Shanafelt, Tait D.

Key Points PRS, based on the known CLL loci, predicts CLL risk with high discrimination. This PRS predicts risk of monoclonal B-cell lymphocytosis, a precursor to CLL and a condition that has clinical impact beyond risk for CLL.

Abstract Physician burnout, a work‐related syndrome involving emotional exhaustion, depersonalization and a sense of reduced personal accomplishment, is prevalent internationally. Rates of burnout symptoms that have been associated with adverse effects on patients, the healthcare workforce, costs and physician health exceed 50% in studies of both physicians‐in‐training and practicing physicians. This problem represents a public health crisis with negative impacts on individual physicians, patients and healthcare organizations and systems. Drivers of this epidemic are largely rooted within healthcare organizations and systems and include excessive workloads, inefficient work processes, clerical burdens, work–home conflicts, lack of input or control for physicians with respect to issues affecting their work lives, organizational support structures and leadership culture. Individual physician‐level factors also play a role, with higher rates of burnout commonly reported in female and younger physicians. Effective solutions align with these drivers. For example, organizational efforts such as locally developed practice modifications and increased support for clinical work have demonstrated benefits in reducing burnout. Individually focused solutions such as mindfulness‐based stress reduction and small‐group programmes to promote community, connectedness and meaning have also been shown to be effective. Regardless of the specific approach taken, the problem of physician burnout is best addressed when viewed as a shared responsibility of both healthcare systems and individual physicians. Although our understanding of physician burnout has advanced considerably in recent years, many gaps in our knowledge remain. Longitudinal studies of burnout's effects and the impact of interventions on both burnout and its effects are needed, as are studies of effective solutions implemented in combination. For medicine to fulfil its mission for patients and for public health, all stakeholders in healthcare delivery must work together to develop and implement effective remedies for physician burnout.

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.

AbstractThe prevalence of liver dysfunction and its association with outcomes in patients with previously untreated chronic lymphocytic leukemia (CLL) is unknown. Newly diagnosed (<12 months) previously untreated CLL patients seen at Mayo Clinic, Rochester, MN between 9/1993 and 4/2016 who had baseline assessment of at least one liver function test (LFT) were included in this analysis. The prevalence of liver dysfunction at baseline, proportion of patients who acquired LFT abnormalities, time to first therapy (TTFT) and overall survival (OS) were assessed. An abnormal LFT was present in 82/2336 (3.5%) patients at diagnosis and was associated with advanced Rai stage (Rai III–IV) (21% vs. 6%; P < .001), lower hemoglobin (13.1 g/dL vs. 13.9 g/dL; P < .001), and lower platelet count (187 × 109/L vs. 200 × 109/L; P = .03). Additionally, 236 patients with normal LFTs at diagnosis developed acquired liver dysfunction during follow‐up. Patients with abnormal LFTs at diagnosis had a shorter OS compared to those with normal LFTs (HR 1.80 95% CI 1.13‐2.87; P = .014, adjusted for age, sex, Rai stage, and treatment), although TTFT was not different. Of 52 patients who underwent a liver biopsy, CLL was present in liver tissue in 39/52 (73%) patients, with the portal tracts the most common region involved. Histopathology findings of liver involvement by CLL had limited correlation with choice of CLL therapy. In conclusion, approximately 1 of 25 newly diagnosed CLL patients has abnormal LFTs at diagnosis. Although the TTFT was not different among patients with abnormal LFTs, these patients have a shorter OS compared to those with normal LFTs.

AbstractBackgroundSecond hematologic cancers in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) are well documented and include Hodgkin lymphoma, therapy‐related acute myeloid leukemia/myelodysplastic syndromes, and transformation to diffuse large B‐cell lymphoma. Although cutaneous T‐cell lymphoma (CTCL) has been reported in patients with CLL, the incidence and comparison to expected rates are unknown. We evaluated the incidence of CTCL among patients with CLL or other non‐Hodgkin lymphoma (NHL) subtypes using data from the Surveillance, Epidemiology, and End Results (SEER) Program.MethodsWe searched the SEER 13 registries for patients with a diagnosis of CLL and NHL between 1992 and 2008. Among patients identified, we evaluated the incidence of CTCL.ResultsAmong 31,286 patients with CLL, the incidence of CTCL was not significantly higher in men than women: 104.2 (95% CI, 50.0–191.8) and 28.1 (95% CI, 3.4–101.3) per 1,000,000 person‐years, respectively (P = 0.06). Among 97,691 patients with NHL, the incidence of CTCL was similar in men and women (97.9 [95% CI, 62.0–146.9] and 92.0 [95% CI, 56.2–142.1] per 1,000,000 person‐years, respectively; P = 0.84). The incidence of CTCL among males with CLL (standardized incidence ratio [SIR], 3.0 [95% CI, 1.4–5.5]), males with NHL (SIR, 3.7 [95% CI, 2.3–5.5]), and females with NHL (SIR, 5.9 [95% CI, 3.6–9.1]) was significantly higher than expected in the general population (all P < 0.001).ConclusionThe risk of CTCL is greater in men with CLL than in the general population. In patients with NHL, both men and women are at greater risk for CTCL than in the general population.