Background & Aims The drug-induced liver injury network (DILIN) is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study. Methods In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI. Results Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P=.09) and mortality was significantly higher (16% vs 5.2%; P<.001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared to those without liver disease (6.7% vs. 1.5%, p=0.006). Forty-one cases with latency ≤ 7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared to individuals younger than 65 y, individuals 65 y or older (n=149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died. Conclusion Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared to patients without. Further studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.

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Background Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis (CF) in 10% of patients.. Methods This randomized, double-blind, placebo-controlled study enrolled 238 patients ≥6 years with nmCF to receive oral ataluren 10 mg/kg in the morning, 10 mg/kg mid-day, and 20 mg/kg in the evening or matching placebo for 48 weeks. The primary endpoint was relative change in % predicted forced expiratory volume in one second (FEV1) at Week 48; the secondary endpoint was the rate of pulmonary exacerbations. This study is registered with ClinicalTrials.gov, number NCT00803205. Findings There was no statistically significant difference in relative change from baseline in % predicted FEV1between ataluren and placebo at Week 48(-2•5% vs -5•5%, p=0.1235). The rate of pulmonary exacerbations was not statistically different between treatment arms (rate ratio 0.77 (95% CI 0.57, 1.05), p=0.0992). However, post hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5.7% difference in relative change from baseline in % predicted FEV1 between ataluren and placebo at Week 48 (-0.7% vs -6.4%, nominal p=0•008, adjusted for multiplicity p = 0•024) and 40% fewer exacerbations in ataluren-treated patients (OR 0.60 (95% CI 0•42, 0•86), nominal p=0•006, adjusted for multiplicity p = 0•018). Interpretation While there was no statistically significant improvement in lung function or exacerbation rate in the ITT population of cystic fibrosis patients with nonsense mutations treated with ataluren, treatment might be beneficial for nmCF patients not receiving chronic inhaled tobramycin.

TO THE EDITOR Bruton tyrosine kinase (BTK) inhibitors have improved chronic lymphocytic leukemia (CLL) outcomes and offer a chemotherapyfree option [1]. The BTK inhibitor ibrutinib, alone or with a CD20 antibody, demonstrated better efficacy versus chemoimmunotherapy in treatment-naïve (TN) CLL [2][3][4]. However, cardiovascular toxicity is a concern with continuous ibrutinib use [5,6].Acalabrutinib is a next-generation, selective BTK inhibitor approved for CLL/small lymphocytic leukemia (SLL). Acalabrutinib, alone or with obinutuzumab, showed favorable efficacy in clinical trials [7,8]. ELEVATE-TN demonstrated superior efficacy for acalabrutinib-obinutuzumab versus obinutuzumab-chlorambucil with acceptable tolerability in TN CLL [9]. We report 4-year followup results from ELEVATE-TN.ELEVATE-TN is a phase 3, randomized, multicenter, open-label study (NCT02475681) that enrolled patients aged ≥65 years, or 18-65 years with comorbidities (Cumulative Illness Rating Scale-Geriatric score >6, creatinine clearance 30-69 mL/min by Cockcroft-Gault), who had TN CLL or SLL requiring treatment, Eastern Cooperative Oncology Group performance status score of ≤2, and adequate hematologic, hepatic, and renal function [9]. Patients were randomized (1:1:1) to acalabrutinib 100 mg twice daily (until disease progression or unacceptable toxicity) with or without obinutuzumab (fixed-duration, up to 6 cycles) or obinutuzumab plus chlorambucil (up to 6 cycles). Crossover to acalabrutinib monotherapy was permitted in patients who progressed on obinutuzumab-chlorambucil. The primary study endpoint was independent review committee (IRC)-assessed progression-free survival (PFS). After primary analysis, PFS was investigatorassessed.Key secondary/exploratory endpoints were investigator-assessed PFS, investigator-assessed overall response rate (ORR), overall survival (OS), undetectable minimal residual disease (uMRD) rate, and safety. The study was not powered to compare acalabrutinib versus acalabrutinib-obinutuzumab. Informed consent was obtained from all patients before enrollment. Study details were previously published [9].In total, 535 patients were randomized (acalabrutinib-obinutuzumab, n = 179; acalabrutinib, n = 179; obinutuzumab-chlorambucil, n = 177). Median age was 70 years (range, 41.0-91.0); 14% had del(17)(p13.1) and/or mutated TP53 and 63% had unmutated immunoglobulin heavy chain variable (IGHV) gene (Supplementary Table 1).At a median follow-up of 46.9 months (range, 0.0-59.4), treatment was ongoing in 74.9% (n = 134) and 69.3% (n = 124) of patients in the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms, respectively (Supplementary Table 2). Sixty-