Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma.

BACKGROUND: In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes. METHODS: In this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization. RESULTS: A total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P = 0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival. CONCLUSIONS: At a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).

Axicabtagene ciloleucel vs standard of care in second-line large B-cell lymphoma: outcomes by metabolic tumor volume.

ABSTRACT: Metabolic tumor volume (MTV) assessed using 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography, a measure of tumor burden, is a promising prognostic indicator in large B-cell lymphoma (LBCL). This exploratory analysis evaluated relationships between baseline MTV (categorized as low [median or less] vs high [greater than median]) and clinical outcomes in the phase 3 ZUMA-7 study (NCT03391466). Patients with LBCL relapsed within 12 months of or refractory to first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel (axi-cel; autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (2-3 cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem cell transplantation in patients who had a response). All P values are descriptive. Within high- and low-MTV subgroups, event-free survival (EFS) and progression-free survival (PFS) were superior with axi-cel vs standard care. EFS in patients with high MTV (vs low MTV) was numerically shorter with axi-cel and was significantly shorter with standard care. PFS was shorter in patients with high MTV vs low MTV in both the axi-cel and standard-care arms, and median MTV was lower in patients in ongoing response at data cutoff vs others. Median MTV was higher in patients treated with axi-cel who experienced grade ≥3 neurologic events or cytokine release syndrome (CRS) than in patients with grade 1/2 or no neurologic events or CRS, respectively. Baseline MTV less than or equal to median was associated with better clinical outcomes in patients receiving axi-cel or standard care for second-line LBCL. The trial was registered at www.clinicaltrials.gov as #NCT03391466.

Long-Term Outcomes of Brugada Substrate Ablation: A Report from BRAVO (Brugada Ablation of VF Substrate Ongoing Multicenter Registry).

BACKGROUND: Treatment options for high-risk Brugada syndrome (BrS) with recurrent ventricular fibrillation (VF) are limited. Catheter ablation is increasingly performed but a large study with long-term outcome data is lacking. We report the results of the multicenter, international BRAVO (Brugada Ablation of VF Substrate Ongoing Registry) for treatment of high-risk symptomatic BrS. METHODS: We enrolled 159 patients (median age 42 years; 156 male) with BrS and spontaneous VF in BRAVO; 43 (27%) of them had BrS and early repolarization pattern. All but 5 had an implantable cardioverter-defibrillator for cardiac arrest (n=125) or syncope (n=34). A total of 140 (88%) had experienced numerous implantable cardioverter-defibrillator shocks for spontaneous VF before ablation. All patients underwent a percutaneous epicardial substrate ablation with electroanatomical mapping except for 8 who underwent open-thoracotomy ablation. RESULTS: In all patients, VF/BrS substrates were recorded in the epicardial surface of the right ventricular outflow tract; 45 (29%) patients also had an arrhythmic substrate in the inferior right ventricular epicardium and 3 in the posterior left ventricular epicardium. After a single ablation procedure, 128 of 159 (81%) patients remained free of VF recurrence; this number increased to 153 (96%) after a repeated procedure (mean 1.2±0.5 procedures; median=1), with a mean follow-up period of 48±29 months from the last ablation. VF burden and frequency of shocks decreased significantly from 1.1±2.1 per month before ablation to 0.003±0.14 per month after the last ablation (P<0.0001). The Kaplan-Meier VF-free survival beyond 5 years after the last ablation was 95%. The only variable associated with a VF-free outcome in multivariable analysis was normalization of the type 1 Brugada ECG, both with and without sodium-channel blockade, after the ablation (hazard ratio, 0.078 [95% CI, 0.008 to 0.753]; P=0.0274). There were no arrhythmic or cardiac deaths. Complications included hemopericardium in 4 (2.5%) patients. CONCLUSIONS: Ablation treatment is safe and highly effective in preventing VF recurrence in high-risk BrS. Prospective studies are needed to determine whether it can be an alternative treatment to implantable cardioverter-defibrillator implantation for selected patients with BrS. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04420078.

Earlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large B-cell lymphoma.

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel-related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel.

Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML.

Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.

Phenotype, Genotype, and Drug Resistance in Subtype C HIV-1 Infection.

