Publications by authors named "Simon Harrison"

163 Publications

Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group.

Lancet Oncol 2021 Mar;22(3):e105-e118

Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.
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http://dx.doi.org/10.1016/S1470-2045(20)30756-7DOI Listing
March 2021

Autologous stem cell transplantation in elderly multiple myeloma patients aged ≥65 years: a two-centre Australian experience.

Intern Med J 2021 Feb;51(2):280-283

University Hospital Geelong, Barwon Health, Geelong, Victoria, Australia.

There are currently limited Australian data on the outcomes of autologous stem cell transplantation (ASCT) in elderly multiple myeloma (MM) patients. We present the largest cohort of elderly MM patients aged ≥65 years undergoing ASCT in Australia and report their outcomes based on our two-centre experience. Our study affirms that ASCT is well tolerated, safe and effective in elderly MM patients aged ≥65 years and should be considered an important component of treatment in patients who are fit enough for the procedure.
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http://dx.doi.org/10.1111/imj.15182DOI Listing
February 2021

Successful identification of predictive profiles for infection utilising systems-level immune analysis: a pilot study in patients with relapsed and refractory multiple myeloma.

Clin Transl Immunology 2021 7;10(1):e1235. Epub 2021 Jan 7.

National Centre for Infections in Cancer, Peter MacCallum Cancer Centre Melbourne VIC Australia.

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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http://dx.doi.org/10.1002/cti2.1235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790592PMC
January 2021

A Wolf in Sheep's clothing: A case report series of oral manifestations of multiple myeloma.

Aust Dent J 2020 Nov 20. Epub 2020 Nov 20.

Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Multiple myeloma is the most common haematological malignancy accounting for 10 % of all haematological cancers. Treatment of myeloma has evolved in recent years leading to improved survival. Lesions related to myeloma are frequently observed within the oral cavity and jawbone. In addition, many of the therapeutic agents have side effects with implications for provision of dental treatment. This case series aims to highlight some of these presentations to remind dental practitioners to be vigilant. Observation of suspicious lesions within the oral cavity or jawbone might warrant further investigation.
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http://dx.doi.org/10.1111/adj.12808DOI Listing
November 2020

A randomised trial of two 2-dose influenza vaccination strategies for patients following autologous haematopoietic stem cell transplantation.

Clin Infect Dis 2020 Nov 11. Epub 2020 Nov 11.

Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Background: Seroprotection and seroconversion rates are not well understood for 2-dose inactivated influenza vaccination (IIV) schedules in autologous haematopoietic stem cell transplantation (autoHCT) patients.

Materials/methods: A randomised single-blind controlled trial of IIV in autoHCT patients in their first year post-transplant was conducted. Patients were randomised 1:1 to high dose (HD) IIV followed by standard dose (SD) vaccine (HD-SD arm) or two SD vaccines (SD-SD arm), 4 weeks apart. Haemagglutination inhibition (HI) assay for IIV strains was performed at baseline, 1, 2 and 6 months post-first dose. Evaluable primary outcomes were seroprotection (HI titre ≥40) and seroconversion (4-fold titre rise) rates and secondary outcomes: geometric mean titres (GMT), GMT ratios (GMR), adverse events, influenza-like-illness (ILI) and laboratory-confirmed influenza (LCI) rates and factors associated with seroconversion.

Results: Sixty-eight patients were enrolled (34 per arm) with median age of 61.5 years, majority male (68%) with myeloma (68%). Median time from autoHCT to vaccination was 2.3 months. For HD-SD and SD-SD arms, percentage of patients achieving seroprotection was 75.8% and 79.4% for H1N1, 84.9% and 88.2% for H3N2 (all p>0.05) and 78.8% and 97.1% for influenza-B/Yamagata (p=0.03), respectively. Seroconversion rates, GMT and GMR, number of ILI or LCIs were not significantly different between arms. Adverse event rates were similar. Receipt of concurrent cancer therapy was independently associated with higher odds of seroconversion (OR 4.3, 95% CI 1.2-14.9, p=0.02).

Conclusions: High seroprotection and seroconversion rates against all influenza strains can be achieved with vaccination as early as 2 months post-autoHCT with either two-dose vaccine schedules.
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http://dx.doi.org/10.1093/cid/ciaa1711DOI Listing
November 2020

Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial.

Lancet Oncol 2020 12 29;21(12):1630-1642. Epub 2020 Oct 29.

