Ibrutinib combinations in CLL therapy: scientific rationale and clinical results

Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). This drug irreversibly inhibits Bruton tyrosine kinase (BTK) by covalently binding to the C481 residue in the BTK kinase domain. BTK is a pivotal protein for B cell receptor signaling and tissue homing of CLL cells. Preclinical investigations have established the importance of the B cell receptor pathway in the maintenance and survival of normal and malignant B cells, underscoring the importance of targeting this axis for CLL. Clinical trials demonstrated overall and progression-free survival benefit with ibrutinib in multiple CLL subgroups, including patients with relapsed or refractory disease, patients with 17p deletion, elderly patients, and treatment-naïve patients. Consequently, ibrutinib was approved by the US Food and Drug Administration for newly diagnosed and relapsed disease. Ibrutinib has transformed the treatment of CLL; however, several limitations have been identified, including low complete remission rates, development of resistance, and uncommon substantial toxicities. Further, ibrutinib must be used until disease progression, which imposes a financial burden on patients and society. These limitations were the impetus for the development of ibrutinib combinations. Four strategies have been tested in recent years: combinations of ibrutinib with immunotherapy, chemoimmunotherapy, cell therapy, and other targeted therapy. Here, we review the scientific rationale for and clinical outcome of each strategy. Among these strategies, ibrutinib with targeted agent venetoclax results in high complete response rates and, importantly, high rates of undetectable minimal residual disease. Although we concentrate here on ibrutinib, similar combinations are expected or ongoing with acalabrutinib, tirabrutinib, and zanubrutinib, second-generation BTK inhibitors. Future investigations will focus on the feasibility of discontinuing ibrutinib combinations after a defined time; the therapeutic benefit of adding a third agent to ibrutinib-containing combinations; and profiling of resistant clones that develop after combination treatment. A new standard of care for CLL is expected to emerge from these investigations.Subject terms: Combination drug therapy, Medical research     

Source apportionment of methane escaping the subsea permafrost system in the outer Eurasian Arctic Shelf

The East Siberian Arctic Shelf holds large amounts of inundated carbon and methane (CH₄). Holocene warming by overlying seawater, recently fortified by anthropogenic warming, has caused thawing of the underlying subsea permafrost. Despite extensive observations of elevated seawater CH₄ in the past decades, relative contributions from different subsea compartments such as early diagenesis, subsea permafrost, methane hydrates, and underlying thermogenic/ free gas to these methane releases remain elusive. Dissolved methane concentrations observed in the Laptev Sea ranged from 3 to 1,500 nM (median 151 nM; oversaturation by ∼3,800%). Methane stable isotopic composition showed strong vertical and horizontal gradients with source signatures for two seepage areas of δ¹³C-CH₄ = (−42.6 ± 0.5)/(−55.0 ± 0.5) ‰ and δD-CH₄ = (−136.8 ± 8.0)/(−158.1 ± 5.5) ‰, suggesting a thermogenic/natural gas source. Increasingly enriched δ¹³C-CH₄ and δD-CH₄ at distance from the seeps indicated methane oxidation. The Δ¹⁴C-CH₄ signal was strongly depleted (i.e., old) near the seeps (−993 ± 19/−1050 ± 89‰). Hence, all three isotope systems are consistent with methane release from an old, deep, and likely thermogenic pool to the outer Laptev Sea. This knowledge of what subsea sources are contributing to the observed methane release is a prerequisite to predictions on how these emissions will increase over coming decades and centuries.

