Pridopidine subtly ameliorates motor skills in a mouse model for vanishing white matter.

The leukodystrophy vanishing white matter (VWM) is characterized by chronic and episodic acute neurological deterioration. Curative treatment is presently unavailable. Pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B) cause VWM and deregulate the integrated stress response (ISR). Previous studies in VWM mouse models showed that several ISR-targeting compounds ameliorate clinical and neuropathological disease hallmarks. It is unclear which ISR components are suitable therapeutic targets. In this study, effects of 4-phenylbutyric acid, tauroursodeoxycholic acid, or pridopidine (PDPD), with ISR targets upstream or downstream of eIF2B, were assessed in VWM mice. In addition, it was found that the composite ataxia score represented motor decline of VWM mice more accurately than the previously used neuroscore. 4-phenylbutyric acid and tauroursodeoxycholic acid did not improve VWM disease hallmarks, whereas PDPD had subtle beneficial effects on motor skills. PDPD alone does not suffice as treatment in VWM mice but may be considered for combination therapy. Also, treatments aimed at ISR components upstream of eIF2B do not improve chronic neurological deterioration; effects on acute episodic decline remain to be investigated.

Methotrexate Polyglutamates Exposure - Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate.

Methotrexate polyglutamates (MTX-PG) concentrations in red blood cells (RBCs) have been suggested as a biomarker of response in patients with rheumatoid arthritis (RA) receiving low-dose MTX therapy. We investigated the association and interpatient variability between RBC-MTX-PG3-5 -exposure and response in patients with RA starting MTX. Data of three prospective cohorts were available. The relationship between exposure and Disease Activity Score in 28 joints (DAS28) was analyzed using a population pharmacokinetic-pharmacodynamic model. Relevant covariates were tested using full covariate modeling and backward elimination. From 395 patients, 3,401 MTX-PG concentrations and 1,337 DAS28 measurements were available between 0 and 300 days after MTX treatment onset. The developed model adequately described the time course of MTX-PG3-5 and DAS28. The median MTX-PG3-5 level at month 1 was 30.9 nmol/L (interquartile range (IQR): 23.6-43.7; n = 41) and at month 3: 69.3 nmol/L (IQR: 17.9-41.2; n = 351). Clearance of MTX-PG3-5 from RBCs was 28% lower (95% confidence interval (CI): 23.6-32.8%) in a woman and 10% lower (95% CI: 7.7-12.4%) in a 65-year-old compared with a 35-year-old patient. MTX-PG3-5 concentrations associated with DAS28: half-maximal effective concentration (EC50 ) was 9.14 nmol/L (95% CI: 4.2 nmol/L-14.1 nmol/L). EF at 80% (EC80 ) above 47 nmol/L was regarded as the optimal response. Independent of the MTX-PG 3-5 - response association, co-administration of disease-modifying antirheumatic drugs and corticosteroids improved response (additive effect on maximum effect (Emax )), whereas smoking, high body mass index and low albumin decreased Emax . In patients with RA starting MTX, RBC-MTX-PG3-5 was associated with clinical response. A dose increase is suggested when MTX-PG3-5 at month 1 is below 9.15 nmol/L, continued with the same dose when the concentration is above 47 nmol/L, and consider other treatment options above 78 nmol/L from 3 months onwards.

Intraoperative Visualization and Treatment of Salivary Gland Dysfunction in Sjögren's Syndrome Patients Using Contrast-Enhanced Ultrasound Sialendoscopy (CEUSS).

In sialendoscopy, ducts are dilated and the salivary glands are irrigated with saline. Contrast-enhanced ultrasound sialendoscopy (CEUSS), using microbubbles, may facilitate the monitoring of irrigation solution penetration in the ductal system and parenchyma. It is imperative to test CEUSS for its safety and feasibility in Sjögren's syndrome (SS) patients. CEUSS was performed on 10 SS patients. The primary outcomes were safety, determined by the occurrence of (serious) adverse events ((S)AEs), and feasibility. The secondary outcomes were unstimulated and stimulated whole saliva (UWS and SWS) flow rates, xerostomia inventory (XI), clinical oral dryness score, pain, EULAR Sjögren's syndrome patient reported index (ESSPRI), and gland topographical alterations. CEUSS was technically feasible in all patients. Neither SAEs nor systemic reactions related to the procedure were observed. The main AEs were postoperative pain (two patients) and swelling (two patients). Eight weeks after CEUSS, the median UWS and SWS flow had increased significantly from 0.10 to 0.22 mL/min (p = 0.028) and 0.41 to 0.61 mL/min (p = 0.047), respectively. Sixteen weeks after CEUSS, the mean XI was reduced from 45.2 to 34.2 (p = 0.02). We conclude that CEUSS is a safe and feasible treatment for SS patients. It has the potential to increase salivary secretion and reduce xerostomia, but this needs further investigation.

