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Marginal zone lymphomas (MZLs) are a rare, indolent group of non‐Hodgkin lymphomas with different diagnostic, genetic and clinical features and therapeutic implications. The most common is extranodal MZL of mucosa‐associated lymphoid tissue, followed by splenic MZL and nodal MZL. Patients with MZL generally have good outcomes with long survival rates but frequently have a relapsing/remitting course requiring several lines of therapy. The heterogeneous presentation and relapsing course present the clinician with several diagnostic and therapeutic challenges. This position statement presents evidence‐based recommendations in the setting of Australia and New Zealand. [ABSTRACT FROM AUTHOR]

Background Neutropenic sepsis frequently requires admission to an intensive care unit (ICU). Differences between subgroups of patients with neutropenic sepsis are not well characterized. Aims To investigate clinical outcomes among patients with neutropenic sepsis and hematological malignancy, metastatic solid cancer, or no cancer diagnosis. Methods Retrospective cohort study of all patients admitted to ICU in Australia or New Zealand between January 2000 and December 2022 with a primary admission diagnosis of sepsis and total white cell count <1.0 × 109 cells/L. Results We identified 8617 ICU admissions with neutropenic sepsis (hematological malignancy n = 4660; metastatic solid cancer n = 1034; no cancer n = 2800). Patients with hematological malignancy were younger (median, 61.5 years) with low rates of chronic comorbidities (4.7%) and were usually admitted to ICU from the ward (67.4%). Mechanical ventilation rates were 20.2% and in-hospital mortality was 30.6%. Patients with metastatic solid cancers were older (median, 66.3 years), with higher rates of chronic comorbidities (9.9%), and were usually admitted to the ICU from the emergency department (50.8%). Mechanical ventilation rates were 16.9% and in-hospital mortality was 42.4%. Patients with no documented cancer had highest rates of mechanical ventilation (41.7%) and mortality (46.3%). Neutropenia was independently associated with mortality among patients with solid cancers or no cancer but did not confer increased risk among patients with hematological malignancy (odds ratio, 0.98; 95% confidence interval,.90–1.06; P =.60). Conclusions Patients with neutropenic sepsis and hematological malignancy, metastatic solid cancer, or no cancer diagnosis constitute 3 distinct clinical groups. Management approaches should be tailored accordingly. [ABSTRACT FROM AUTHOR]

Background: Sepsis occurs in 12–27% of patients with haematological malignancy within a year of diagnosis. Sepsis mortality has improved in non-cancer patients in the last two decades, but longitudinal trends in patients with haematological malignancy are not well characterised. We aimed to compare outcomes, including temporal changes, in patients with and without a haematological malignancy admitted to ICU with a primary diagnosis of sepsis in Australia and New Zealand over the past two decades. Methods: We performed a retrospective cohort study of 282,627 patients with a primary intensive care unit (ICU) admission diagnosis of sepsis including 17,313 patients with haematological malignancy, admitted to 216 intensive care units (ICUs) in Australia or New Zealand between January 2000 and December 2022. Annual crude and adjusted in-hospital mortality were reported. Risk factors for in-hospital mortality were determined using a mixed methods logistic regression model and were used to calculate annual changes in mortality. Results: In-hospital sepsis mortality decreased in patients with haematological malignancy, from 55.6% (95% CI 46.5–64.6%) in 2000 to 23.1% (95% CI 20.8–25.5%) in 2021. In patients without haematological malignancy mortality decreased from 33.1% (95% CI 31.3–35.1%) to 14.4% (95% CI 13.8–14.8%). This decrease remained significant after adjusting for mortality predictors including age, SOFA score and comorbidities, as estimated by adjusted annual odds of in-hospital death. The reduction in odds of death was of greater magnitude in patients with haematological malignancy than those without (OR 0.954, 95% CI 0.947–0.961 vs. OR 0.968, 95% CI 0.966–0.971, p < 0.001). However, absolute risk of in-hospital mortality remained higher in patients with haematological malignancy. Older age, higher SOFA score, presence of comorbidities, and mechanical ventilation were associated with increased mortality. Leukopenia (white cell count < 1.0 × 109 cells/L) was not associated with increased mortality in patients with haematological malignancy (p = 0.60). Conclusions: Sepsis mortality has improved in patients with haematological malignancy admitted to ICU. However, mortality remains higher in patients with haematological malignancy than those without. Key points: Among patients with haematological malignancy and sepsis admitted to intensive care, mortality has fallen by over 50% in the last two decades. Improvements are independent of organ failure, neutropenia, and age; however, mortality remains higher than for patients with no malignancy. [ABSTRACT FROM AUTHOR]

