Covalent Bruton's Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia.

Inhibitors of Bruton's tyrosine kinase (BTK) are among the most widely used therapies for chronic lymphocytic leukemia (CLL) and established a new expectation for efficacy and safety in the treatment of this disease. Currently there are 3 covalent inhibitors of BTK approved for the treatment of CLL: ibrutinib, acalabrutinib, and zanubrutinib. The first-in-class covalent BTK inhibitor is ibrutinib, which as monotherapy has excellent efficacy in the front-line setting with a 7-year progression free survival (PFS) of 59%. Ibrutinib-based therapies have also demonstrated superiority over standard chemoimmunotherapy in the front-line and the relapsed/refractory setting. Acalabrutinib is a second-generation BTK inhibitor that has higher selectivity to BTK. Acalabrutinib has efficacy in both frontline and relapsed CLL and is associated with a decreased incidence of atrial fibrillation and hypertension when compared to ibrutinib. Like acalabrutinib, zanubrutinib was designed to be more selective for BTK than ibrutinib and to maximize BTK inhibition in tissues. Zanubrutinib has demonstrated clinical efficacy in first line and relapsed/refractory setting. These agents are indicated as monotherapy, with dosing until disease progression or intolerable toxicity, and are mainly differentiated by safety profile, although efficacy differences may exist as well. Combination with CD20 monoclonal antibodies and/or BCL2 inhibitors are alternative options for use. Here we will review efficacy and safety considerations with these agents.

A randomized controlled pilot trial of anakinra and pioglitazone for protein metabolism in patients on maintenance haemodialysis.

BACKGROUND: Chronic inflammation and insulin resistance are highly prevalent in patients on maintenance haemodialysis (MHD) and are strongly associated with protein energy wasting. We conducted a pilot, randomized, placebo-controlled trial of recombinant human interleukin-1 receptor antagonist (IL-1ra) and pioglitazone to explore the safety, feasibility and efficacy for insulin-mediated protein metabolism in patients undergoing MHD. METHODS: Twenty-four patients were randomized to receive IL-1ra, pioglitazone or placebo for 12 weeks. Changes in serum inflammatory markers and insulin-mediated protein synthesis, breakdown and net balance in the whole-body and skeletal muscle compartments were assessed using hyperinsulinaemic-hyperaminoacidemic clamp technique at baseline and Week 12. RESULTS: Among 24 patients, median (interquartile range) age was 51 (40, 61), 79% were African American and 21% had diabetes mellitus. All patients initiated on intervention completed the study, and no serious adverse events were observed. There was a statistically significant decrease in serum high-sensitivity C-reactive protein in the pioglitazone group compared with placebo, but not in the IL-1ra group. No significant differences in the changes of whole-body or skeletal muscle protein synthesis, breakdown and net balance were found between the groups. CONCLUSIONS: In this pilot study, there were no statistically significant effects of 12 weeks of IL-1ra or pioglitazone on protein metabolism in patients on MHD. CLINICALTRIALS: gov registration: NCT02278562.

Treatment of Acute Myeloid Leukemia in Older Adults.

Acute Myeloid Leukemia (AML) is an aggressive myeloid malignancy predominantly affecting older adults. Despite the advancements in new therapies for AML, older and medically unfit patients continue to suffer from poor outcomes due to disease-related factors such as the mutational profile and patient-related factors such as comorbidities and performance status. In this review, we discuss a spectrum of therapeutic options for older patients with AML starting with a historical perspective and ending with therapies being investigated in clinical trials. We review the standard of care treatment options including combination venetoclax and hypomethylating agents, in addition to targeted therapies such as FLT3 and IDH inhibitors. Lastly, we shed light on challenges facing the care of older adults and their representation in clinical trials.

High tissue-sodium associates with systemic inflammation and insulin resistance in obese individuals.