The East Siberian Arctic Shelf (ESAS) is the world’s largest and shallowest shelf sea system, formed through inundation of northeast Siberia during sea level transgression in the early Holocene. The ESAS holds substantial but poorly constrained amounts of organic carbon and methane (CH₄). These carbon/methane stores are contained in unknown partitions as gas hydrates, unfrozen sediment, subsea permafrost, gas pockets within and below the subsea permafrost, and as underlying thermogenic gas (1–3). Methane release to the atmosphere from these compartments could potentially have significant effects on the global climate (4, 5), yet there are large uncertainties regarding the size and the vulnerability toward remobilization of these inaccessible and elusive subsea carbon/methane pools. Conceptual development and modeling have predicted that warming of the ESAS system by a combination of geothermal heat and climate-driven Holocene heat flux from overlying seawater, recently further enhanced by Anthropocene warming, may lead to thawing of subsea permafrost (6, 7). Subsea permafrost drilling in the Laptev Sea, in part at the same sites as 30 y ago, has recently confirmed that the subsea permafrost has indeed come near the point of thawing (8). In addition to mobilization of the carbon/methane stored within the subsea permafrost, its degradation can also lead to the formation of pathways for gaseous methane from underlying reservoirs, allowing further methane release to the overlying water column (3, 9).Near-annual ship-based expeditions to the ESAS over the past two decades have documented widespread seep locations with extensive methane releases to the water column (3, 10). Methane levels are often found to be 10 to 100 times higher than the atmospheric equilibrium and are particularly elevated in areas of strong ebullition from subsea gas seeps (“methane hotspots”). Similarly, elevated dissolved methane concentrations in bottom waters appear to be spatially related to the thermal state of subsea permafrost as deduced from modeling results and/or geophysical surveys (7, 9). Currently, we lack critical knowledge on the quantitative or even relative contributions of the different subsea pools to the observed methane release, a prerequisite for robust predictions on how these releases will develop. An important distinction needs to be made between pools that release methane gradually, such as methane produced microbially in shallow sediments during early diagenesis or in thawing subsea permafrost, versus pools with preformed methane that may release more abruptly once pathways are available, such as from disintegrating methane hydrates and pools of thermogenic (natural) gas below the subsea permafrost. Multidimensional isotope analysis offers a useful means to disentangle the relative importance of these different subsea sources of methane to the ESAS: Stable isotope data (δ¹³C-CH₄ and δD-CH₄) provide useful information on methane formation and removal pathways, and the radiocarbon content of methane (Δ¹⁴C-CH₄) helps to determine the age and methane source reservoir (see SI Appendix, text S1 for details on these isotope systematics and typical isotopic signatures for the ESAS subsea system).Here, we present triple-isotope–based source apportionment of methane conducted as part of the Swedish–Russian–US investigation of carbon–climate–cryosphere interactions in the East Siberian Arctic Ocean (SWERUS-C3) program. To this end, the distribution of dissolved methane, its stable carbon and hydrogen isotope composition, as well as natural radiocarbon abundance signature, were investigated with a focus on the isotopic fingerprint of methane escaping the seabed to pinpoint the subsea sources of elevated methane in the outer Laptev Sea.     

Two Cases of Prenatally Diagnosed Membranous and Muscular Ventricular Septal Aneurysms

A ventricular septal aneurysm is a rare heart defect located in the muscular or membranous part of the septum. Muscular ventricular septal aneurysms are usually isolated, with a favorable prognosis. Membranous ventricular septal aneurysms are often associated with other heart anomalies, could result in serious complications, and may require surgical treatment. We describe 2 cases of prenatally diagnosed ventricular septal aneurysms: an isolated membranous ventricular septal aneurysm with a good outcome, which was initially misdiagnosed as an atrioventricular septal defect; and a muscular ventricular septal aneurysm associated with a hypoplastic aortic arch and severe hydrocephaly, which resulted in termination of the pregnancy. To our knowledge, the combination of a muscular ventricular septal aneurysm with an extracardiac anomaly has not been reported previously.     

BKCa Channel Activation Attenuates the Pathophysiological Progression of Monocrotaline-Induced Pulmonary Arterial Hypertension in Wistar Rats

Cardiovascular Drugs and Therapy - In the present study, the therapeutic efficacy of a selective BKCa channel opener (compound X) in the treatment of monocrotaline (MCT)-induced pulmonary arterial...     

Utility of pulmonary ultrasound to identify interstitial lung disease in patients with rheumatoid arthritis

Clinical Rheumatology - To analyze the diagnostic utility of lung ultrasound (US) to detect interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients comparing with high-resolution...     

Analysis of late risk of systemic blood pressures <120/80 mm Hg

We studied categories of blood pressure (BP) <120/80 mm Hg as predictors of hypertension 10 to 22 years later by logistic regression analyses with 6 covariates. There was progressively increased risk for subjects with systolic BP 100 to 109 and 110 to 119 mm Hg (vs <100 mm Hg) or diastolic BP 70 to 74 and 75 to 79 mm Hg (vs <70 mm Hg). These relations were similar in men, women, and several ethnic groups but stronger in subjects <40 years old. These data suggest a definition of optimal BP of <100/70 mm Hg, similar to usual BP levels in children <10 years old.     

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil‐based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3‐19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9‐6.2), 49.6 ng/mL (14.4‐302.0), and 226.3 ng ? h/mL (70.5‐861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine‐CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.     

CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions

Journal of Neurology - The ataxias are a group of disorders that manifest with balance, movement, speech and visual problems. They can arise due to dysfunction of the cerebellum, the vestibular...