Department of Hematology, University Hospital, Nantes, France.

Background: Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.

Methods: In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m subcutaneously or intravenously and dexamethasone (20 mg orally). Treatment was given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle until disease progression, unacceptable toxicity, or patient withdrawal. Randomisation was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Sponsors, investigators, study site personnel, and patients were masked to the treatment allocation throughout the study. The primary endpoint was independent review committee-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02755597.

Findings: Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6-21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3-not estimable) with venetoclax versus 11·5 months (9·6-15·0) with placebo (hazard ratio [HR] 0·63 [95% CI 0·44-0·90]; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 [18%] of 193 patients in the venetoclax group vs seven [7%] of 96 patients in the placebo group), pneumonia (30 [16%] vs nine [9%]), thrombocytopenia (28 [15%] vs 29 [30%]), anaemia (28 [15%] vs 14 [15%]), and diarrhoea (28 [15%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related.

Interpretation: The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option.

Funding: AbbVie and Genentech.
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http://dx.doi.org/10.1016/S1470-2045(20)30525-8DOI Listing
December 2020

Outcomes Following Extracorporeal Photopheresis for Chronic Lung Allograft Dysfunction Following Lung Transplantation: A Single-Center Experience.

Transplant Proc 2021 Jan-Feb;53(1):296-302. Epub 2020 Oct 7.

Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.

Introduction: Survival following lung transplantation (LTx) is limited by the development of chronic lung allograft dysfunction (CLAD), for which there are few effective therapies and no standardized management. Several small studies have demonstrated the effectiveness of extracorporeal photopheresis (ECP) as a therapeutic option for CLAD.

Methods: A retrospective descriptive audit of 12 LTx recipients who received rescue ECP for CLAD over 5 years (2013-2018) at the Alfred Hospital, Melbourne, Australia, was completed. Nonresponders to ECP were defined as patients who experienced a 20% decrease in forced expiratory volume (FEV) within 6 weeks of commencing therapy.

Results: Mean time since LTx was 849 days and mean time since diagnosis of CLAD was 131 days. Fifty-eight percent of patients were male (n = 7) and 67% responded to ECP therapy (n = 8). Among responders, the mean (95% confidence interval) decline in FEV pre-ECP was 9.0 mL/day (5-12 mL/day), compared to 1.4 mL/day (0-4 mL/day) post-ECP (P = .01). Among nonresponders, mean (95% confidence interval) decline in FEV was 7.2 mL/day (4-10 mL/day) pre-ECP and 5.0 mL/day (3-7 mL/day) post ECP (P = .2). Nonresponders were more likely to be female (P = .01) and neutropenic (P = .005). Patients with prior exposure to anti-thymocyte globulin had a lowered response to ECP.

Conclusion: Rescue ECP arrested the decline of lung function in 67% of patients with CLAD. Sex, pre-ECP neutrophil count, and exposure to anti-thymocyte globulin may help determine response to ECP. Future clinical trials are needed to confirm this effect, help predict response to therapy, and ultimately guide the placement of ECP in the treatment algorithm for CLAD.
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http://dx.doi.org/10.1016/j.transproceed.2020.09.003DOI Listing
October 2020

Conventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells.

Front Immunol 2020 3;11:2153. Epub 2020 Sep 3.

Australian Cancer Research Foundation Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia.

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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http://dx.doi.org/10.3389/fimmu.2020.02153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494758PMC
September 2020

Through the Magical Pink Walkway: A Behavior Setting's Invitation to Embodied Sense-Makers.

Authors:
Simon Harrison

Front Psychol 2020 10;11:1576. Epub 2020 Sep 10.

Department of English, City University of Hong Kong, Kowloon, Hong Kong.

This paper examines an intersection between ecological psychology and the enactive approach brought about by studying sense-making in relation to a behavior setting in Hong Kong and adopting a focus on embodied action and gesture. A cosmetics pop-up store embedded in a downtown shopping mall provides the basis for a case study involving a two-pronged analysis. I first use Barker's behavior setting theory to describe the publicly accessible structure and dynamics of the store, which reveals a bounded spatiotemporal entity with several interdependent behavior-milieu parts. I then analyze video recordings of my research participant encountering, entering, and exploring this environment. Following an enactive-informed micro-ethnographic approach to embodied communication, I examine her movements, postures, gestures, and language use as she joins the behavior setting. These fine-grained descriptions of her embodied actions provide an empirical basis to analyze enactive sense-making. On the one hand, they disclose the affective and emotional experience of perceiving relevant affordances in the environment, and on the other hand, they show the specificity of sensorimotor abilities required to join the setting's standing pattern of behavior.
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http://dx.doi.org/10.3389/fpsyg.2020.01576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511542PMC
September 2020

Identifying unwarranted variation in clinical practice between healthcare providers in England: Analysis of administrative data over time for the Getting It Right First Time programme.