BACKGROUND: Virologic failure in subtype C is characterized by high resistance to first-line antiretroviral (ARV) drugs, including efavirenz, nevirapine, and lamivudine, with nucleoside resistance including type 2 thymidine analog mutations, K65R, a T69del, and M184V. However, genotypic algorithms predicting resistance are mainly based on subtype B viruses and may under- or overestimate drug resistance in non-B subtypes. To explore potential treatment strategies after first-line failure, we compared genotypic and phenotypic susceptibility of subtype C human immunodeficiency virus 1 (HIV-1) following first-line ARV failure. METHODS: AIDS Clinical Trials Group 5230 evaluated patients failing an initial nonnucleoside reverse-transcriptase inhibitor (NNRTI) regimen in Africa and Asia, comparing the genotypic drug resistance and phenotypic profile from the PhenoSense (Monogram). Site-directed mutagenesis studies of K65R and T69del assessed the phenotypic impact of these mutations. RESULTS: Genotypic algorithms overestimated resistance to etravirine and rilpivirine, misclassifying 28% and 32%, respectively. Despite K65R with the T69del in 9 samples, tenofovir retained activity in >60%. Reversion of the K65R increased susceptibility to tenofovir and other nucleosides, while reversion of the T69del showed increased resistance to zidovudine, with little impact on other NRTI. CONCLUSIONS: Although genotype and phenotype were largely concordant for first-line drugs, estimates of genotypic resistance to etravirine and rilpivirine may misclassify subtype C isolates compared to phenotype.

Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors.

Genome-wide association (GWA) studies of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci, some containing genes encoding proteins important in male germ cell development. Deletions of one of these genes, DMRT1, lead to male-to-female sex reversal and are associated with development of gonadoblastoma. To further explore genetic association with TGCT, we undertook a pathway-based analysis of SNP marker associations in the Penn GWAs (349 TGCT cases and 919 controls). We analyzed a custom-built sex determination gene set consisting of 32 genes using three different methods of pathway-based analysis. The sex determination gene set ranked highly compared with canonical gene sets, and it was associated with TGCT (FDRG = 2.28 × 10(-5), FDRM = 0.014 and FDRI = 0.008 for Gene Set Analysis-SNP (GSA-SNP), Meta-Analysis Gene Set Enrichment of Variant Associations (MAGENTA) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) analysis, respectively). The association remained after removal of DMRT1 from the gene set (FDRG = 0.0002, FDRM = 0.055 and FDRI = 0.009). Using data from the NCI GWA scan (582 TGCT cases and 1056 controls) and UK scan (986 TGCT cases and 4946 controls), we replicated these findings (NCI: FDRG = 0.006, FDRM = 0.014, FDRI = 0.033, and UK: FDRG = 1.04 × 10(-6), FDRM = 0.016, FDRI = 0.025). After removal of DMRT1 from the gene set, the sex determination gene set remains associated with TGCT in the NCI (FDRG = 0.039, FDRM = 0.050 and FDRI = 0.055) and UK scans (FDRG = 3.00 × 10(-5), FDRM = 0.056 and FDRI = 0.044). With the exception of DMRT1, genes in the sex determination gene set have not previously been identified as TGCT susceptibility loci in these GWA scans, demonstrating the complementary nature of a pathway-based approach for genome-wide analysis of TGCT.

Predicting resistance as indicator for need to switch from first-line antiretroviral therapy among patients with elevated viral loads: development of a risk score algorithm.

BACKGROUND: In resource-limited settings, where resistance testing is unavailable, confirmatory testing for patients with high viral loads (VL) delays antiretroviral therapy (ART) switches for persons with resistance. We developed a risk score algorithm to predict need for ART change by identifying resistance among persons with persistently elevated VL. METHODS: We analyzed data from a Phase IV open-label trial. Using logistic regression, we identified demographic and clinical characteristics predictive of need for ART change among participants with VLs ≥1000 copies/ml, and assigned model-derived scores to predictors. We designed three models, including only variables accessible in resource-limited settings. RESULTS: Among 290 participants with at least one VL ≥1000 copies/ml, 51 % (148/290) resuppressed and did not have resistance testing; among those who did not resuppress and had resistance testing, 47 % (67/142) did not have resistance and 53 % (75/142) had resistance (ART change needed for 25.9 % (75/290)). Need for ART change was directly associated with higher baseline VL and higher VL at time of elevated measure, and inversely associated with treatment duration. Other predictors included body mass index and adherence. Area under receiver operating characteristic curves ranged from 0.794 to 0.817. At a risk score ≥9, sensitivity was 14.7-28.0 % and specificity was 96.7-98.6 %. CONCLUSIONS: Our model performed reasonably well and may be a tool to quickly transition persons in need of ART change to more effective regimens when resistance testing is unavailable. Use of this algorithm may result in public health benefits and health system savings through reduced transmissions of resistant virus and costs on laboratory investigations.

Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated With Virologic Failure: Results From the Multinational PEARLS (ACTG A5175) Clinical Trial.

