Abstract: Pneumococcal carriage studies have suggested that pneumococcal colonization in adults is largely limited to the oral cavity and oropharynx. In this study we used total abundance-based β-diversity (dissimilarity) and β-diversity components to characterize age-related differences in pneumococcal serotype composition of respiratory samples. qPCR was applied to detect pneumococcal serotypes in nasopharyngeal samples collected from 946 toddlers and 602 adults, saliva samples collected from a subset of 653 toddlers, and saliva and oropharyngeal samples collected from a subset of 318 adults. Bacterial culture rates from nasopharyngeal samples were used to characterize age-related differences in rates of colonizing bacteria. Dissimilarity in pneumococcal serotype composition was low among saliva and nasopharyngeal samples from children. In contrast, respiratory samples from adults exhibited high serotype dissimilarity, which predominantly consisted of abundance gradients and was associated with reduced nasopharyngeal colonization. Age-related serotype dissimilarity was high among nasopharyngeal samples and relatively low for saliva samples. Reduced nasopharyngeal colonization by pneumococcal serotypes coincided with significantly reduced Moraxella catarrhalis and Haemophilus influenzae and increased Staphylococcus aureus nasopharyngeal colonization rates among adults. Findings from this study suggest that within-host environmental conditions, utilized in the upper airways by pneumococcus and other bacteria, undergo age-related changes. It may result in a host-driven ecological succession of bacterial species colonizing the nasopharynx and lead to competitive exclusion of pneumococcus from the nasopharynx but not from the oral habitat. This explains the poor performance of nasopharyngeal samples for pneumococcal carriage among adults and indicates that in adults saliva more accurately represents the epidemiology of pneumococcal carriage than nasopharyngeal samples.

Abstract: Background : Ibr is the only once-daily inhibitor of Bruton tyrosine kinase with significant overall survival benefit demonstrated in 2 randomized phase 3 studies in first-line CLL (RESONATE-2; ECOG1912). Both Ibr and Ven, an oral inhibitor of BCL2, are approved in the US for treatment of CLL/SLL. The combination of Ibr + Ven may have synergistic anti-tumor activity given the capacity of Ibr to mobilize CLL cells from protected niches within lymphoid tissue to the blood where they may have greater dependence on BCL2 for survival. Recent clinical studies of Ibr + Ven in patients (pts) with CLL or mantle cell lymphoma show high rates of remission with undetectable minimal residual disease (uMRD) (Jain, NEJM 2018; Hillmen, JCO 2019; Tam, NEJM 2018). CAPTIVATE (PCYC-1142) is a multi-center phase 2 study (NCT02910583) evaluating the combination of Ibr + Ven to achieve deep response, including uMRD, in first-line treatment of CLL/SLL. We present results from the MRD cohort with 12 cycles of Ibr + Ven prior to MRD-guided randomized treatment discontinuation (data not yet available). Methods : Pts aged & lt;70 y with previously untreated CLL/SLL requiring therapy received single-agent Ibr lead-in (420 mg/day PO) for 3 cycles followed by Ibr + Ven (5-week ramp-up to 400 mg/day PO) for 12 cycles. The key endpoints prior to MRD-guided randomization included uMRD ( & lt;10-4 by 8-color flow cytometry), Ven-related tumor lysis syndrome (TLS) risk, pharmacokinetics, and adverse events (AEs). MRD status was evaluated in peripheral blood (PB) after 6, 9, and 12 cycles of Ibr + Ven combination, and in bone marrow (BM) after 12 cycles of Ibr + Ven. Results : We enrolled 164 pts (median age 58 y; del(17p) in 16%; del(17p) or TP53 mutation in 20%; del(11q) without del(17p) in 16%; complex karyotype in 19%; unmutated IGHV in 59%; lymph nodes ≥5 cm in 32%). In total, 151 pts (92%) completed Ibr lead-in and all 12 cycles of Ibr + Ven. uMRD was achieved at any time after baseline in 75% of pts (122/163) in PB and 72% (111/155) in BM (Figure). The proportion of pts who had uMRD in PB increased over time from 57% after 6 cycles of combined Ibr + Ven to 68% after 9 cycles and 73% after 12 cycles of Ibr + Ven. The high rates of BM uMRD were consistent across high-risk subgroups, including in pts with del(17p) (75%), del(17p) or TP53 mutation (70%), del(11q) (84%), complex