J Eval Clin Pract 2020 Sep 30. Epub 2020 Sep 30.

Getting It Right First Time programme, NHS Improvement, London, UK.

Rationale, Aims, And Objectives: The Getting It Right First Time programme aims to reduce variation in clinical practice that unduly impacts on outcomes for patients in the National Health Service (NHS) in England; often termed "unwarranted variation." However, there is no "gold standard" method for detecting unwarranted variation. The aim of this study was to describe a method to allow such variation in recorded practice or patient outcomes between NHS trusts to be detected using data over multiple time periods. By looking at variation over time, it was hoped that patterns that could be missed by looking at data at a single time point, or averaged over a longer time period, could be identified.

Methods: This was a retrospective time-series analysis of observational administrative data. Data were extracted from the Hospital Episodes Statistics database for two exemplar aspects of clinical practice within the field of urology: (a) use of ureteric stents on first emergency admission to treat urinary tract stones and (b) waiting times for definitive surgery for urinary retention. Data were categorized into 3-month time periods and three rules were used to detect unwarranted variation in the outcome metric relative to the national average: (a) two of any three consecutive values greater than two standard deviations above the mean, (b) four of any five consecutive values greater than one standard deviation above the mean, and (c) eight consecutive values above the mean.

Results: For the urinary tract stones dataset, 24 trusts were identified as having unwarranted variation in the outcomes using funnel plots and 23 trusts using the time-series method. For the urinary retention data, 18 trusted were identified as having unwarranted variation in the outcomes using funnel plots and 22 trusts using the time-series method.

Conclusions: The time-series method may complement other methods to help identify unwarranted variation.
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http://dx.doi.org/10.1111/jep.13477DOI Listing
September 2020

Glucose-regulated protein 78 (GRP78) as a potential novel biomarker and therapeutic target in multiple myeloma.

Expert Rev Hematol 2020 11 18;13(11):1201-1210. Epub 2020 Oct 18.

Department of Haematology, St. Vincent's Hospital Melbourne , Fitzroy, Australia.

Introduction: Glucose-regulated protein 78 (GRP78) is a stress-inducible molecular chaperone expressed within the endoplasmic reticulum where it acts as a master regulator of the unfolded protein response (UPR) pathway. At times of ER stress, activation of the UPR, a multimolecular pathway, limits proteotoxicity induced by misfolded proteins. In malignancies, including multiple myeloma which is characterized by an accumulation of misfolded immunoglobulins, GRP78 expression is increased, with notable translocation of GRP78 to the cell surface. Studies suggest cell-surface GRP78 (csGRP78) to be of prognostic significance with emerging evidence that it interacts with a myriad of co-ligands to activate signaling pathways promoting cell proliferation and survival or apoptosis.

Areas Covered: This review focuses on the role of ER and csGRP78 in physiology and oncogenesis in multiple myeloma, addressing factors that shift the balance in GRP78 signaling from survival to apoptosis. The role of GRP78 as a potential prognostic biomarker is explored and current therapeutics in development aimed at targeting csGRP78 are addressed. We conducted a PubMed literature search using the keywords 'GRP78,' 'multiple myeloma' reviewing studies prior to 2020.

Expert Opinion: Cell-surface GRP78 expression is a potential novel prognostic biomarker in myeloma and targeting of csGRP78 is promising and requires further investigation.
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http://dx.doi.org/10.1080/17474086.2020.1830372DOI Listing
November 2020

Low rates of invasive fungal disease in patients with multiple myeloma managed with new generation therapies: Results from a multi-centre cohort study.

Mycoses 2021 Jan 17;64(1):30-34. Epub 2020 Sep 17.

Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Introduction: A multi-centre study to determine the outcomes and risks for invasive fungal disease (IFD) in myeloma (MM) patients treated with second-generation immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies was conducted.

