Search

Ruxolitinib (RUX) is a kinase inhibitor used in the treatment of various medical conditions and its mechanism of action involves suppression of the immune system. While beneficial in treatment of polycythemia vera, myelofibrosis and other indications, it can also increase a patient’s susceptibility to various infections, including bacterial, viral and fungal. We present a case of a patient being treated with RUX who presented with a disseminated fungal infection. This case emphasises the need for vigilance of endemic fungal infections in individuals who are on RUX therapy.

Neuroinflammation is implicated in the development and maintenance of alcohol use disorder (AUD) and neuroimmune therapeutics show promise in treating AUD. Proinflammatory signaling contributes to progressive elevations in the dysfunction of mood and alcohol craving. The current study sought to examine potential biobehavioral mechanisms of neuroimmune modulation in AUD under experimental conditions. In a community sample of individuals with AUD who completed a placebo-controlled crossover trial of ibudilast, we tested the effect of ibudilast on the relationship between mood states and alcohol craving. Multilevel modeling analyses tested the hypothesis that ibudilast would moderate the effect of positive and negative mood states on alcohol craving during stress and cue exposures. Results revealed that after stress-induction, participants' feelings of depression and happiness were more strongly predictive of their craving for alcohol while taking ibudilast as compared with placebo (

JAK 2 inhibitors are widely used for the treatment of primary myelofibrosis. Ruxolitinib is the most commonly used JAK inhibitor in clinical practice. We report two cases of Primary Myelofibrosis who developed tuberculosis on active treatment with ruxolitinib. Our first case was a 48 year male who developed disseminated tuberculosis during fourth month of treatment and second case was a 50 year male developing tubercular lymphadenitis during second month of treatment respectively. These case reports indicate reactivation of underling tubercular infection as a very dreaded complication of this treatment. The prevalence of tuberculosis is much higher in India compared to the west. A thorough pretreatment evaluation should ideally be done using Mantoux test or interferon gamma release assay (IGRA) to rule out latent tuberculosis. Furthermore, the patients should be counselled regarding the possibility of reactivation of infections including tuberculosis. Also, proper follow up is the need of hour in all patients on any kind of immunomodulators.

A 75-year-old woman was diagnosed with primary idiopathic thrombocytopenic purpura (ITP). The patient had no history of thrombotic events. We could not administer the standard dose of glucocorticoid because of her old age, and her platelet count did not increase with glucocorticoid monotherapy.

Introduction : Treatment options in patients with myelofibrosis (MF) presenting with thrombocytopenia are limited. Final results of the phase 2 study (NCT01348490) of ruxolitinib in patients with MF and low baseline platelet counts (50–100 × 109/L) are reported. Patients and Methods : Patients received ruxolitinib 5 mg twice daily (BID), with optional up-titration to a maximum of 15 mg BID, provided platelet count remained ≥40 × 109/L. Assessments included spleen volume and length, Total Symptom Score (TSS), quality of life, and safety. Results : Of 66 patients, 52 (78.8%) completed the first 24 weeks of treatment. Median (range) percentage change from baseline in spleen volume and TSS (coprimary endpoints) were −20.5% (−55.8% to 38.5%, n=51) and −39.8% (−98.6% to 226.4%, n=53), respectively; greatest median reductions were in the 10 mg BID final titrated dose group. Of patients achieving ≥35% or ≥10% reduction in spleen volume, 8/11 (72.7%) and 21/34 (61.8%), respectively, were in the 10 mg BID final titrated dose group. Thirty-seven of 65 patients (56.9%) had ≥20% improvement in TSS, and 35/66 patients (53.0%) were Patient Global Impression of Change responders. Treatment-emergent adverse events led to dose interruption in 17/66 patients (25.8%), most commonly thrombocytopenia (n=3). Conclusion : A starting dose of ruxolitinib 5 mg BID with gradual up-titration and dose optimization based on hematologic parameters and response was efficacious and generally well-tolerated in patients with MF and low platelet counts. Median improvement in spleen volume and symptoms was greatest for patients receiving ruxolitinib 10 mg BID.

Abstract: Hyperglycemia and its associated disorders like Diabetes mellitus are engulfing the world’s population at a faster pace. New-age medications like the SGLT 2 inhibitors have found their place in the run to combat DM. Drugs with these properties have proven to be effective in treating hyperglycemia, obesity, and major cardiac disorders. The interesting fact about these drugs is that they act independently of insulin levels in the patient’s body. The fact that they even bypass the side effects shown by currently used anti-diabetic medications has attracted the world’s hope to neutralize diabetes mellitus. The invention of Remogliflozin Etabonate (RGE), an SGLT 2 inhibitor, has therefore added a silver lining to the gliflozin-family of drugs in the fight against DM. This is due to its least side effects as well as its effective mechanisms to treat hyperglycemia. It can be administered not only as a single entity but also can be co-administered in combination with other anti-hyperglycemic agents. RGE is already sold in the Indian market as REMO-ZEN, by Glenmark Pharmaceuticals. It has been studied thoroughly for its pharmacokinetic and pharmacodynamic profile. It is a benzylpyrazole glucoside. Various analytical methods have been formulated for its detection, quantification, and routine quality control activities. RGE can be studied with the help of UV-visible spectrophotometry, High-Performance Liquid Chromatography (HPLC) and Hyphenated techniques like Liquid Chromatography- Mass Spectroscopy (LC-MS/MS). This review briefs about the overall chemical, pharmacological, pharmacokinetic and pharmacodynamics properties of RGE. It mainly discusses various analytical techniques used for determining and estimating RGE.

Background Though weight gain has been reported in some clinical trials of CFTR modulators, the effect of elexacaftor-tezacaftor-ivacaftor on body weight, body mass index (BMI), blood pressure, lipids and glycemic control in the real-world setting remains incompletely described. Methods We performed a single-center, retrospective, observational analysis of the effect of elexacaftor-tezacaftor-ivacaftor on body weight and cardiometabolic parameters in 134 adult CF patients of the Washington University Adult Cystic Fibrosis Center. Body weight, BMI, and blood pressure were extracted from outpatient clinic visits for the year preceding and the period following the initiation of elexacaftor-tezacaftor-ivacaftor. Other metabolic parameters were extracted at baseline and at latest available follow-up. Results A mean of 12.2 months of follow-up data was available for analysis. The mean rate of change in BMI was 1.47 kg/m2/yr (95% CI, 1.08 to 1.87) greater after initiation of elexacaftor-tezacaftor-ivacaftor. Significant increases in blood pressure were observed. In those without CFRD, random blood glucose and hemoglobin A1c were decreased after elexacaftor-tezacaftor-ivacaftor initiation. In those with CFRD, elexacaftor-tezacaftor-ivacaftor increased serum total cholesterol, HDL-cholesterol, and LDL-cholesterol. Conclusions In this single-center, retrospective, observational study of 134 adults with CF, initiation of elexacaftor-tezacaftor-ivacaftor was associated with increases in BMI at a mean follow up of 12.2 months. Changes in other cardiometabolic risk factors were also observed. Widespread use of elexacaftor-tezacaftor-ivacaftor may be expected to increase the incidence of overnutrition in the CF population.