BACKGROUND: Evaluation of pretreatment HIV genotyping is needed globally to guide treatment programs. We examined the association of pretreatment (baseline) drug resistance and subtype with virologic failure in a multinational, randomized clinical trial that evaluated 3 antiretroviral treatment (ART) regimens and included resource-limited setting sites. METHODS: Pol genotyping was performed in a nested case-cohort study including 270 randomly sampled participants (subcohort), and 218 additional participants failing ART (case group). Failure was defined as confirmed viral load (VL) >1000 copies/mL. Cox proportional hazards models estimated resistance-failure association. RESULTS: In the representative subcohort (261/270 participants with genotypes; 44% women; median age, 35 years; median CD4 cell count, 151 cells/µL; median VL, 5.0 log10 copies/mL; 58% non-B subtypes), baseline resistance occurred in 4.2%, evenly distributed among treatment arms and subtypes. In the subcohort and case groups combined (466/488 participants with genotypes), used to examine the association between resistance and treatment failure, baseline resistance occurred in 7.1% (9.4% with failure, 4.3% without). Baseline resistance was significantly associated with shorter time to virologic failure (hazard ratio [HR], 2.03; P = .035), and after adjusting for sex, treatment arm, sex-treatment arm interaction, pretreatment CD4 cell count, baseline VL, and subtype, was still independently associated (HR, 2.1; P = .05). Compared with subtype B, subtype C infection was associated with higher failure risk (HR, 1.57; 95% confidence interval [CI], 1.04-2.35), whereas non-B/C subtype infection was associated with longer time to failure (HR, 0.47; 95% CI, .22-.98). CONCLUSIONS: In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible. CLINICAL TRIALS REGISTRATION: NCT00084136.

Parametric modeling of whole-genome sequencing data for CNV identification.

Copy number variants (CNVs) constitute an important class of genetic variants in human genome and are shown to be associated with complex diseases. Whole-genome sequencing provides an unbiased way of identifying all the CNVs that an individual carries. In this paper, we consider parametric modeling of the read depth (RD) data from whole-genome sequencing with the aim of identifying the CNVs, including both Poisson and negative-binomial modeling of such count data. We propose a unified approach of using a mean-matching variance stabilizing transformation to turn the relatively complicated problem of sparse segment identification for count data into a sparse segment identification problem for a sequence of Gaussian data. We apply the optimal sparse segment identification procedure to the transformed data in order to identify the CNV segments. This provides a computationally efficient approach for RD-based CNV identification. Simulation results show that this approach often results in a small number of false identifications of the CNVs and has similar or better performances in identifying the true CNVs when compared with other RD-based approaches. We demonstrate the methods using the trio data from the 1000 Genomes Project.

Clinical and genetic determinants of plasma nevirapine exposure following an intrapartum dose to prevent mother-to-child HIV transmission.

OBJECTIVE: Nevirapine is metabolized by cytochrome P450 (CYP) 2B6 and CYP3A4. We characterized relationships between clinical parameters, human genetics, pharmacokinetics, and human immunodeficiency virus type 1 (HIV-1) drug resistance mutations in pregnant women following single-dose intrapartum nevirapine. METHODS: In AIDS Clinical Trials Group study A5207, women received nevirapine at onset of labor and were randomly assigned to receive lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir for 7 or 21 days. Plasma nevirapine level was quantified on postpartum day 1 and on weeks 1, 3, and 5. We assayed 214 polymorphisms in CYP2B6 and other genes and evaluated associations with pharmacokinetic parameters, including elimination constant, time to protein-adjusted 50% inhibitory concentration (IC50), and week 5 nevirapine level below the quantification limit. RESULTS: Among 301 women with evaluable pharmacokinetic and genotype data, lower body mass index and random assignment to receive lopinavir/ritonavir were associated with more rapid nevirapine elimination. Among those of African ancestry, longer time to IC50 was associated with CYP2B6 983T → C (P = .004) but not with CYP2B6 516G → T (P = .8). Among Indians, slower nevirapine elimination was associated with CYP2B6 516G → T (P = .04). Emergent resistance was infrequent and not associated with pharmacokinetics or CYP2B6 genotype. CONCLUSIONS: The effects on plasma drug exposure following single-dose nevirapine may be greater for CYP2B6 983T → C than for 516G → T and are less pronounced than at steady state.

Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7).

