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In a study conducted at three institutions, ibrutinib was associated with major responses in 73% of patients with Waldenström's macroglobulinemia who had received at least one previous treatment. Toxic effects of grade 2 or higher included neutropenia in 22% of the patients. Waldenström’s macroglobulinemia is a malignant B-cell lymphoma that is associated with an accumulation of clonal lymphoplasmacytic cells and monoclonal IgM secretion. 1 Despite advances in treatment, the disease eventually progresses in most patients, and new treatment options are needed. Whole-genome sequencing has revealed a single activating somatic mutation in MYD88 (resulting in a predicted protein change from leucine to proline at amino acid position 265) and multiple activating mutations in the C-terminal domain of CXCR4 in patients with Waldenström’s macroglobulinemia. 2 , 3 In tumor cells, MYD88L265P triggers activation of nuclear factor κB (NF-κB) through two divergent pathways involving Bruton’s tyrosine kinase (BTK) . . .

A randomized trial comparing ibrutinib plus rituximab with rituximab alone in patients with Waldenström’s macroglobulinemia showed significantly higher rates of progression-free survival and overall response with the addition of ibrutinib.

Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65–84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1–2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22·1 months (IQR 18·4–23·2), 22 (71%) of 31 patients achieved an objective response (95% CI 52·0–85·8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response. The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials. Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.

We aimed to assess efficacy and tolerability of vorinostat in combination with bortezomib for treatment of patients with relapsed or refractory multiple myeloma. In our randomised, double-blind, placebo-controlled, phase 3 trial, we enrolled adults (≥18 years) at 174 university hospitals in 31 countries worldwide. Eligible patients had to have non-refractory multiple myeloma that previously responded to treatment (one to three regimens) but were currently progressing, ECOG performance statuses of 2 or less, and no continuing toxic effects from previous treatment. We excluded patients with known resistance to bortezomib. We randomly allocated patients (1:1) using an interactive voice response system to receive 21 day cycles of bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11) in combination with oral vorinostat (400 mg) or matching placebo once-daily on days 1–14. We stratified patients by baseline tumour stage (International Staging System stage 1 or stage ≥2), previous bone-marrow transplantation (yes or no), and number of previous regimens (1 or ≥2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed adverse events in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number 00773747. Between Dec 24, 2008, and Sept 8, 2011, we randomly allocated 317 eligible patients to the vorinostat group (315 of whom received at least one dose) and 320 to the placebo group (all of whom received at least one dose). Median PFS was 7·63 months (95% CI 6·87–8·40) in the vorinostat group and 6·83 months (5·67–7·73) in the placebo group (hazard ratio [HR] 0·77, 95% CI 0·64–0·94; p=0·0100). 312 (99%) of 315 patients in the vorinostat group and 315 (98%) of 320 patients in the placebo group had adverse events (300 [95%] adverse events in the vorinostat group and 282 [88%] in the control group were regarded as related to treatment). The most common grade 3–4 adverse events were thrombocytopenia (143 [45%] patients in the vorinostat group vs 77 [24%] patients in the placebo group), neutropenia (89 [28%] vs 80 [25%]), and anaemia (53 [17%] vs 40 [13%]). Although the combination of vorinostat and bortezomib prolonged PFS relative to bortezomib and placebo, the clinical relevance of the difference in PFS between the two groups is not clear. Different treatment schedules of bortezomib and vorinostat might improve tolerability and enhance activity. Merck.

Natural killer (NK) cells contribute to immunity and reproduction. Guiding these functions, and NK cell education, are killer cell Ig-like receptors (KIR), NK cell receptors that recognize HLA class I. In most human populations, these highly polymorphic receptors and ligands combine with extraordinary diversity. To assess how much of this diversity is necessary, we studied KIR and HLA class I at high resolution in the Yucpa, a small South Amerindian population that survived an approximate 15,000-year history of population bottleneck and epidemic infection, including recent viral hepatitis. The Yucpa retain the three major HLA epitopes recognized by KIR. Through balancing selection on a few divergent haplotypes the Yucpa maintain much of the KIR variation found worldwide. HLA-C*07, the strongest educator of C1-specific NK cells, has reached unusually high frequency in the Yucpa. Concomitantly, weaker variants of the C1 receptor, KIR2DL3, were selected and have largely replaced the form of KIR2DL3 brought by the original migrants from Asia. HLA-C1 and KIR2DL3 homozygosity has previously been correlated with resistance to viral hepatitis. Selection of weaker forms of KIR2DL3 in the Yucpa can be seen as compensation for the high frequency of the potent HLA-C*07 ligand. This study provides an estimate of the minimal KIR-HLA system essential for long-term survival of a human population. That it contains all functional elements of KIR diversity worldwide, attests to the competitive advantage it provides, not only for surviving epidemic infections, but also for rebuilding populations once infection has passed.

In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenström's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58–74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2–6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5–18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66–94), and the estimated 18 month overall survival rate was 97% (95% CI 79–100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3–11·7) increased to 11·4 g/dL (10·9–12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8–13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenström's macroglobulinaemia. Pharmacyclics LLC, an AbbVie Company.