Aim: Thrombocytopenia and bleeding are common in myelodysplastic syndromes (MDS), but optimal management is unknown. We conducted a survey to identify current clinical practice regarding platelet transfusion (PLT‐T) and tranexamic acid (TXA) to inform future trial design. Method: A 25‐question survey was distributed to members of the ALLG from December 2020 to July 2021. Results: Sixty‐four clinicians across Australia, New Zealand and Singapore responded. Clinicians treated a median of 15 MDS patients annually. Twenty‐nine (45%) reported having institutional guidelines regarding prophylactic PLT‐T. Although 60 (94%) said they would consider using TXA, most (58/64; 91%) did not have institutional guidelines. Clinical scenarios showed prophylactic PLT‐T was more likely administered for patients on disease‐modifying therapy (49/64; 76%, commonest threshold <10 × 109/L) or with minor bleeding (32/64 [50%] transfusing at threshold <20 × 109/L, 23/64 [35%] at <10 × 109/L). For stable untreated patients, 29/64 (45%) would not give PLT‐T and 32/64 (50%) would. Most respondents (46/64; 72%) were interested in participating in trials in this area. Potential barriers included resource limitations, funding and patient/clinician acceptance. Conclusion: Real‐world management of MDS‐related thrombocytopenia varies and there is a need for clinical trials to inform practice. [ABSTRACT FROM AUTHOR]

In the unique landscape of immunology research in New Zealand, this article explores the collaborative networks spanning the two main islands, through a conversation with Associate Professor Joanna Kirman and Dr Robert Weinkove. The discussions delve into their dynamic collaborations with countries such as Asia, Australia and the United States, from their laboratories at the University of Otago and the Malaghan Institute of Medical Research, respectively, provides insight into the translational research landscape of New Zealand, and the integration of Māori culture into all aspects of scientific research and clinical practise. Kirman's work in understanding immunological memory in tuberculosis and Weinkove's research in cancer immunotherapies, particularly CAR‐T cells, are highlighted. The natural beauty and accessibility of New Zealand supports its research diversity. [ABSTRACT FROM AUTHOR]

Despite widespread vaccination rates, we are living with high transmission rates of SARS‐CoV‐2. Although overall hospitalisation rates are falling, the risk of serious infection remains high for patients who are immunocompromised because of haematological malignancies. In light of the ongoing pandemic and the development of multiple agents for treatment, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID‐19 management in patients with haematological disorders. It is our recommendation that both patients with haematological malignancies and treating specialists be educated regarding the preventive and treatment options available and that patients continue to receive adequate vaccinations, keeping in mind the suboptimal vaccine responses that occur in haematology patients, in particular, those with B‐cell malignancies and on B‐cell‐targeting or depleting therapy. Patients with haematological malignancies should receive treatment for COVID‐19 in accordance with the severity of their symptoms, but even mild infections should prompt early treatment with antiviral agents. The issue of de‐isolation following COVID‐19 infection and optimal time to treatment for haematological malignancies is discussed but remains an area with evolving data. This position statement is to be used in conjunction with advice from infectious disease, respiratory and intensive care specialists, and current guidelines from the National COVID‐19 Clinical Evidence Taskforce and the New Zealand Ministry of Health and Cancer Agency Te Aho o Te Kahu COVID‐19 Guidelines. [ABSTRACT FROM AUTHOR]

Central venous access devices (CVADs) are commonly used in malignancies. We conducted an online, anonymous cross‐sectional survey of practice regarding CVAD management in haematology centres among clinicians in Australia and New Zealand. We identified variation in clinical practice regarding CVAD selection, insertion, management and removal. These findings highlight research gaps in CVAD care. [ABSTRACT FROM AUTHOR]

Ibrutinib is a small molecule inhibitor of Bruton's tyrosine kinase indicated for the treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL). The Named Patient Program in Australia and New Zealand (ANZ NPP) provided access to ibrutinib treatment to 1126 R/R CLL/SLL and 330 R/R MCL patients, prior to Pharmaceutical Benefits Scheme listing. This study aimed to assess the duration of treatment for the ANZ NPP patients, as an indicator of efficacy and tolerability of ibrutinib in the real world. Based on the NPP data, ibrutinib provided a median of 47 months clinical benefit for participants with CLL/SLL and 14 months clinical benefit for those with MCL; outcomes that are consistent with the clinical trial results and further support the well-established efficacy and safety profile of ibrutinib in the real world. [ABSTRACT FROM AUTHOR]