Efficacy and safety of intravenous imatinib in COVID-19 ARDS: a randomized, double-blind, placebo-controlled clinical trial.

PURPOSE: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. RESULTS: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI - 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (- 1.17 ml/kg, 95% CI - 1.87 to - 0.44). CONCLUSIONS: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

Explaining Blood-Brain Barrier Permeability of Small Molecules by Integrated Analysis of Different Transport Mechanisms.

The blood-brain barrier (BBB) represents a major obstacle to delivering drugs to the central nervous system (CNS), resulting in the lack of effective treatment for many CNS diseases including brain cancer. To accelerate CNS drug development, computational prediction models could save the time and effort needed for experimental evaluation. Here, we studied BBB permeability focusing on active transport (influx and efflux) as well as passive diffusion using previously published and self-curated data sets. We created prediction models based on physicochemical properties, molecular substructures, or their combination to understand which mechanisms contribute to BBB permeability. Our results show that features that predicted passive diffusion over membranes overlap with features that explain endothelial permeation of approved CNS-active drugs. We also identified physical properties and molecular substructures that positively or negatively predicted BBB transport. These findings provide guidance toward identifying BBB-permeable compounds by optimally matching physicochemical and molecular properties to BBB transport mechanisms.

Pharmacokinetics and pharmacodynamics of imatinib for optimal drug repurposing from cancer to COVID-19.

INTRODUCTION: In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations. AIMS: This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters. METHODS: 648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Cttrough) and total average area under the concentration-time curve (AUCtave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. RESULTS: AUCtave and Cttrough were respectively 2.21-fold (95%CI 2.07-2.37) and 1.53-fold (95%CI 1.44-1.63) lower for cancer compared to COVID-19 patients. Cttrough, not AUCtave, associated significantly with P/F (ß=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. CONCLUSION: COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Cttrough and AUCtave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.

Myelotoxicity of Temozolomide Treatment in Patients with Glioblastoma Is It Time for a More Mechanistic Approach?

Glioblastoma multiforme is the most common primary central nervous system tumor, with an incidence of 3 [...].

Optimizing Antiviral Dosing for HSV and CMV Treatment in Immunocompromised Patients.

Herpes simplex virus (HSV) and cytomegalovirus (CMV) are DNA viruses that are common among humans. Severely immunocompromised patients are at increased risk of developing HSV or CMV disease due to a weakened immune system. Antiviral therapy can be challenging because these drugs have a narrow therapeutic window and show significant pharmacokinetic variability. Above that, immunocompromised patients have various comorbidities like impaired renal function and are exposed to polypharmacy. This scoping review discusses the current pharmacokinetic (PK) and pharmacodynamic (PD) knowledge of antiviral drugs for HSV and CMV treatment in immunocompromised patients. HSV and CMV treatment guidelines are discussed, and multiple treatment interventions are proposed: early detection of drug resistance; optimization of dose to target concentration by therapeutic drug monitoring (TDM) of nucleoside analogs; the introduction of new antiviral drugs; alternation between compounds with different toxicity profiles; and combinations of synergistic antiviral drugs. This research will also serve as guidance for future research, which should focus on prospective evaluation of the benefit of each of these interventions in randomized controlled trials.

Pharmacological Optimization of PSMA-Based Radioligand Therapy.