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA, Trikafta) is the newest Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator drug approved by the Food and Drug Administration. Post-marketing reports with earlier CFTR modulators suggest these medications can impact mood, and in clinical trials an adverse effect of headache was reported with all currently approved CFTR modulators. However, there are no other documented reports of mental status changes during clinical trials or in post-marketing reports with elexacaftor/tezacaftor/ivacaftor. In this case series, we describe 6 patients who reported "mental fogginess" or other mental status changes shortly after initiation of this drug. The mechanism of this patient-reported side effect is still unclear. All patients noticed a change within the first 3 months of therapy. The management differed in each case, with all four cystic fibrosis (CF) care teams utilizing a patient-centered decision-making approach to address this concern.

BACKGROUND Risk assessment is essential in pulmonary arterial hypertension (PAH) management. We investigated the effect of riociguat on REVEAL Lite 2 score, an abridged version of the REVEAL risk score, and its association with long-term outcomes in PATENT. METHODS PATENT-1 was a randomized, double-blind study of riociguat vs placebo in patients with PAH. In the PATENT-2 open-label extension, all patients received riociguat up to 2.5 mg three times daily (n = 396). REVEAL Lite 2 scores were calculated at baseline, PATENT-1 Week 12, and PATENT-2 Week 12, with patients stratified as low- (1-5), intermediate- (6-7), or high-risk (≥8). Kaplan-Meier and Cox proportional hazards analyses assessed association of riociguat with survival and clinical worsening-free survival (CWFS). RESULTS REVEAL Lite 2 score improved with riociguat 2.5 mg at PATENT-1 Week 12 (least-squares mean difference vs placebo: -0.8; p = 0.0004). More patients receiving riociguat 2.5 mg stabilized or improved risk stratum at PATENT-1 Week 12 vs placebo (p = 0.0005) and achieved low-risk status. REVEAL Lite 2 score at baseline and PATENT-1 Week 12 were associated with survival and CWFS (all p < 0.0001), as was change in score from baseline to Week 12 (p = 0.0002 and p < 0.0001, respectively). Survival and CWFS differed between risk strata at baseline (p < 0.0001) and PATENT-1 Week 12 (p < 0.0001). CONCLUSIONS This analysis confirms the risk-reduction benefits of riociguat in patients with PAH and further contributes to the validation of REVEAL Lite 2 in facilitating PAH risk assessment.

Background: To evaluate the effects of teneligliptin on glycosylated hemoglobin (HbA1c) levels, continuous glucose monitoring (CGM)-derived time in range, and glycemic variability in elderly type 2 diabetes mellitus patients.Methods: This randomized, double-blinded, placebo-controlled study was conducted in eight centers in Korea (clinical trial registration number: NCT03508323). Sixty-five participants aged ≥65 years, who were treatment-naïve or had been treated with stable doses of metformin, were randomized at a 1:1 ratio to receive 20 mg of teneligliptin (n=35) or placebo (n=30) for 12 weeks. The main endpoints were the changes in HbA1c levels from baseline to week 12, CGM metrics-derived time in range, and glycemic variability.Results: After 12 weeks, a significant reduction (by 0.84%) in HbA1c levels was observed in the teneligliptin group compared to that in the placebo group (by 0.08%), with a between-group least squares mean difference of –0.76% (95% confidence interval [CI], –1.08 to –0.44). The coefficient of variation, standard deviation, and mean amplitude of glycemic excursion significantly decreased in participants treated with teneligliptin as compared to those in the placebo group. Teneligliptin treatment significantly decreased the time spent above 180 or 250 mg/dL, respectively, without increasing the time spent below 70 mg/dL. The mean percentage of time for which glucose levels remained in the 70 to 180 mg/dL time in range (TIR70–180) at week 12 was 82.0%±16.0% in the teneligliptin group, and placebo-adjusted change in TIR70–180 from baseline was 13.3% (95% CI, 6.0 to 20.6).Conclusion: Teneligliptin effectively reduced HbA1c levels, time spent above the target range, and glycemic variability, without increasing hypoglycemia in our study population.

Purpose: Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition. Patients and Methods: We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247. Results: Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance. Conclusions: BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.

Enflicoxib is a newly developed NSAID of the coxib class. The optimal therapeutic dose to be confirmed in the field studies was established using a combination of pharmacokinetic (PK) modelling and pharmacodynamic (PD) studies. First, a PK study was performed to determine the plasmatic profile of enflicoxib and its active pyrazol metabolite in dogs. Thereafter, two studies using a urate crystal‐induced acute arthritis model allowed to correlate efficacy with plasmatic concentrations. Finally, a population PK model was developed to establish the Minimum Effective Concentration (MEC) and the Maximum Tolerated Concentration (MTC). Enflicoxib plasma concentrations were highest for the first 48 h. Thereafter, pyrazol metabolite concentrations were higher and persisted up to the end of the study. No reduction on the lameness (CLS) or pain scores (PS) was observed in the first hours after enflicoxib administration so no MEC could be established for the parent compound. Both CLS and PS were greatly reduced when the pyrazol metabolite achieved concentrations of 411 ng/ml or higher, so this concentration was established as the MEC for the pyrazol metabolite. Enflicoxib MTC was established at 6723 ng/ml whereas for the pyrazol metabolite it was 4258 ng/ml. The population PK model showed that a loading enflicoxib dose of 8 mg/kg followed by weekly maintenance doses of 4 mg/kg would achieve stable concentrations of the pyrazol metabolite within the therapeutic window (between the MEC and the MTC), and it was considered the most adequate posology to be confirmed in the field clinical studies for the treatment of canine osteoarthritis., A dose proposal for enflicoxib was defined by a combination of pharmacodynamic studies and pharmacokinetic modelling based on urate crystal‐induced arthritis studies in Beagle dogs. Plasma concentrations were related to the efficacy to establish the Minimum Effective Concentration (MEC) and to the Maximum Tolerated Concentration (MTC). For the pyrazol metabolite, the MEC was established at 411 ng/ml. Enflicoxib MTC was 6723 ng/ml whereas MTC for the pyrazol metabolite was 4258 ng/ml. An enflicoxib loading dose of 8 mg/kg followed by weekly maintenance enflicoxib doses of 4 mg/kg is proposed for clinical studies on canine osteoarthritis.

Clinical Practice Points • Selpercatinib and pralsetinib both have high extracranial efficacy in RET fusion-positive non-small cell lung cancer (NSCLC). • We present a case of a patient with RET fusion-positive NSCLC who had a durable extracranial response to pralsetinib, but had leptomeningeal progression. She subsequently had both a clinical and radiographic CNS response to selpercatinib. • Future studies should compare the intracranial efficacy with these 2 RET inhibitors, with implications on choice and sequence of their use.