BACKGROUND AND AIMS: High sodium intake is associated with obesity and insulin resistance, and high extracellular sodium content may induce systemic inflammation, leading to cardiovascular disease. In this study, we aim to investigate whether high tissue sodium accumulation relates with obesity-related insulin resistance and whether the pro-inflammatory effects of excess tissue sodium accumulation may contribute to such association. METHODS AND RESULTS: In a cross-sectional study of 30 obese and 53 non-obese subjects, we measured insulin sensitivity determined as glucose disposal rate (GDR) using hyperinsulinemic euglycemic clamp, and tissue sodium content using 23Na magnetic resonance imaging. Median age was 48 years, 68% were female and 41% were African American. Median (interquartile range) BMI was 33 (31.5, 36.3) and 25 (23.5, 27.2) kg/m2 in the obese and non-obese individuals, respectively. In obese individuals, insulin sensitivity negatively correlated with muscle (r = -0.45, p = 0.01) and skin sodium (r = -0.46, p = 0.01). In interaction analysis among obese individuals, tissue sodium had a greater effect on insulin sensitivity at higher levels of high-sensitivity C-reactive protein (p-interaction = 0.03 and 0.01 for muscle and skin Na+, respectively) and interleukin-6 (p-interaction = 0.024 and 0.003 for muscle and skin Na+, respectively). In interaction analysis of the entire cohort, the association between muscle sodium and insulin sensitivity was stronger with increasing levels of serum leptin (p-interaction = 0.01). CONCLUSIONS: Higher muscle and skin sodium are associated with insulin resistance in obese patients. Whether high tissue sodium accumulation has a mechanistic role in the development of obesity-related insulin resistance through systemic inflammation and leptin dysregulation remains to be examined in future studies. CLINICALTRIALS: gov registration: NCT02236520.

Efficacy and Safety of Direct Oral Anticoagulants in Patients With Antiphospholipid Syndrome: A Systematic Review and Meta-Analysis.

Due to a high risk of recurrent thromboembolism in patients with antiphospholipid syndrome (APS), long-term anticoagulation is recommended. For decades, vitamin K antagonists (VKAs) have been the gold standard for thromboprophylaxis in these patients. Due to the widespread use of direct oral anticoagulants (DOACs) in various thromboembolic conditions and their potential advantages compared to VKAs, several studies have been conducted to evaluate their safety and efficacy in APS. We performed a literature search using PubMed, Embase, and Cochrane databases for studies comparing DOACs to VKAs in patients with APS. Relative risk (RR) and the corresponding 95% confidence intervals (95% CI) were estimated for recurrent thromboembolic events, bleeding, and mortality. A total of 1437 patients pooled from 12 studies were analyzed. The risk of recurrent thrombosis, especially arterial thrombosis, doubled with DOACs compared to VKAs (RR 2.61, 95% CI 1.44-4.71; p=0.001). The risk further increased in patients with a triple-positive antiphospholipid antibody profile (RR 4.50, 95% CI 1.91-10.63; p=0.0006) and with the use of rivaroxaban (RR 1.95, 95% CI 1.10-3.45; p=0.02). The risk of major bleeding and mortality were not significantly different between the two arms. A trend favoring DOACs compared to VKAs was observed for all bleeding events.  This meta-analysis comes in agreement with previous studies and supports the use of VKAs in APS. Our study revealed that VKAs remain the gold standard for the management of APS, especially triple-positive APS. DOACs, particularly rivaroxaban, are not as effective in preventing recurrent thromboembolism in high-risk APS patients. Further studies are needed to evaluate the role of DOACs apart from rivaroxaban with a focus on their efficacy in the management of isolated or double-positive APS.

Time from diagnosis to treatment is associated with survival in patients with acute myeloid leukaemia: An analysis of 55 985 patients from the National Cancer Database.

Acute myeloid leukaemia (AML) is conventionally thought of as a medical emergency. However, several studies on the association of time from diagnosis to treatment with survival did not have concordant results. Here we analyse 55 985 AML patients from the National Cancer Database, and we show that in patients less than 60 years old a five-day delay in chemotherapy initiation leads to worse long-term survival. The difference is small [hazard ratio (HR) 1.05, 95% confidence interval (CI) 1.01-1.09 in multivariate analysis] but statistically significant. This study raises the issue of power to detect small differences in retrospective studies.

Tissue Sodium in Patients With Early Stage Hypertension: A Randomized Controlled Trial.