karyotype (83%), and unmutated IGHV status (81%). In pts with uMRD in PB with matched BM samples, 93% had uMRD in both PB and BM. Response by iwCLL criteria was achieved in 97% of pts. With median follow-up of 14.7 mo (range, 0.5-19.9) only 3 pts (2%) had disease progression (1 Richter's transformation during single-agent Ibr lead-in; 1 after discontinuation of Ibr lead-in due to AE; and 1 during treatment with Ibr + Ven) and no pts died. At baseline, 24% of pts were high-risk for Ven-related TLS, which was reduced to 2% after 3 cycles of single-agent Ibr lead-in. One pt met laboratory TLS criteria. Laboratory TLS was reported as an AE in 3 other pts during the first 2 weeks of Ven ramp-up but none met Howard criteria. No pts developed clinical TLS. Mean plasma levels of Ven (area under the curve; AUC) (n=151) was higher when co-administered with ibrutinib compared with historical data for single-agent Ven but was within the AUC range observed in doses previously studied. No change in Ibr AUC (n=112) was observed with concurrent Ven. Median duration of treatment was 14.7 mo (range 0.5-19.9) with Ibr and 12.0 mo (range 0.8-12.7) with Ven. The most common AEs of any grade (in ≥20% of pts) were diarrhea (31%) and arthralgia (22%) during single-agent Ibr, and diarrhea (60%), neutropenia (40%), nausea (34%), upper respiratory tract infection (24%), and fatigue (20%) during Ibr + Ven. Overall, AEs leading to dose reductions occurred in 20% of pts (Ibr: 14%; Ven: 9%). AEs leading to discontinuation were infrequent, occurring in 7% of pts overall (Ibr: 5%; Ven: 4%). Conclusions : First-line treatment with Ibr + Ven represents an all oral, once-daily, chemotherapy-free regimen that provides high rates of uMRD in both PB and BM in pts with CLL. The safety profile of Ibr + Ven was consistent with AEs known for both agents. Results from the MRD-guided randomized treatment discontinuation cohort and Fixed duration cohort of CAPTIVATE await further follow-up, and are expected to provide the evidence to support a time-limited treatment option with a fixed-duration regimen of 12 cycles of Ibr + Ven in pts with CLL. Disclosures Tam: Novartis: Honoraria; Pharmacyclics LLC, an AbbVie company: Honoraria; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria. Siddiqi:Astra Zeneca: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Kite: Research Funding; TG Therapeutics: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Juno: Consultancy, Research Funding. Allan:Bayer: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Janssen: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kipps:Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Opat:Celgene: Consultancy, Honoraria, Research Funding; Epizyme: Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Barr:Astra Zeneca: Consultancy, Research Funding; Verastem: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy. Tedeschi:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jacobs:AbbVie: Consultancy, Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy; AstraZeneca: Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; Genentech: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau. Badoux:AbbVie: Honoraria, Other: Travel, Accommodations, Expenses. Ghia:ArQule: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Juno/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Sukbuntherng:Pharmacyclics LLC, an AbbVie Company (self),: Employment; Theras, Inc. (spouse): Employment; AbbVie: Equity Ownership; Global Blood Therapeutics: Equity Ownership; Portola: Equity Ownership. Salem:AbbVie: Employment, Other: Stock/stock options. Russell:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Eckert:Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses; AbbVie: Equity Ownership. Zhou:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Ninomoto:Amgen: Equity Ownership; AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment; Celgene: Equity Ownership. James:Pharmacyclics LLC, an AbbVie Company: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; AbbVie: Equity Ownership. Wierda:Cyclcel: Research Funding; KITE pharma: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; Loxo Oncology Inc.: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Acerta Pharma Inc: Research Funding. OffLabel Disclosure: Ibrutinib in combination with venetoclax is not approved in any indication.

