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PurposeIn previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics.Patients and methodsPatients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed.ResultsOf 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC (P = .042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with BIRC3 and BRAF mutations at EOCT and with TP53, NOTCH1, XPO1, and BRAF mutations at EOT.ConclusionEfficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS.

Mediation models have been widely used in many disciplines to better understand the underlying processes between independent and dependent variables. Despite their popularity and importance, the appropriate sample sizes for estimating those models are not well known. Although several approaches (such as Monte Carlo methods) exist, applied researchers tend to use insufficient sample sizes to estimate their models of interest, which might result in unstable and inaccurate estimation of the model parameters including mediation effects. In the present study, sample size requirements were investigated for four frequently used mediation models: one simple mediation model and three complex mediation models. For each model, path and structural equation modeling approaches were examined, and partial and complete mediation conditions were considered. Both the percentile bootstrap method and the multivariate delta method were compared for testing mediation effects. A series of Monte Carlo simulations was conducted under various simulation conditions, including those concerning the level of effect sizes, the number of indicators, the magnitude of factor loadings, and the proportion of missing data. The results not only present practical and general guidelines for substantive researchers to determine minimum required sample sizes but also improve understanding of which factors are related to sample size requirements in mediation models.

Objective: To examine race, gender, and alcohol use level as moderators of the association between protective behavioral strategies (PBS) and alcohol-related problems. Participants: A sample of 12,011 participants who reported recent drinking (87.7% White, 61% Women) from Project INTEGRATE, a study that combined individual participant data (IPD) from 24 brief motivational intervention trials for college students. Methods: Hierarchical regressions were conducted to determine whether there was a moderated effect of PBS on alcohol problems across alcohol use levels, and whether the moderated protective effect of PBS by alcohol use differed by gender and race. Results: The protective association between PBS and alcohol-related problems was greater for those who drank less. This moderated effect did not differ across men and women or across racial groups. Conclusions: College drinking prevention programs should ensure that students are aware of the limits of PBS as a mitigator of alcohol problems.

Multimorbidity negatively affects health‐related quality of life (HRQoL), though the underlying mechanism remained unclear. This study aims to investigate the mediating role of depressive symptoms and multimorbidity treatment burden (MTB) in the association between disease burden and HRQoL in multimorbid patients with hypertension and to determine differences in mediating effects between and within age groups (< 60 years vs. 60 and above). Disease burden, depressive symptoms, MTB, and HRQoL were assessed by self‐reported questionnaires. We conducted path analysis with all subjects and multi‐group path analyses with two age groups. Results from the path analysis with all subjects (n = 498) showed a significant direct effect of disease burden on HRQoL and a significant indirect effect via depressive symptoms and MTB. No significant differences in mediating effects were found between age groups. However, in the older patients, depressive symptoms had a greater indirect effect than MTB. Our results underscore the importance of addressing both depressive symptoms and MTB in interventions tailored to the patient's age. [ABSTRACT FROM AUTHOR]

Latent growth models (LGMs) are an application of structural equation modeling and frequently used in developmental and clinical research to analyze change over time in longitudinal outcomes. Maximum likelihood (ML), the most common approach for estimating LGMs, can fail to converge or may produce biased estimates in complex LGMs especially in studies with modest samples. Bayesian estimation is a logical alternative to ML for LGMs, but there is a lack of research providing guidance on when Bayesian estimation may be preferable to ML or vice versa. This study compared the performance of Bayesian versus ML estimators for LGMs by evaluating their accuracy via Monte Carlo (MC) simulations. For the MC study, longitudinal data sets were generated and estimated using LGM via both ML and Bayesian estimation with three different priors, and parameter recovery across the two estimators was evaluated to determine their relative performance. The findings suggest that ML estimation is a reasonable choice for most LGMs, unless it fails to converge, which can occur with limiting data situations (i.e., just a few time points, no covariate or outcome, modest sample sizes). When models do not converge using ML, we recommend Bayesian estimation with one caveat that the influence of the priors on estimation may have to be carefully examined, per recent recommendations on Bayesian modeling for applied researchers.

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

BackgroundSelective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab.MethodsAdult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616.FindingsBetween Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax.InterpretationA substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies.FundingAbbVie Inc and Genentech Inc.

Cure rates for pulmonary disease caused by the Mycobacterium avium complex (MAC) are poor. While β-lactam are front line antibiotics against Mycobacterium abscessus pulmonary disease, they have not been used or recommended to treat MAC lung infections. Through a comprehensive screen of oral β-lactams, we have discovered that selected pairs combining either a penem/carbapenem or penicillin with a cephalosporin are strongly bactericidal at clinically achieved concentrations. These dual β-lactam combinations include tebipenem and sulopenem, both in phase 3, and Food and Drug Administration-approved amoxicillin and cefuroxime. They could therefore immediately enter clinical trials or clinical practice. [ABSTRACT FROM AUTHOR]