Prostate cancer (PCa) is the most common malignancy in men of middle and older age. The standard treatment strategy for PCa ranges from active surveillance in low-grade, localized PCa to radical prostatectomy, external beam radiation therapy, hormonal treatment and chemotherapy. Recently, the use of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) for metastatic castration-resistant PCa has been approved. PSMA is predominantly, but not exclusively, expressed on PCa cells. Because of its high expression in PCa, PSMA is a promising target for diagnostics and therapy. To understand the currently used RLT, knowledge about pharmacokinetics (PK) and pharmacodynamics (PD) of the PSMA ligand and the PSMA protein itself is crucial. PK and PD properties of the ligand and its target determine the duration and extent of the effect. Knowledge on the concentration-time profile, the target affinity and target abundance may help to predict the effect of RLT. Increased specific binding of radioligands to PSMA on PCa cells may be associated with better treatment response, where nonspecific binding may increase the risk of toxicity in healthy organs. Optimization of the radioligand, as well as synergistic effects of concomitant agents and an improved dosing strategy, may lead to more individualized treatment and better overall survival.

Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1.

OBJECTIVE: Vanishing white matter (VWM) is a leukodystrophy, characterized by stress-sensitive neurological deterioration and premature death. It is currently without curative treatment. It is caused by bi-allelic pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B). eIF2B is essential for the regulation of the integrated stress response (ISR), a physiological response to cellular stress. Preclinical studies on VWM mouse models revealed that deregulated ISR is key in the pathophysiology of VWM and an effective treatment target. Guanabenz, an α2-adrenergic agonist, attenuates the ISR and has beneficial effects on VWM neuropathology. The current study aimed at elucidating guanabenz's disease-modifying potential and mechanism of action in VWM mice. Sephin1, an ISR-modulating guanabenz analog without α2-adrenergic agonistic properties, was included to separate effects on the ISR from α2-adrenergic effects. METHODS: Wild-type and VWM mice were subjected to placebo, guanabenz or sephin1 treatments. Effects on clinical signs, neuropathology, and ISR deregulation were determined. Guanabenz's and sephin1's ISR-modifying effects were tested in cultured cells that expressed or lacked the α2-adrenergic receptor. RESULTS: Guanabenz improved clinical signs, neuropathological hallmarks, and ISR regulation in VWM mice, but sephin1 did not. Guanabenz's effects on the ISR in VWM mice were not replicated in cell cultures and the contribution of α2-adrenergic effects on the deregulated ISR could therefore not be assessed. INTERPRETATION: Guanabenz proved itself as a viable treatment option for VWM. The exact mechanism through which guanabenz exerts its ameliorating impact on VWM requires further studies. Sephin1 is not simply a guanabenz replacement without α2-adrenergic effects.

Estimation of glomerular filtration rate for drug dosing in patients with very high or low body mass index.

An accurate estimated glomerular filtration rate (eGFR) is essential in drug dosing. This study demonstrates the limitations of indexed (ml/min/1.73 m2 ) and de-indexed (ml/min) eGFR based drug dosing in patients with obesity or underweight. This systematic study aimed to determine the most appropriate approach to estimate the GFR for standardized eGFR based drug dosing in these patients. (Raw) data of 12 studies were selected to investigate the accuracy and bias of both the indexed and de-indexed estimations of the Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI), and of the Cockcroft-Gault (CG) in patients with obesity or underweight. Accuracy was calculated as the proportion of eGFR values within 30% of the measured GFR (P30) using an inert tracer (e.g., iohexol, inulin, 51 Cr-EDTA, or iothalamate clearance). An accuracy of at least 80% was considered acceptable. GFR values estimated with the CG, MDRD, and CKD-EPI differ significantly within a patient with obesity or underweight regardless of whether it is indexed or de-indexed. All studies, with two exceptions, show that all three equations are inaccurate for patients with underweight or class II obesity (P30: 55%-94%). De-indexing eGFR improves not or modestly the accuracy, and mostly remains below the 80% (P30: 62%-100%). CG was highly inaccurate in obese and underweight patients (P30: 7%-82%). Although these results show that CG is obsolete, the accuracy of MDRD and CKD-EPI is low in patients with obesity or underweight and de-indexing is not the solution. Better education and more accurate methods for appropriate drug dosing (e.g., measured GFR with inert tracer, therapeutic drug monitoring, or 24-h creatinine clearance) are recommended.