Patients with post‐haemopoietic stem cell transplant or chimeric antigen receptor T ‐cell (CAR‐T) therapy face a significant risk of morbidity and mortality from coronavirus disease 2019 because of their immunosuppressed state. As case numbers in Australia and New Zealand continue to rise, guidance on management in this high‐risk population is needed. Whilst we have learned much from international colleagues who faced high infection rates early in the pandemic, guidance relevant to local health system structures, medication availability and emerging therapies is essential to equip physicians to manage our patients optimally. [ABSTRACT FROM AUTHOR]

Co-expression of chimeric switch receptors (CSRs) specific for PD-L1 improves the antitumor effects of chimeric antigen receptor (CAR) T cells. However, the effects of trans-recognition between CSRs and PD-L1 expressed by activated CAR T cells remain unclear. Here, we design a CSR specific for PD-L1 (CARP), containing the transmembrane and cytoplasmic signaling domains of CD28 but not the CD3 ζ chain. We show that CARP T cells enhance the antitumor activity of anti-mesothelin CAR (CARMz) T cells in vitro and in vivo. In addition, confocal microscopy indicates that PD-L1 molecules on CARMz T cells accumulate at cell-cell contacts with CARP T cells. Using single-cell RNA-sequencing analysis, we reveal that CARP T cells promote CARMz T cells differentiation into central memory-like T cells, upregulate genes related to Th1 cells, and downregulate Th2-associated cytokines through the CD70-CD27 axis. Moreover, these effects are not restricted to PD-L1, as CAR19 T cells expressing anti-CD19 CSR exhibit similar effects on anti-PSCA CAR T cells with truncated CD19 expression. These findings suggest that target trans-recognition by CSRs on CAR T cells may improve the efficacy and persistence of CAR T cells via the CD70-CD27 axis. Co-expression of PD-L1-specific chimeric switch receptors (CSRs) improves the antitumor effects of chimeric antigen receptor (CAR) T cells. Here, CSRs are shown to promote the differentiation of mesothelin-targeting CAR T cells into central memory-like cells and improve their efficacy. [ABSTRACT FROM AUTHOR]

Objectives: Metastasis is the principal cause of breast cancer mortality. Vaccines targeting breast cancer antigens have yet to demonstrate clinical efficacy, and there remains an unmet need for safe and effective treatment to reduce the risk of metastasis, particularly for people with triple‐negative breast cancer (TNBC). Certain glycolipids can act as vaccine adjuvants by specifically stimulating natural killer T (NKT) cells to provide a universal form of T‐cell help. Methods: We designed and made a series of conjugate vaccines comprising a prodrug of the NKT cell‐activating glycolipid α‐galactosylceramide covalently linked to tumor‐expressed peptides, and assessed these using E0771‐ and 4T1‐based breast cancer models in vivo. We employed peptides from the model antigen ovalbumin and from clinically relevant breast cancer antigens HER2 and NY‐ESO‐1. Results: Glycolipid‐peptide conjugate vaccines that activate NKT cells led to antigen‐presenting cell activation, induced inflammatory cytokines, and, compared with peptide alone or admixed peptide and α‐galactosylceramide, specifically enhanced CD8+ T‐cell responses against tumor‐associated peptides. Primary tumor growth was delayed by vaccination in all tumor models. Using 4T1‐based cell lines expressing HER2 or NY‐ESO‐1, a single administration of the relevant conjugate vaccine prevented tumor colonisation of the lung following intravenous inoculation of tumor cells or spontaneous metastasis from breast, respectively. Conclusion: Glycolipid‐peptide conjugate vaccines that activate NKT cells prevent lung metastasis in breast cancer models and warrant investigation as adjuvant therapies for high‐risk breast cancer. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) have a major impact on quality of life (QoL). We performed a post hoc analysis of two multicenter trials of azacitidine-based disease-modifying therapy for patients with MDS and low blast count acute myeloid leukemia (AML), to identify factors associated with QoL. 231 patients were included (median age 70 years). At baseline, higher initial hemoglobin, but not neutrophil or platelet count, was associated with better global QoL and physical function (p < 0.001 and p = 0.001, respectively). During therapy, increase in hemoglobin was associated with improvement in QoL and physical function (p = 0.005 and p < 0.001, respectively). Lower initial hemoglobin was associated with higher dyspnea and fatigue scores (p < 0.001 and p = 0.001, respectively), and hemoglobin response was associated with improvement in dyspnea and fatigue (p < 0.001 for each). In patients with MDS and low blast count AML, hemoglobin level was strongly correlated with global QoL, physical functioning, dyspnea and fatigue, both before and during azacitidine-based therapy. [ABSTRACT FROM AUTHOR]

