Australians with chronic lymphocytic leukaemia continue to have high rates of second primary malignancies in the modern era.

Population-based studies have demonstrated a high risk of second cancers, especially of the skin, among patients with chronic lymphocytic leukaemia (CLL). We describe age-standardised incidence ratios (SIRs) of second primary malignancies (SPM) in Australian patients with relapsed/refractory CLL treated with at least two lines of therapy, including ibrutinib. From December 2014 to November 2017, 156 patients were identified from 13 sites enrolled in the Australasian Lymphoma and Related Diseases Registry, and 111 had follow-up data on rates of SPM. At 38.4 months from ibrutinib therapy commencement, 25% experienced any SPM. SIR for melanoma and all cancers (excluding nonmelanomatous skin cancers) were 15.8 (95% confidence interval (CI): 7.0-35.3) and 4.6 (95% CI: 3.1-6.9) respectively. These data highlight the importance of primary preventive interventions and surveillance, particularly as survival from CLL continues to improve.

The establishment of a multiple myeloma clinical registry in the Asia-Pacific region: The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR).

BACKGROUND: Multiple myeloma (MM) is the second most common haematological cancer worldwide. Along with related diseases including monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukaemia (PCL) and plasmacytoma, MM incidence is rising, yet it remains incurable and represents a significant disease burden. Clinical registries can provide important information on management and outcomes, and are vital platforms for clinical trials and other research. The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR) was developed to monitor and explore variation in epidemiology, treatment regimens and their impact on clinical outcomes across this region. Here we describe the registry's design and development, initial data, progress and future plans. METHODS: The APAC MRDR was established in 2018 as a multicentre collaboration across the Asia-Pacific, collecting prospective data on patients newly diagnosed with MM, MGUS, PCL and plasmacytoma in Korea, Singapore, Malaysia and Taiwan, with China recently joining. Development of the registry required a multidisciplinary team of clinicians, researchers, legal and information technology support, and financial resources, as well as local clinical context from key opinion leaders in the APAC region. Written informed consent is obtained and data are routinely collected throughout treatment by hospital staff. Data are stored securely, meeting all local privacy and ethics requirements. Data were collected from October 2018 to March 2024. RESULTS: Over 1700 patients from 24 hospitals have been enrolled onto the APAC MRDR to date, with the majority (86%) being newly diagnosed with MM. Bortezomib with an immunomodulatory drug was most frequently used in first-line MM therapy, and lenalidomide-based therapy was most common in second-line. Establishment and implementation challenges include regulatory and a range of operational issues. CONCLUSION: The APAC MRDR is providing 'real-world' data to participating sites, clinicians and policy-makers to explore factors influencing outcomes and survival, and to support high quality studies. It is already a valuable resource that will continue to grow and support research and clinical collaboration in MM and related diseases across the APAC region.

Immunoglobulin replacement vs prophylactic antibiotics for hypogammaglobulinemia secondary to hematological malignancy.

ABSTRACT: Immunoglobulin replacement and prophylactic antibiotics are commonly used to prevent infections in patients with secondary hypogammaglobulinemia due to hematological malignancies but have never been directly compared. In this randomized controlled feasibility trial conducted in 7 hospitals in Australia and New Zealand, we enrolled patients with secondary hypogammaglobulinemia with either a history of recurrent/severe infection or an immunoglobulin G level <4 g/L. Participants were randomized in a 1:2 ratio to immunoglobulin (0.4 g/kg per 4 weeks IV) or daily antibiotics (trimethoprim-sulfamethoxazole 160 mg/800 mg or, if contraindicated, 100 mg doxycycline) for 12 months. Participants allocated to antibiotics were allowed to crossover after grade ≥3 infections. The primary outcome was proportion of patients alive on the assigned treatment 12 months after randomization. Between August 2017 and April 2019, 63 patients were randomized: 42 to antibiotics and 21 to immunoglobulin. Proportion of participants alive on allocated treatment at 12 months was 76% in the immunoglobulin and 71% in the antibiotic arm (Fisher exact test P=.77; odds ratio, 0.78; 95% CI, 0.22-2.52). The lower quartile for time to first major infection (median, not reached) was 11.1 months for the immunoglobulin and 9.7 months for the antibiotic arm (log-rank test, P=.65). Three participants in the immunoglobulin and 2 in the antibiotic arm had grade ≥3 treatment-related adverse events. A similar proportion of participants remained on antibiotic prophylaxis at 12 months to those on immunoglobulin, with similar rates of major infections. Our findings support the feasibility of progressing to a phase 3 trial. Trial registration #ACTRN12616001723471.