Methods: Clinical and microbiology records were reviewed to capture patient demographics, disease characteristics, treatment, IFD episodes and outcomes. Categorical and continuous variables between patients with IFD and without IFD were compared using chi-square test, Fisher's exact test and Mann-Whitney rank sum test, respectively, with P-value < .05 considered statistically significant.

Results: Five out of 148 (3.4%) MM patients were diagnosed with five episodes of IFI: 3 were proven, 1 probable and 1 possible. Median time from commencement of new generation therapy to IFD diagnosis was 4.0 months (Interquartile range [IQR]: 3.4-5.7). In patients with IFD, median cumulative steroid dose over 60 days was 1119 mg (IQR: 1066-1333 mg). None of the patients with IFD had prolonged neutropenia (neutrophil count < 0.5 × 10 /L for more than 10 days). Common sites of infection were the respiratory tract (40.0%) and bloodstream (40.0%). Cryptococcus neoformans (n = 2) and Candida krusei (n = 1) were the fungal pathogens isolated in the three proven cases. 30-day mortality rate was 40.0%. Patients with IFD were younger (median 58 versus 68 years, P = .52) and treated with more lines of therapy (median 5 vs 3, P = .04).

Conclusion: IFD rate is low in heavily treated MM patients treated with second-generation therapy including monoclonal antibodies. Patients do not appear to have traditional risk factors such as prolonged neutropenia.
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http://dx.doi.org/10.1111/myc.13178DOI Listing
January 2021

British Association of Urological Surgeons suprapubic catheter practice guidelines - revised.

BJU Int 2020 10 28;126(4):416-422. Epub 2020 Jul 28.

Nottingham City Hospital, Nottingham, UK.

Aims: To report the updated and revised British Association of Urological Surgeons (BAUS) guideline on indications, safe insertion and subsequent care of suprapubic catheters (SPCs).

Methods: The existing BAUS guideline on the insertion of SPCs was reviewed and has been updated in light of both activity and outcome data published since the original guideline was written. A systematic review of all new data from 2010 onwards was carried out. This updated guideline is largely evidence-based but, where evidence was lacking, is based on the consensus of expert opinion from members of the BAUS Section of Female, Neurological and Urodynamic Urology.

Results: Suprapubic catheterization is widely used and generally considered a safe procedure. There is, however, a small risk of serious complications including bowel injury. The BAUS has produced an updated consensus statement on SPC use with the aim of minimizing risks and establishing best practice. Areas for future research and development are also highlighted. This review has been commissioned and approved by the BAUS and the Section of Female, Neurological and Urodynamic Urology.

Conclusions: While SPC insertion is generally regarded as a safe procedure, the risk of serious morbidity and death must always be considered and outlined to patients. These revised guidelines should assist in minimizing the morbidity associated with SPC usage.
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http://dx.doi.org/10.1111/bju.15123DOI Listing
October 2020

Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis.

Leukemia 2021 02 23;35(2):562-572. Epub 2020 May 23.

Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK.

The randomized, phase 3 ICARIA-MM study investigated isatuximab (Isa) with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory multiple myeloma and ≥2 prior lines. This prespecified subgroup analysis examined efficacy in patients with renal impairment (RI; estimated glomerular filtration rate <60 mL/min/1.73 m²). Isa 10 mg/kg was given intravenously once weekly in cycle 1, and every 2 weeks in subsequent 28-day cycles. Patients received standard doses of Pd. Median progression-free survival (PFS) for patients with RI was 9.5 months with Isa-Pd (n = 55) and 3.7 months with Pd (n = 49; hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.30-0.85). Without RI, median PFS was 12.7 months with Isa-Pd (n = 87) and 7.9 months with Pd (n = 96; HR 0.58; 95% CI, 0.38-0.88). The overall response rate (ORR) with and without RI was higher with Isa-Pd (56 and 68%) than Pd (25 and 43%). Complete renal response rates were 71.9% (23/32) with Isa-Pd and 38.1% (8/21) with Pd; these lasted ≥60 days in 31.3% (10/32) and 19.0% (4/21) of patients, respectively. Isa pharmacokinetics were comparable between the subgroups, suggesting no need for dose adjustment in patients with RI. In summary, the addition of Isa to Pd improved PFS, ORR and renal response rates.
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http://dx.doi.org/10.1038/s41375-020-0868-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862055PMC
February 2021

Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID-19 pandemic.