Background Sodium (Na+) stored in skin and muscle tissue is associated with essential hypertension. Sodium magnetic resonance imaging is a validated method of quantifying tissue stores of Na+. In this study, we evaluated tissue Na+ in patients with elevated blood pressure or stage I hypertension in response to diuretic therapy or low Na+ diet. Methods and Results In a double-blinded, placebo-controlled trial, patients with systolic blood pressure 120 to 139 mm Hg were randomized to low sodium diet (<2 g of sodium), chlorthalidone, spironolactone, or placebo for 8 weeks. Muscle and skin Na+ using sodium magnetic resonance imaging and pulse wave velocity were assessed at the beginning and end of the study. Ninety-eight patients were enrolled to undergo baseline measurements and 54 completed randomization. Median baseline muscle and skin Na+ in 98 patients were 16.4 mmol/L (14.9, 18.9) and 13.1 mmol/L (11.1, 16.1), respectively. After 8 weeks, muscle Na+ increased in the diet and chlorthalidone arms compared with placebo. Skin sodium was decreased only in the diet arm compared with placebo. These associations remained significant after adjustment for age, sex, body mass index, systolic blood pressure, and urinary sodium. No changes were observed in pulse wave velocity among the different groups when compared with placebo. Conclusions Diuretic therapy for 8 weeks did not decrease muscle or skin sodium or improve pulse wave velocity in patients with elevated blood pressure or stage I hypertension. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02236520.

Effect Modification of Body Mass Index and Kidney Function on Insulin Sensitivity Among Patients With Moderate CKD and Healthy Controls.

INTRODUCTION: Insulin resistance and obesity are prevalent in chronic kidney disease (CKD) patients. The interaction of body mass index (BMI) and kidney function across the continuum of estimated glomerular filtration rate (eGFR) is unknown. METHODS: In a cross-sectional study of 139 patients, 52 with CKD stages 3 and 4 and 87 patients with normal eGFR, we measured the insulin sensitivity index (ISI) using the hyperinsulinemic euglycemic clamp and homeostasis model assessment of insulin resistance (HOMA-IR). We investigated the interaction between eGFR and BMI in their association with ISI and HOMA-IR using linear models with robust standard errors. RESULTS: Median age was 56 (42, 66) years, 50.4% were female, and 36% were African American. Patients with low eGFR (∼30 ml/min per 1.73 m2) had low ISI (2.3 mg/min per µU/ml) regardless of BMI. Among patients with preserved eGFR (>90 ml/min per 1.73m2), BMI had a greater effect on ISI (6.3 mg/min per µU/ml at a BMI of 20 kg/m2 vs. 4.6 mg/min per µU/ml at a BMI of 30 kg/m2) (P for interaction = 0.046). In models adjusted for demographics, and log transformed interleukin-6, high-sensitivity C-reactive protein, leptin, and adiponectin, a 1-SD (28 ml/min per 1.73 m2) lower eGFR was associated with a statistically significant 1.14-unit decrease in ISI (95% confidence interval = -1.80, -0.48) among nonobese patients. Among obese patients, the effect estimate was -0.25 (95% confidence interval = -0.88, 0.39). The association between BMI and HOMA-IR was stronger in patients with lower eGFR (P for interaction = 0.005). CONCLUSION: Both eGFR and BMI are independently associated with insulin sensitivity, but the strength of the association between BMI and insulin sensitivity varies significantly across eGFR.

KD-PACE Salvage Therapy for Aggressive Relapsed Refractory Multiple Myeloma, Plasma Cell Leukemia and Extramedullary Myeloma.