Despite being an important patient group, adult cystic fibrosis patients with an FEV1 below 40%predicted have been excluded from clinical trials with elexacaftor/tezacaftor/ivacaftor. We conducted a real-life 3 months follow-up study in 14 adult CF patients (median FEV1 34%predicted) demonstrating significant treatment effects in terms of FEV1 (an increase of 12%predicted at 4 weeks, remaining stable thereafter). Corresponding decreases in lung clearance index LCI (by 31%predicted, down from baseline 247%predicted) and ventilation heterogeneity in the acinar compartment (Sacin) (by 411%predicted, down from baseline 798%predicted) suggest a distinct peripheral lung effect. One patient had intermittent treatment interruptions because of drug-induced liver injury. Our real-life data confirm that treatment with elexacaftor/tezacaftor/ivacaftor is effective in severely obstructive patients, and this is the first study to show time evolution of ventilation distribution improvement, pointing to the peripheral lung as the main site of treatment effect.

There remains a lack of prognosis models for patients with chronic thromboembolic pulmonary hypertension (CTEPH). This study aims to develop a nomogram predicting 3-, 5-, and 7-year survival in patients with CTEPH and verify the prognostic model. Patients with CTEPH diagnosed in Fuwai Hospital were enrolled consecutively between May 2013 and May 2019. Among them, 70% were randomly split into a training set and the other 30% as a validation set for external validation. Cox proportional hazards model was used to identify the potential survival-related factors which were candidate variables for the establishment of nomogram and the final model was internally validated by the bootstrap method. A total of 350 patients were included in the final analysis and the median follow-up period of the whole cohort was 51.2 months. Multivariate analysis of Cox proportional hazards regression showed body mass index, mean right atrial pressure, N-terminal pro-brain natriuretic peptide (per 500 ng/ml increase in concentration), presence of anemia, and main treatment choice were the independent risk factors of mortality. The nomogram demonstrated good discrimination with the corrected C-index of 0.82 in the training set, and the C-index of 0.80 (95% CI: 0.70 to 0.91) in the external validation set. The calibration plots also showed a good agreement between predicted and actual survival in both training and validation sets. In conclusion, we developed an easy-to-use nomogram with good apparent performance using 5 readily available variables, which may help physicians to identify CTEPH patients at high risk for poor prognosis and implement medical interventions.

Background HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors. Methods We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data. Results Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 amplification had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplification (HR 2.284, P =.004). Conclusion A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis.

Background: The benefits of baricitinib, which is a Janus kinase inhibitor, in coronavirus disease-2019 (COVID-19) are inadequately defined. We performed a systematic review and meta-analysis of randomised, controlled trials and observational studies of baricitinib to determine its clinical efficacy and adverse events in patients with COVID-19. Methods: Major databases were searched from 2019 to 2021 inclusive. The primary outcome was the coefficient of mortality. We also compared increasing different doses of baricitinib, intensive care unit admission, the requirement for mechanical ventilation, the oxygenation index, and adverse events between baricitinib treatment and placebo or other treatments. Findings: Twelve studies of 3564 patients were included and assessed qualitatively (Jadad and Newcastle–Ottawa Scale scores). Baricitinib effectively improved the mortality rate (relative risk of mortality = 0.56; 95% confidence interval: 0.46–0.69; P < 0.00001; I2 = 2%), and this result was unchanged by subgroup analysis. Baricitinib also improved intensive care unit admission, the requirement for invasive mechanical ventilation, and the oxygenation index. Data from these studies also showed that baricitinib slightly reduced the risk of adverse events. With regard to the choice of the drug dosage of baricitinib, the high-dose group appeared to have additional benefits for clinical efficacy. Interpretation: Our study shows that baricitinib may be a promising, safe, and effective anti-severe acute respiratory syndrome-coronavirus-2 drug candidate, with the advantages of a low cost, easy production, and convenient storage. Funding Information: We gratefully acknowledge the financial supports by the Basic research program of Guangzhou (202102010224), Clinical Transformation program of the first affiliated hospital of Guangzhou medical university (ZH201802, ZH201914), High-level university program of Guangzhou medical university (2017(160)) and Opening Project of State Key Laboratory of Respiratory Disease (SKLRD-0P-202115). Declaration of Interests: The authors have no potential conflict of interest to disclose.

A 6-year-old female presenting with an abdominal mass was found to have an unresectable undifferentiated sarcoma. The tumor did not respond to multi-agent chemotherapy. However, molecular testing identified an NTRK3 fusion, and treatment was changed to larotrectinib monotherapy. Following 6 months of therapy, the patient achieved a very good partial response with 96% reduction in tumor size. She underwent proton beam radiation therapy with continued larotrectinib therapy and achieved a complete response. This case report shows that an NTRK fusion positive undifferentiated sarcoma can be safely treated with larotrectinib and radiation therapy and highlights the importance of early molecular testing.

Summary Background We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration. Methods This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per μL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2–8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8–24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [ clinicaltrials.gov ( NCT03824483 ). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort. Findings Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52–70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0–27·3), 33 (89%) of 37 patients (95% CI 75–97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8–12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0–18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli. Interpretation BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics. Funding Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.

Background Pralsetinib, an RET inhibitor, has shown a dramatic response in patients with RET fusion- or mutation-positive tumours in previous studies. As a novel target agent, however, the safety of pralsetinib remains to be determined. Herein, we present two cases of extrapulmonary tuberculosis (TB) that developed during pralsetinib therapy. Methods From April 2020, we administered pralsetinib to a total of 10 patients with RET fusion-positive non-small cell lung cancer under the compassionate use program. We retrospectively analysed the clinical efficacy of and adverse events related to pralsetinib therapy. Results Of the nine patients with measurable lesions, seven achieved a partial response. Additionally, one patient without measurable lesions also showed a clinical response. As of January 8, 2021, nine patients were still receiving pralsetinib therapy, while only one had discontinued pralsetinib therapy. Most adverse events were mild and manageable. However, two patients experienced extrapulmonary TB shortly after starting pralsetinib. The disease was well controlled with anti-TB medication, and the cancer lesions were managed through ongoing pralsetinib therapy. Conclusion The development of TB during pralsetinib therapy is worth noting, although further large studies are required to demonstrate definitive relationship between causality and underlying mechanism.

Introduction Over the last few years, improved outcomes in patients with chronic lymphocytic leukemia (CLL) have been credited to the introduction of novel agents for its treatment. However, the overall cardiovascular safety profile of these agents has not been studied adequately. Methods We searched the Food and Drug Administration Adverse Event Reporting System (FAERS) database for adverse events reported for several of these novel agents: ibrutinib, acalabrutinib, venetoclax, and idelalisib. Results A total of 6074 cardiac adverse events were identified; ibrutinib (4832/36581; 13.2%) was found to have the highest risk of cardiac adverse events. The frequency of atrial fibrillation was highest (41.5%) in the ibrutinib group, while the idelalisib and acalabrutinib groups had the highest reported frequencies of heart failure (25.1%) and myocardial infarction (13.6%), respectively. Hypertension was noted to be relatively higher in the acalabrutinib (25.6%) and venetoclax (11.8%) groups. Overall reported mortality associated with cardiac events was highest in the venetoclax (29.4%) and idelalisib (27.1%) groups. Conclusion Novel agents in the CLL armamentarium have been associated with several cardiovascular adverse events. Further studies are needed to identify high-risk groups that would benefit from robust cardiovascular surveillance after initiation of treatment with these novel agents.

