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A decade after International Myeloma Working Group (IMWG) biomarkers (SLiM criteria) were introduced, this real-world study examined their impact on diagnosis, therapy and outcomes in myeloma. Using the ANZ MRDR, 3489 newly diagnosed patients from 2013 to 2023, comprising 3232 diagnosed by CRAB ('CRAB patients', including 1758 who also satisfied ≥1 SLiM criteria) and 257 by SLiM ('SLiM patients') criteria were analysed. CRAB patients had higher R-ISS and lower performance status, with no difference in cytogenetic risk. SLiM patients had improved progression-free survival (PFS, 37.5 vs. 32.2 months, hazard ratio [HR] 1.31 [1.08-1.59], p = 0.003), overall survival (80.9 vs. 73.2 months, HR 1.64 [1.26-2.13], p < 0.001) and PFS2 (54.6 vs. 40.3 months, HR 1.51 [1.22-1.86], p < 0.001) compared with CRAB patients, partially explained by earlier diagnosis, with no differential impact between the plasma cell and light-chain criteria on PFS. However, 34% of CRAB patients did not manifest SLiM characteristics, raising the possibility that SLiM features are associated with different biological behaviours contributing to a better prognosis, for example, improved PFS2 in SLiM patients suggested less disease resistance at first relapse. These data support earlier initiation of therapy by SLiM. The superior survival outcomes of SLiM versus CRAB patients highlight the importance of defining these subgroups when interpreting therapeutic outcomes at induction and first relapse.

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.

Comprehensive clinical characteristics of Australian patients with classical Hodgkin Lymphoma (cHL) have not previously been systematically collected and described. We report real-world data of 498 eligible patients from the first 5 years of the Lymphoma and Related Diseases Registry (LaRDR), including baseline characteristics, histologic subtype, and treatment patterns in first-line therapy. Patient demographics and distribution of histopathological subtypes of cHL are similar to reported international cohorts. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was the most common therapy for both early and advanced-stage disease, and 48% of patients with the early-stage disease received radiotherapy. Treatment patterns are consistent with international guidelines. In comorbid patients ≥60 years of age with advanced-stage disease, there is greater variation in treatment. In patients with a recorded response, the objective response rate (ORR) was 96% in early-stage disease, and 88% in advanced-stage disease. Early progression-free survival data suggest Australian patients with cHL have good outcomes, similar to other international studies.

The frequency and causes of early mortality in patients with newly diagnosed multiple myeloma (NDMM) have not been well described in the era of novel agents. We investigated early mortality in a prospective cohort study of all patients with NDMM registered on the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) at 36 institutions between July 2011 and March 2020. Early mortality was defined as death from any cause within the first 12 months after diagnosis. A total of 2377 patients with NDMM were included in the analysis, with a median (interquartile range) age of 67.4 (58.9-74.60 years, and 60% were male. Overall, 216 (9.1%) patients died within 12 months, with 119 (4.5%) having died within 6 months. Variables that were independent predictors of early mortality after adjustment in multivariable regression included age (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.05-1.08; p < 0.001), Eastern Cooperative Oncology Group performance status (OR 1.50, 95% CI 1.26-1.79; p < 0.001), serum albumin (OR 0.95, 95% CI 0.93-0.98; p < 0.001), cardiac disease (OR 1.96, 95% CI 1.35-2.86; p < 0.001) and International Staging System (OR 1.40, 95% CI 1.07-1.82; p = 0.01). For those with a primary cause of death available, it was reported as disease-related in 151 (78%), infection 13 (7%), other 29 (15%). Infection was listed as a contributing factor for death in 38% of patients.

BACKGROUND: Lymphoma is a malignancy of lymphocytes and lymphoid tissues comprising a heterogeneous group of diseases, with up to 80 entities now described. Lymphoma is the 6th most common cancer in Australia, affecting patients of all ages, with rising incidence rates. With the proliferation of efficacious novel agents, therapeutic strategies are increasingly diverse and survival is improving. There is a clear need for contemporary robust and detailed data on diagnostic, investigational and management strategies for this disease in Australia, New Zealand and worldwide, to inform and benchmark local and international standards of care. Clinical quality registries can provide these data, and support development of strategies to address variations in management, including serving as platforms for clinical trials and other research activities. The Lymphoma and Related Diseases Registry (LaRDR) was developed to capture details of patient demographics, disease characteristics, and management throughout their disease course and therapy and to develop outcome benchmarks nationally and internationally for lymphoma. This report describes the aims, development and implementation of the LaRDR, as well as challenges addressed in the process. METHODS: The LaRDR was established in 2016 as a multicentre, collaborative project at sites across Australia with a secure online database which collects prospective data on patients with a new diagnosis of lymphoma or chronic lymphocytic leukaemia (CLL). LaRDR development required multidisciplinary participation including specialist haematology, information technology, and biostatistical support, as well as secure funding. Here we describe the database development, data entry, ethics approval process, registry governance and support for participating sites and the coordinating centre. RESULTS: To date more than 5,300 patients have been enrolled from 28 sites in Australia and New Zealand. Multiple challenges arose during the development, wh

