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The combination of the BCL2 inhibitor venetoclax plus obinutuzumab was more effective in the treatment of older medically ill patients with untreated chronic lymphocytic leukemia than was chlorambucil plus obinutuzumab. Progression-free survival at 2 years was 88% with venetoclax and 64% with chlorambucil.

Obinutuzumab, a glycoengineered anti-CD20 antibody with increased killing capacity, outperformed rituximab when used in combination with chlorambucil in patients with chronic lymphocytic leukemia who had coexisting illnesses. Chronic lymphocytic leukemia (CLL), which is characterized by a neoplastic accumulation of B lymphocytes, 1 is the most common leukemia in Western countries. The majority of patients with CLL are older than 70 years of age, and many present with coexisting conditions. 2 , 3 In the past, CLL was treated with chemotherapy without improving survival. 4 – 8 The addition of the monoclonal anti-CD20 antibody rituximab to fludarabine and cyclophosphamide has been shown to prolong overall survival in physically fit patients with previously untreated CLL. 9 – 11 However, randomized trials have not shown that targeting the CD20 antigen in patients with CLL and coexisting conditions . . .

Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia. CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30–69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942. Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8–43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22–0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7–40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma). 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia. F Hoffmann-La Roche and AbbVie.

Purpose A phase 1 study evaluated the QTc prolongation potential of siltuximab, a chimeric, anti-interleukin-6 mAb, in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or low-volume MM. Methods Patients with baseline QTcF and QTcB ≤ 500 ms, QRS < 100 ms, PR < 200 ms and no significant cardiac disease received siltuximab 15 mg/kg q3w, the highest dosage used in clinical studies, for 4 cycles. Twelve-lead ECGs obtained at multiple time points pre- and post-infusion at cycles 1 and 4 were evaluated by central cardiology laboratory. No effect on QTc interval was concluded if the upper limit of least square (LS) mean 90 % CI for QTc change from baseline at each time point was <20 ms. Results An effect on QTc prolongation was ruled out, as the upper bound of 90 % CI was <10 ms at each time point in 27 evaluable patients (13 MGUS, 13 SMM, 1 low-volume MM) with no differences between disease types. Maximum mean QTc increase from baseline occurred 3 h after cycle 1 infusion (QTcF = 3.2 [LS mean 90 % CI −0.01, 6.45] ms; QTcB = 2.7 [−0.69, 6.14] ms). At all other time points, mean QTcF and QTcB increase from baseline was ≤1.5 ms and upper bound 90 % CI was ≤5.1 ms. Twenty patients had mostly low-grade AEs, including nausea, fatigue (20 % each); thrombocytopenia, headache (each 13 %); dyspnea, leukopenia, neutropenia, paresthesia, abnormal hepatic function, URTI (each 10 %). Three MGUS patients achieved 50 % M-protein reduction. There was no association between siltuximab pharmacokinetics and QTc interval. Conclusions Siltuximab did not affect the QTc interval. Overall safety was similar to other single-agent siltuximab studies.

The adjuvanted recombinant zoster vaccine (Shingrix) can prevent herpes zoster in older adults and autologous haemopoietic stem cell transplant recipients. We evaluated the safety and immunogenicity of this vaccine in adults with haematological malignancies receiving immunosuppressive cancer treatments. In this phase 3, randomised, observer-blind, placebo-controlled study, done at 77 centres worldwide, we randomly assigned (1:1) patients with haematological malignancies aged 18 years and older to receive two doses of the adjuvanted recombinant zoster vaccine or placebo 1–2 months apart during or after immunosuppressive cancer treatments, and stratified participants according to their underlying diseases. The co-primary objectives of the study were the evaluation of safety and reactogenicity of the adjuvanted recombinant zoster vaccine compared with placebo from the first vaccination up to 30 days after last vaccination in all participants; evaluation of the proportion of participants with a vaccine response in terms of anti-glycoprotein E humoral immune response to the adjuvanted recombinant zoster vaccine at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia; and evaluation of the anti-glycoprotein E humoral immune responses to the vaccine compared with placebo at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. We assessed immunogenicity in the per-protocol cohort for immunogenicity and safety in the total vaccinated cohort. The study is registered with ClinicalTrials.gov, number NCT01767467, and with the EU Clinical Trials Register, number 2012-003438-18. Between March 1, 2013, and Sept 10, 2015, we randomly assigned 286 participants to adjuvanted recombinant zoster vaccine and 283 to placebo. 283 in the vaccine group and 279 in the placebo group were vaccinated. At month 2, 119 (80·4%, 95% CI 73·1–86·5) of 148 participants had a humoral vaccine response to adjuvanted recombinant zoster vaccine, compared with one (0·8%, 0·0–4·2) of 130 participants in the placebo group, and the adjusted geometric mean anti-glycoprotein E antibody concentration was 23 132·9 mIU/mL (95% CI 16 642·8–32 153·9) in the vaccine group and 777·6 mIU/mL (702·8–860·3) in the placebo group (adjusted geometric mean ratio 29·75, 21·09–41·96; p<0·0001) in all patients, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. Humoral and cell-mediated immune responses persisted above baseline until month 13 in all strata and, as expected, vaccine was more reactogenic than placebo (within 7 days after vaccination pain was reported by 221 [79·5%] of 278 vaccine group participants and 45 [16·4%] of 274 placebo group participants; fatigue was reported by 162 [58·3%] of 278 vaccine group participants and 102 [37·2%] of 274 placebo group participants). Incidences of unsolicited or serious adverse events, potential immune-mediated diseases, disease-related events, and fatal serious adverse events were similar between the groups. The immunocompromised adult population with haematological malignancies is at high risk for herpes zoster. The adjuvanted recombinant zoster vaccine, which is currently licensed in certain countries for adults aged 50 years and older, is likely to benefit this population. GlaxoSmithKline Biologicals SA.