Apixaban is used to treat venous thromboembolism (VTE) at 10 mg twice daily (BID) for 7 days, followed by 5 mg BID without dose adjustment, and non-valvular atrial fibrillation (NVAF) at 5 mg BID or 2.5 mg BID with dose adjustment criteria (DAC) including age, body weight, and renal function. The anti-factor Xa activity (AXA), prothrombin time (PT), and activated partial thromboplastin time (APTT) in patients with VTE receiving 10 mg BID of apixaban remains unclear. Twenty-six patients (70.8±15.4 years, 10 males) with VTE receiving 10 mg BID of apixaban were enrolled. The patients were divided into two groups based on whether they met the DAC of NVAF: DAC group (n=8) and non-DAC group (n=18). Trough and peak AXA values, PT, and APTT were measured at 10 mg BID dosage and then at 5 mg BID dosage. Coagulation markers in recipients of 10 mg BID therapy were significantly higher than those of 5 mg BID recipients. A significant and strong positive correlation was observed between AXA and PT at trough and peak times. The AXA values and PT in the DAC group were significantly higher than those in the non-DAC group. No significant inter-group differences were seen in APTT. This study provides the first report of AXA distribution in VTE patients receiving 10 mg BID of apixaban. Our findings indicate that coagulation markers may differ in patients with VTE-prescribed higher doses of apixaban and a DAC may be warranted in such patients.

Direct-acting oral anticoagulants (DOACs) vary in bioavailability and sites of absorption in the gastrointestinal tract (GIT). Data on DOAC use after major GIT surgery are limited. The aim of this case series was to report the impact of surgical resection or bypass of the GIT on rivaroxaban and apixaban peak plasma concentrations. This was a case series of patients who received rivaroxaban or apixaban after GIT surgery, during the period of July 1, 2019, to December 31, 2020. Peak plasma concentrations of rivaroxaban and apixaban were assessed for the expected concentrations. Of the 27 assessed patients, 18 (66.7%) received rivaroxaban, and 9 (33.3%) received apixaban. After rivaroxaban therapy, 4 of 5 patients (80%) who underwent gastrectomy, and 3 of 3 patients (100%) who underwent duodenum and proximal jejunum exclusion had peak plasma concentrations of rivaroxaban lower than the effective range, whereas 11 of 11 patients (100%) who underwent distal bowel or ileostomy had peak rivaroxaban plasma within the effective range. After apixaban therapy, 5 of 6 patients (83.3%) who underwent total or partial gastrectomy achieved effective peak concentrations. All the patients who underwent proximal and distal bowel resection or bypass had peak concentrations of apixaban within the effective range. In conclusion, surgical resection or bypass of the upper GIT could affect DOAC absorption and subsequently peak plasma concentrations. This effect was more observed among rivaroxaban recipients. An injectable anticoagulant or vitamin K antagonist may be preferred if DOAC concentrations cannot be measured after GIT surgery.

Portomesenteric thrombosis is an important but rarely reported complication following bariatric surgery. It has been suggested that the incidence of portal vein thrombosis is directly related to many risk factors inherent in the bariatric population as well as factors related to local and systemic effects of laparoscopic surgery. Possible aetiologies vary from systemic inherited hypercoagulable states to a direct inflammatory reaction of portosystemic vessels. Here we present a case report of a 47-year-old obese women who underwent a robotic sleeve gastrectomy with subsequent development of a main portal vein, complete right intrahepatic portal vein and splenic vein thrombosis ultimately found to have a compound mutation of the methylenetetrahydrofolate reductase C677T and A1298C alleles.

Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. A total of 233 patients were randomized to asciminib (n = 157) or bosutinib (n = 76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% confidence interval, 2.19-22.30; 2-sided P = .029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant/intolerant to ≥2 prior TKIs. This trial was registered at www.clinicaltrials.gov as #NCT03106779.

Introduction Baricitinib–remdesivir (BARI-REM) combination is superior to remdesivir (REM) in reducing recovery time and accelerating clinical improvement among hospitalized patients with coronavirus disease 2019 (COVID-19), specifically those receiving high-flow oxygen/noninvasive ventilation. Here we assessed the cost-effectiveness of BARI-REM versus REM in hospitalized patients with COVID-19 in the USA. Methods A three-state model was developed addressing costs and patient utility associated with COVID-19 hospitalization, immediate post hospital care, and subsequent lifetime medical care. Analysis was performed from the perspective of a payer and a hospital. Both perspectives evaluated two subgroups: all patients and patients who required oxygen. The primary measures of benefit in the model were patient quality-adjusted life years (QALYs) accrued during and after hospitalization, cost per life years gained, cost per death avoided, and cost per use of mechanical ventilation avoided. Results In the base-case payer perspective with a lifetime horizon, treatment with BARI-REM versus REM resulted in an incremental total cost of $7962, a gain of 0.446 life years and gain of 0.3565 QALYs over REM. The incremental cost-effectiveness ratios of using BARI-REM were estimated as $22,334 per QALY and $17,858 per life year. The base-case and sensitivity analyses showed that the total incremental cost per QALY falls within the reduced willingness-to-pay threshold of $50,000/QALY applied under health emergencies. In all hospitalized patients, treatment with BARI-REM versus REM reduced total hospital expenditures per patient by $1778 and total reimbursement payments by $1526, resulting in a $252 reduction in net costs per patient; it also resulted in a net gain of 0.0018 QALYs and increased survival of COVID-19 hospitalizations by 2.7%. Conclusion Our study showed that BARI-REM is cost-effective compared to using REM for hospitalized patients with COVID-19. The base-case results of this cost-effectiveness model were most sensitive to average annual medical costs for recovered patients. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01982-6.

INTRODUCTION: Apalutamide and darolutamide are next-generation androgen receptor inhibitors that have demonstrated superior efficacy compared to placebo in men with non-metastatic castration-resistant prostate cancer (nmCRPC) receiving androgen deprivation therapy (ADT). In the absence of head-to-head studies, the present study sought to indirectly compare the efficacy and tolerability between these two treatments. METHODS: This anchored matching-adjusted indirect comparison (MAIC) used patient-level data from the phase 3, randomized, controlled SPARTAN study (apalutamide + ADT), weighted to match aggregate published data from the ARAMIS study (darolutamide + ADT) for clinically relevant baseline measures. Hazard ratios (HR) and 95% credible intervals (CrI) were estimated for efficacy endpoints: metastasis-free survival (MFS), prostate-specific antigen (PSA) progression, progression-free survival (PFS), and overall survival (OS). Odds ratios were estimated for tolerability outcomes: adverse events and serious adverse events. RESULTS: Before weighting, baseline characteristics from SPARTAN versus ARAMIS were different for median PSA (7.8 vs. 9.2 ng/mL), Eastern Cooperative Oncology Group performance status of 1 (23% vs. 31%), use of bone-targeted agents (10% vs. 4%), median time from initial diagnosis (94.9 vs. 85.4 months), and proportion of patients from North America (35% vs. 12%) and Europe (50% vs. 64%). After matching (n = 455), our analysis demonstrated that apalutamide + ADT had a Bayesian probability of being more effective than darolutamide + ADT for MFS [98.3%; HR 0.70 (95% CrI 0.51, 0.98)], PSA progression [~ 100%; HR 0.46 (95% CrI 0.33, 0.64)], and PFS [93.2%; HR 0.79 (95% CrI 0.59, 1.08)]. Results for OS and tolerability were similar between apalutamide + ADT and darolutamide + ADT. CONCLUSION: This anchored MAIC analysis of pivotal phase 3 studies in patients with nmCRPC suggests that apalutamide + ADT is more effective than darolutamide + ADT for MFS, progression-free survival (PFS), and prostate-specific antigen (PSA) progression, with a similar OS benefit and tolerability profile. TRIAL REGISTRATION: ARAMIS ClinicalTrials.gov number: NCT02200614; SPARTAN ClinicalTrials.gov number: NCT01946204. ispartof: ADVANCES IN THERAPY vol:39 issue:1 pages:518-531 ispartof: location:United States status: published