Treatment resistance and toxicities remain a risk following chimeric antigen receptor (CAR) T-cell therapy. Herein, we report pharmacokinetics, pharmacodynamics, and product and apheresis attributes associated with outcomes among patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) in ZUMA-7. Axi-cel peak expansion associated with clinical response and toxicity, but not response durability. In apheresis material and final product, a naive T-cell phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved response durability, event-free survival, progression-free survival, and a lower number of prior therapies. This phenotype was not associated with high-grade cytokine release syndrome (CRS) or neurologic events. Higher baseline and postinfusion levels of serum inflammatory markers associated with differentiated/effector products, reduced efficacy, and increased CRS and neurologic events, thus suggesting targets for intervention. These data support better outcomes with earlier CAR T-cell intervention and may improve patient care by informing on predictive biomarkers and development of next-generation products. SIGNIFICANCE: In ZUMA-7, the largest randomized CAR T-cell trial in LBCL, a naive T-cell product phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved efficacy, decreased toxicity, and a lower number of prior therapies, supporting earlier intervention with CAR T-cell therapy. In addition, targets for improvement of therapeutic index are proposed. This article is featured in Selected Articles from This Issue, p. 4.

Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma.

The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.0002 for B cell GES; P = 0.0165 for CD19 expression) but not SOC (P = 0.9374 for B cell GES; P = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression (P = 8.56 × 10-9 for B cell GES high; P = 0.0019 for B cell GES low; P = 3.85 × 10-9 for CD19 gene high; P = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.

Long-term outcomes of patients with large B-cell lymphoma treated with axicabtagene ciloleucel and prophylactic corticosteroids.

ZUMA-1 safety management cohort 6 investigated the impact of prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab on the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs) following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). Prior analyses of cohort 6 with limited follow-up demonstrated no Grade ≥3 CRS, a low rate of NEs, and high response rates, without negatively impacting axi-cel pharmacokinetics. Herein, long-term outcomes of cohort 6 (N = 40) are reported (median follow-up, 26.9 months). Since the 1-year analysis (Oluwole, et al. Blood. 2022;138[suppl 1]:2832), no new CRS was reported. Two new NEs occurred in two patients (Grade 2 dementia unrelated to axi-cel; Grade 5 axi-cel-related leukoencephalopathy). Six new infections and eight deaths (five progressive disease; one leukoencephalopathy; two COVID-19) occurred. Objective and complete response rates remained at 95% and 80%, respectively. Median duration of response and progression-free survival were reached at 25.9 and 26.8 months, respectively. Median overall survival has not yet been reached. Eighteen patients (45%) remained in ongoing response at data cutoff. With ≥2 years of follow-up, prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab continued to demonstrate CRS improvement without compromising efficacy outcomes, which remained high and durable.

A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility.

Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including KITLG, SPRY4, BAK1, TERT, DMRT1 and ATF7IP. In our GWAS, we genotyped 349 TGCT cases and 919 controls and replicated top hits in an independent set of 439 cases and 960 controls in an attempt to find novel TGCT susceptibility loci. We identified a second marker (rs7040024) in the doublesex and mab-3-related transcription factor 1 (DMRT1) gene that is independent of the previously described risk allele (rs755383) at this locus. In combined analysis that mutually conditions on both DMRT1 single nucleotide polymorphism markers, TGCT cases had elevated odds of carriage of the rs7040024 major A allele [per-allele odds ratio (OR) = 1.48, 95% confidence interval (CI) 1.23, 1.78; P = 2.52 × 10(-5)] compared with controls, while the association with rs755383 persisted (per allele OR = 1.26, 95% CI 1.08, 1.47, P = 0.0036). In similar analyses, the association of rs7040024 among men with seminomatous tumors did not differ from that among men with non-seminomatous tumors. In combination with KITLG, the strongest TGCT susceptibility locus found to date, men with TGCT had greatly elevated odds (OR = 14.1, 95% CI 5.12, 38.6; P = 2.98 × 10(-7)) of being double homozygotes for the risk (major) alleles at DMRT (rs7040024) and KITLG (rs4474514) when compared with men without TGCT. Our findings continue to corroborate that genes influencing male germ cell development and differentiation have emerged as the major players in inherited TGCT susceptibility.

Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma.

PURPOSE: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. PATIENTS AND METHODS: Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2-3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). RESULTS: Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and <65 years. CONCLUSIONS: Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.

A retrospective analysis of the effect of patient-specific factors on voriconazole concentrations in oncology patients.

