Medicine (St Vincent's) - Research Publications

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    ASTCT Clinical Practice Recommendations for Transplantation and Cellular Therapies in Multiple Myeloma
    Dhakal, B ; Shah, N ; Kansagra, A ; Kumar, A ; Lonial, S ; Garfall, A ; Cowan, A ; Poudyal, BS ; Costello, C ; Gay, F ; Cook, G ; Quach, H ; Einsele, H ; Schriber, J ; Hou, J ; Costa, L ; Aljurf, M ; Chaudhry, M ; Beksac, M ; Prince, M ; Mohty, M ; Janakiram, M ; Callander, N ; Biran, N ; Malhotra, P ; Otero, PR ; Moreau, P ; Abonour, R ; Iftikhar, R ; Silberman, R ; Mailankody, S ; Gregory, T ; Lin, Y ; Carpenter, P ; Hamadani, M ; Usmani, S ; Kumar, S (ELSEVIER SCIENCE INC, 2022-06-01)
    Over the past decade, therapeutic options in multiple myeloma (MM) have changed dramatically. Given the unprecedented efficacy of novel agents, the role of hematopoietic cell transplantation (HCT) in MM remains under scrutiny. Rapid advances in myeloma immunotherapy including the recent approval of chimeric antigen receptor (CAR) T-cell therapy will impact the MM therapeutic landscape. The American Society for Transplantation and Cellular Therapy convened an expert panel to formulate clinical practice recommendations for role, timing, and sequencing of autologous (auto-HCT), allogeneic (allo-HCT) and CAR T-cell therapy for patients with newly diagnosed (NDMM) and relapsed/refractory MM (RRMM). The RAND-modified Delphi method was used to generate consensus statements. Twenty consensus statements were generated. The panel endorsed continued use of auto-HCT consolidation for patients with NDMM as a standard-of-care option, whereas in the front line allo-HCT and CAR-T were not recommended outside the setting of clinical trial. For patients not undergoing auto-HCT upfront, the panel recommended its use in first relapse. Lenalidomide as a single agent was recommended for maintenance especially for standard risk patients. In the RRMM setting, the panel recommended the use of CAR-T in patients with 4 or more prior lines of therapy. The panel encouraged allo-HCT in RRMM setting only in the context of clinical trial. The panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MM.
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    COVID-19 vaccination in haematology patients: an Australian and New Zealand consensus position statement
    McCaughan, G ; Di Ciaccio, P ; Ananda-Rajah, M ; Gilroy, N ; MacIntyre, R ; Teh, B ; Weinkove, R ; Curnow, J ; Szer, J ; Enjeti, AK ; Ross, DM ; Mulligan, S ; Trotman, J ; Dickinson, M ; Quach, H ; Choi, P ; Polizzotto, MN ; Tam, CS ; Ho, PJ ; Ku, M ; Gregory, G ; Gangatharan, S ; Hapgood, G ; Cochrane, T ; Cheah, C ; Gibbs, S ; Wei, A ; Johnston, A ; Greenwood, M ; Prince, HM ; Latimer, M ; Berkahn, L ; Wight, J ; Armytage, T ; Hamad, N (WILEY, 2021-05-01)
    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.
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    Myeloma natural killer cells are exhausted and have impaired regulation of activation
    D'Souza, C ; Keam, SP ; Yeang, HXA ; Neeson, M ; Richardson, K ; Hsu, AK ; Canfield, R ; Bezman, N ; Robbins, M ; Quach, H ; Ritchie, DS ; Harrison, SJ ; Trapani, JA ; Prince, HM ; Beavis, PA ; Darcy, PK ; Neeson, PJ (FERRATA STORTI FOUNDATION, 2021-09-01)
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    Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID-19 pandemic
    Di Ciaccio, P ; McCaughan, G ; Trotman, J ; Ho, PJ ; Cheah, CY ; Gangatharan, S ; Wight, J ; Ku, M ; Quach, H ; Gasiorowski, R ; Polizzotto, MN ; Prince, HM ; Mulligan, S ; Tam, CS ; Gregory, G ; Hapgood, G ; Spencer, A ; Dickinson, M ; Latimer, M ; Johnston, A ; Armytage, T ; Lee, C ; Cochrane, T ; Berkhahn, L ; Weinkove, R ; Doocey, R ; Harrison, SJ ; Webber, N ; Lee, H-P ; Chapman, S ; Campbell, BA ; Gibbs, SDJ ; Hamad, N (WILEY, 2020-05-15)
    The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.