Dorzagliatin is a novel allosteric glucokinase activator targeting both pancreatic and hepatic glucokinase currently under clinical investigation for treatment of type 2 diabetes (T2D). This study aimed to investigate the effect of renal impairment (RI) on dorzagliatin’s pharmacokinetics (PKs) and safety, and to guide appropriate clinical dosing in patients with diabetic kidney disease, including end‐stage renal disease (ESRD). Based on the results from physiologically‐based pharmacokinetic modeling, the predicted outcome of RI on dorzagliatin PK property would be minimum that the plasma exposure area under concentration (AUC) of dorzagliatin in patients with ESRD would increase at about 30% with minimal change in peak concentration (Cmax) comparing to those in healthy volunteers (HVs). To definitively confirm the prediction, a two‐part RI study was designed and conducted based on regulatory guidance starting with the patients with ESRD matched with HVs. Results of the RI study showed minimum difference between patients with ESRD and HVs with respect to dorzagliatin exposure with geometric mean ratio of ESRD to HV at 0.81 for Cmax and 1.11 for AUC. The elimination half‐life, volume of distribution, and systemic clearance for dorzagliatin were similar between the two groups. Dorzagliatin was well‐tolerated in patients with ESRD during the study. Therefore, RI showed no significant impact on dorzagliatin PK, suggesting that dorzagliatin can be readily used in patients with T2D at all stages of RI without need for dose adjustment.

Background Polycythemia vera (PV) is a myeloproliferative neoplasm affecting >100,000 people in the United States annually. Patients (pts) with PV are at risk for thromboembolic events (TEs), premature death, and high symptom burden. Hydroxyurea (HU) is recommended for high-risk pts with PV; however, up to 40% of pts become resistant and/or intolerant to the drug (Demuynck T, et al. Ann Hematol. 2019;98:1421-1426). Ruxolitinib (RUX), a Janus kinase (JAK) 1/JAK2 inhibitor, is currently the only FDA-approved treatment option for pts with PV who are resistant to or intolerant of HU. We conducted a retrospective chart review to characterize the reasons pts were switched from HU to RUX and to describe the real-world dosing patterns of RUX in pts with PV. Methods This retrospective medical chart review was conducted at US community hematology/oncology practices in the Cardinal Health Oncology Provider Extended Network. Eligible pts were ≥18 y old, initiated RUX therapy during the index period (January 1, 2015, to December 31, 2016), were previously treated with HU for ≥3 mo, and were seen at least twice during the 6 mo following RUX initiation. Data were collected for the 12 mo prior to RUX initiation (including near the time of HU discontinuation), near the time of RUX initiation (index), and up to the last provider visit. Pt and clinical characteristics were collected, including blood counts, symptoms, TEs, cardiovascular disease risk factors, phlebotomy, and HU and RUX treatment patterns. Target enrollment was 250 pts; interim results are presented here. Results Providers identified 99 pts for inclusion; mean (SD) age was 64 (9.9) y, 56% were male, and 68% had high-risk PV (ie, age ≥60 y and/or history of TE). All pts had been tested for the JAK2V617F mutation, and 99% were positive. At the time of HU discontinuation, 28% of pts had reached an HU dose of ≥2 g/d; median (range) HU treatment duration was 9.7 (3.6-182.4) mo. Causes of HU discontinuation were resistance (63%), intolerance (17%), resistance and intolerance (11%), and other reasons (9%; Table). The most frequent reasons for HU discontinuation due to resistance were hematocrit (Hct) ≥45% (79%), symptoms (45%), leukocytosis (32%), thrombocytosis (31%), and splenomegaly (22%). The most frequent intolerance signs and symptoms were nausea (43%), stomatitis (25%), fever (18%), and skin ulcers (14%). With respect to the RUX starting dose, 44 pts (44%) initiated RUX at the US package insert-recommended dose of 10 mg twice daily (BID); median (range) treatment duration for these pts was 26.4 (3.2-52.0) mo (Table). During the first 6 mo of RUX treatment, dose modification was noted in 19 pts (43%) who initiated at 10 mg BID (dose increase, n=13 [30%]; dose decrease, n=5 [11%]; dose interruption, n=1 [2%]). The most common reasons for dose increase were continued need for phlebotomy (39%) and symptoms (39%). Five pts required a dose reduction; the most common reason was low hemoglobin levels (n=3). Overall, pts starting at 10 mg BID had more dose modifications in the first 6 mo of RUX treatment (43%), with fewer dose modifications needed after 6 mo (25%). Hct control (Hct Conclusions In this interim analysis of real-world data pertaining to pts with PV who discontinued HU and were subsequently treated with RUX, the most common resistance events leading to HU discontinuation were Hct ≥45%, uncontrolled symptoms, leukocytosis, thrombocytosis, and splenomegaly. Discontinuations due to intolerance were most commonly attributed to nausea, stomatitis, fever, and skin ulcers. Of pts who were switched from HU to RUX, the duration of HU treatment was shorter and the proportion of pts treated with HU doses of ≥2 g/d was higher than has been reported for all pts discontinuing HU, irrespective of their next line of therapy (Grunwald MR, et al. ASH Annual Meeting 2017. Poster 1633). Less than half of pts initiated RUX at the recommended dose of 10 mg BID; 41% of pts dosed in accordance with the recommended starting dose experienced dosing modifications (primarily dose increases); however, the majority of pts who discontinued RUX had no dosing modifications during their treatment. Results from the entire cohort of 250 pts will be presented. Disclosures Altomare: Amgen: Consultancy; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy; Rigel: Consultancy. Nguyen:Incyte: Employment, Equity Ownership. Parasuraman:Incyte: Employment, Equity Ownership. Paranagama:Incyte: Employment, Equity Ownership. Kish:Cardinal Health: Employment. Lord:Cardinal Health: Employment, Equity Ownership. Colucci:Incyte: Employment, Equity Ownership.