Introduction WHO recommends assisted partner notification (APN) for people living with HIV (PLHIV). These services have not been widely scaled in Central Asia. We describe the results from an APN intervention implemented within a programme focused on PLHIV and people who inject drugs in Kazakhstan, the Kyrgyz Republic and Tajikistan. Methods Routine data from index cases and their partners were analysed from equal‐length periods before and after APN launch. Prior to APN index cases could recruit partners using passive referral, and under APN, had their choice of passive referral or APN (provider, contract or dual‐referral). We compared the demographic characteristics of index cases and their sexual/injecting partners from the pre‐APN and APN periods, described the number/proportion of HIV cases found (positivity rate) and evaluated predictors of HIV infection among partners using logistic regression. Results Under APN 2676 PLHIV served as index cases and recruited 3735 partners for testing, compared to 4418 index cases and 2240 partners during the pre‐APN period. A total of 322 (8.6%) partners were rapid test positive during APN versus 161 (7.2%, p = 0.048) before APN. Women represented 38% of APN index cases (vs. 42% pre‐APN), 52% of partners tested (vs. 50% pre‐APN) and 56% of all PLHIV identified (vs. 63% pre‐APN). Compared to the pre‐APN period, the number of partners tested per index case recruited increased (0.5 to 1.4, p < 0.001) and the number of index cases needed to find one HIV‐positive partner decreased significantly (27.4 to 8.3, p < 0.001) under APN. Conclusions APN was feasibly integrated within a people who inject drugs and PLHIV‐focused HIV programme, and was acceptable to high‐risk populations in Central Asia. Under APN, large numbers of sexual and injecting partners of PLHIV – including women and non‐marital partners – were tested while maintaining high positivity rates. Relative to the pre‐APN period, APN approximately tripled the number of partners recruited per index case and reduced the number of index cases needed to find a positive partner by >3 times.

Introduction HIV testing programmes have struggled to reach the most marginalized populations at risk for HIV. Social network methods such as respondent‐driven sampling (RDS) and peer‐based active case‐finding (ACF) may be effective in overcoming barriers to reaching these populations. We compared the client characteristics, proportion testing HIV positive (yield), and number of new cases found through two RDS strategies and an ACF approach to HIV case‐finding among people who inject drugs (PWID) in Tajikistan. Methods Routine programme data from adult PWID recruited to testing under the HIV Flagship Project in Tajikistan were analysed to compare client demographic and clinical characteristics across the three approaches. We also compared the number of previously untested clients, the number of new HIV cases found, and the yield across the case‐finding strategies, and evaluated predictors of new HIV diagnosis using fixed‐effects logistic regression. Results From 24 October 2016 to 30 June 2017, Flagship tested 10,300 PWID for HIV, including 2143 under RDS with unrestricted waves (RDS1, yield: 1.5%), 3517 under restricted RDS (RDS2, yield: 2.6%), and 4640 under ACF (yield: 1.5%). Clients recruited under ACF were similar in age (35.8 vs. 36.8) and gender (91% vs. 90% male) to those recruited through RDS, though ACF clients were more likely to report being a first‐time tester (85.1% vs. 68.3%, p < 0.001). After controlling for age, sex, previous testing history and accounting for clustering at the site level, we found that clients tested under both RDS1 (aOR: 1.74, 95% CI: 1.04 to 2.90) and RDS2 (aOR: 1.54, 95% CI: 1.11 to 2.15) had higher odds of testing newly positive for HIV relative to clients recruited through ACF. We did not find significant differences in the odds of new HIV infection between those recruited from RDS1 versus RDS2 (aOR: 1.12, 95% CI: 0.67 to 1.86). Conclusions RDS‐based interventions resulted in higher yields and overall case‐finding, especially when recruitment was restricted. However, ACF identified a higher proportion of first‐time testers. To find at least 90% of PWID living with HIV in Tajikistan, it may be necessary to implement multiple case‐finding approaches concurrently to maximize testing coverage.