Background: Prophylactic immunoglobulin (Ig) replacement and prophylactic oral antibiotics (PA) are used to prevent infections in patients with haematological malignancies and acquired hypogammaglobulinemia. Ig has been shown to reduce infection risk, but is costly and in limited supply. PA have been shown to reduce infection risk in other patient populations and are less expensive, but have side-effects and can increase antimicrobial resistance rates. Guidelines and clinical practice vary internationally, with some recommending a trial of PA prior to commencing Ig replacement, and others omitting PA. The efficacy, safety and cost-effectiveness of Ig and PA have not been directly compared in a randomised controlled trial (RCT) in patients with acquired hypogammaglobulinemia secondary to haematological malignancies. Aim(s): To determine the feasibility of delivering PA as an alternative to Ig replacement in patients with haematological malignancies and acquired hypogammaglobulinemia. Method(s): Phase II, multicentre, feasibility RCT (ACTRN12616001723471). Eligible patients had acquired hypogammaglobulinemia due to a haematological malignancy, a history of recurrent or severe bacterial infections or an IgG level <4g/L (excluding paraprotein), and had a life expectancy more than 12 months. Exclusion criteria included prior allogeneic haematopoietic stem cell transplant and prior Ig replacement in the preceding 3 months. Patients were randomised to receive Ig (0.4g/kg IV every 4 weeks, modified to achieve an IgG trough level >= lower limit of reference range; or 0.1g/kg/week SC, modified to achieve an IgG trough level of >= lower limit of reference rage) or daily oral prophylactic antibiotics (trimethoprim-sulfamethoxazole 160mg/800mg, with 100mg doxycycline as an alternative for hypersensitivity) for 12 months at a 1:2 ratio. Randomisation was stratified by site. Patients allocated to PA were allowed to cross over to Ig if they experienced a CTCAE >= Grade 3 infection.

Aim: To determine the feasibility of an electronic dataset comprising hospital laboratory data, transfusion data (any fresh or manufactured product) and clinical outcomes in Australian hospitals. To provide a 'issing link' in monitoring alignment of practice with, and impact of, Australian national patient blood management (PBM) policies and guidelines. Method(s): Using the platform of the Australian and New Zealand Massive Transfusion Registry, all data from adult patients transfused any blood product at participating sites for 2017, including laboratory (for transfusion and other laboratory records) and hospital information systems data (for patient demographics, co-morbidities, admission and clinical outcome data) were extracted. Data were securely sent, imported into the database and data linkage algorithms applied. Analyses were performed using Stata software. Result(s): Selected results from data analyses of the first pilot site are presented. During 2017, 5859 patients received at least 1 transfusion product during a total of 11 201 separate admissions; of these, 3407 (30%) were day-admissions. Length-of-stay (LoS) was >=10 days for 51% of admissions. 21% of hospital stays included ICU admission, of which 25% (577/2307 ICU admissions) were >10 days LoS in ICU. In-hospital mortality was 9.6% (565 deaths/5859 patients), of which 28 deaths (5% of 565 deaths) were LoS <1-day Emergency admissions. Transfused blood products included 24 766 RBC (red blood cells), 9365 PLT (platelets), 7701 FFP (fresh frozen plasma), 4422 Cryo (cryoprecipitate), 52 251 grams IVIg (intravenous immunoglobulin) and 6301 vials of Prothrombinex. Conclusion(s): This study demonstrates feasibility of a potential national dataset linking comprehensive information from readily available electronic hospital data sources on all patients transfused any type of blood product, including immunoglobulins and coagulation factor concentrates, with clinical outcomes data adjusted for demographics and c