BACKGROUND: Patients with advanced/aggressive multiple myeloma have limited treatment options to achieve rapid disease control. In eligible patients, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide is often used. However, many patients are refractory to or have toxicities from bortezomib and there is a need for bridging therapy. We have used a modified regimen incorporating the second-generation proteasome inhibitor carfilzomib (carfilzomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide [KD-PACE]) instead of bortezomib for relapsed/refractory multiple myeloma. PATIENTS AND METHODS: This 2-center retrospective study included consecutive patients receiving KD-PACE for relapsed or refractory multiple myeloma, plasma cell leukemia, or extramedullary myeloma. The primary outcome was the feasibility of KD-PACE as a bridging therapy to a more definitive treatment option. RESULTS: Fifty-two patients were included. The median age was 57 years, and 67% were male. Thirty-one patients were bridged with KD-PACE to autologous hematopoietic stem cell transplant (29%), allogenic hematopoietic stem cell transplant (27%), or a clinical trial (12%). Patients bridged to autologous hematopoietic stem cell transplant, allogenic hematopoietic stem cell transplant, or a clinical trial had a superior progression-free survival (8.3 months vs 2.3 months in the nonbridged group; P < .001) and overall survival (median, 16.7 months vs 4.3 months in the nonbridged group; P < .001). No unexpected toxicities occurred from the treatment regimen. CONCLUSION: KD-PACE is a promising treatment option for select patients with advanced/aggressive forms of myeloma requiring rapid disease control before a more definitive salvage therapy such as auto/allotransplantation or a clinical trial.

Peripheral Insulin Resistance Is Associated with Copeptin in Patients with Chronic Kidney Disease.

Background: Insulin resistance is associated with cardiovascular disease risk and worsened kidney function. Patients with CKD have higher levels of insulin resistance. Elevated levels of copeptin (a surrogate for vasopressin levels) have been associated with an increased incidence and progression of CKD, and with incident diabetes mellitus. The purpose of our study was to examine the relationship between insulin resistance, copeptin, and CKD. Methods: We performed a cross-sectional study to investigate if insulin resistance was associated with higher copeptin levels in nondiabetic patients with stage 3-4 CKD versus controls. We measured plasma copeptin levels and used data from 52 patients with stage 3-4 CKD and 85 controls (eGFR ≥60 ml/min per 1.73 m2) enrolled in the Insulin Resistance in Chronic Kidney Disease (IRCKD) study. We then used a multivariable linear-regression model to assess the independent relationship between peripheral or hepatic insulin resistance and copeptin across levels of eGFR. Results: We found that in patients with CKD (eGFR of 30-60 ml/min per 1.73 m2), but not in controls, peripheral insulin resistance was significantly correlated with higher levels of log copeptin (r=-0.21, P=0.04). In patients with CKD, when adjusted for age, sex, BMI, serum osmolality, log IL6, and log leptin/adiponectin ratio, each 1 SD decrease in insulin sensitivity was associated with a 39% increase in serum copeptin levels. The relationship between hepatic insulin resistance, copeptin, and eGFR is similar between controls and patients with reduced eGFR. Conclusion: Peripheral insulin resistance is associated with elevated copeptin levels in nondiabetic patients with stage 3-4 CKD. Further research into how the interaction between peripheral insulin resistance and elevated vasopressin affects CKD progression could be of interest.

Sodium activates human monocytes via the NADPH oxidase and isolevuglandin formation.

AIMS: Prior studies have focused on the role of the kidney and vasculature in salt-induced modulation of blood pressure; however, recent data indicate that sodium accumulates in tissues and can activate immune cells. We sought to examine mechanisms by which salt causes activation of human monocytes both in vivo and in vitro. METHODS AND RESULTS: To study the effect of salt in human monocytes, monocytes were isolated from volunteers to perform several in vitro experiments. Exposure of human monocytes to elevated Na+ex vivo caused a co-ordinated response involving isolevuglandin (IsoLG)-adduct formation, acquisition of a dendritic cell (DC)-like morphology, expression of activation markers CD83 and CD16, and increased production of pro-inflammatory cytokines tumour necrosis factor-α, interleukin (IL)-6, and IL-1ß. High salt also caused a marked change in monocyte gene expression as detected by RNA sequencing and enhanced monocyte migration to the chemokine CC motif chemokine ligand 5. NADPH-oxidase inhibition attenuated monocyte activation and IsoLG-adduct formation. The increase in IsoLG-adducts correlated with risk factors including body mass index, pulse pressure. Monocytes exposed to high salt stimulated IL-17A production from autologous CD4+ and CD8+ T cells. In addition, to evaluate the effect of salt in vivo, monocytes and T cells isolated from humans were adoptively transferred to immunodeficient NSG mice. Salt feeding of humanized mice caused monocyte-dependent activation of human T cells reflected by proliferation and accumulation of T cells in the bone marrow. Moreover, we performed a cross-sectional study in 70 prehypertensive subjects. Blood was collected for flow cytometric analysis and 23Na magnetic resonance imaging was performed for tissue sodium measurements. Monocytes from humans with high skin Na+ exhibited increased IsoLG-adduct accumulation and CD83 expression. CONCLUSION: Human monocytes exhibit co-ordinated increases in parameters of activation, conversion to a DC-like phenotype and ability to activate T cells upon both in vitro and in vivo sodium exposure. The ability of monocytes to be activated by sodium is related to in vivo cardiovascular disease risk factors. We therefore propose that in addition to the kidney and vasculature, immune cells like monocytes convey salt-induced cardiovascular risk in humans.