One of the central molecules in capillary formation during angiogenesis is the integrin alpha V beta 3. The aim of this study was to inhibit alphaV-mediated angiogenesis in vitro using RNAs (siRNA) as well as antisense oligodeoxyribonucleotides (asON). Five siRNAs, against the alphaV chain of alpha V beta 3, and three asON, which had the respective sequence of the antisense sequence of three of the siRNAs molecules, were examined. Two of the siRNAs and their respective asON were designed on the basis of computer-predicted secondary structure analysis of alpha V mRNA. The different molecules were transfected into human umbilical vein endothelials cells (HUVEC) using lipofection. Following stimulation by PMA, two siRNAs showed a dose-dependent inhibition of PMA-induced alpha V mRNA and protein upregulation, as assessed by real-time RT-PCR and flow cytometry. At a concentration of 25 nM a complete inhibition of protein upregulation was found using siRNAs while transfection of the respective asON sequences reduced the protein upregulation only by 44%. To evaluate the anti-angiogenic potential a cell culture model of human angiogenesis based on the co-cultivation of endothelial cells and dermal fibroblasts was used. Transfection of the siRNA sequence (50 nM) resulted in an inhibition of the total length of capillary-like tubules by 40.6% in comparison to 21.1% using the respective asON sequence. In conclusion, siRNA-based downregulation of alpha V expression showed a stronger inhibition of capillary tube formation in an angiogenesis in vitro assay, than asON having the same sequence as the antisense strand of the siRNAs. Therefore, siRNAs are useful tools for functional alpha V knock-down experiments and might be a therapeutic alternative for antagonists which bind directly to the integrins alpha V beta 3 or alpha V beta 5.

One of the central molecules in capillary formation during angiogenesis is the integrin αVβ3. The aim of this study was to inhibit alphaV-mediated angiogenesis in vitro using RNAs (siRNA) as well as antisense oligodeoxyribonucleotides (asON). Five siRNAs, against the alphaV chain of αVβ3, and three asON, which had the respective sequence of the antisense sequence of three of the siRNAs molecules, were examined. Two of the siRNAs and their respective asON were designed on the basis of computer-predicted secondary structure analysis of αV mRNA. The different molecules were transfected into human umbilical vein endothelials cells (HUVEC) using lipofection. Following stimulation by PMA, two siRNAs showed a dose-dependent inhibition of PMA-induced αV mRNA and protein upregulation, as assessed by real-time RT-PCR and flow cytometry. At a concentration of 25 nM a complete inhibition of protein upregulation was found using siRNAs while transfection of the respective asON sequences reduced the protein upregulation only by 44%. To evaluate the anti-angiogenic potential a cell culture model of human angiogenesis based on the co-cultivation of endothelial cells and dermal fibroblasts was used. Transfection of the siRNA sequence (50 nM) resulted in an inhibition of the total length of capillary-like tubules by 40.6% in comparison to 21.1% using the respective asON sequence. In conclusion, siRNA-based downregulation of αV expression showed a stronger inhibition of capillary tube formation in an angiogenesis in vitro assay, than asON having the same sequence as the antisense strand of the siRNAs. Therefore, siRNAs are useful tools for functional αV knock-down experiments and might be a therapeutic alternative for antagonists which bind directly to the integrins αVβ3 or αVβ5.

One of the central molecules in capillary formation during angiogenesis is the integrin alphaVbeta3. The aim of this study was to inhibit alphaV-mediated angiogenesis in vitro using RNAs (siRNA) as well as antisense oligodeoxyribonucleotides (asON). Five siRNAs, against the alphaV chain of alphaVbeta3, and three asON, which had the respective sequence of the antisense sequence of three of the siRNAs molecules, were examined. Two of the siRNAs and their respective asON were designed on the basis of computer-predicted secondary structure analysis of alphaV mRNA. The different molecules were transfected into human umbilical vein endothelials cells (HUVEC) using lipofection. Following stimulation by PMA, two siRNAs showed a dose-dependent inhibition of PMA-induced alphaV mRNA and protein upregulation, as assessed by real-time RT-PCR and flow cytometry. At a concentration of 25 nM a complete inhibition of protein upregulation was found using siRNAs while transfection of the respective asON sequences reduced the protein upregulation only by 44%. To evaluate the anti-angiogenic potential a cell culture model of human angiogenesis based on the co-cultivation of endothelial cells and dermal fibroblasts was used. Transfection of the siRNA sequence (50 nM) resulted in an inhibition of the total length of capillary-like tubules by 40.6% in comparison to 21.1% using the respective asON sequence. In conclusion, siRNA-based downregulation of alphaV expression showed a stronger inhibition of capillary tube formation in an angiogenesis in vitro assay, than asON having the same sequence as the antisense strand of the siRNAs. Therefore, siRNAs are useful tools for functional alphaV knock-down experiments and might be a therapeutic alternative for antagonists which bind directly to the integrins alphaVbeta3 or alphaVbeta5.