Venetoclax, a potent B-cell lymphoma-2 (BCL-2) inhibitor, has demonstrated clinical efficacy in chronic lymphocytic leukemia (CLL). VENICE II is an open-label, single-arm, phase 3b study (NCT02980731) evaluating the impact of venetoclax monotherapy (400 mg once daily) for ≤2 years on health-related quality of life (HRQoL) of patients with relapsed/refractory CLL. The primary endpoint was mean change in the global health status (GHS)/quality of life (QoL) subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) from baseline to Week 48. Overall, 210 patients received ≥1 dose of venetoclax; median treatment duration was 67.4 weeks. The primary endpoint was met with mean improvement of +9.3 points (n = 156, 95% confidence interval 6.1–12.5; p=.004) in GHS/QoL. At Week 48, clinically meaningful improvements were observed for role functioning, fatigue, and insomnia domains of EORTC QLQ-C30, suggesting venetoclax monotherapy has a positive impact on HRQoL. No new safety signals were reported. [ABSTRACT FROM AUTHOR]

Patients with invasive fungal disease (IFD) are at significant risk of morbidity and mortality. A productive partnership between patients, their carers/families, and the multidisciplinary team managing the infection and any underlying conditions, is essential. Sharing information and addressing knowledge gaps are required to ensure those at risk of IFD avoid infection, while those with suspected or confirmed infection optimise their therapy and avoid toxicities. This new addition to the Australian and New Zealand consensus guidelines for the management of IFD and antifungal use in the haematology/oncology setting outlines the key information needs of patients and their carers/families. It specifically addresses risk factor reduction, antifungal agents and adherence, and the risks and benefits of complementary and alternative therapies. Knowledge gaps are also identified to help inform the future research agenda. [ABSTRACT FROM AUTHOR]

Prostate cancer is the second most common cancer in men worldwide. Despite an abundance of prostate-specific antigens, immunotherapies have yet to become a standard of care, potentially limited by T-cell dysfunction. Up to 10% of human circulating T-cells, and a significant fraction in the urogenital tract, are mucosal-associated invariant T (MAIT) cells. MAIT cells express stereotyped T-cell receptors that recognize riboflavin metabolites derived from microbes presented by MR-1. We evaluated the number, phenotype and function of circulating MAIT cells, alongside two other innate-like T (ILT) -cell subsets, in men with prostate cancer and age- and sex-matched controls. MAIT cells in men with prostate cancer circulated at similar frequencies to controls, but their cytokine production and proliferation was impaired. In contrast, the function of two other ILT-cell populations (natural killer T-cells and Vγ9Vδ2 T-cells) was not impaired. In both patients and controls, MAIT cells expressed high levels of the immune checkpoint molecule PD-1 at rest, while upregulation of PD-1 in response to the MR-1 ligand 5-amino-6D-ribitylaminouracil (5-A-RU) was greater in patients. 5-A-RU also induced upregulation of PD-L1 and -L2 RNA in primary mononuclear cells. We confirmed that circulating MAIT cell number and function were preserved before and during anti-PD1 therapy with pembrolizumab in a cohort of patients with melanoma. In vitro , 5-A-RU enhanced mononuclear cell cytotoxicity against the PD-L1 positive prostate cancer cell line PC3 in an MR-1-dependent manner. Addition of pembrolizumab enhanced this cytotoxicity, and was associated with increased MAIT cell expression of CD107a and IFN-γ. We conclude that prostate cancer is associated with MAIT-cell dysfunction, and that this might be overcome through the application of potent MR-1 ligands with PD-1 blockade. These findings may have implications for the development of cancer immunotherapies that exploit MAIT cells. [ABSTRACT FROM AUTHOR]

This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck. The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL. After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Australia and New Zealand have achieved excellent community control of COVID‐19 infection. In light of the imminent COVID‐19 vaccination roll out in both countries, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID‐19 vaccination in patients with haematological disorders. It is our recommendation that patients with haematological malignancies, and some benign haematological disorders, should have expedited access to high‐efficacy COVID‐19 vaccines, given that these patients are at high risk of morbidity and mortality from COVID‐19 infection. Vaccination should not replace other public health measures in these patients, given that the effectiveness of COVID‐19 vaccination, specifically in patients with haematological malignancies, is not known. Given the limited available data, prospective collection of safety and efficacy data of COVID‐19 vaccination in this patient group is a priority. [ABSTRACT FROM AUTHOR]

