between 60 and 79 years, and 7.8% prevalence in those 80 years of age or older. The prevalence of non-CLL-type MBL was significantly higher (P < .001) among males (3.1%) than females (2.0%). Using the genome-wide complex trait analysis tool, the heritability of non-CLL-type MBL was estimated to be ~26%, suggesting inherited genetics plays a role in etiology. To identify common inherited variants, we first evaluated the known CLL susceptibility variants, many of which also associated with CLL-type MBL. Among the 42 variants, none were statistically associated (all P > .05) with non-CLL-type MBL. We next conducted a genome-wide association study to identify novel variants, and the most significant variant resided in 10q26.3 (minor allele frequency [MAF]control = 0.7%, MAFMBL = 3.5%, OR = 6.4, 95% CI 3.6-11.3, P = 5.7 * 10-8). Among the 6,478 individuals (192 with non-CLL-type MBL and 6,286 without MBL) followed for incident hematologic malignancies, 36 developed lymphoid and 23 developed myeloid malignancies after a median of 4.2 years of follow up. Similar to CLL-type MBL, non-CLL-type MBL was associated with a 5.2-fold risk for lymphoid malignancies (95% CI 2.0-13.0, P < .001). Elevated but not significant risks were observed for myeloid malignancies (HR = 2.3, 95% CI 0.5-10.3, P = 0.27). The lymphoid malignancies developed by individuals with non-CLL-type MBL included diffuse large B-cell lymphoma, multiple myeloma, marginal zone lymphoma, and other low-grade lymphomas. We recently reported that individuals with CLL-type MBL are at higher risk for developing melanoma (HR = 1.9, 95% CI 1.3-2.8). Interestingly, non-CLL-type MBL had no evidence of an association with melanoma risk (HR = 0.4, 95% CI 0.1-1.8). We did not observe a significant difference in overall survival between individuals with non-CLL-type MBL vs those without MBL. Conclusions: In the largest screening cohort to date, we evaluated the etiology and clinical outcomes of non-CLL-type MBL, an understudied yet common condition that occurs in ~4 million adults in the United States. Non-CLL-type MBL is more common in men and older individuals, and evidence supports that inherited genetics plays an etiological role with 10q26.3 locus identified as a novel susceptibility locus. Individuals with non-CLL-type MBL had significantly increased risk of lymphoid malignancies, similar to CLL-type MBL, but, distinct from CLL-type MBL, no evidence of an increased risk of melanoma. Our study provides insights into the prevalence, genetic predispositions and clinical consequences of non-CLL-type MBL and how it differs from the classic CLL-type MBL.

Introduction: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), changed the treatment landscape by demonstrating improved overall survival (OS) compared with chemotherapy/chemoimmunotherapy across multiple phase 3 trials in patients (pts) with CLL, including those with high-risk genomic features. Recently, data were reported for pts treated with ibrutinib in the phase 3 RESONATE-2 trial with up to 10 years of follow-up, representing the longest follow-up of any BTKi used in first-line treatment of CLL. With the most robust long-term follow-up data among BTKis, ibrutinib therapy trials are uniquely positioned to assess the long-term OS benefit of first-line BTKi treatment in pts with CLL across pt subgroups. We previously demonstrated that first-line ibrutinib is associated with OS rates that are similar to those in the age-matched general population, with a median follow-up of 5.9 years since initial diagnosis (Ghia P et al. HemaSphere 2024), but it remains unclear whether this holds true for pts with high-risk genomic features. This updated analysis evaluated long-term OS outcomes with a median follow-up of 8 years since randomization and 10 years since initial diagnosis in a pooled population of pts with previously untreated CLL, including those with high-risk features, who received first-line ibrutinib treatment in 2 phase 3 trials with comparison of survival estimates to the US age-matched general population. Methods: Data were pooled for pts who received first-line treatment with single-agent ibrutinib or ibrutinib + rituximab in the RESONATE-2 (NCT01722487) and ECOG-ACRIN E1912 (NCT02048813) trials, respectively. OS probabilities from the time of randomization and from the time of initial diagnosis for ibrutinib-treated pts were compared with an age-matched general population using 2021 life tables for the total US population published by the Centers for Disease Control and Prevention using the Kaplan-Meier method. Subgroup analyses were performed for high-risk pts, defined as those with del(11q), del(17p), mutated TP53, and/or unmutated IGHV (uIGHV). Results: A total of490 pts were pooled across the 2 studies: 352 pts (71.8%) were treated with ibrutinib + rituximab, and 135 pts (27.6%) were treated with single-agent ibrutinib; 3 pts did not receive study treatment. The median age at time of randomization was 61 years; 36.5% (179/490) were aged ≥65 years, 21.8% had del(11q), 7.8% had del(17p) and/or mutated TP53, and 54.7% had uIGHV. The median time from initial CLL diagnosis to randomization was 20.9 months (range, 0.0-341.8); the median follow-up was 123.5 months (10.3 years) from initial diagnosis and 99.2 months (8.3 years) from the time of randomization. From the time of randomization, estimated 9-year OS rates were 81.2% (95% CI, 76.8-84.9) in all ibrutinib-treated pts versus 82.0% (95% CI, 78.3-85.2) in the age-matched population (hazard ratio [HR] 1.17; 95% CI, 0.86-1.58). In high-risk pts, estimated 9-year OS rates were 79.5% (95% CI, 73.5-84.3) for ibrutinib-treated pts versus 83.2% (95% CI, 78.5-86.9) in the age-matched general population (HR 1.24; 95% CI, 0.84-1.84). In pts aged ≥65 years, estimated 9-year OS rates were 68.7% (95% CI, 60.5-75.6) for ibrutinib-treated pts and 68.7% (95% CI, 61.4-75.0) in the age-matched general population (HR 1.12; 95% CI, 0.77-1.63). In pts aged <65 years, estimated 9-year OS rates were 89.3% (95% CI, 84.6-92.7) for ibrutinib-treated pts and 90.0% (95% CI, 86.1-92.9) in the age-matched general population (HR 1.15; 95% CI, 0.68-1.94). From the time of initial diagnosis, estimated 15-year OS rates were 78.4% (95% CI, 72.8-83.0) in all ibrutinib-treated pts versus 72.0% (95% CI, 67.8-75.7) in the age-matched general population (HR 0.83; 95% CI, 0.62-1.11). Study treatment had been discontinued in 59.8% (293/490) of pooled ibrutinib-treated pts; the most frequent reasons for discontinuation were adverse events (43.0%; 126/293) and progressive disease (20.5%; 60/293). Study treatment was ongoing in 31.8% of pooled pts (156/490). Conclusions: With the longest follow-up time for any commercially available targeted therapy, this pooled analysis demonstrates that, regardless of evaluation from randomization or initial diagnosis, and irrespective of age or high-risk features, first-line treatment with ibrutinib provides long-term OS benefit with survival estimates that appear similar to those of a US age-matched cohort.

