Clinical significance of circulating dendritic cells in patients with systemic lupus erythematosus.

Dendritic cells are a complex group of mainly bone-marrow-derived leukocytes that play a role in autoimmune diseases. The total number of circulating dendritic cells (tDC), and their plasmacytoid dendritic cell (pDC) and myeloid dendritic cell (mDC1 and mDC2) subpopulations were assessed using flow cytometry. The number of tDC and their subsets were significantly lower in systemic lupus erythematosus patients than in the control group. The count of tDC and their subsets correlated with the number of T cells. The number of tDC and pDC subpopulation were lower in the patients with lymphopenia and leukopenia than in the patients without these symptoms. Our data suggest that fluctuations in blood dendritic cell count in systemic lupus erythematosus patients are much more significant in pDC than in mDC, what may be caused by their migration to the sites of inflammation including skin lesions. Positive correlation between dendritic cell number and TCD4+, TCD8+ and CD19+ B cells, testify of their interactions and influence on SLE pathogenesis. The association between dendritic cell number and clinical features seems to be less clear

appendix 6: Chronic lymphocytic leukaemia: eUpdate published online September 2016 (http://www.esmo.org/Guidelines/Haematological-Malignancies)

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OCEAN: a randomized Phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma

Melflufen is a novel peptide-drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. It has emerged as a potential new multiple myeloma treatment, particularly for late-stage forms of the disease. Here we describe the rationale and design of OCEAN (NCT03151811), a randomized, head-to-head, superiority, open-label, global, Phase III study evaluating the efficacy and safety of melflufen + dexamethasone versus pomalidomide + dexamethasone. Eligible patients with relapsed refractory multiple myeloma have received 2-4 previous treatments and are refractory to both lenalidomide and their last treatment. Patients are excluded if they have previously received pomalidomide. The primary endpoint is progression-free survival, and key secondary endpoints include overall response rate, duration of response and overall survival

Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study.

RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1-66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098-0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266-0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047-0.145]; OS: HR [95% CI]: 0.366 [0.181-0.736]). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time

Pseudogaucher cells obscuring multiple myeloma: a case report

Gaucher-like or pseudo-Gaucher cells have been noted in a variety of conditions including acute lymphoblastic leukemia, Hodgkin's disease, thalassemia, and multiple myeloma. They have an eccentric, lobulated nucleus, foamy cytoplasm but lack the tubular inclusions seen in Gaucher cells. The pseudo-Gaucher cells have distinct appearances on electron microscopy which distinguish them from true Gaucher cells

Panics and Principles: A History of Drug Education Policy in New South Wales 1965-1999

When the problem of young people using illegal drugs for recreation emerged in New South Wales in the 1960s drug education was promoted by governments and experts as a humane alternative to policing. It developed during the 1970s and 1980s as the main hope for preventing drug problems amongst young people in the future. By the 1990s drug policy experts, like their temperance forbears, had become disillusioned with drug education, turning to legislative action for the prevention of alcohol and other drug problems. However, politicians and the community still believed that education was the best solution. Education Departments, reluctant to expose schools to public controversy, met minimal requirements. This thesis examines the ideas about drugs, education and youth that influenced the construction and implementation of policies about drug education in New South Wales between 1965 and 1999. It also explores the processes that resulted in the defining of drug problems and beliefs about solutions, identifying their contribution to policy and the way in which this policy was implemented. The thesis argues that the development of drug education over the last fifty years has been marked by three main cycles of moral panic about youth drug use. It finds that each panic was triggered by the discovery of the use of a new illegal substance by a youth subculture. Panics continued, however, because of the tension between two competing notions of young people’s drug use. In the traditional dominant view ‘drug’ meant illegal drugs, young people’s recreational drug use was considered to be qualitatively different to that of adults, and illegal drugs were the most serious and concerning problem. In the newer alternative ‘public health’ view which began developing in the 1960s, illicit drug use was constructed as part of normal experimentation, alcohol, tobacco and prescribed medicines were all drugs, and those who developed problems with their use were sick, not bad. These public health principles were formulated in policy documents on many occasions. The cycles of drug panic were often an expression of anxiety about the new approach and they had the effect of reasserting the dominant view. The thesis also finds that the most significant difference between the two discourses lies in the way that alcohol is defined, either as a relatively harmless beverage or as a drug that is a major cause of harm. Public health experts have concluded that alcohol poses a much greater threat to the health and safety of young people than illegal drugs. However, parents, many politicians and members of the general community have believed for the last fifty years that alcohol is relatively safe. Successive governments have been influenced by the economic power of the alcohol industry to support the latter view. Thus the role of alcohol and its importance to the economy in Australian society is a significant hindrance in reconciling opposing views of the drug problem and developing effective drug education. The thesis concludes that well justified drug education programs have not been implemented fully because the rational approaches to drug education developed by experts have not been supported by the dominant discourse about the drug problem. Politicians have used drug education as a populist strategy to placate fear but the actual programs that have been developed attempt to inform young people and the community about the harms and benefits of all drugs. When young people take up the use of a new mood altering drug, the rational approach developed by public health experts provokes intense anxiety in the community and the idea that legal substances such as alcohol, tobacco and prescribed drugs can cause serious harm to young people is rejected in favour of an approach that emphasizes the danger of illegal drug use

Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies

© 2019 by The American Society of Hematology Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n 5 195) and PCYC-1115/1116 (RESONATE-2, n 5 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n 5 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n 5 173, 52% any-grade; n 5 15, 5% grade 3) and fatigue (n 5 119, 36% any-grade; n 5 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n 5 60, 18%) and pneumonia (n 5 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade $3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n 5 4), anemia (n 5 3), and atrial fibrillation (n 5 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069

Phenotypic heterogeneity in IGHV-mutated CLL patients has prognostic impact and identifies a subset with increased sensitivity to BTK and PI3Kδ inhibition

The majority of chronic lymphocytic leukemia (CLL) patients are diagnosed with early-stage disease but the currently used prognostic tools appear to be less informative in this group of patients.1 This is especially problematic for patients with mutated immunoglobulin genes (M-CLL) as they have a more diverse clinical course when compared with patients with unmutated immunoglobulin genes (U-CLL).1, 2, 3, 4 Given the emergence of promising targeted, less toxic, therapeutics in CLL,5, 6 there is an increased need to identify patients who might benefit from early treatment with these new agents