Intern Med J 2020 06 15;50(6):667-679. Epub 2020 May 15.

Department of Haematology, St Vincent's Hospital, Sydney, New South Wales, Australia.

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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http://dx.doi.org/10.1111/imj.14859DOI Listing
June 2020

Levofloxacin prophylaxis in patients with myeloma.

Lancet Oncol 2020 02;21(2):e67

Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.

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http://dx.doi.org/10.1016/S1470-2045(19)30824-1DOI Listing
February 2020

Deep profiling of apoptotic pathways with mass cytometry identifies a synergistic drug combination for killing myeloma cells.

Cell Death Differ 2020 07 27;27(7):2217-2233. Epub 2020 Jan 27.

Baxter Laboratory for Stem Cell Biology, Stanford School of Medicine, Stanford, CA, USA.

Multiple myeloma is an incurable and fatal cancer of immunoglobulin-secreting plasma cells. Most conventional therapies aim to induce apoptosis in myeloma cells but resistance to these drugs often arises and drives relapse. In this study, we sought to identify the best adjunct targets to kill myeloma cells resistant to conventional therapies using deep profiling by mass cytometry (CyTOF). We validated probes to simultaneously detect 26 regulators of cell death, mitosis, cell signaling, and cancer-related pathways at the single-cell level following treatment of myeloma cells with dexamethasone or bortezomib. Time-resolved visualization algorithms and machine learning random forest models (RFMs) delineated putative cell death trajectories and a hierarchy of parameters that specified myeloma cell survival versus apoptosis following treatment. Among these parameters, increased amounts of phosphorylated cAMP response element-binding protein (CREB) and the pro-survival protein, MCL-1, were defining features of cells surviving drug treatment. Importantly, the RFM prediction that the combination of an MCL-1 inhibitor with dexamethasone would elicit potent, synergistic killing of myeloma cells was validated in other cell lines, in vivo preclinical models and primary myeloma samples from patients. Furthermore, CyTOF analysis of patient bone marrow cells clearly identified myeloma cells and their key cell survival features. This study demonstrates the utility of CyTOF profiling at the single-cell level to identify clinically relevant drug combinations and tracking of patient responses for future clinical trials.
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http://dx.doi.org/10.1038/s41418-020-0498-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308383PMC
July 2020

Retinal ischemia due to extramedullary plasmacytomas of the orbit.

J Clin Neurosci 2020 Feb 22;72:447-449. Epub 2020 Jan 22.

Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia; Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Visual disturbance is a common complaint in patients with multiple myeloma, both at diagnosis and later in their course, and has a broad differential. Here, we report a novel cause of visual disturbance, namely retinal ischemia due to extramedullary plasmacytomas of the orbit. A 69 year-old male patient with known multiple myeloma presented with reduced vision in his left eye. The patient had been initially diagnosed with IgG myeloma 9 months earlier and multiples lines of medical therapy had been unsuccessful. Ophthalmology review was organised and fundoscopic examination showed evidence of retinal ischemia. Computed tomography of the orbits demonstrated multiple enhancing masses within both orbits, consistent with extramedullary plasmacytomas. The presence of retinal ischemia was thus attributed to mass effect on the orbital vessels. Extramedullary plasmacytomas within the orbit are a rare manifestation of multiple myeloma, but important to consider as a possible cause of visual disturbance.
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http://dx.doi.org/10.1016/j.jocn.2020.01.052DOI Listing
February 2020

Understanding volume-outcome relationships in nephrectomy and cystectomy for cancer: evidence from the UK Getting it Right First Time programme.

BJU Int 2020 02 19;125(2):234-243. Epub 2019 Nov 19.

Getting it Right First Time Programme, NHS England and NHS Improvement, London, UK.

Objectives: To investigate volume-outcome relationships in nephrectomy and cystectomy for cancer.

Materials And Methods: Data were extracted from the UK Hospital Episodes Statistics database, which records data on all National Health Service (NHS) hospital admissions in the England. Data were included for a 5-year period (April 2013-March 2018 inclusive) and data on emergency and paediatric admissions were excluded. Data were extracted on the NHS trust and surgeon undertaking the procedure, the surgical technique used (open, laparoscopic or robot-assisted) and length of hospital stay during the procedure. This dataset was supplemented by data on mortality from the UK Office for National Statistics. A number of volume thresholds and volume measures were investigated. Multilevel modelling was used to adjust for hierarchy and confounding factors.