Relationship between Biodistribution and Tracer Kinetics of 11C-Erlotinib, 18F-Afatinib and 11C-Osimertinib and Image Quality Evaluation Using Pharmacokinetic/Pharmacodynamic Analysis in Advanced Stage Non-Small Cell Lung Cancer Patients.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) driven by activating epidermal growth factor receptor (EGFR) mutations are best treated with therapies targeting EGFR, i.e., tyrosine kinase inhibitors (TKI). Radiolabeled EGFR-TKI and PET have been investigated to study EGFR-TKI kinetics and its potential role as biomarker of response in NSCLC patients with EGFR mutations (EGFRm). In this study we aimed to compare the biodistribution and kinetics of three different EGFR-TKI, i.e., 11C-erlotinib, 18F-afatinib and 11C-osimertinib. METHODS: Data of three prospective studies and 1 ongoing study were re-analysed; data from thirteen patients (EGFRm) were included for 11C-erlotinib, seven patients for 18F-afatinib (EGFRm and EGFR wild type) and four patients for 11C-osimertinib (EGFRm). From dynamic and static scans, SUV and tumor-to-blood (TBR) values were derived for tumor, lung, spleen, liver, vertebra and, if possible, brain tissue. AUC values were calculated using dynamic time-activity-curves. Parent fraction, plasma-to-blood ratio and SUV values were derived from arterial blood data. Tumor-to-lung contrast was calculated, as well as (background) noise to assess image quality. RESULTS: 11C-osimertinib showed the highest SUV and TBR (AUC) values in nearly all tissues. Spleen uptake was notably high for 11C-osimertinib and to a lesser extent for 18F-afatinib. For EGFRm, 11C-erlotinib and 18F-afatinib demonstrated the highest tumor-to-lung contrast, compared to an inverse contrast observed for 11C-osimertinib. Tumor-to-lung contrast and spleen uptake of the three TKI ranked accordingly to the expected lysosomal sequestration. CONCLUSION: Comparison of biodistribution and tracer kinetics showed that 11C-erlotinib and 18F-afatinib demonstrated the highest tumor-to-background contrast in EGFRm positive tumors. Image quality, based on contrast and noise analysis, was superior for 11C-erlotinib and 18F-afatinib (EGFRm) scans compared to 11C-osimertinib and 18F-afatinib (EGFR wild type) scans.

The INVENT COVID trial: a structured protocol for a randomized controlled trial investigating the efficacy and safety of intravenous imatinib mesylate (Impentri®) in subjects with acute respiratory distress syndrome induced by COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to a disruptive increase in the number of intensive care unit (ICU) admissions with acute respiratory distress syndrome (ARDS). ARDS is a severe, life-threatening medical condition characterized by widespread inflammation and vascular leak in the lungs. Although there is no proven therapy to reduce pulmonary vascular leak in ARDS, recent studies demonstrated that the tyrosine kinase inhibitor imatinib reinforces the endothelial barrier and prevents vascular leak in inflammatory conditions, while leaving the immune response intact. METHODS: This is a randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trial of intravenous (IV) imatinib mesylate in 90 mechanically ventilated subjects with COVID-19-induced ARDS. Subjects are 18 years or older, admitted to the ICU for mechanical ventilation, meeting the Berlin criteria for moderate-severe ARDS with a positive polymerase chain reaction test for SARS-CoV2. Participants will be randomized in a 1:1 ratio to either imatinib (as mesylate) 200 mg bis in die (b.i.d.) or placebo IV infusion for 7 days, or until ICU discharge or death. The primary study outcome is the change in Extravascular Lung Water Index (EVLWi) between day 1 and day 4. Secondary outcome parameters include changes in oxygenation and ventilation parameters, duration of invasive mechanical ventilation, number of ventilator-free days during the 28-day study period, length of ICU stay, and mortality during 28 days after randomization. Additional secondary parameters include safety, tolerability, and pharmacokinetics. DISCUSSION: The current study aims to investigate the efficacy and safety of IV imatinib in mechanically ventilated subjects with COVID-19-related ARDS. We hypothesize that imatinib decreases pulmonary edema, as measured by extravascular lung water using a PiCCO catheter. The reduction in pulmonary edema may reverse hypoxemic respiratory failure and hasten recovery. As pulmonary edema is an important contributor to ARDS, we further hypothesize that imatinib reduces disease severity, reflected by a reduction in 28-day mortality, duration of mechanical ventilation, and ICU length of stay. TRIAL STATUS: Protocol version and date: V3.1, 16 April 2021. Recruitment started on 09 March 2021. Estimated recruitment period of approximately 40 weeks. TRIAL REGISTRATION: ClinicalTrials.gov NCT04794088 . Registered on 11 March 2021.