Background: Clinical trials comparing transfusion of fresher vs. older red blood cells (RBCs) have not focused on patients experiencing massive transfusion (MT). The clinical impact of storage lesions may be accentuated in this patient group. Method(s): 2007-2018 data from 25 participating hospitals in the Australian and New Zealand Massive Transfusion Registry were analysed to determine the association between in-hospital mortality and RBC storage time (ST) in MT cases (>=5 RBCs within 4 hours, any bleeding context). Logistic regression was used with in-hospital mortality as the outcome, number of transfused RBCs as a co-variate, and mean storage time quartiles of transfused RBCs as the predictor, along with an interaction term. Two sensitivity analyses were run using (1) maximum storage time of the transfused RBCs and (2) proportion of RBCs >=30 days old as predictors. Result(s): Mean storage times for the database's 7890 MT episodes were (by quartile) STmean-Q1 = 13.0 days; STmean-Q2 = 18.9 days; mean-Q3 = 23.5 days; STmean-Q4 = 30.6 days. Using the first quartile (freshest blood) as a control, the second quartile had a higher in-hospital mortality (OR = 1.30 [95% CI: 1.03 to 1.64; P = 0.02]). Difference in mortality for other quartiles compared to the first were not statistically significant, nor was the interaction term for mean storage time and number of RBCs. Sensitivity analyses showed no difference in mortality between quartiles based on maximum storage time or proportion of longer-stored (>=30 days) RBCs. Conclusion(s): No systematic correlation between in-hospital mortality and storage time of transfused RBCs was observed. The one statistically significant result (mortality of storage-timeQ2 vs. storage-timeQ1) was not detected in either sensitivity analysis. These results are consistent with those of large multi-centre trials on the subject1-4. We find no previous study addressing this research question in a large cohort of MT patients.

Aim: Using Australian and New Zealand (NZ) Massive Transfusion Registry (ANZ-MTR) describe Whole Blood (WB) use in massive transfusion (MT) (>=5 red blood cells (RBC) in any 4 h period) in NZ and compare transfusion requirements, laboratory parameters and patient outcomes for WB recipients (WB-R) with those receiving only RBC units (RBC-R). Method(s): All adult MT recipients between 2011 and 2018, at 4 NZ sites with access to WB, were included in the analysis. Result(s): Three hundred fifteen of 1947 (16.1%) MT recipients received >=1 WB unit. WB was most commonly used in vascular surgery (21%), trauma (17%), gastrointestinal (14%), cardiac surgery (11%). WB-R received a median of 2 (IQR 1, 2) WB units and commenced transfusion sooner relative to time of hospital admission than RBC-R. WB-R received fewer RBC (9 (6,16) vs 10 (7,15), P = 0.013), more fresh frozen plasma (FFP) (6 (2,11) vs 5 (2, 9), p < 0.001) and more recombinant FVIIa (P = 0.02) than RBC-R. There were no differences in fibrinogen concentrate, prothrombin complex or other fresh blood products given. In first 4-h of MT, WB-R had shorter APTT compared to RBC-R (42 (34, 60) vs 47 (36, 71) seconds; P = 0.01). Nadir haemoglobin, platelet count and fibrinogen for the 2 groups were similar. WB-R had higher in-hospital mortality (31.4% vs 25.3%, P = 0.024), but similar ICU length of stay and ventilation time. After adjusting for age, sex, number of RBC and FFP units, clinical context and hospital site there was no significant association between WB use and mortality (adjusted odds ratio WB Plasma Reduced 1.19 (95% CI 0.80-1.78) and WB Leucodepleted 1.42 (95% CI 0.94-2.15)).

Aim: Patients with haematologic malignancies are major recipients of blood products; however comprehensive Australian data about clinical outcomes of transfusion are limited. As part of a feasibility study to establish a national comprehensive dataset of all transfusions and their outcomes, we analysed transfusion data for adult haematology/oncology patients from the first pilot site. Method(s): Hospital electronic data on adult patients receiving any blood product (>=1 RBC [red blood cells], platelet, FFP [fresh frozen plasma], cryoprecipitate, or plasma derivative) during 2017 were imported, linked and analysed using the expanded platform of the Australian and New Zealand Massive Transfusion Registry. Data included laboratory (for transfusion and blood tests) and hospital information systems records (for patient demographics, co-morbidities, admission and clinical outcome data). Haematology/oncology patients were identified by ICD-10-AM diagnostic codes. Analyses were performed using Stata software. Result(s): Of 5859 transfused admitted patients, 767 (13%) were haematology/ oncology patients. Of these 38% were acute leukaemias, 25% myeloma, 15% NHL (non-Hodgkin lymphoma), 7% chronic leukaemias, and 15% MDS and other haematopoietic neoplasms. Patient median age was 66.7y, [IQR, 57, 74], and 58% were male. Haematology/oncology patients were 30% (3365/11201) of all admissions where a transfusion was performed; of which 56% were day-admissions. 61% of patients were admitted only once; 34% had 2-10 admissions and 5% had 11-100 admissions. They accounted for 33% RBCs, 69% platelets, 20% cryoprecipitate, 5% FFP and 13% IVIg (intravenous immunoglobulin; in grams) transfused. For outpatients receiving platelet transfusions, median [IQR] platelet count was 17 x109/L [10, 51]. Conclusion(s): Haematology/oncology patients represented 13% of all transfused patients, but required significant proportions of the transfusion product inventory, including 69% of all platelets, cons