Lymphocytes such as T‐cells can be genetically transduced to express a synthetic chimeric antigen receptor (CAR) that re‐directs their cytotoxic activity against a tumour‐expressed antigen of choice. Autologous (patient‐derived) CAR T‐cells have been licensed to treat certain relapsed and refractory B‐cell malignancies, and numerous CAR T‐cell products are in clinical development. As living gene‐modified cells, CAR T‐cells exhibit unique pharmacokinetics, typically proliferating within the recipient during the first 14 days after administration before contracting in number, and sometimes exhibiting long‐term persistence. The relationship between CAR T‐cell dose and exposure is highly variable, and may be influenced by CAR design, patient immune function at the time of T‐cell harvest, phenotype of the CAR T‐cell product, disease burden, lymphodepleting chemotherapy and subsequent immunomodulatory therapies. Recommended CAR T‐cell doses are typically established for a specific product and indication, although for some products, stratification of dose based on disease burden may mitigate toxicity while maintaining efficacy. Re‐evaluation of CAR T‐cell dosing may be necessary following changes to the lymphodepleting regimen, for different disease indications, and following significant manufacturing changes, if product comparability cannot be demonstrated. Dose escalation trials have typically employed 3 + 3 designs, although this approach has limitations, and alternative phase I trial designs may facilitate the identification of CAR T‐cell doses that strike an optimal balance of safety, efficacy and manufacturing feasibility. [ABSTRACT FROM AUTHOR]

Introduction: A pandemic coronavirus, SARS-CoV-2, causes COVID-19, a potentially life-threatening respiratory disease. Patients with cancer may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe COVID-19. Community transmission of COVID-19 could overwhelm health care services, compromising delivery of cancer care. This interim consensus guidance provides advice for clinicians managing patients with cancer during the pandemic.Main Recommendations: During the COVID-19 pandemic: In patients with cancer with fever and/or respiratory symptoms, consider causes in addition to COVID-19, including other infections and therapy-related pneumonitis. For suspected or confirmed COVID-19, discuss temporary cessation of cancer therapy with a relevant specialist. Provide information on COVID-19 for patients and carers. Adopt measures within cancer centres to reduce risk of nosocomial SARS-CoV-2 acquisition; support population-wide social distancing; reduce demand on acute services; ensure adequate staffing; and provide culturally safe care. Measures should be equitable, transparent and proportionate to the COVID-19 threat. Consider the risks and benefits of modifying cancer therapies due to COVID-19. Communicate treatment modifications, and review once health service capacity allows. Consider potential impacts of COVID-19 on the blood supply and availability of stem cell donors. Discuss and document goals of care, and involve palliative care services in contingency planning.Changes in Management AsA Result Of This Statement: This interim consensus guidance provides a framework for clinicians managing patients with cancer during the COVID-19 pandemic. In view of the rapidly changing situation, clinicians must also monitor national, state, local and institutional policies, which will take precedence.Endorsed By: Australasian Leukaemia and Lymphoma Group; Australasian Lung Cancer Trials Group; Australian and New Zealand Children's Haematology/Oncology Group; Australia and New Zealand Society of Palliative Medicine; Australasian Society for Infectious Diseases; Bone Marrow Transplantation Society of Australia and New Zealand; Cancer Council Australia; Cancer Nurses Society of Australia; Cancer Society of New Zealand; Clinical Oncology Society of Australia; Haematology Society of Australia and New Zealand; National Centre for Infections in Cancer; New Zealand Cancer Control Agency; New Zealand Society for Oncology; and Palliative Care Australia. [ABSTRACT FROM AUTHOR]