Economic evaluation: immunoglobulin vs prophylactic antibiotics in hypogammaglobulinemia and hematological malignancies.

ABSTRACT: Patients with hematological malignancies are at high risk of developing hypogammaglobulinemia (HGG) and infections. Immunoglobulin (Ig) is one recommended option to prevent these infections, but it is expensive, and its cost-effectiveness compared with other prevention strategies remains unknown. We conducted a trial-based economic evaluation from the Australian health care system perspective to estimate the 12-month cost-effectiveness of prophylactic Ig vs prophylactic antibiotics in 63 adults with HGG and hematological malignancies participating in the RATIONAL feasibility trial. Two analyses were conducted: (1) cost-utility analysis to assess the incremental cost per quality-adjusted life year (QALY) gained; and (2) cost-effectiveness analysis to assess the incremental cost per serious infection prevented (grade ≥3) and per any infection (any grade) prevented. Over 12 months, the total cost per patient was significantly higher in the Ig group than in the antibiotic group (mean difference, AU$29 140; P < .001). Most patients received IVIg, which was the main cost driver; only 2 patients in the intervention arm received subcutaneous Ig. There were nonsignificant differences in health outcomes. Results showed Ig was more costly than antibiotics and associated with fewer QALYs. The incremental cost-effectiveness ratio of Ig vs antibiotics was AU$111 262 per serious infection prevented, but Ig was more costly and associated with more infections when all infections were included. On average and for this patient population, Ig prophylaxis may not be cost-effective compared with prophylactic antibiotics. Further research is needed to confirm these findings in a larger population and considering longer-term outcomes. The trial was registered at the Australian and New Zealand Clinical Trials Registry as #ACTRN12616001723471.

A large dataset of annotated incident reports on medication errors.

Incident reports of medication errors are valuable learning resources for improving patient safety. However, pertinent information is often contained within unstructured free text, which prevents automated analysis and limits the usefulness of these data. Natural language processing can structure this free text automatically and retrieve relevant past incidents and learning materials, but to be able to do so requires a large, fully annotated and validated corpus of incident reports. We present a corpus of 58,658 machine-annotated incident reports of medication errors that can be used to advance the development of information extraction models and subsequent incident learning. We report the best F1-scores for the annotated dataset: 0.97 and 0.76 for named entity recognition and intention/factuality analysis, respectively, for the cross-validation exercise. Our dataset contains 478,175 named entities and differentiates between incident types by recognising discrepancies between what was intended and what actually occurred. We explain our annotation workflow and technical validation and provide access to the validation datasets and machine annotator for labelling future incident reports of medication errors.

Rule-Based Natural Language Processing Pipeline to Detect Medication-Related Named Entities: Insights for Transfer Learning.

We document the procedure and performance of a rule-based NLP system that, using transfer learning, automatically extracts essential named entities related to drug errors from Japanese free-text incident reports. Subsequently, we used the rule-based annotated data to fine-tune a pre-trained BERT model and examined the performance of medication-related incident report prediction. The rule-based pipeline achieved a macro-F1-score of 0.81 in an internal dataset and the BERT model fine-tuned with rule-annotated data achieved a macro-F1-score of 0.97 and 0.75 for named entity recognition and relation extraction tasks, respectively. The model can be deployed to other, similar problems in medication-related clinical texts.

Efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment-naïve and relapsed/refractory severe aplastic anaemia: protocol for the DIAAMOND-Ava-FIRST and DIAAMOND-Ava-NEXT Bayesian Optimal Phase II trials.