Interest in cell heterogeneity and differentiation has recently led to increased use of time-lapse microscopy. Previous studies have shown that cell fate may be determined well in advance of the event. We used a mixture of automation and manual review of time-lapse live cell imaging to track the positions, contours, divisions, deaths and lineage of 44 B-lymphocyte founders and their 631 progeny in vitro over a period of 108 hours. Using this data to train a Support Vector Machine classifier, we were retrospectively able to predict the fates of individual lymphocytes with more than 90% accuracy, using only time-lapse imaging captured prior to mitosis or death of 90% of all cells. The motivation for this paper is to explore the impact of labour-efficient assistive software tools that allow larger and more ambitious live-cell time-lapse microscopy studies. After training on this data, we show that machine learning methods can be used for realtime prediction of individual cell fates. These techniques could lead to realtime cell culture segregation for purposes such as phenotype screening. We were able to produce a large volume of data with less effort than previously reported, due to the image processing, computer vision, tracking and human-computer interaction tools used. We describe the workflow of the software-assisted experiments and the graphical interfaces that were needed. To validate our results we used our methods to reproduce a variety of published data about lymphocyte populations and behaviour. We also make all our data publicly available, including a large quantity of lymphocyte spatio-temporal dynamics and related lineage information.

The transcriptional network regulating antibody-secreting cell (ASC) differentiation has been extensively studied, but our current understanding is limited. The mechanisms of action of known "master" regulators are still unclear, while the participation of new factors is being revealed. Here, we identify Zbtb20, a Bcl6 homologue, as a novel regulator of late B cell development. Within the B cell lineage, Zbtb20 is specifically expressed in B1 and germinal center B cells and peaks in long-lived bone marrow (BM) ASCs. Unlike Bcl6, an inhibitor of ASC differentiation, ectopic Zbtb20 expression in primary B cells facilitates terminal B cell differentiation to ASCs. In plasma cell lines, Zbtb20 induces cell survival and blocks cell cycle progression. Immunized Zbtb20-deficient mice exhibit curtailed humoral responses and accelerated loss of antigen-specific plasma cells, specifically from the BM pool. Strikingly, Zbtb20 induction does not require Blimp1 but depends directly on Irf4, acting at a newly identified Zbtb20 promoter in ASCs. These results identify Zbtb20 as an important player in late B cell differentiation and provide new insights into this complex process.

The ability to build structures with atomic precision is one of the defining features of nanotechnology. Achieving true atomic- level functionality, however, requires the ability to control the wavefunctions of individual atoms. Here, we investigate an approach that could enable just that. By collecting and analysing transport spectra of a single donor atom in the channel of a silicon FinFET, we present experimental evidence for the emergence of a new type of hybrid molecule system. Our experiments and simulations suggest that the transistor's gate potential can be used to control the degree of hybridization of a single electron donor state between the nuclear potential of its donor atom and a nearby quantum well. Moreover, our theoretical analysis enables us to determine the species of donor (arsenic) implanted into each device as well as the degree of confinement imposed by the gate.

Solid-state quantum computer architectures with qubits encoded using single atoms are now feasible given recent advances in atomic doping of semiconductors. Here we present a charge qubit consisting of two dopant atoms in a semiconductor crystal, one of which is singly ionised. Surface electrodes control the qubit and a radio-frequency single electron transistor provides fast readout. The calculated single gate times, of order 50ps or less, are much shorter than the expected decoherence time. We propose universal one- and two-qubit gate operations for this system and discuss prospects for fabrication and scale up.

We review progress at the Australian Centre for Quantum Computer Technology towards the fabrication and demonstration of spin qubits and charge qubits based on phosphorus donor atoms embedded in intrinsic silicon. Fabrication is being pursued via two complementary pathways: a 'top-down' approach for near-term production of few-qubit demonstration devices and a 'bottom-up' approach for large-scale qubit arrays with sub-nanometre precision. The 'top-down' approach employs a low-energy (keV) ion beam to implant the phosphorus atoms. Single-atom control during implantation is achieved by monitoring on-chip detector electrodes, integrated within the device structure. In contrast, the 'bottom-up' approach uses scanning tunnelling microscope lithography and epitaxial silicon overgrowth to construct devices at an atomic scale. In both cases, surface electrodes control the qubit using voltage pulses, and dual single-electron transistors operating near the quantum limit provide fast read-out with spurious-signal rejection.