Association Between the Magnitude of Intravenous Busulfan Exposure and Development of Hepatic Veno-Occlusive Disease in Children and Young Adults Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation.

Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk.

Elevated acute phase proteins affect pharmacokinetics in COVID-19 trials: Lessons from the CounterCOVID - imatinib study.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (Cmax ) and trough concentration (Ctrough ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19.

Genetic susceptibility to acute graft versus host disease in pediatric patients undergoing HSCT.

The most frequent complication of allogeneic hematopoietic stem cell transplantation is acute Graft versus Host Disease (aGVHD). Proliferation and differentiation of donor T cells initiate inflammatory response affecting the skin, liver, and gastrointestinal tract. Besides recipient-donor HLA disparities, disease type, and the conditioning regimen, variability in the non-HLA genotype have an impact on aGVHD onset, and genetic variability of key cytokines and chemokines was associated with increased risk of aGVHD. To get further insight into the recipient genetic component of aGVHD grades 2-4 in pediatric patients, we performed an exome-wide association study in a discovery cohort (n = 87). Nine loci sustained correction for multiple testing and were analyzed in a validation group (n = 168). Significant associations were replicated for ERC1 rs1046473, PLEK rs3816281, NOP9 rs2332320 and SPRED1 rs11634702 variants through the interaction with non-genetic factors. The ERC1 variant was significant among patients that received the transplant from HLA-matched related individuals (p = 0.03), bone marrow stem cells recipients (p = 0.007), and serotherapy-negative patients (p = 0.004). NOP9, PLEK, and SPRED1 effects were modulated by stem cell source, and serotherapy (p < 0.05). Furthermore, ERC1 and PLEK SNPs correlated with aGVHD 3-4 independently of non-genetic covariates (p = 0.02 and p = 0.003). This study provides additional insight into the genetic component of moderate to severe aGVHD.

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial.

BACKGROUND: The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. METHODS: This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10). FINDINGS: Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. INTERPRETATION: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. FUNDING: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.

Intraoperative visualisation and treatment of salivary glands in Sjögren's syndrome by contrast-enhanced ultrasound sialendoscopy (CEUSS): protocol for a phase I single-centre, single-arm, exploratory study.

INTRODUCTION: We established a promising sialendoscopic treatment for in vivo enhancement of salivation in salivary glands affected by Sjögren's syndrome (SS). In this technique, the ducts of the salivary glands are irrigated with saline and steroids. This allows for dilatation of ductal strictures and removal of debris. Unfortunately, it is not possible to assess the delivery and penetration of saline or medications in the ductal system and parenchyma. To address this problem, we will conduct contrast-enhanced ultrasound sialendoscopy (CEUSS) using sulphur hexafluoride microbubbles. To the best of our knowledge, microbubbles have never been used for the treatment of salivary glands in SS. It is, therefore, imperative to test this application for its safety and feasibility. METHODS AND ANALYSIS: A single-arm phase I study will be performed in 10 SS patients. Under local anaesthesia, ultrasound (US) guided infusion of the parotid and submandibular glands with microbubbles will be performed. Continuous US imaging will be used to visualise the glands, including the location of strictures and occlusions. Main outcomes will be the evaluation of safety and technical feasibility of the experimental treatment. Secondary outcomes will consist of determinations of unstimulated whole mouth saliva flow, stimulated whole mouth saliva flow, stimulated parotid saliva flow, clinical oral dryness, reported pain, xerostomia, disease activity, salivary cytokine profiles and clinical SS symptoms. Finally, salivary gland topographical alterations will be evaluated by US. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the Medical Ethics Committee of the Amsterdam University Medical Centre, Amsterdam, The Netherlands (NL68283.029.19). data will be presented at national and international conferences and published in a peer-reviewed journal. The study will be implemented and reported in line with the Standard Protocol Items: Recommendations for Interventional Trials' statement. TRIAL REGISTRATION NUMBERS: The Netherlands Trial Register: NL7731, MREC Trial Register: NL68283.029.19; Pre-results.