INTRODUCTION: Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve haematological responses in sAA. Avatrombopag is a second-generation TPO-A with potential advantages over eltrombopag. However, to date avatrombopag has not been studied in sAA. METHODS AND ANALYSIS: Investigator-initiated, single-arm registry-based Bayesian Optimal Phase II trial of avatrombopag conducted in two cohorts, patients with untreated sAA (FIRST cohort) and in patients with sAA that has relapsed or is refractory to IST (NEXT cohort). In the FIRST cohort, participants receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily, with dose adjusted according to platelet count. Participants in the NEXT cohort receive avatrombopag at 60 mg oral daily from day 1 until day 180, with or without additional IST at the discretion of the treating clinician.For each cohort, two primary endpoints (haematological response and acquired clonal evolution) are jointly monitored and the trial reviewed at each interim analysis where a 'go/no-go' decision is made by evaluating the posterior probability of the events of interests. ETHICS AND DISSEMINATION: The trial has received ethics approval (Monash Health RES-18-0000707A). The trial conduct will comply with ICH-GCP and all applicable regulatory requirements. The results of the trial will be submitted to a peer-review journal for publication. TRIAL REGISTRATION NUMBER: ACTRN12619001042134, ACTRN12619001043123.

The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry.

The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.

Sickle cell disease in Australia: a snapshot from the Australian Haemoglobinopathy Registry.

BACKGROUND: Sickle cell disease (SCD) is the most common monogenic disorder worldwide. In deoxygenated conditions, the altered beta chain (haemoglobin S [HbS]) polymerises and distorts the erythrocyte, resulting in pain crises, vasculopathy and end-organ damage. Clinical complications of SCD cause substantial morbidity, and therapy demands expertise and resources. Optimising care for patients and planning resource allocation for the future requires an understanding of the disease in the Australian population. The Australian Haemoglobinopathy Registry (HbR) is a collaborative initiative of specialist centres collating and analysing data on patients with haemoglobin disorders. AIMS: To provide a snapshot of SCD in Australia over a 12-month period based on data from the HbR. METHODS: Patients with a clinically significant sickling disorder across 12 clinical sites were included for analysis. Data include demographic and diagnostic details, as well as details of the clinical management of the condition over a 12-month period. RESULTS: Data on 359 SCD patients demonstrate a shift in the demographic of patients in Australia, with a growing proportion of sub-Saharan African ethnicities associated with the HbSS genotype. Acute and chronic complications are common, and patients require significant outpatient and inpatient support. Prevalence of disease complications and therapeutic trends are in keeping with other high-income countries. CONCLUSIONS: This study provides the first national picture of SCD in Australia, describing the characteristics and needs of SCD patients, elucidating demand for current and novel therapy and facilitating the planning of services for this vulnerable population.

Australian experience with ibrutinib in patients with relapsed/refractory mantle cell lymphoma: a study from the Lymphoma and Related Diseases Registry.

Bruton's tyrosine kinase inhibitors (BTKi) have an established role in the management of patients with relapsed/refractory mantle cell lymphoma (MCL). However, scant data exist on outcomes of patients ineligible for clinical trials testing these therapies. We describe a contemporary cohort of relapsed/refractory MCL patients from the Australasian Lymphoma and Related Diseases Registry treated with ibrutinib December 2014 until July 2018, to determine the proportion potentially eligible for original trials, reasons for ineligibility and survival outcomes. Of 44 patients, 41% met one or more exclusion criteria from previous phase II/III MCL BTKi studies. Median progression-free and overall survival were 13.7 months (95% CI 6.2-28.1) and 15.6 months (95% CI 10.8-29.6) respectively and were shorter in patients excluded from clinical trials based on ECOG ≥2. Ibrutinib has demonstrable clinical effectiveness in a population enriched for unfit and trial-ineligible patients, and a need for more inclusive enrollment criteria in future BTKi studies is highlighted.

Messaging Should Reflect the Nuanced Relationship between Land Change and Zoonotic Disease Risk.

A hallmark of the media publicity surrounding COVID-19 has been the message that land change causes zoonotic diseases to spill over from wild animals to humans. The secondary peer-reviewed literature sends a similar message. However, as indicated in the primary peer-reviewed literature, the complexity of interacting variables involved in zoonotic disease spillover makes it unlikely for such a claim to be universally applicable. The secondary peer-reviewed literature and the mainstream media also differ markedly from the primary peer-reviewed literature in their lack of nuance in messaging about the relationship between land change and spillover risk. We advocate accurate, nuanced messaging for the sake of the local communities at greatest risk from zoonotic disease, for the sake of scientific credibility, and so that proportionate attention may be given to other possible drivers of spillover risk.

The cost of blood: a study of the total cost of red blood cell transfusion in patients with ß-thalassemia using time-driven activity-based costing.