Results: Data were available for 18 107 nephrectomy and 6762 cystectomy procedures for cancer. There was little evidence of trust or surgeon volume influencing readmission rates or mortality. There was some evidence of shorter length of hospital stay for high-volume surgeons, although the volume measure and threshold used were important.

Conclusions: We found little evidence that further centralization of nephrectomy or cystectomy for cancer surgery will improve the patient outcomes investigated. It may be that length of stay can be optimized though training and support for lower-volume centres, rather than further centralization.
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http://dx.doi.org/10.1111/bju.14939DOI Listing
February 2020

Time from autologous to allogeneic hematopoietic stem cell transplantation impacts post-transplant outcomes in multiple myeloma.

Bone Marrow Transplant 2020 06 3;55(6):1172-1174. Epub 2019 Sep 3.

Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1038/s41409-019-0642-xDOI Listing
June 2020

Prolonged survival with the early use of a novel extracorporeal photopheresis regimen in patients with Sézary syndrome.

Blood 2019 10;134(16):1346-1350

Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.

Extracorporeal photopheresis (ECP) has demonstrated therapeutic benefit in patients with Sézary syndrome (SS) and erythrodermic mycosis fungoides (e-MF). To examine the efficacy of ECP in the modern era of novel therapies, we conducted a retrospective analysis of 65 patients with a diagnosis of SS or e-MF with blood involvement who were treated with ECP at our institute. Overall survival (OS), time to next treatment (TTNT), and skin response rate (RR) were used as the study end points to determine patient outcome. The median follow-up from diagnosis was 48 months (range 1-225 months), with a median predicted OS of 120 months. The majority (88%) of patients commenced ECP at treatment lines 1 to 3, either as a monotherapy or in conjunction with other systemic agents. The use of ECP monotherapy resulted in a significantly longer median TTNT when compared with interferon-α (P = .0067), histone deacetylase inhibitors (P = .0003), novel immunotherapy agents (P = .028), low-dose methotrexate (P < .0001), and chemotherapy (P < .0001). In particular, early commencement of ECP at treatment lines 1 to 3 yielded a TTNT of 47 months. The results of our study support the utilization of ECP for SS/e-MF, and we recommend that ECP should be considered as early as possible in the treatment paradigm for these patients.
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http://dx.doi.org/10.1182/blood.2019000765DOI Listing
October 2019

The freshwater isopod Asellus aquaticus as a model biomonitor of environmental pollution: A review.

Chemosphere 2019 Nov 28;235:498-509. Epub 2019 Jun 28.

School of Biological, Earth & Environmental Sciences, University College Cork, Ireland. Electronic address:

Anthropogenic substances pollute freshwater systems worldwide, with serious, long-lasting effects to aquatic biota. Present methods of detecting elevated levels of trace metal pollutants are typically accurate but expensive, and therefore not suitable for applications requiring high spatial resolution. Additionally, these methods are not efficient solutions for the determination of long-term averages of pollution concentration. This is the rationale for the implementation of a biomonitoring programme as an alternative means of pollutant detection. This review summarises recent literature concerning the past and potential uses of the benthic isopod Asellus aquaticus as a biomonitor for pollution in freshwater systems. Recent studies indicate that A. aquaticus is well suited for this purpose. However, the mechanisms by which it bioaccumulates toxins have yet to be fully understood. In particular, the interactions between coexisting trace metal pollutants in the aquatic environment have only recently been considered, and it remains unclear how a biomonitoring programme should adapt to the effects of these interactions. It is evident that failing to account for these additional stressors will result in an ineffective biomonitoring programme; for this reason, a comprehensive understanding of the bioaccumulation mechanisms is required in order to reliably anticipate the effects of any interferences on the outcome.
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http://dx.doi.org/10.1016/j.chemosphere.2019.06.217DOI Listing
November 2019

The Use of Optimal Treatment for DLBCL Is Improving in All Age Groups and Is a Key Factor in Overall Survival, but Non-Clinical Factors Influence Treatment.

Cancers (Basel) 2019 Jul 2;11(7). Epub 2019 Jul 2.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria 3004, Australia.