OBJECTIVE: To identify patient-specific factors significantly associated with voriconazole exposure. DESIGN SETTING, AND PARTICIPANTS: Retrospective, single center at an academic medical center. Consecutive, adult oncology inpatients who received voriconazole by mouth and had at least one voriconazole level over a 14-month period. Voriconazole was ordered for 292 patients during the study period, a level was obtained in 41 patients. Nine patients were excluded; the study population was comprised of 32 patients. METHODS AND RESULTS: Univariate and multivariable regression analyses were utilized to predict the patient-specific factors significantly associated with level. A total of 36 levels meeting inclusion/exclusion criteria were performed in 32 patients. Sixty percent of levels (22/36) were between 1 and 5.5 µg/mL. Data were available to calculate a Child Pugh score for 66% (21/32) of patients. Using multivariable linear regression, three covariates were found to be statistically significant: age, international normalized ratio (INR), and alkaline phosphatase (ALP). Three outliers were notable in the ALP category, when removing the three individuals from the model, only an increasing INR remains significantly associated with increasing voriconazole level (p = 0.0093). No correlation was found with trough level and Child Pugh score. CONCLUSIONS: Sixty percent of voriconazole trough levels were between 1 and 5.5 µg/mL (range 0.1-7.4 µg/mL), only increasing INR was significantly associated with rising voriconazole level. Increasing Child Pugh score was not associated with increasing level. More investigation is warranted into the usefulness of the Child Pugh score for guidance of dose modifications in non-cirrhotic patients with acute hepatic injury.

Practical and analytical aspects of using friend controls in case-control studies: experience from a case-control study of childhood cancer.

We report empirical data on the use of friend controls, specifically response rates, case-control concordance and analytical approaches. The data derive from a North American multi-institutional study of childhood cancer that was conducted in 2002-07 and that focused on paternal exposures. Case parents nominated friends as potential controls; up to three controls participated per case. For 137 (69%) of the 199 case families, at least one control parent participated. Of 374 potential controls contacted, 247 (66%) participated. Case fathers with controls were markedly more likely to be non-Hispanic White, college graduates and non-smokers compared with case fathers without controls. Odds ratios adjusted for demographic characteristics were generally similar but occasionally differed between analyses that included only members of matched sets and those that included all participants, i.e., controls and cases with and without controls. For demographic characteristics, simulations demonstrated that the observed concordance of cases and controls within matched sets exceeded that expected under random ascertainment, indicating probable overmatching. However, the observed concordance of smoking and other exposures was similar to the expectation under random ascertainment, suggesting little overmatching on exposures. Although not ideal, friend controls were convenient, had a reasonably high response rate and provided controls closely matched on race/ethnicity, education and age.

Position and distance specificity are important determinants of cis-regulatory motifs in addition to evolutionary conservation.

Computational discovery of cis-regulatory elements remains challenging. To cope with the high false positives, evolutionary conservation is routinely used. However, conservation is only one of the attributes of cis-regulatory elements and is neither necessary nor sufficient. Here, we assess two additional attributes--positional and inter-motif distance specificity--that are critical for interactions between transcription factors. We first show that for a greater than expected fraction of known motifs, the genes that contain the motifs in their promoters in a position-specific or distance-specific manner are related, both in function and/or in expression pattern. We then use the position and distance specificity to discover novel motifs. Our work highlights the importance of distance and position specificity, in addition to the evolutionary conservation, in discovering cis-regulatory motifs.

Impact of Changes Over Time in the Stanford University Genotypic Resistance Interpretation Algorithm.

INTRODUCTION: The Stanford HIV-1 genotypic resistance interpretation algorithm has changed substantially over its lifetime. In many studies, the algorithm version used is not specified. It is easy to assume that results across versions are comparable, but the effects of version changes on resistance calls are unknown. We evaluate these effects for 20 antiretroviral drugs. METHODS: We calculated resistance interpretations for the same 5993 HIV-1 sequences, from participants in AIDS Clinical Trials Group studies, under 14 versions of the Stanford algorithm from 2002 to 2017. Trends over time were assessed using repeated-measures logistic regression. Changes in rule structure and scoring were examined. RESULTS: For most drugs, the proportion of high-level resistance calls on the same sequences was greater using more recent algorithm versions; 16/20 drugs showed significant upward trends. Some drugs, especially tenofovir, had a substantial increase. Only darunavir had a decrease. Algorithm changes impacted calls for subtype C more than B. For intermediate and high-level resistance combined, effects were weaker and more varied. Over time, rules in the Stanford algorithm have become more complex and contain more subrules. The types of rule changes responsible for trends varied widely by drug. DISCUSSION: Reporting the Stanford algorithm version used for resistance analysis is strongly recommended. Caution should be used when comparing results between studies, unless the same version of the algorithm was used. Comparisons using different Stanford versions may be valid for drugs with few changes over time, but for most comparisons, version matters, and for some drugs, the impact is large.