Summary: Optimal red cell transfusion support in myelodysplastic syndromes (MDS) has not been tested and established. The aim of this study was to demonstrate feasibility of recruitment and follow‐up in an outpatient setting with an exploratory assessment of quality of life (QoL) outcomes (EORTC QLQ‐C30 and EQ‐5D‐5L). We randomised MDS patients to standardised transfusion algorithms comparing current restrictive transfusion thresholds (80 g/l, to maintain haemoglobin 85–100 g/l) with liberal thresholds (105 g/l, maintaining 110–125 g/l). The primary outcomes were measures of compliance to transfusion thresholds. Altogether 38 patients were randomised (n = 20 restrictive; n = 18 liberal) from 12 participating sites in UK, Australia and New Zealand. The compliance proportion for the intention‐to‐treat population was 86% (95% confidence interval 75–94%) and 99% (95–100%) for restrictive and liberal arms respectively. Mean pre‐transfusion haemoglobin concentrations for restrictive and liberal arms were 80 g/l (SD6) and 97 g/l (SD7). The total number of red cell units transfused on study was 82 in the restrictive and 192 in the liberal arm. In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm. Our findings support the feasibility and need for a definitive trial to evaluate the effect of different red cell transfusion thresholds on patient‐centred outcomes. [ABSTRACT FROM AUTHOR]

Introduction Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL. Methods and analysis Eligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×104 CAR T-cells/ kg with a maximum dose of 1×106 CAR T-cells/ kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy. Ethics and dissemination Ethical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings. [ABSTRACT FROM AUTHOR]

The efficacy of paracetamol (acetaminophen) as an antipyretic during febrile neutropenia (FN) has not previously been established. We conducted a randomized double-blind placebo-controlled feasibility trial: hemato-oncology patients at high FN risk were randomly assigned to six hourly oral paracetamol (1 g) or placebo during the first 42 hours of FN. Fifty-three participants were screened, thirty-seven enrolled; 22 developed FN and commenced treatment (13 paracetamol; 9 placebo); recruitment rates were below, and retention rates met, pre-defined feasibility criteria. During the first 24 hours of FN, paracetamol recipients had significantly lower peak temperature than placebo: mean 38.2 (standard deviation 0.8) °C versus 38.9 (0.4) °C; difference −0.78 °C (95% CI −1.38 to −0.18); p =.013. Bacterial load measurement was not informative. Paracetamol lowers body temperature during FN, and definitive trials to determine its impact on FN outcomes are needed. Australian New Zealand Clinical Trials Registry reference ACTRN12613000601730; funded by Health Research Council of New Zealand. [ABSTRACT FROM AUTHOR]

Background: Acquired hypogammaglobulinaemia secondary to haematological malignancies is associated with increased infection risk. Immunoglobulin (Ig) replacement reduces major infections but not mortality, and is costly. No prospective randomised trials have compared Ig replacement with prophylactic antibiotics. Aims: To identify variation in current practice regarding management of secondary hypogammaglobulinaemia in Australia and New Zealand, to identify barriers to best practice, and to inform the development of a clinical trial assessing antibiotic prophylaxis in secondary hypogammaglobulinaemia. Methods: We conducted an online survey of current clinical practice regarding management of secondary hypogammaglobulinaemia among haematologists in Australia and New Zealand. Results: Seventy‐two haematologists responded; 89% of whom reported commencing Ig replacement for secondary hypogammaglobulinaemia in the setting of recurrent or severe infection. Most monitored trough immunoglobulin G levels, most often 3 monthly. Criteria for stopping Ig replacement varied. Most respondents recommended influenza and pneumococcal vaccination, while only 21% reported using antibiotic prophylaxis. Few respondents (3%) reported prescribing prophylactic antibiotics before commencing Ig replacement. Most reported an interest in recruiting patients to a clinical trial comparing Ig replacement with prophylactic antibiotics. Conclusion: In comparison to limited international data, this survey finds variation in practice, which may be due to differences in local policies governing access to Ig. These findings highlight the need for research into the indications for Ig commencement and cessation, and will inform design of prospective trials of infection prevention in secondary hypogammaglobulinaemia. [ABSTRACT FROM AUTHOR]

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II–IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 105 peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4+ and CD8+ T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation. [ABSTRACT FROM AUTHOR]