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    Patient-reported outcome measures in multiple myeloma: Real-time reporting to improve care (My-PROMPT) - a pilot randomized controlled trial
    Moore, EM ; King, TA ; Wood, EM ; Ruseckaite, R ; Klarica, D ; Spencer, A ; Ho, PJ ; Quach, H ; Prince, HM ; McQuilten, ZK (WILEY, 2020-04-20)
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    Successful identification of predictive profiles for infection utilising systems-level immune analysis: a pilot study in patients with relapsed and refractory multiple myeloma
    Doerflinger, M ; Garnham, AL ; Freytag, S ; Harrison, SJ ; Prince, HM ; Quach, H ; Slavin, MA ; Pellegrini, M ; Teh, BW (WILEY, 2021-01-01)
    OBJECTIVES: Patients with multiple myeloma (MM) are at increased risk for infection. Clinical assessment of infection risk is increasingly challenging in the era of immune-based therapy. A pilot systems-level immune analysis study to identify predictive markers for infection was conducted. METHODS: Patients with relapsed and/or refractory MM (RRMM) who participated in a treatment trial of lenalidomide and dexamethasone were evaluated. Data on patient demographics, disease and episodes of infection were extracted from clinical records. Peripheral blood mononuclear cells (PBMCs) collected at defined intervals were analysed, with or without mitogen re-stimulation, using RNA sequencing and mass cytometry (CyTOF). CyTOF-derived cell subsets and RNAseq gene expression profiles were compared between patients that did and did not develop infection to identify immune signatures that predict infection over a 3-month period. RESULTS: Twenty-three patients participated in the original treatment trial, and we were able to access samples from 17 RRMM patients for further evaluation in our study. Nearly half the patients developed an infection (8/17) within 3 months of sample collection. Infections were mostly clinically diagnosed (62.5%), and the majority involved the respiratory tract (87.5%). We did not detect phenotypic or numerical differences in immune cell populations between patients that did and did not develop infections. Transcriptional profiling of stimulated PBMCs revealed distinct Th2 immune pathway signatures in patients that developed infection. CONCLUSION: Immune cell counts were not useful predictors of infection risk. Functional assessment of stimulated PBMCs has identified potential immune profiles that may predict future infection risk in patients with RRMM.
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    Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma
    Tam, CS ; Quach, H ; Nicol, A ; Badoux, X ; Rose, H ; Prince, HM ; Leahy, MF ; Eek, R ; Wickham, N ; Patil, SS ; Huang, J ; Prathikanti, R ; Cohen, A ; Elstrom, R ; Reed, W ; Schneider, J ; Flinn, IW (ELSEVIER, 2020-10-13)
    Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% [n = 14]; FL, 14% [n = 5]). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.
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    Conventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells
    Cooke, RE ; Quinn, KM ; Quach, H ; Harrison, S ; Prince, HM ; Koldej, R ; Ritchie, D (FRONTIERS MEDIA SA, 2020-09-03)
    New diagnoses of multiple myeloma (MM) tend to occur after the age of 60, by which time thymic output is severely reduced. As a consequence, lymphocyte recovery after lymphopenia-inducing anti-MM therapies relies on homeostatic proliferation of peripheral T cells rather than replenishment by new thymic emigrants. To assess lymphocyte recovery and phenotype in patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), we tracked CD4+ and CD8+ T cell populations at serial time points throughout treatment and compared them to age-matched healthy donors (HD). Anti-MM therapies and autologous stem cell transplant (ASCT) caused a permanent reduction in the CD4:8 ratio, a decrease in naïve CD4+ T cells, and an increase in effector memory T cells and PD1-expressing CD4+ T cells. Transcriptional profiling highlighted that genes associated with fatty acid β-oxidation were upregulated in T cells in RRMM, suggesting increased reliance on mitochondrial respiration. High mitochondrial mass was seen in all T cell subsets in RRMM but with relatively suppressed reactive oxygen species and mitochondrial membrane potential, indicating mitochondrial dysfunction. These findings highlight that anti-MM and ASCT therapies perturb the composition of the T cell compartment and drive substantial metabolic remodeling, which may affect the fitness of T cells for immunotherapies. This is particularly pertinent to chimeric antigen receptor (CAR)-T therapy, which might be more efficacious if T cells were stored prior to ASCT rather than at relapse.
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    Imaging of patients with multiple myeloma and associated plasma cell disorders: consensus practice statement by the Medical Scientific Advisory Group to Myeloma Australia
    Creeper, K ; Augustson, B ; Kusel, K ; Fulham, MJ ; Ho, J ; Quach, H ; Mollee, P ; Weber, N ; Talaulikar, D ; Johnston, A ; Murphy, N ; Joshua, D ; Ward, C ; Ling, S ; Gibson, J ; Szer, J ; Harrison, S ; Zannettino, A ; Jaksic, W ; Lee, C ; Spencer, A ; Kalff, A ; Szabo, F ; Romeril, K ; Chan, H ; Gibbs, S ; Horvath, N ; Prince, HM (WILEY, 2021-10-01)
    Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18-24 months. Cross-sectional imaging modalities are more sensitive for the detection and monitoring of bone and bone marrow disease and are now included in the International Myeloma Working Group current consensus criteria for initial diagnosis and treatment response assessment. The aim of this consensus practice statement is to review the evidence supporting these modalities. A more detailed Position Statement can be found on the Myeloma Australia website.