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

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Erythropoietin treatment during complement inhibition with eculizumab in a patient with paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis leading to anemia and other clinical manifestations. Transfusions are often required to support hemoglobin at tolerable levels. A PNH patient with aplastic anemia was treated with the complement inhibitor eculizumab, followed by concurrent treatment with recombinant human erythropoietin (rHuEpo). Eculizumab alone reduced hemolysis, increased PNH red blood cell (RBC) mass, and decreased transfusions. Addition of rHuEpo during eculizumab therapy, enhanced erythropoiesis, further increased PNH RBC mass and hemoglobin levels, and rendered the patient transfusion independent for more than two years. These data show that driving erythropoiesis during eculizumab treatment provided further benefit to a patient with PNH and underlying bone marrow failure

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

DAPK3 participates in the mRNA processing of immediate early genes in Chronic Lymphocytic Leukaemia

Cross‐linking of the B cell receptor (BCR) induces transcriptional activation of immediate early genes (IEGs) including EGR1 and DUSP2 in chronic lymphocytic leukaemia (CLL). Here, we have shown that this transcriptional activation correlated with histone H3 threonine 6 and 11 phosphorylation. Both transcription and histone post‐translational modifications are repressed by ibrutinib, a small molecule inhibitor used in CLL treatment. Moreover, we have identified the Death‐Associated Protein Kinase 3 (DAPK3), as the kinase mediating these histone phosphorylation marks in response to activation of the BCR signalling pathway with this kinase being recruited to RNA polymerase II in an anti‐IgM‐dependent manner. DAPK inhibition mimics ibrutinib‐induced repression of both IEG mRNA and histone H3 phosphorylation and has anti‐proliferative effect comparable to ibrutinib in CLL in vitro. DAPK inhibitor (DAPKi) does not repress transcription itself but impacts on mRNA processing and has a broader anti‐tumour effect than ibrutinib, by repressing both anti‐IgM‐ and CD40L‐dependent activation

The STELLAR trial protocol: a prospective multicentre trial for Richter’s syndrome consisting of a randomised trial investigation CHOP-R with or without acalabrutinib for newly diagnosed RS and a single-arm platform study for evaluation of novel agents in relapsed disease

Background Transformation of chronic lymphocytic leukaemia (CLL) to diffuse large B-cell lymphoma (DLCBL) type Richter’s syndrome (RS) carries a dismal prognosis. Standard-of-care chemoimmunotherapy for de novo RS is inadequate with median survival of less than one year. Patients are frequently elderly or have co-morbidities limiting dose-intense chemotherapy. Treatment of relapsed/refractory (R/R) RS and RS emerging after CLL-directed therapy represent urgent unmet clinical needs. Agents targeting Bruton’s tyrosine kinase (BTK) deliver improved outcomes for patients with high-risk CLL and expand effective treatments to frailer patients. Acalabrutinib is an oral, second-generation BTK inhibitor with a favourable toxicity profile and demonstrated activity in CLL and B-cell lymphomas. Combination of acalabrutinib with standard-of-care CHOP-R chemoimmunotherapy offers a sound rationale to test in a prospective trial for de novo RS. Methods The prospective multicentre STELLAR study is designed in two elements, consisting of a randomised study to evaluate the safety and activity of CHOP-R chemoimmunotherapy in combination with acalabrutinib in newly diagnosed RS and single-arm studies of novel agents for other RS patient cohorts. Eligible patients with newly diagnosed DLBCL-type RS are randomised between six cycles of CHOP-R therapy and six cycles CHOP-R plus acalabrutinib, followed by acalabrutinib maintenance. The primary endpoint of the randomised component is progression free survival (PFS). Cohort 1 enrols RS patients with progressive disease following chemoimmunotherapy for acalabrutinib monotherapy. Patients with RS diagnosed while on ibrutinib may enrol in Cohort 2, a single-arm study of CHOP-R plus acalabrutinib. The primary endpoint for the single-arm studies is overall response rate (ORR). Secondary endpoints for all cohorts are overall survival (OS), quality of life and proportion of patients proceeding to stem cell transplantation. The study will be accompanied by exploratory analysis of the mutational landscape of RS and the relationship between dynamic changes in sequential circulating tumour DNA samples and clinical outcomes. Discussion The STELLAR randomised trial evaluates the role of CHOP-R plus acalabrutinib in newly diagnosed RS patients. The single-arm platform studies enable the incorporation of promising novel therapies into the protocol. The STELLAR study has potential to identify novel biomarkers of treatment response in this high-risk malignancy. Trial registration EudraCT: 2017–004401-40, registered on the 31-Oct-2017. IRSCTN: https://www.isrctn.com/ISRCTN52839057, registered on the 04-Mar-2019. ClinicalTrials.gov: NCT03899337, registered on 02-April-2019

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