Abstract: Background: CAPTIVATE (PCYC-1142; NCT02910583) is an international, multicenter phase 2 study of first-line Ibr + Ven in CLL with 2 cohorts: the Minimal Residual Disease (MRD) and FD cohorts. FD Ibr + Ven provides deep, durable responses (Ghia, ASCO 2021; Wierda, J Clin Oncol 2021). Here, we report efficacy and safety of FD Ibr + Ven in pts with high-risk features. Methods: Pts aged ≤70 y with previously untreated CLL received 3 cycles of Ibr then 12 cycles of Ibr + Ven (Ibr 420 mg/d orally; Ven ramp-up to 400 mg/d orally). Pts in the FD cohort received no further treatment. Pts in the MRD cohort were randomized to subsequent treatment according to MRD status, including a placebo arm for pts who achieved confirmed undetectable MRD (uMRD) with 12 cycles of Ibr + Ven. Data from the FD cohort and MRD cohort placebo arm were pooled for pts with high-risk features (del(17p), TP53 mutated, or unmutated IGHV) treated with FD Ibr + Ven. Results: Of 202 pts treated with FD Ibr + Ven in the FD cohort (n=159) or MRD cohort placebo arm (n=43), 129 pts had high-risk features (Table). Median time on study for these pts was 28.7 mo (range 0.8-45.1). 94% of pts completed planned treatment with Ibr and Ven. Median treatment duration was 13.8 mo (range 0.7-24.9) for Ibr and 11.1 mo (range 9.9-22.1) for Ven. Best response rates of CR and uMRD in peripheral blood and bone marrow were high (Table). The 18-mo landmark estimate for duration of CR was 95%. 24-mo PFS rate was 94%, which was similar to pts without high-risk features (97%). Only 3% of pts discontinued Ibr or Ven due to AEs. The AE profile of Ibr + Ven in pts with high-risk features showed no new safety findings for this FD regimen (Table). Conclusion: First-line Ibr + Ven for a fixed duration provides durable treatment-free remissions and sustained PFS in pts with CLL. These clinical outcomes are maintained in pts with high-risk features, with PFS rates that were similar to pts without high-risk features. Table. Baseline characteristics, efficacy outcomes, and safety Pts with high-risk features (n=129) BASELINE CHARACTERISTICS Median age, y (range) 60 (33-70) Rai stage III/IV, n (%) 36 (28) Bulky disease ≥5 cm, n (%) 47 (36) Genomic risk features, n (%) del(17p) and/or TP53 mutated 29 (22) Unmutated IGHV 119 (92) Complex karyotypea 27 (21) EFFICACY OUTCOMES Overall response rate, n (%) 126 (98) CR, n (%) 76 (59) 18-mo DOCR, % (95% CI) 95 (85-98) uMRD & lt;10-4 by flow, n (%) Peripheral blood 114 (88) Bone marrow 93 (72) 24-mo PFS rate, % (95% CI) 94 (88-97) 24-mo OS rate, % (95% CI) 98 (93-99) SAFETY OUTCOMES Grade 3/4 AEs in ≥5% of pts, n (%) Neutropenia 38 (29) Hypertension 12 (9) Neutrophil count decreased 9 (7) aDefined as ≥3 abnormalities by CpG-stimulated cytogenetics. Citation Format: John N. Allan, Ian W. Flinn, Tanya Siddiqi, Paolo Ghia, Constantine S. Tam, Thomas J. Kipps, Paul M. Barr, Anna Elinder Camburn, Alessandra Tedeschi, Xavier C. Badoux, Ryan Jacobs, Bryone J. Kuss, Livio Trentin, Cathy Zhou, Anita Szoke, Maoko Naganuma, William G. Wierda. Fixed-duration (FD) ibrutinib (Ibr) + venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL) in patients (pts) with high-risk features: phase 2 CAPTIVATE study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT028.

Abstract: Staphylococcus aureus causes a broad spectrum of diseases in humans and animals. It is frequently associated with inflammatory skin disorders such as atopic dermatitis, where it aggravates symptoms. Treatment of S. aureus -associated skin infections with antibiotics is discouraged due to their broad-range deleterious effect on healthy skin microbiota and their ability to promote the development of resistance. Thus, novel S. aureus -specific antibacterial agents are desirable. We constructed two chimeric cell wall-lytic enzymes, Staphefekt SA.100 and XZ.700, which are composed of functional domains from the bacteriophage endolysin Ply2638 and the bacteriocin lysostaphin. Both enzymes specifically killed S. aureus and were inactive against commensal skin bacteria such as Staphylococcus epidermidis , with XZ.700 proving more active than SA.100 in multiple in vitro activity assays. When surface-attached mixed staphylococcal cultures were exposed to XZ.700 in a simplified microbiome model, the enzyme selectively removed S. aureus and retained S. epidermidis . Furthermore, XZ.700 did not induce resistance in S. aureus during repeated rounds of exposure to sublethal concentrations. Finally, we demonstrated that XZ.700 formulated as a cream is effective at killing S. aureus on reconstituted human epidermis and that an XZ.700-containing gel significantly reduces bacterial numbers compared to an untreated control in a mouse model of S. aureus -induced skin infection.