Tissue sodium stores in peritoneal dialysis and hemodialysis patients determined by 23-sodium magnetic resonance imaging.

BACKGROUND: Tissue sodium content in patients on maintenance hemodialysis (MHD) and peritoneal dialysis (PD) were previously explored using 23Sodium magnetic resonance imaging (23NaMRI). Larger studies would provide a better understanding of sodium stores in patients on dialysis as well as the factors influencing this sodium accumulation. METHODS: In this cross-sectional study, we quantified the calf muscle and skin sodium content in 162 subjects (10 PD, 33 MHD patients, and 119 controls) using 23NaMRI. Plasma levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were measured to assess systemic inflammation. Sixty-four subjects had repeat 23NaMRI scans that were analyzed to assess the repeatability of the 23NaMRI measurements. RESULTS: Patients on MHD and PD exhibited significantly higher muscle and skin sodium accumulation compared to controls. African American patients on dialysis exhibited greater muscle and skin sodium content compared to non-African Americans. Multivariable analysis showed that older age was associated with both higher muscle and skin sodium. Male sex was also associated with increased skin sodium deposition. Greater ultrafiltration was associated with lower skin sodium in patients on PD (Spearman's rho=-0.68, P = 0.035). Higher plasma IL-6 and hsCRP levels correlated with increased muscle and skin sodium content in the overall study population. Patients with higher baseline tissue sodium content exhibited greater variability in tissue sodium stores on repeat measurements. CONCLUSIONS: Our findings highlight greater muscle and skin sodium content in dialysis patients compared to controls without kidney disease. Tissue sodium deposition and systemic inflammation seen in dialysis patients might influence one another bidirectionally.

Supervised Exercise Intervention and Overall Activity in CKD.

INTRODUCTION: Patients are often instructed to engage in multiple weekly sessions of exercise to increase physical activity. We aimed to determine whether assignment to a supervised exercise regimen increases overall weekly activity in individuals with chronic kidney disease (CKD). METHODS: We performed a secondary analysis of a pilot randomized 2 × 2 factorial design trial examining the effects of diet and exercise (10%-15% reduction in caloric intake, 3 supervised exercise sessions/wk, combined diet restriction/exercise, and control). Activity was measured as counts detected by accelerometer. Counts data were collected on all days for which an accelerometer was worn at baseline, month 2, and month 4 follow-up. The primary outcome was a relative change from baseline in log-transformed counts/min. Generalized estimating equations were used to compare the primary outcome in individuals in the exercise group and the nonexercise group. RESULTS: We examined 111 individuals randomized to aerobic exercise or usual activity (n = 48 in the exercise group and n = 44 controls). The mean age was 57 years, 42% were female, and 28% were black. Median overall adherence over all time was 73%. Median (25th, 75th percentile) counts/min over nonsupervised exercise days at months 2 and 4 were 237.5 (6.5, 444.4) for controls and 250.9 (7.7, 529.8) for the exercise group (P = 0.74). No difference was observed in the change in counts/min between the exercise and control groups over 3 time points (ß [fold change], 0.96, 95% confidence interval [CI], 0.91, 1.02). CONCLUSION: Engaging in a supervised exercise program does not increase overall weekly physical activity in individuals with stage 3 to 4 CKD.

Effects of diet and exercise on adipocytokine levels in patients with moderate to severe chronic kidney disease.