Background Coronavirus disease 2019 (COVID-19) has spread worldwide and is also an important disease in Japan. Thus, the optimal treatment strategy for severe COVID-19 should be established urgently. The effects of combination treatment with baricitinib—a Janus kinase inhibitor, remdesivir, and dexamethasone (BRD) are unknown. Methods Patients who received combination therapy with BRD at the Japanese Red Cross Medical Center were enrolled in the study. All patients received baricitinib (≤14 d), remdesivir (≤10 d), and dexamethasone (≤10 d). The efficacy and adverse events were evaluated. Results In total, 44 patients with severe COVID-19 were enrolled in this study. The 28-d mortality rate was low at 2.3% (1/44 patients). The need for invasive mechanical ventilation was avoided in most patients (90%, 17/19 patients). Patients who received BRD therapy had a median hospitalization duration of 11 d, time to recovery of 9 d, duration of intensive care unit stay of 6 d, duration of invasive mechanical ventilation of 5 d, and duration of supplemental oxygen therapy of 5 d. Adverse events occurred in 15 patients (34%). Liver dysfunction, thrombosis, iliopsoas hematoma, renal dysfunction, ventilator-associated pneumonia, infective endocarditis, and herpes zoster occurred in 11%, 11%, 2%, 2%, 2%, 2%, and 2% of patients, respectively. Conclusions Combination therapy with BRD was effective in treating severe COVID-19, and the incidence rate of adverse events was low. The results of the present study are encouraging; however, further randomized clinical studies are needed.

Background The global COVID-19 pandemic is currently underway. A massive worldwide vaccination campaign is still underway, representing the most promising weapon available to stop the pandemic. Methods and Results However, research continues to investigate the most effective drug treatments to reduce and avoid the most serious complications caused by COVID-19 infection. Recently, new evidence of good therapeutic efficacy against COVID-19 has emerged for the antiviral Remdesivir and the immunomodulatory Baricitinib, also in combination. The first one showed SARS-CoV-2 antireplicative activity, the second one useful to reduce the hyperinflammatory state caused by cytokine storm in the most severe phases of the infection. Conclusions In this short communication we describe the molecular pharmacological mechanisms and the latest evidence for the use of these therapeutic agents in the treatment of COVID-19 infection.

Thrombosis is the most common adverse event in patients with polycythemia vera (PV) and essential thrombocythemia (ET). Little is known about the use of nonvitamin K antagonist oral anticoagulants (NOACs) in patients with myeloproliferative neoplasms. We sought to evaluate the efficacy and safety of NOAC in a cohort of patients with PV and ET, who experienced venous thromboembolism (VTE). We enrolled 48 consecutive patients with PV (70.8%) and ET [median age 67.0 (interquartile range, 58.5-72.0) years], who experienced VTE. Patients received apixaban (39.6%), rivaroxaban (33.3%), or dabigatran (27.1%). During a median follow-up of 30 (interquartile range, 20.5-41.5) months, recurrent thrombotic events and bleeding were recorded. Four thrombotic events (3.3 per 100 patient-years) were reported. Three deep vein thrombosis episodes (2.5 per 100 patient-years) were experienced by 2 patients with PV, who received apixaban (5 mg bid) and dabigatran (150 mg bid), and 1 patient with ET, who received dabigatran (150 mg bid). One ischemic stroke occurred in a patient with PV on rivaroxaban (20 mg/d). There was 1 major bleeding (0.8 per 100 patient-years) in a patient with ET on dabigatran (150 mg bid) and 3 clinically relevant nonmajor bleeding (2.5 per 100 patient-years): 2 on rivaroxaban (20 mg/d) and 1 on apixaban (5 mg bid). We did not observe significant differences related to the type of NOAC. Three deaths (2.5 per 100 patient-years) unrelated to either VTE or bleeding were recorded. This study shows that NOACs may be effective and safe as secondary prevention of VTE in patients with myeloproliferative neoplasms.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a life-threatening complication described after administration of recombinant adenoviral vector encoding the spike protein antigen of Severe Acute Respiratory Syndrome CoronaVirus-2. The syndrome is characterized by platelet consumption and thrombosis. High levels of antibodies to platelet factor 4 (PF4)–polyanion complexes were identified in many patients with VITT by enzyme-linked immunosorbent assay (ELISA). A 64-year-old woman presented with thrombocytopenia, right renal vein thrombosis with renal infarction, right intra-right atrium and intra-right ventricle thrombosis and pulmonary embolism after ChAdOx1-S vaccine administration. ELISA for antibodies to PF4–polyanion complexes tested positive, while functional tests were not. Thrombocytopenia was refractory to intravenous immunoglobulins and corticosteroids. Eltrombopag was introduced and platelet gradually rose to normal values. VITT is a novel complication yet to be understood. The clinical case we reported highlights the difficulties in the management of this disorder and discloses a new potential therapy in refractory conditions.

Background Flares of juvenile idiopathic arthritis (JIA) have been described in the context of various infections. Flares of rheumatic diseases in adults have been described following infection with SARS-CoV-2 in several cohorts. So far, the effect of infection with SARS-CoV-2 on the course of JIA is unknown. Methods The database of the German Center for Pediatric and Adolescent Rheumatology was searched for patients with confirmed infection with SARS-CoV-2 and subsequent disease flare, admitted from July 2020 until June 2021. cJADAS-27, ESR and C-reactive protein, as well as uveitis activity, medication at the time of flare and treatment of flare was extracted. Patient cases were described individually. Results Out of 988 patients admitted, five patients with remission off medication (n = 2) or inactive disease on medication (n = 3) were identified, with flare symptoms up to four weeks after infection with SARS-CoV-2. Conclusions Flares can occur after infection with SARS-CoV-2 in patients with JIA in remission or inactive disease on medication. Treating physicians need to be aware of this fact, especially when counseling patients with rheumatic diseases about the respective dangers of COVID-19 and vaccination against SARS-CoV-2.

Cong Wei,1,&ast; Xiaoting Zhang,1,&ast; Dan Liang,1 Jilong Yang,1 Jingwen Du,1 Chunyan Yue,1 Lan Deng1,2 1Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2Department of Hematology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lan DengDepartment of Hematology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of ChinaTel +86 13724862939Email denglan_76@126.comChunyan YueDepartment of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of ChinaTel +86 15521117300Email doctor_yy@126.comBackground: Graft-versus-host disease (GVHD) is a main complication following allogeneic hematopoietic stem cell transplantation and is a leading cause of non-relapse-related death. Unsatisfactory response to standard first-line therapy with glucocorticoids is a predictor of a poor prognosis in patients with GVHD. Ruxolitinib is a selective Janus kinases 1/2 inhibitor which has been shown to control acute (a) and chronic (c) GVHD while maintaining graft-versus-tumor effects.Objective: This study aims to evaluate the efficacy and safety of ruxolitinib in the treatment of steroid-refractory GVHD (SR-GVHD) in a population of Chinese patients.Methods: We report the results of 55 patients, including 23 patients with aGVHD and 32 patients with cGVHD, who were treated with ruxolitinib as salvage therapy between August, 2017 and December, 2020.Results: In patients with aGVHD, the overall response rate (ORR) was 86.9%, and the 1-year overall survival (OS) was 82.6% (95% CI, 67.1– 98.1%). The 1-year OS was significantly improved in responders than in non-responders (90.0% vs 33.3%, P=0.004). In patients with cGVHD, the ORR was 78.1%, and the 1-year OS was 81.3% (95% CI, 67.8– 94.8%). There was no significant difference in the 1-year OS between responders and non-responders (84.0% vs 71.4%, P=0.327). Cytopenia, cytomegalovirus-reactivation and infections were common adverse events, particularly in patients with aGVHD.Conclusion: Our real-world data from Chinese patients further confirm that ruxolitinib is a safe and effective treatment for SR-GVHD.Keywords: ruxolitinib, allogeneic hematopoietic stem cell transplantation, graft-versus-host disease, steroid-refractory