BACKGROUND: To accurately quantify the costs of care for patients with transfusion-dependent thalassemia (TDT), and to evaluate cost-effectiveness of new treatments, data are required on costs of regular red blood cell (RBC) transfusions. However, no previous studies have evaluated the costs of RBC transfusion specifically in chronically transfused patients. METHODS AND MATERIALS: We performed a time-driven activity-based costing (TDABC) study using a health care provider perspective. This was performed over a 1-month period, capturing every step of the transfusion pathway for patients with TDT at a designated provider of specialist thalassemia services in Australia. Detailed process maps were developed to outline treatments and processes directly related to transfusion. For each process map, detailed data collection, including timing of activities, was performed multiple times to account for variation in practice. Costs associated with RBC transfusion were broken down into fixed, process, and RBC procurement costs. RESULTS: The total per-unit cost was US$695.59 (95% confidence interval, US$694.45-US$696.73). Approximately 40% of cost was for procurement of the RBC unit, with process costs accounting for 55%. The single largest contributor to process costs was attributed to iron chelation medication (approximately 80%). In sensitivity analyses, seniority of staff, time to perform processes, and probabilities of different processes occurring did not substantially influence the RBC transfusion cost; however the number of RBC units per transfusion episode did impact the overall cost per RBC unit. CONCLUSIONS: We found significant costs associated with RBC transfusion for TDT, with the product cost contributing less than one-half of the total cost.

Optimal Dose, Timing and Ratio of Blood Products in Massive Transfusion: Results from a Systematic Review.

Optimal dose, timing and ratio to red blood cells (RBC) of blood component therapy (fresh frozen plasma [FFP], platelets, cryoprecipitate or fibrinogen concentrate) to reduce morbidity and mortality in critically bleeding patients requiring massive transfusion is unknown. We performed a systematic review for randomized controlled trials (RCT) in MEDLINE, The Cochrane Library, Embase, CINAHL, PubMed the Transfusion Evidence Library and using multiple clinical trials registries to 21 February 2017. Sixteen RCTs were identified: six completed (five in adult trauma patients, one pediatric burn patients) and ten ongoing trials. Of the completed trials: three were feasibility trials, comparing a FFP, platelets and RBC ratio of 1:1:1 to laboratory-guided transfusion practice [n=69], early cryoprecipitate compared to standard practice [n=41], and early fibrinogen concentrate compared to placebo [n=45]; one trial compared the effect of FFP, platelets and RBC ratio of 1:1:1 with 1:1:2 on 24-hour and 30-day mortality [n=680]; one compared whole blood to blood component therapy on 24-hour blood use [n=107]; one compared a FFP to RBC ratio of 1:1 with 1:4 [n=16]. Data from two trials were pooled in a meta-analysis for 28-day mortality because the transfusion ratios achieved were similar. Results from these two trials suggest higher transfusion ratios were associated with transfusion of more FFP and platelets without evidence of significant difference with respect to mortality or morbidity. On the limited evidence available, there is insufficient basis to recommend a 1:1:1 over a 1:1:2 ratio or standard care for adult patients with critical bleeding requiring massive transfusion.

Major haemorrhage fatalities in the Australian national coronial database.

OBJECTIVE: The aim of the study is to describe the epidemiology of major bleeding fatalities. METHODS: A case series analysis of Australia's National Coronial Information System was conducted. Keywords were used to search for closed cases of major haemorrhage in the state of Victoria for the period 1 January 2009 to 31 December 2011. Coroners' findings, autopsy reports and police reports of cases were reviewed. Demographic data were extracted, and cases were assigned to a clinical bleeding context. RESULTS: A total of 427 cases of major bleeding causing death were identified. The cohort was predominately men (69%), with a median age of 63 years (interquartile range 45-77 years). Trauma accounted for 38%, gastrointestinal haemorrhage 28%, surgical/procedural bleeding 14%, ruptured/leaking aneurysms 12% and other 8%. Most events began in homes (46%), hospitals (22%) and at the roadside (17%). Of those whose haemorrhage began in the community, 69% did not survive to hospital. CONCLUSIONS: Major bleeding fatalities occurred across a diverse range of contexts, with trauma and gastrointestinal bleeding accounting for most deaths. The majority of patients did not survive to reach hospital. Major haemorrhage occurring entirely outside hospital may be underrecognised from analyses of datasets based primarily on traumatic or in-hospital bleeding. These findings have implications for management of pre-hospital resuscitation and development of clinical practice guidelines for identification and management of major bleeding in the community.