Ipilimumab plus nivolumab and chemoradiotherapy followed by surgery in patients with resectable and borderline resectable T3-4N0-1 non-small cell lung cancer: the INCREASE trial.

BACKGROUND: The likelihood of a tumor recurrence in patients with T3-4N0-1 non-small cell lung cancer following multimodality treatment remains substantial, mainly due distant metastases. As pathological complete responses (pCR) in resected specimens are seen in only a minority (28-38%) of patients following chemoradiotherapy, we designed the INCREASE trial (EudraCT-Number: 2019-003454-83; Netherlands Trial Register number: NL8435) to assess if pCR rates could be further improved by adding short course immunotherapy to induction chemoradiotherapy. Translational studies will correlate changes in loco-regional and systemic immune status with patterns of recurrence. METHODS/DESIGN: This single-arm, prospective phase II trial will enroll 29 patients with either resectable, or borderline resectable, T3-4N0-1 NSCLC. The protocol was approved by the institutional ethics committee. Study enrollment commenced in February 2020. On day 1 of guideline-recommended concurrent chemoradiotherapy (CRT), ipilimumab (IPI, 1 mg/kg IV) and nivolumab (NIVO, 360 mg flat dose IV) will be administered, followed by nivolumab (360 mg flat dose IV) after 3 weeks. Radiotherapy consists of once-daily doses of 2 Gy to a total of 50 Gy, and chemotherapy will consist of a platinum-doublet. An anatomical pulmonary resection is planned 6 weeks after the last day of radiotherapy. The primary study objective is to establish the safety of adding IPI/NIVO to pre-operative CRT, and its impact on pathological tumor response. Secondary objectives are to assess the impact of adding IPI/NIVO to CRT on disease free and overall survival. Exploratory objectives are to characterize tumor inflammation and the immune contexture in the tumor and tumor-draining lymph nodes (TDLN), and to explore the effects of IPI/NIVO and CRT and surgery on distribution and phenotype of peripheral blood immune subsets. DISCUSSION: The INCREASE trial will evaluate the safety and local efficacy of a combination of 4 modalities in patients with resectable, T3-4N0-1 NSCLC. Translational research will investigate the mechanisms of action and drug related adverse events. TRIAL REGISTRATION: Netherlands Trial Registration (NTR): NL8435 , Registered 03 March 2020.

Response and Adherence to Nilotinib in Daily practice (RAND study): an in-depth observational study of chronic myeloid leukemia patients treated with nilotinib.

INTRODUCTION: This comprehensive observational study aimed to gain insight into adherence to nilotinib and the effect of (non)adherence on exposure (Cmin) and treatment outcomes. METHODS: Chronic myeloid leukemia (CML) patients using nilotinib were followed for 12 months. Adherence was measured by Medication Event Monitoring System (MEMS), pill count, and Medication Adherence Report Scale (MARS-5). Nilotinib Cmin and patient-reported outcomes (i.e., quality of life, side effects, beliefs, satisfaction) were measured at baseline, 3, 6, and 12 months. RESULTS: Sixty-eight patients (57.5 ± 15.0 years, 49% female) participated. Median adherence to nilotinib (MEMS and pill count) was ≥ 99% and adherence < 90% was rare. Self-reported nonadherence (MARS-5) increased in the first year of treatment to a third of patients. In line with the strong beliefs in the necessity of taking nilotinib, forgetting to take a dose was more prevalent than intentionally adjusting/skipping doses. Nilotinib Cmin were generally above the therapeutic target in 95% of patients. Patients reported a variety of side effects, of which fatigue was most frequent. The mean Cmin was higher in patients who reported severe itching and fatigue. The overall 1-year MMR rate ranged from 47 to 71%. CONCLUSION: Substantial nonadherence (< 90%) to nilotinib was rare and nilotinib Cmin were generally above the therapeutic target. Lack of response in our group of patients was not related to nonadherence or inadequate Cmin. Nevertheless, a considerable number of patients experienced difficulties in adhering to the twice daily fasted dosing regimen, emphasizing the importance of continuous support of medication adherence in CML. CLINICAL TRIAL REGISTRATION: NTR3992 (Netherlands Trial Register, www.trialregister.nl ).