Objective To compare the bleeding risk in patients with gastrointestinal (GI) cancer with that in patients with non-GI cancer treated with anticoagulation for acute cancer-associated venous thromboembolism (Ca-VTE). Patients and Methods Consecutive patients with Ca-VTE seen at the Mayo Thrombophilia Clinic between March 1, 2013, and April 20, 2020, were observed prospectively to assess major bleeding and clinically relevant nonmajor bleeding (CRNMB). Results In the group of 1392 patients with Ca-VTE, 499 (35.8%) had GI cancer including 272 with luminal GI cancer (lower GI, 208; upper GI, 64), 176 with pancreatic cancer, and 51 with hepatobiliary cancer. The rate of major bleeding and CRNMB in patients with GI cancer was similar to that in 893 (64.2%) patients with non-GI cancer treated with apixaban, rivaroxaban, or enoxaparin. Apixaban had a higher rate of major bleeding in luminal GI cancer compared with the non-GI cancer group (15.59 vs 3.26 per 100 person-years; P=.004) and compared with enoxaparin in patients with luminal GI cancer (15.59 vs 3.17; P=.04). Apixaban had a lower rate of CRNMB compared with rivaroxaban in patients with GI cancer (3.83 vs 9.40 per 100 person-years; P=.03). Patients treated with rivaroxaban in the luminal GI cancer group had a major bleeding rate similar to that of patients with non-GI cancer (2.04 vs 4.91 per 100 person-years; P=.37). Conclusion Apixaban has a higher rate of major bleeding in patients with luminal GI cancer compared with patients with non-GI cancer and compared with enoxaparin in patients with luminal GI cancer. Rivaroxaban shows no increased risk of major bleeding in patients with GI cancer or luminal GI cancer compared with patients with non-GI cancer. Trial Registration ClinicalTrials.gov identifier: NCT03504007 .

Background: In patients with atrial fibrillation who survive an anticoagulation-associated intracerebral haemorrhage, a decision must be made as to whether restarting or permanently avoiding anticoagulation is the best long-term strategy to prevent recurrent stroke and other vascular events. In APACHE-AF, we aimed to estimate the rates of non-fatal stroke or vascular death in such patients when treated with apixaban compared with when anticoagulation was avoided, to inform the design of a larger trial. Methods: APACHE-AF was a prospective, randomised, open-label, phase 2 trial with masked endpoint assessment, done at 16 hospitals in the Netherlands. Patients who survived intracerebral haemorrhage while treated with anticoagulation for atrial fibrillation were eligible for inclusion 7–90 days after the haemorrhage. Participants also had a CHA2DS2-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less. Participants were randomly assigned (1:1) to receive oral apixaban (5 mg twice daily or a reduced dose of 2·5 mg twice daily) or to avoid anticoagulation (oral antiplatelet agents could be prescribed at the discretion of the treating physician) by a central computerised randomisation system, stratified by the intention to start or withhold antiplatelet therapy in participants randomised to avoiding anticoagulation, and minimised for age and intracerebral haemorrhage location. The primary outcome was a composite of non-fatal stroke or vascular death, whichever came first, during a minimum follow-up of 6 months, analysed using Cox proportional hazards modelling in the intention-to-treat population. APACHE-AF is registered with ClinicalTrials.gov (NCT02565693) and the Netherlands Trial Register (NL4395), and the trial is closed to enrolment at all participating sites. Findings: Between Jan 15, 2015, and July 6, 2020, we recruited 101 patients (median age 78 years [IQR 73–83]; 55 [54%] were men and 46 [46%] were women; 100 [99%] were White and one [1%] was Black) a median of 46 days (IQR 21–74) after intracerebral haemorrhage. 50 were assigned to apixaban and 51 to avoid anticoagulation (of whom 26 [51%] started antiplatelet therapy). None were lost to follow-up. Over a median follow-up of 1·9 years (IQR 1·0–3·1; 222 person-years), non-fatal stroke or vascular death occurred in 13 (26%) participants allocated to apixaban (annual event rate 12·6% [95% CI 6·7–21·5]) and in 12 (24%) allocated to avoid anticoagulation (11·9% [95% CI 6·2–20·8]; adjusted hazard ratio 1·05 [95% CI 0·48–2·31]; p=0·90). Serious adverse events that were not outcome events occurred in 29 (58%) of 50 participants assigned to apixaban and 29 (57%) of 51 assigned to avoid anticoagulation. Interpretation: Patients with atrial fibrillation who had an intracerebral haemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomised controlled trials large enough to allow identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous. Funding: Dutch Heart Foundation (grant 2012T077).

The article presents a clinical case of successful triple combination therapy in a female patient with functional class III idiopathic pulmonary arterial hypertension. Supplementing the previous macitentan and riociguat treatment with selexipag reduced the severity of clinical manifestations of pulmonary hypertension. Also, the treatment efficacy was demonstrated by improvement of laboratory and instrumental indexes. Time-related changes were evaluated at 3 months after initiation of the selexipag treatment.

Psoriasis is a chronic immune-mediated skin disease with a significant impact on patients' quality of life. Mild-to-moderate forms of the disease usually require long-term topical treatment, but prolonged use of corticosteroids and vitamin D analogues is limited by adverse effects. With further understanding of psoriasis pathogenesis, new molecules are emerging aiming to fulfil these clinical needs. Tapinarof, an aryl hydrocarbon receptor modulator, has completed a phase III study and demonstrated good efficacy results, even in long treatment courses, with a favourable safety profile. It additionally appears to have a promising remitting effect as patients presented with an average relapsing time of over 3 months. Roflumilast, a phosphodiesterase type 4 inhibitor, also underwent a phase III study with significant lesion improvement and notable pruritus management, and with no reported side effects. Roflumilast was evaluated as an option for intertriginous areas with good outcomes in a small sample, but larger trials are required. The Janus kinase-signal transducer and activator of transcription pathway has been targeted in recent clinical investigations with promising options, currently with brepocitinib pending phase IIb results. Ongoing preclinical studies involving interleukin-2 inhibition, RNA modulators and amygdalin analogues may lead to forthcoming clinical trials. New topical drugs are successfully emerging and future research comparing them to classical options will dictate their clinical role in the treatment of psoriasis.