Profiling clinical platelet and plasma use to inform blood supply and contingency planning: PUPPY, the prospective utilization of platelets and plasma study.

BACKGROUND: Demand for platelet (PLT) and plasma transfusions is increasing. Improved clinical supply and contingency planning requires greater understanding of usage profiles and urgency of clinical requirement. STUDY DESIGN AND METHODS: This study was a random-sample survey of PLT and plasma units produced in Victoria, Australia, to determine product disposition, recipient demographics, clinical indications for transfusion, and urgency (or "deferability") of need. PLTs and fresh-frozen plasma (FFP) were tagged with a case report form before distribution. RESULTS: A total of 1252 PLT and 1837 FFP units were tagged, comprising 8.3 and 13.3% of all products issued during the study period. The fate of 1243 PLT and 1808 FFP units was determined. Of products issued, 72.2% of PLTs and 87.8% of FFP were transfused. Hematologic and oncologic disorders accounted for 63.9% of PLT transfusions, with acute myeloid leukemia alone accounting for 26%. Conversely, surgical patients received the largest proportion of FFP (40.4%), predominantly for cardiothoracic, solid organ transplant, and vascular surgery. Approximately 15% of PLT transfusions and 35% of plasma transfusions were required within 1 hour, and 80% of PLT transfusions and 90% of FFP transfusions were required within 24 hours. Wastage rates were higher in regional blood banks. CONCLUSION: The PUPPY study is a comprehensive and detailed population-based assessment of PLT and plasma usage, including urgency of use. It identifies specific clinical areas with high demand for PLT and FFP transfusion and demonstrates the high urgency of need for both products. These data inform clinical supply and contingency planning activities.

Demographic and socio-cultural correlates of medical mistrust in two Australian States: Victoria and South Australia.

Studies on medical mistrust have mainly focused on depicting the association between medical mistrust and access/utilization of healthcare services. The effect of broader socio-demographic and psycho-social factors on medical mistrust remains poorly documented. The study examined the effect of broader socio-demographic factors, acculturation, and discrimination on medical mistrust among 425 African migrants living in Victoria and South Australia, Australia. After adjusting for socio-demographic factors, low medical mistrust scores (i.e., more trusting of the system) were associated with refugee (ß=-4.27, p<0.01) and family reunion (ß=-4.01, p<0.01) migration statuses, being Christian (ß=-2.21, p<0.001), and living in rural or village areas prior to migration (ß=-2.09, p<0.05). Medical mistrust did not vary by the type of acculturation, but was positively related to perceived personal (ß=0.43, p<0.001) and societal (ß=0.38, p<0.001) discrimination. In order to reduce inequalities in healthcare access and utilisation and health outcomes, programs to enhance trust in the medical system among African migrants and to address discrimination within the community are needed.

Assessment of the urgency and deferability of transfusion to inform emergency blood planning and triage: the Bloodhound prospective audit of red blood cell use.

BACKGROUND: Careful planning is essential to ensure blood availability during shortages. Triaging supply is one proposed strategy; however, few data concerning the urgency of transfusion are available to inform planning. This study sought to determine the proportion of red blood cells (RBCs) used for clinically urgent indications. STUDY DESIGN AND METHODS: A total of 5132 RBC units were randomly selected at point of production and distributed into general statewide inventory over a 9-month period. These selected units carried case report forms, for completion at the point of hospital issue for transfusion. Completed forms were returned to the blood service for collation and analysis, capturing information on indication and clinical urgency of supply, including use for potentially deferrable elective surgery. RESULTS: Data from 5052 RBC units indicated that 95.6% were transfused. Approximately one-third of transfused units were used to support surgery, one-third for hematology/oncology, and one-third for other medical and miscellaneous indications. Where used for surgery, 25.7% (95% confidence interval [CI], 23.4%-28.0%) were for elective procedures, although urgency of surgery was unknown in 17.1% (95% CI, 15.2%-19.2%) of cases. Supply for nonurgent medical indications and elective surgery only accounted for 9.8% (95% CI, 9.0%-10.6%) of use, with 53.4% (95% CI, 52.0%-54.8%) of RBCs required within 24 hours. CONCLUSIONS: The majority of RBCs are transfused with a high degree of clinical urgency, with only a minor proportion required to support elective surgery.