Introduction: Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma for which a cure is usually the therapeutic goal of optimal treatment. Using a large population-based cohort we sought to examine the factors associated with optimal DLBCL treatment and survival.

Methods: DLBCL cases were identified through the population-based Victorian Cancer Registry, capturing new diagnoses for two time periods: 2008-2009 and 2012-2013. Treatment was pre-emptively classified as 'optimal' or 'suboptimal', according to compliance with current treatment guidelines. Univariable and multivariable logistic regression models were fitted to determine factors associated with treatment and survival.

Results: Altogether, 1442 DLBCL cases were included. Based on multivariable analysis, delivery of optimal treatment was less likely for those aged ≥80 years (p < 0.001), women (p = 0.012), those with medical comorbidity (p < 0.001), those treated in a non-metropolitan hospital (p = 0.02) and those who were ex-smokers (p = 0.02). Delivery of optimal treatment increased between 2008-2009 and the 2012-2013 (from 60% to 79%, p < 0.001). Delivery of optimal treatment was independently associated with a lower risk of death (hazard ratio (HR) = 0.60 (95% confidence interval (CI) 0.45-0.81), p = 0.001).

Conclusion: Delivery of optimal treatment for DLBCL is associated with hospital location and category, highlighting possible demographic variation in treatment patterns. Together with an increase in the proportion of patients receiving optimal treatment in the more recent time period, this suggests that treatment decisions in DLBCL may be subject to non-clinical influences, which may have implications when evaluating equity of treatment access. The positive association with survival emphasizes the importance of delivering optimal treatment in DLBCL.
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http://dx.doi.org/10.3390/cancers11070928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678990PMC
July 2019

Renal Impairment at Diagnosis in Myeloma: Patient Characteristics, Treatment, and Impact on Outcomes. Results From the Australia and New Zealand Myeloma and Related Diseases Registry.

Clin Lymphoma Myeloma Leuk 2019 08 16;19(8):e415-e424. Epub 2019 May 16.

Department of Haematology, Alfred Health-Monash University, Melbourne, Victoria, Australia.

Background: Renal impairment (RI) is a common complication of multiple myeloma (MM) and remains a poor prognostic factor despite improved survival with newer therapies.

Patients And Methods: We evaluated baseline characteristics, treatment, and outcomes of newly diagnosed MM patients with RI at diagnosis in the Australia and New Zealand Myeloma and Related Diseases Registry over 5 years to April 2018; we compared patients with RI (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m) with those with eGFR ≥60. In autologous stem cell transplantation (ASCT) analyses, patients aged 70 years and younger and ≥1 year from diagnosis were included.

Results: Overall, 36% of patients with newly diagnosed MM had RI; they were older, had more advanced disease and comorbidities, and worse performance status. Bortezomib-based induction therapy was most commonly used, although administered to fewer RI patients, despite similar response rates. Patients with RI were less likely to receive ASCT; however, recipients had longer progression-free survival (PFS) and overall survival (OS). Patients with RI had shorter OS and PFS after adjusting for age. In ASCT recipients with RI versus no RI, there was no difference in PFS and OS.

Conclusion: Our findings in "real world" MM patients with RI confirm that patient-, disease-, and treatment-related factors (such as suboptimal bortezomib and ASCT use), and delays in commencing therapy, might contribute to poorer outcomes, and support the use of ASCT in patients with RI.
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http://dx.doi.org/10.1016/j.clml.2019.05.010DOI Listing
August 2019

First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study.

Cancer Discov 2019 08 15;9(8):1036-1049. Epub 2019 May 15.

Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.

RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar-plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable. SIGNIFICANCE: CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in wild-type and mutant malignancies..
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http://dx.doi.org/10.1158/2159-8290.CD-18-1455DOI Listing
August 2019

The problem of agricultural 'diffuse' pollution: Getting to the point.

Sci Total Environ 2019 Aug 25;677:700-717. Epub 2019 Apr 25.

School of Biological, Earth and Environmental Sciences, University College Cork, Ireland.