Abstract: Respiratory tract infections (RTI) in children remain a cause of disease burden worldwide. Nasopharyngeal (NP) & oropharyngeal (OP) swabs are used for respiratory pathogen detection, but hold disadvantages particularly for children, highlighting the importance and preference for a child friendly detection method. We aimed to evaluate the performance and tolerability of a rhinorrhea swab (RS) in detecting viral pathogens when compared to a combined OP(/NP) or mid‐turbinate (MT) nasal swab. This study was conducted between September 2021 and July 2022 in the Netherlands. Children aged 0−5 years, with an upper RTI and nasal discharge, were included and received a combined swab and a RS. Multiplex polymerase chain reaction (PCR) and severe acute respiratory syndrome coronavirus‐2 PCR were used for viral pathogen detection. Tolerability was evaluated with a questionnaire and visual analog scale (VAS) scores. During 11 months 88 children were included, with a median age of 1.00 year [interquartile range 0.00−3.00]. In total 122 viral pathogens were detected in 81 children (92%). Sensitivity and specificity of the RS compared to a combined swab were respectively 97% (95% confidence interval [CI] 91%−100%) and 78% (95% CI 45%−94%). Rhinorrhea samples detected more pathogens than the (combined) nasal samples, 112 versus 108 respectively. Median VAS scores were significantly lower for the RS in both children (2 vs. 6) and their parents (0 vs. 5). A RS can therefore just as effectively/reliably detect viral pathogens as the combined swab in young children and is better tolerated by both children and their parents/caregivers.

Abstract: In the early COVID-19 pandemic, SARS-CoV-2 testing was only accessible and recommended for symptomatic persons or adults. This restriction hampered assessment of the true incidence of SARS-CoV-2 infection in children as well as detailed characterization of the SARS-CoV-2 disease spectrum and how this spectrum compared with that of other common respiratory illnesses. Objective To estimate the community incidence of SARS-CoV-2 infection in children and parents and to assess the symptoms and symptom severity of respiratory illness episodes involving SARS-CoV-2–positive test results relative to those with SARS-CoV-2–negative test results. Design, Setting, and Participants This cohort study randomly selected Dutch households with at least 1 child younger than 18 years. A total of 1209 children and adults from 307 households were prospectively followed up between August 25, 2020, and July 29, 2021, covering the second and third waves of the COVID-19 pandemic. Participation included SARS-CoV-2 screening at 4- to 6-week intervals during the first 23 weeks of participation (core study period; August 25, 2020, to July 29, 2021). Participants in all households finishing the core study before July 1, 2021, were invited to participate in the extended follow-up and to actively report respiratory symptoms using an interactive app until July 1, 2021. At new onset of respiratory symptoms or a SARS-CoV-2 positive test result, a household outbreak study was initiated, which included daily symptom recording, repeated polymerase chain reaction testing (nose-throat swabs and saliva and fecal samples), and SARS-CoV-2 antibody measurement (paired dried blood spots) in all household members. Outbreaks, households, and episodes of respiratory illness were described as positive or negative depending on SARS-CoV-2 test results. Data on participant race and ethnicity were not reported because they were not uniformly collected in the original cohorts and were therefore not representative or informative. Exposures SARS-CoV-2–positive and SARS-CoV-2–negative respiratory illness episodes. Main Outcomes and Measures Age-stratified incidence rates, symptoms, and symptom severity for SARS-CoV-2–positive and SARS-CoV-2–negative respiratory illness episodes. Results Among 307 households including 1209 participants (638 female [52.8%]; 403 [33.3%] aged & amp;lt;12 years, 179 [14.8%] aged 12-17 years, and 627 [51.9%] aged ≥18 years), 183 household outbreaks of respiratory illness were observed during the core study and extended follow-up period, of which 63 (34.4%) were SARS-CoV-2 positive (59 outbreaks [32.2%] during the core study and 4 outbreaks [2.2%] during follow-up). SARS-CoV-2 incidence was similar across all ages (0.24/person-year [PY]; 95% CI, 0.21-0.28/PY). Overall, 33 of 134 confirmed SARS-CoV-2 episodes (24.6%) were asymptomatic. The incidence of SARS-CoV-2–negative respiratory illness episodes was highest in children younger than 12 years (0.94/PY; 95% CI, 0.89-0.97/PY). When comparing SARS-CoV-2–positive vs SARS-CoV-2–negative respiratory illness episodes in children younger than 12 years, no differences were observed in number of symptoms (median [IQR] , 2 [2-4] for both groups), symptom severity (median [IQR] maximum symptom severity score, 6 [4-9] vs 7 [6-13]), or symptom duration (median [IQR] , 6 [5-12] days vs 8 [4-13] days). However, among adults, SARS-CoV-2–positive episodes had a significantly higher number (median [IQR], 6 [4-8] vs 3 [2-4]), severity (median [IQR] maximum symptom severity score, 15 [9-19] vs 7 [6-11] ), and duration (median [IQR] 13 [8-29] days vs 5 [3-11] days; P   & amp;lt; .001 for all comparisons) of symptoms vs SARS-CoV-2–negative episodes. Conclusions and Relevance In this cohort study, during the first pandemic year when mostly partial or full in-person learning occurred, the SARS-CoV-2 incidence rate in children was substantially higher than estimated from routine testing or seroprevalence data and was similar to that of adult household members. Unlike in unvaccinated adults, SARS-CoV-2 symptoms and symptom severity in children were similar to other common respiratory illnesses. These findings may prove useful when developing pediatric COVID-19 vaccine recommendations.

Abstract: In this study, we compared the bioNexia test (bioMérieux, Marcy-l'Étoile, France), a new immunochromatographic assay for the detection of Legionella pneumophila serogroup 1 in urine, with the BinaxNOW urinary antigen test (Alere, Waltham, Massachusetts, USA). After 15 min of incubation (in accordance with the manufacturers' instructions), the sensitivities and specificities were, respectively, 76.5% and 97.2% for the bioNexia test and 87.1% and 100% for the BinaxNOW test. After a prolonged incubation time of 60 min, the sensitivities and specificities increased to, respectively, 89.4% and 97.2% for the bioNexia test and 91.8% and 100% for the BinaxNOW test. When the tests were read after 15 min, the concentration of discrepant urine samples increased the sensitivities to 94.1% for both tests. In conclusion, we found that although the bioNexia test showed lower sensitivity for the detection of L. pneumophila antigen in nonconcentrated urine compared to the BinaxNOW test, a prolonged incubation time as well as the use of concentrated samples showed comparable sensitivities for both tests.

Abstract: The CAPTIVATE study investigated first-line ibrutinib plus venetoclax for chronic lymphocytic leukemia in 2 cohorts: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and Fixed Duration (FD cohort). We report outcomes of fixed-duration ibrutinib plus venetoclax in patients with high-risk genomic features [del(17p), TP53 mutation, and/or unmutated immunoglobulin heavy chain (IGHV)] i n CAPTIVATE. Patients and Methods: Patients received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day). FD cohort patients (n = 159) received no further treatment. Forty-three MRD cohort patients with confirmed undetectable MRD (uMRD) after 12 cycles of ibrutinib plus venetoclax received randomized placebo treatment. Results: Of 195 patients with known status of genomic risk features at baseline, 129 (66%) had ≥1 high-risk feature. Overall response rates were & gt;95% regardless of high-risk features. In patients with and without high-risk features, respectively, complete response (CR) rates were 61% and 53%; best uMRD rates: 88% and 70% (peripheral blood) and 72% and 61% (bone marrow); 36-month progression-free survival (PFS) rates: 88% and 92%. In subsets with del(17p)/TP53 mutation (n = 29) and unmutated IGHV without del(17p)/TP53 mutation (n = 100), respectively, CR rates were 52% and 64%; uMRD rates: 83% and 90% (peripheral blood) and 45% and 80% (bone marrow); 36-month PFS rates: 81% and 90%. Thirty-six–month overall survival (OS) rates were & gt;95% regardless of high-risk features. Conclusions: Deep, durable responses and sustained PFS seen with fixed-duration ibrutinib plus venetoclax are maintained in patients with high-risk genomic features, with similar PFS and OS to those without high-risk features. See related commentary by Rogers, p. 2561