WHAT IS KNOWN AND OBJECTIVE Heparin-induced thrombocytopenia (HIT) is an adverse hematologic drug reaction that results in thrombocytopenia. This potentially life-threatening event is due to the administration of heparin products, such as unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH). The incidence of HIT occurs in

Purpose Lorlatinib is a third-generation tyrosine kinase inhibitor currently approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. This open-label, phase 1, randomized two-sequence, two-treatment, two-period, crossover study investigated the absolute oral bioavailability of lorlatinib in healthy participants. Methods Eligible participants were randomized to receive two treatments in one of two sequences: lorlatinib 100 mg single oral dose followed by lorlatinib 50 mg intravenous (IV) dose, or lorlatinib IV dose followed by lorlatinib oral dose, each with at least a 10-day washout between successive lorlatinib doses. Blood samples for pharmacokinetics were collected for up to 144 hours (h) after dosing. Validated liquid chromatographic-tandem mass spectrometry was used to determine plasma concentrations of lorlatinib and its benzoic acid metabolite PF-06895751. Results In total, 11 participants were enrolled (mean age 37.6 years, all male). The adjusted geometric mean (90% confidence interval) for the absolute oral bioavailability was 80.78% (75.73–86.16%). Using non-compartmental analysis, the estimated arithmetic mean elimination plasma half-life of lorlatinib was 25.5 and 27.0 h after the oral and IV doses, respectively. No deaths, serious adverse events (AEs), or severe AEs were reported, and most treatment-emergent AEs were mild in severity, with two events of transaminase increase of moderate severity. All treatment-emergent AEs were resolved by the end of the study. Conclusion Both oral and IV lorlatinib were well-tolerated in healthy participants and oral lorlatinib is highly bioavailable after oral administration.

It is unclear whether elderly patients established on direct oral anticoagulants (DOACs) have greater exposure to these drugs, which could subsequently increase their risk of bleeding. We assessed DOAC exposure and factors affecting it in a real-world elderly cohort of patients. For this, 151 medically stable hospital inpatients (76 established on apixaban, 61 on rivaroxaban, 14 on dabigatran) with a median [interquartile range (IQR)] age of 84 (78-89) years were recruited. Patients provided blood samples for measurement of peak and trough plasma DOAC concentrations. There was up to 48-fold and 13-fold variation in trough and peak plasma drug concentrations respectively. A significantly greater proportion of patients on apixaban had peak plasma drug concentrations within the reported ranges compared to those on either rivaroxaban or dabigatran (82·9% vs. 44·3% vs. 64·3% respectively; P < 0·001). A third of the variability in DOAC plasma concentrations was attributed to the influences of DOAC dosage, renal function and gender. To what extent the observed increases in DOAC exposure in the older patients is the cause of their increased risk of bleeding, which could potentially be ameliorated by dosing titration, requires further investigation.

A 71-year-old woman with a four-year history of chronic lymphocytic leukemia (CLL) received ibrutinib as initial treatment due to progressive anemia and thrombocytopenia. Eleven months after the start of the treatments, although her cytopenia had ameliorated, she developed classic Hodgkin lymphoma, a rare form of Richter's transformation. She was successfully treated with two courses of adriamycin, vinblastin, bleomycin and dacarbazine followed by radiotherapy. In general, several clinical, genetic and molecular factors are associated with Richter's transformation. In addition, our present case suggested that ibrutinib could be a potential risk factor for Richter's transformation in CLL patients.

The Janus kinase inhibitor ruxolitinib is approved for the treatment of myelofibrosis (MF) and improved overall survival (OS) versus control therapy in the phase 3 COMFORT trials. The aim of this retrospective analysis was to examine the real-world impact of ruxolitinib on OS in patients with MF. The US Medicare Fee-for-Service claims database (parts A/B/D) was used to identify patients with ≥ 1 inpatient or ≥ 2 outpatient claims with an MF diagnosis (January 2010–December 2017). Eligible patients with MF were ≥ 65 years old (intermediate-1 or higher risk based on age). Patients were divided into 3 groups based on ruxolitinib approval status at diagnosis and ruxolitinib exposure: (1) preapproval, ruxolitinib-unexposed; (2) post-approval, ruxolitinib-unexposed; and (3) post-approval, ruxolitinib-exposed. In total, 1677 patients with MF were included (preapproval [all ruxolitinib-unexposed], n = 278; post-approval, n = 1399 [ruxolitinib-unexposed, n = 1127; ruxolitinib-exposed, n = 272]). Overall, median age was 78 years, and 39.8% were male. Among patients with valid death dates (preapproval, n = 119 [42.8%]; post-approval, ruxolitinib-unexposed, n = 382 [33.9%]; post-approval ruxolitinib-exposed, n = 54 [19.9%]), 1-year survival rates were 55.6%, 72.5%, and 82.3%, and median OS was 13.2 months, 44.4 months, and not reached, respectively. Risk of mortality was significantly lower post- versus preapproval regardless of exposure to ruxolitinib (ruxolitinib-unexposed: adjusted hazard ratio [HR], 0.67; ruxolitinib-exposed: adjusted HR, 0.36; P P = 0.002). Findings from this study complement clinical data of ruxolitinib in MF by demonstrating a survival benefit in a real-world setting.

In the MYF2001 trial, treatment of Janus kinase (JAK) inhibitor-relapsed/refractory intermediate-2 or high-risk myelofibrosis (MF) with imetelstat 9.4 mg/kg every 3 weeks demonstrated encouraging median overall survival of 29.9 months. To provide historical context, external real-world data (RWD) were collected from a study of 96 patients who had discontinued ruxolitinib and were subsequently treated with best available therapy (BAT) at Moffitt Cancer Center. A closely matched cohort was identified using the MYF2001 eligibility criteria, including patients with MF who had discontinued ruxolitinib due to lack or loss of response. Overall survival was measured from time of JAK inhibitor discontinuation to death or censored at last follow-up. To improve comparability, propensity score weighting approaches using average treatment effect for overlap population (ATO) and stabilized inverse probability treatment weighting (sIPTW) were used for 10 critical baseline covariates. Fifty-seven patients treated with imetelstat 9.4 mg/kg from MYF2001 and 38 patients treated with BAT from RWD were analyzed with improved balanced baseline covariates after propensity score adjustment, showing significantly lower risk of death with imetelstat compared with BAT (hazard ratio: 0.35; p = 0.0019). With sIPTW, results were similar. Results of sensitivity analyses were consistent with the primary analysis. In conclusion, treatment with imetelstat was associated with longer overall survival compared to BAT (30 vs 12 months, respectively) in closely matched patients with MF after JAK inhibitor failure, warranting further evaluation of imetelstat in this poor-prognosis patient population.

Introduction Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non–small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear. Methods This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients’ clinicopathologic characteristics and treatment outcomes were analyzed. Results Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M × 2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R × 2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A × 2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%. Conclusions The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.

Objective: We aimed to analyze clinical outcomes from patients with severe COVID-19 pneumonia that received either baricitinib plus dexamethasone or dexamethasone monotherapy. Methodology: We performed a retrospective comparative study. Data from hospitalized patients with severe COVID-19 pneumonia (saturation