Despite introduction of legislation such as the EU Nitrates and Water Framework Directives (Directives 91/676/EEC and 2000/60/EC respectively), agricultural practices are often still regarded as a major factor in poor water quality across many EU member states. Elevated inputs of nutrients, organic matter and agro-chemicals to receiving waters from agricultural lands in particular are now widely recognised as potentially major causes of deteriorating water quality. Such inputs may emanate from diffuse sources such as agricultural fields, and small point- or intermediate-sources, including farmyards and farm trackways. However, while inputs from these latter intermediate sources may be substantial, their overall contribution to catchment-wide water quality at high temporal or spatial resolution is still largely unknown. In this study, we surveyed water chemistry throughout the multiple natural and artificial watercourses within a single drainage network at high spatial resolution in a predominantly dairy farming area in Southern Ireland. We found that most headwaters at the time of study were impacted by organic inputs via drainage ditches emanating from the vicinity of farmyards. These farmyard drains were found to have elevated concentrations of ammonium, phosphorus, potassium, suspended sediment and biochemical oxygen demand above background levels in the study catchment. Concomitant assessment of macro-invertebrate communities at study sites indicated that the ecological quality of headwaters was also impaired by these inputs. The individual and aggregate contributions of farmyard drains to water quality within a single catchment, when mapped at high spatial resolution, indicates that they constitute a major contribution to catchment scale 'diffuse' agricultural inputs. However, our data also suggest that engineering farmyard drains to maximise their retention and attenuation function may prove to be a cost-effective means of mitigating the effects of point source farmyard inputs.
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http://dx.doi.org/10.1016/j.scitotenv.2019.04.169DOI Listing
August 2019

FDG-PET/CT in managing infection in patients with hematological malignancy: clinician knowledge and experience in Australia.

Leuk Lymphoma 2019 10 5;60(10):2471-2476. Epub 2019 Apr 5.

Department of Infectious Diseases, Peter MacCallum Cancer Centre , Melbourne , Australia.

PET/CT is useful for investigation of neutropenic fever (NF) and potential invasive fungal infection (IFI) in those with hematological malignancies (HM). An online survey evaluating the utility and current practices regarding PET/CT scanning for investigation of NF was distributed to infectious diseases (ID) clinicians and hematologists via email lists hosted by key professional bodies. One-hundred and forty-five clinicians responded (120 ID; 25 hematologists). Access to PET/CT was fair but timeliness of investigation was limited (within 3 days in 35% and 46% of ID and hematology respondents, respectively). Among those with experience with PET/CT for infection ( = 109), 40% had utilized PET/CT for prolonged NF and 20% for diagnosing IFI. The majority of respondents indicated the desire to utilize PET/CT more frequently for infection indications. There is a strong desire among surveyed Australian clinicians to use PET/CT for prolonged NF and potential IFI. However, access to PET/CT is a current barrier to uptake.
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http://dx.doi.org/10.1080/10428194.2019.1590571DOI Listing
October 2019

Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Siltuximab in High-Risk Smoldering Multiple Myeloma.

Clin Cancer Res 2019 07 19;25(13):3772-3775. Epub 2019 Mar 19.

University Hospital, Internal Medicine V and National Center for Tumor Diseases Heidelberg, Heidelberg, Germany.

Purpose: IL6 is important for the growth and survival of myeloma cells. This study evaluated blocking IL6 with siltuximab to delay the transition from high-risk smoldering multiple myeloma (SMM) to multiple myeloma.

Patients And Methods: In a randomized, double-blind, placebo-controlled, multicenter study, 85 patients with high-risk SMM were randomized to 15 mg/kg siltuximab (43 patients) or placebo (42 patients). The primary endpoint was 1-year progression-free survival (PFS) rate, based on IMWG CRAB criteria. Secondary endpoints included progressive disease indicator rate, PFS, and safety.

Results: Median age was 62 years (range: 21-84); 57% were male and 87% had a baseline Eastern Cooperative Oncology Group score of 0. The 1-year PFS rate was 84.5% (siltuximab) and 74.4% (placebo). After a median follow-up of 29.2 months, 32.6% of PFS events occurred with siltuximab and 42.9% with placebo. Median PFS was not reached with siltuximab but was 23.5 months with placebo [HR 0.50 (95% confidence interval, 0.24-1.04); = 0.0597]. The safety profile of siltuximab was comparable with placebo. Most adverse events in the siltuximab group were grade 2/3; the most common serious adverse events were infections/infestations, and renal/urinary disorders. Mortality was low in both groups (3 deaths in the siltuximab group and 4 in the placebo group).

Conclusions: Although this study did not meet the prespecified protocol hypothesis criteria, data suggest that siltuximab may delay the progression of high-risk SMM.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3470DOI Listing
July 2019