Chronic lymphocytic leukemia (CLL), one of the most common types of leukemia among adults in the US, is characterized by the accumulation of CD5+CD19+ monoclonal B cells. Current clinical treatment approaches for progressive CLL patients focus on novel agents targeting Bruton Tyrosine Kinase (BTK) and Bcl-2. Although clinical trials combining novel agent have shown significant efficacy with high overall response and, in some cases, achievement of high rates of undetectable measurable residual disease (MRD), CLL remains incurable with a majority of patients eventually experiencing relapse of their disease. Therefore, it remains of high interest to expand therapeutic options. Transcriptional chemical inducers of proximity (TCIPs) are small molecules designed and developed by Dr. Gerald R. Crabtree at Stanford University. TCIPs are a new class of anticancer drugs that recruit endogenous cancer drivers or a downstream transcription factor to the promoters of cell death genes and activate their expression, resulting in apoptosis of cancer cells. Current TCIPs are produced by covalently linking small molecules that bind B-cell lymphoma 6 (BCL6) to those that bind to transcriptional activators, such as Bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinases 9 (CDK9). The Stanford team has demonstrated TCIPs generate remarkable killing in diffuse large B cell lymphoma (DLBCL) cell lines, including chemotherapy-resistant, TP53-mutant lines, with a half maximal effective concentration (EC50) of 1-10nM at 72hours (h) and exhibited cell-specific and tissue-specific effects (Gourisankar et al, 2023). We have initiated TCIPs cytotoxicity assessment in primary leukemic cells from untreated CLL patients. Testing two types of TCIPs with a flow cytometry-based apoptosis assay, we found time and dose-dependent drug-associated killing in primary CLL B cells collected from untreated CLL patients over a 24-72h interval. The IC50 for BRD4-BCL6 TCIP JWZ-7-133 at 72h was 560nM while CDK9-BCL6 TCIP BAK-04-232 at 72h was 10nM. After 24, 48, and 72h exposure of CLL B cells to TCIP JWZ-7-133, the IC50 was 1050, 820 and 560nM, respectively. We also found that TCIP JWZ-7-133 exhibited a similar ability to inhibit leukemic cell viability with an IC50 of 1070nM using a cell viability assay, compared to a flow cytometry-based cell death assay (24h IC50 1050nM). CDK9-BCL6 TCIPs are designed and produced by covalently linking BI-3812 (binding to BCL6) and SNS-032 (binding to CDK9) with a rigid linker. BI-3812 is a potent and efficacious BCL6 inhibitor, inhibiting the BTB domain of BCL6, and SNS-032 is a potent and selective inhibitor of CDK9. When CLL B cells were treated with only BI-3812 or SNS-032 or TCIP BAK-04-232 as single agents for 72h, we found that TCIP BAK-04-232 had superior and significant killing effects compared to the single agents, with an IC50 of 10nM. Specifically this killing activity was more than 10-fold compared to SNS-032 alone (IC50 over 100nM), and more than 1,000-fold compared to BI-3812 alone (IC50 over 10,000nM). There remains an urgent to identify new categories of potent drug, inhibitor, or small molecules to expand potential clinical treatment options for patients with CLL. The results presented here indicate that TCIPs targeting BCL6 and BRD4/CDK9 have a strong capacity to induce high levels of cell death in CLL B cells at nanomolar concentrations, and this remarkable killing effect may be due to its unique gain-of-function drug mechanism. TCIPs provide a completely new drug direction and strategy for the design of anticancer drugs: to rewire cancer drivers to activate apoptosis in cancer cells. This study is the first of a kind demonstration of TCIPs in robustly targeting CLL B cells. Further studies to fully validate the preclinical activity of TCIPs and investigate the molecular mechanism(s) for TCIP mediated killing of leukemic B cells will help to define the role of TCIPs as a novel therapeutic approach in CLL.