CLL/SLL treatment has been transformed with Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib. Zanubrutinib, a next-generation BTKi, was designed to maximize BTK occupancy and minimize toxicity. ALPINE (NCT03734016) is a global, randomized, phase 3 study of zanubrutinib vs. ibrutinib in patients with R/R CLL/SLL; presented here is a preplanned interim analysis conducted ~12 months after 415 patients enrolled between 5 Nov 2018-20 Dec 2019. Patients were randomized 1:1 to zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily) arms; stratification factors were age (<65 y vs. ≥65 y), geographic region, refractory status, and del17p/TP53 mutation. Primary endpoint was investigator-assessed overall response rate (ORR) per 2008 IWCLL guidelines or Lugano criteria; noninferiority of zanubrutinib-to-ibrutinib response ratio was evaluated at noninferiority margin of 0.8558. If noninferiority was demonstrated, superiority of zanubrutinib versus ibrutinib in ORR was tested. Baseline characteristics (zanubrutinib vs. ibrutinib): age ≥65 y: 62.3% vs. 61.5%; male sex: 68.6% vs. 75%; >3 prior therapies: 7.2% vs. 10.1%; del17p: 11.6% vs. 12.5%; TP53 mutation without del17p: 8.2% vs. 5.8%. With median follow-up of 15 months, ORR was 78.3% vs. 62.5% for zanubrutinib vs. ibrutinib, respectively (2-sided p = 0.0006, prespecified α = 0.0099). ORR was higher for zanubrutinib in patients with del(11)q (83.6% vs. 69.1%) and del17p (83.3% vs. 53.8%); zanubrutinib had higher overall 12-months progression-free survival (PFS; 94.9% vs. 84.0%) and overall survival (97.0% vs. 92.7%). Significantly fewer patients had atrial fibrillation/flutter (AF) with zanubrutinib versus ibrutinib (2.5% vs. 10.1%, 2-sided p = 0.0014, prespecified α = 0.0099). Zanubrutinib had lower rates of major bleeding (2.9% vs. 3.9%), adverse events leading to discontinuation (7.8% vs. 13.0%), and death (3.9% vs. 5.8%). Zanubrutinib had higher neutropenia rate (28.4% vs. 21.7%) while grade ≥3 infections (12.7% vs. 17.9%) were lower. In summary, this interim analysis showed zanubrutinib had a superior ORR, improved PFS, and lower AF rate compared with ibrutinib. [ABSTRACT FROM AUTHOR]

Neutropenic infections are life-threatening and require empiric antibiotic treatment. We examined 1139 blood culture isolates from our institution over a 36-year period from neutropenic patients to examine temporal trends and disease associations. Positive associations were found between viridans streptococci and acute myeloid leukaemia, coagulase negative staphylococci and acute lymphoblastic leukaemia and Pseudomonas aeruginosa and indolent B-cell malignancies. [ABSTRACT FROM AUTHOR]

Optimal red cell transfusion thresholds in myelodysplastic syndrome are not established. In this survey of 110 Australasian haematologists' practice in myelodysplastic syndrome-related anaemia, 92% of respondents set transfusion thresholds, and would typically transfuse at a haemoglobin <80 g/L aiming for a post-transfusion haemoglobin 90-100 g/L, reflecting a restrictive transfusion strategy. Higher thresholds were typically used for patients with cardiovascular disease or anaemia symptoms. These results will inform the design of clinical trials comparing transfusion thresholds. [ABSTRACT FROM AUTHOR]

Conventional vaccine adjuvants enhance peptide-specific T-cell and B-cell responses by modifying peptide stability or uptake or by binding to pattern-recognition receptors on antigen-presenting cells (APCs). This article discusses the application of a distinct mechanism of adjuvant activity: the activation of type I, or invariant, natural killer T ( iNKT) cells to drive cellular and humoral immune responses. Using a semi-invariant T-cell receptor (TCR), iNKT cells recognize glycolipid antigens presented on cluster of differentiation (CD)-1d molecules. When their ligands are presented in concert with peptides, iNKT cells can provide T-cell help, 'licensing' APCs to augment peptide-specific T-cell and antibody responses. We discuss the potential benefits and limitations of exploiting iNKT cells as 'universal helpers' to enhance vaccine responses for the treatment and prevention of cancer and infectious diseases. [ABSTRACT FROM AUTHOR]

Background and Aims: Anaemia is a major health burden worldwide. Although the finding of conjunctival pallor on clinical examination is associated with anaemia, inter-observer variability is high, and definitive diagnosis of anaemia requires a blood sample. We aimed to detect anaemia by quantifying conjunctival pallor using digital photographs taken with a consumer camera and a popular smartphone. Our goal was to develop a non-invasive screening test for anaemia. Patients and Methods: The conjunctivae of haemato-oncology in- and outpatients were photographed in ambient lighting using a digital camera (Panasonic DMC-LX5), and the internal rear-facing camera of a smartphone (Apple iPhone 5S) alongside an in-frame calibration card. Following image calibration, conjunctival erythema index (EI) was calculated and correlated with laboratory-measured haemoglobin concentration. Three clinicians independently evaluated each image for conjunctival pallor. Results: Conjunctival EI was reproducible between images (average coefficient of variation 2.96%). EI of the palpebral conjunctiva correlated more strongly with haemoglobin concentration than that of the forniceal conjunctiva. Using the compact camera, palpebral conjunctival EI had a sensitivity of 93% and 57% and specificity of 78% and 83% for detection of anaemia (haemoglobin < 110 g/L) in training and internal validation sets, respectively. Similar results were found using the iPhone camera, though the EI cut-off value differed. Conjunctival EI analysis compared favourably with clinician assessment, with a higher positive likelihood ratio for prediction of anaemia. Conclusions: Erythema index of the palpebral conjunctiva calculated from images taken with a compact camera or mobile phone correlates with haemoglobin and compares favourably to clinician assessment for prediction of anaemia. If confirmed in further series, this technique may be useful for the non-invasive screening for anaemia. [ABSTRACT FROM AUTHOR]