HIV testing programmes have struggled to reach the most marginalized populations at risk for HIV. Social network methods such as respondent?driven sampling (RDS) and peer?based active case?finding (ACF) may be effective in overcoming barriers to reaching these populations. We compared the client characteristics, proportion testing HIV positive (yield), and number of new cases found through two RDS strategies and an ACF approach to HIV case?finding among people who inject drugs (PWID) in Tajikistan. Routine programme data from adult PWID recruited to testing under the HIV Flagship Project in Tajikistan were analysed to compare client demographic and clinical characteristics across the three approaches. We also compared the number of previously untested clients, the number of new HIV cases found, and the yield across the case?finding strategies, and evaluated predictors of new HIV diagnosis using fixed?effects logistic regression. From 24 October 2016 to 30 June 2017, Flagship tested 10,300 PWID for HIV, including 2143 under RDS with unrestricted waves (RDS1, yield: 1.5%), 3517 under restricted RDS (RDS2, yield: 2.6%), and 4640 under ACF (yield: 1.5%). Clients recruited under ACF were similar in age (35.8 vs. 36.8) and gender (91% vs. 90% male) to those recruited through RDS, though ACF clients were more likely to report being a first?time tester (85.1% vs. 68.3%, p < 0.001). After controlling for age, sex, previous testing history and accounting for clustering at the site level, we found that clients tested under both RDS1 (aOR: 1.74, 95% CI: 1.04 to 2.90) and RDS2 (aOR: 1.54, 95% CI: 1.11 to 2.15) had higher odds of testing newly positive for HIV relative to clients recruited through ACF. We did not find significant differences in the odds of new HIV infection between those recruited from RDS1 versus RDS2 (aOR: 1.12, 95% CI: 0.67 to 1.86). RDS?based interventions resulted in higher yields and overall case?finding, especially when recruitment was restricted. However, ACF identified a higher proportion of first?time testers. To find at least 90% of PWID living with HIV in Tajikistan, it may be necessary to implement multiple case?finding approaches concurrently to maximize testing coverage.

Spruce (Piceaabies) wood hemicelluloses have been obtained by the noncatalytic and catalytic oxidative delignification in the acetic acid-water-hydrogen peroxide medium in a processing time of 3–4 h and temperatures of 90–100 °C. In the catalytic process, the H2SO4, MnSO4, TiO2, and (NH4)6Mo7O24 catalysts have been used. A polysaccharide yield of up to 11.7 wt% has been found. The hemicellulose composition and structure have been studied by a complex of physicochemical methods, including gas and gel permeation chromatography, Fourier-transform infrared spectroscopy, and thermogravimetric analysis. The galactose:mannose:glucose:arabinose:xylose monomeric units in a ratio of 5:3:2:1:1 have been identified in the hemicelluloses by gas chromatography. Using gel permeation chromatography, the weight average molar mass Mw of hemicelluloses has been found to attain 47,654 g/mol in noncatalytic delignification and up to 42,793 g/mol in catalytic delignification. Based on the same technique, a method for determining the α and k parameters of the Mark–Kuhn–Houwink equation for hemicelluloses has been developed; it has been established that these parameters change between 0.33–1.01 and 1.57–472.17, respectively, depending on the catalyst concentration and process temperature and time. Moreover, the FTIR spectra of the hemicellulose samples contain all the bands characteristic of heteropolysaccharides, specifically, 1069 cm−1 (C–O–C and C–O–H), 1738 cm−1 (ester C=O), 1375 cm−1 (–C–CH3), 1243 cm−1 (–C–O–), etc. It has been determined by the thermogravimetric analysis that the hemicelluloses isolated from spruce wood are resistant to heating to temperatures of up to ~100 °C and, upon further heating, start destructing at an increasing rate. The antioxidant activity of the hemicelluloses has been examined using the compounds simulating the 2,2-diphenyl-2-picrylhydrazyl free radicals.