Background: Chronic lymphocytic leukemia (CLL) is one of the most common leukemias in the United States (US), with an estimated incidence of 20,700 cases in 2024. Population-based studies conducted in Olmsted County (OC), Minnesota, reported an increase in CLL incidence over a 55-year period (1935 through 1989), which was attributed to increased detection of early-stage cases in individuals over age 50. In an updated study from 2000 to 2010 in OC, we reported no further increase in the incidence of CLL using the 2008 International Workshop on CLL (IWCLL 2008) guidelines. Additionally, when we compared the 1996 National Cancer Institute Working Group (NCI-WG 96) criteria with the IWCLL 2008 guidelines incorporating the monoclonal B-cell lymphocytosis designation, we found that the use of the IWCLL 2008 guidelines reduced the overt CLL incidence, modified the distribution of Rai Stages at diagnosis, and shortened the median time to first treatment (TTFT). Over the last two decades, 5-year survival for CLL has increased due to new therapies and improved supportive care. Herein we provide updated data on the incidence, prevalence, and natural progression of CLL in OC and studied similar features in an expanded 6-county region around Mayo Clinic, Rochester. Methods: We utilized the Rochester Epidemiology Project (REP), a population-based medical records linkage system, to identify CLL cases from 2000 to 2020 using International Classification of Diseases codes. We included individuals residing in OC and the expanded 7-county region (REP-7, including OC), for which data became available starting in 2010. CLL cases were included if they met the IWCLL 2008 criteria. All CLL diagnoses were confirmed by manual review of medical records and data on CLL-related factors were collected, including treatment status, prior history of other cancers, and overall survival (OS). Age- and sex-specific incidence rates were derived from REP census data and adjusted to the 2020 US white population. OS analyses were conducted using the Kaplan-Meier method. TTFT was calculated with death as a competing risk. Cox regression was used to evaluate the effect of decade on TTFT and OS among patients in OC. Results: From 2010-2020, 242 patients were diagnosed with CLL in REP-7, and between 2000-2020, 174 patients were diagnosed in OC. Among the 242 CLL patients in REP-7, the median age at diagnosis was 71 years (range 30-96),158 (65%) were male, 236 (99%) were white, and 74 (31%) had a history of other cancer, with non-melanoma skin cancer being the most common. After age and sex adjustment to the 2020 US white population, the CLL incidence in REP-7 and OC from 2010 to 2020 was 7.8 and 8.1 per 100,000 individuals, respectively. In OC, the age- and sex-adjusted CLL incidence from 2000 to 2020 was 7.5 per 100,000 individuals, showing no significant trend changes over time. Among the 242 patients diagnosed with CLL in REP-7 between 2010 and 2020, 102 received treatment with a median TTFT of 9.8 years. In OC from 2000 to 2020, 79 out of 174 patients received treatment with a median TTFT of 9.4 years. When comparing across two decades in OC, the median TTFT was 12.8 years for the period from 2000 to 2009, decreasing to 5.9 years between 2010 and 2020, but was not significantly different after accounting for age and sex. The median OS for patients diagnosed with CLL in REP-7 from 2010 to 2020 was 11 years. The median OS for patients in OC between 2000 to 2020 was 12.6 years. When comparing across decades in OC, the median OS was 8.9 years for the period from 2000 to 2009, increasing to 13.6 years for those diagnosed between 2010 and 2020, but this trend was not significantly different after accounting for age and sex. Prevalence data for REP-7 and OC were analyzed as of 01/01/2020. Additionally, prevalence data for OC were available for 01/01/2010. In REP-7, the prevalence of CLL was 97 per 100,000 individuals on 01/01/2020. In OC, the CLL prevalence was 86 per 100,000 individuals on 01/01/2010, and 100 per 100,000 individuals on 01/01/2020. Conclusions: We observed no substantial increase in the incidence rates of CLL in REP-7 from 2010 to 2020, nor in the 20 years of available data from OC. However, the prevalence of CLL in OC increased by 16% from 2010 to 2020. Additionally, evidence indicated a longer OS among newly diagnosed CLL cases in OC compared to previous decades, suggesting a potential impact of improved therapeutic approaches on OS.

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.

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.