The article focuses on a study regarding innate-like T cell profile and deficiency Vgamma9Vdelta2 (Vγ9Vδ2) T cells in patient with myeloma who are treated with amino-bisphosphonate. Topics discussed include association of myeloma with immune defects, impairing of anti-cancer immunotherapy, determination of counts of cells such as mucosal-associated invariant T (MAIT), natural killer T (NKT) and Vγ9Vδ2 T cells, and reduction in NKT count and normal MAIT count.

Fever is often the first sign of neutropenic infection, but its prognostic impact has not been established. We aimed to determine whether early peak temperature is associated with mortality in patients with neutropenic sepsis admitted to intensive care units (ICUs). We used a database of admissions to 157 ICUs in Australia and New Zealand between 2005 and 2013 to seek an association between peak temperature within the first 24 h in ICU and in-hospital mortality in neutropenic and non-neutropenic sepsis. Odds ratios for in-hospital death were calculated for four temperature bands, adjusting for illness severity. Two patient cohorts were identified: neutropenic sepsis (N = 4027) and non-neutropenic sepsis ( N = 114,040). In-hospital mortality was higher in neutropenic sepsis than non-neutropenic sepsis. In both cohorts, early peak temperature below 36.5 °C was associated with significantly increased mortality compared to normothermia. Among non-neutropenic patients, an early peak temperature of 37.5 °C or higher was associated with reduced mortality compared to normothermia. In contrast, in patients with neutropenic sepsis, fever was not associated with reduced mortality compared to normothermia. Similar findings were seen in a subgroup of the neutropenic sepsis cohort with a documented haematological malignancy. In neutropenic sepsis patients admitted to ICU, a temperature below 36.5 °C is associated with increased mortality compared with normothermia. In contrast to non-neutropenic sepsis, fever was not associated with a significant reduction in mortality in neutropenic patients. Interventional studies are needed to determine whether physical or pharmacological measures to reduce fever influence outcomes during neutropenic infections. [ABSTRACT FROM AUTHOR]

The original article [1] contains an error in authorship whereby author, Robert Weinkove's name is mistakenly inverted. The configuration noted in this Correction article should be considered instead along with author's updated affiliation. [ABSTRACT FROM AUTHOR]

The article offers information on Maintaining a fit T-cell compartment lymphoma treatment sequencing in the era of chimeric antigen receptor T-cell therapies.

Costimulatory signals are required to achieve robust chimeric antigen receptor (CAR) T cell expansion, function, persistence and antitumor activity. These can be provided by incorporating intracellular signalling domains from one or more T cell costimulatory molecules, such as CD28 or 4‐1BB, into the CAR. The selection and positioning of costimulatory domains within a CAR construct influence CAR T cell function and fate, and clinical experience of autologous anti‐CD19 CAR T cell therapies suggests that costimulatory domains have differential impacts on CAR T cell kinetics, cytotoxic function and potentially safety profile. The clinical impacts of combining costimulatory domains and of alternative costimulatory domains are not yet clearly established, and may be construct‐ and disease‐specific. The aim of this review is to summarise the function and effect of established and emerging costimulatory domains and their combinations within CAR T cells. [ABSTRACT FROM AUTHOR]

A quiz concerning the explanation for the fever and pancytopenia in a patient with Crohn's disease is presented.

Many acute leukemia patients treated with chemotherapy are at high risk of relapse without allogeneic stem cell transplantation, an immunotherapy that is limited by significant toxicity and donor availability. We propose that post-remission vaccination with a simple autologous whole cell vaccine adjuvanted with α-galactosylceramide may be effective to prevent relapse of acute leukemia. [ABSTRACT FROM PUBLISHER]