BACKGROUND AND AIMS: Obesity is a pro-inflammatory risk factor for progression of CKD and cardiovascular disease. We hypothesized that implementation of caloric restriction and endurance exercise would improve adipocytokine profiles in patients with moderate to severe CKD. METHODS AND RESULTS: We enrolled patients with moderate to severe CKD through a multi-center pilot randomized trial of diet and exercise in a 4-arm design (dietary restriction of 10%-15% reduction in caloric intake, exercise three times/week, combined diet and exercise, and control) (NCT01150851). Adipocytokines (adiponectin and leptin) were measured at the beginning and end of the study period as secondary outcomes. Treatment effect was analyzed in a multivariable model adjusted for baseline outcome values, age, gender, site and diabetes. A total of 122 participants were consented, 111 were randomized (42% female, 25% diabetic, and 91% hypertensive), 104 started intervention and 92 completed the study (Figure 1). Plasma adiponectin levels increased significantly in response to diet by 23% (95% CI: 0.2%, 49.8%, p = 0.048) among participants randomized to the caloric restriction and usual activity arm but not to exercise, whereas circulating leptin did not change by either treatment. CONCLUSION: Our data suggest that dietary caloric restriction increases plasma adiponectin levels in stage 3-4 CKD patients, with limited effect on leptin levels. These findings suggest the potential for improving the metabolic milieu of CKD with moderate calorie restriction.

Critical role of Interleukin 21 and T follicular helper cells in hypertension and vascular dysfunction.

T and B cells have been implicated in hypertension, but the mechanisms by which they produce a coordinated response is unknown. T follicular helper (Tfh) cells that produce interleukin 21 (IL21) promote germinal center (GC) B cell responses leading to immunoglobulin (Ig) production. Here we investigate the role of IL21 and Tfh cells in hypertension. In response to angiotensin (Ang) II-induced hypertension, T cell IL21 production is increased, and Il21-/- mice develop blunted hypertension, attenuated vascular end-organ damage, and decreased interleukin 17A (IL17A) and interferon gamma production. Tfh-like cells and GC B cells accumulate in the aorta and plasma IgG1 is increased in hypertensive WT but not Il21-/-mice. Furthermore, Tfh cell deficient mice develop blunted hypertension and vascular hypertrophy in response to Ang II infusion. Importantly, IL21 neutralization reduces blood pressure (BP) and reverses endothelial dysfunction and vascular inflammation. Moreover, recombinant IL21 impairs endothelium-dependent relaxation ex vivo and decreases nitric oxide production from cultured endothelial cells. Finally, we show in humans that peripheral blood T cell production of IL21 correlates with systolic BP and IL17A production. These data suggest that IL21 may be a novel therapeutic target for the treatment of hypertension and its micro- and macrovascular complications.

Acute effects of insulin on circulating natriuretic peptide levels in humans.

BACKGROUND: The natriuretic peptide hormones play an important role in salt and blood pressure regulation. In observational studies, obesity and insulin resistance have been consistently associated with lower concentrations of natriuretic peptides. It has been proposed that insulin influences natriuretic peptide production. OBJECTIVE: We sought to determine the acute effects of insulin administration on natriuretic peptide concentrations. METHODS: 31 men and women (11 lean, 10 overweight, and 10 obese), ages 30-70 years, without cardiovascular disease or overt diabetes underwent a hyperinsulinemic-euglycemic insulin clamp. Plasma concentrations of N-terminal pro atrial natriuretic peptide (NT-proANP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) were measured at baseline and steady-state (the final 30 minutes of the clamp protocol). RESULTS: From baseline to steady-state, insulin levels increased from a mean level of 9.5 to 176.7 µU/ml (p<0.001). Over this period, circulating NT-proANP concentrations decreased by 9% (-1933 ng/L, p = 0.01). The changes in NT-proANP did not differ between lean, overweight, and obese individuals. Steady-state NT-proANP levels, adjusted for baseline, were lower in individuals with greater insulin resistance, independent of BMI. In contrast to NT-proANP, NT-proBNP levels did not change significantly during the clamp (p = 0.41). CONCLUSION: Insulin administration was associated with a moderate decrease in circulating NT-proANP, but not NT-proBNP. The lowest NT-proANP concentrations were found in insulin-resistant individuals. Further investigations are warranted to elucidate potential mechanisms underlying the effects of insulin on the cardiac hormonal axis.