Medicine (St Vincent's) - Research Publications

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    Breakthrough COVID-19 is mild in vaccinated patients with hematological malignancy receiving tixagevimab-cilgavimab as pre-exposure prophylaxis
    Hall, VG ; Lim, C ; Saunders, NR ; Klimevski, E ; Nguyen, THO ; Kedzierski, L ; Seymour, JF ; Wadhwa, V ; Thursky, KA ; Yong, MK ; Kedzierska, K ; Slavin, MA ; Teh, BW (TAYLOR & FRANCIS LTD, 2023-09)
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    Occupational exposure to extremely low-frequency magnetic fields and follicular lymphoma risk: a family case-control study
    Odutola, MK ; van Leeuwen, MT ; Bruinsma, FJ ; Benke, G ; Turner, MC ; Trotman, J ; Turner, J ; Seymour, JF ; Prince, HM ; Milliken, ST ; Tiley, C ; Hertzberg, M ; Roncolato, F ; Opat, S ; Lindeman, R ; Verner, E ; Underhill, CR ; Cardis, E ; Giles, G ; Vajdic, CM (BMJ PUBLISHING GROUP, 2023-10)
    OBJECTIVES: We aimed to examine the relationship between occupational exposure to extremely low-frequency magnetic fields (ELF-MFs) and follicular lymphoma (FL) risk. METHODS: We conducted a family case-control study between 2011 and 2016 in Australia and included 681 cases. Controls were either a family member of cases (related (n=294), unrelated (n=179)) or were unrelated recruited for a similarly designed Australian multiple myeloma study (n=711). We obtained detailed job histories using lifetime work calendars. We assigned exposure to ELF-MFs using an enhanced job exposure matrix, with a lag period of 10 years. We examined associations with FL risk using logistic regression accounting for relatedness between cases and controls. We performed sensitivity analyses including by control type, by sex, complete case analyses, ELF-MF exposure percentiles in addition to quartiles, ELF-MF exposure in the maximum exposed job, a shorter lag period (1 year) and the cumulative exposure in the most recent time period (1-9 years). RESULTS: We observed no association with the average intensity, duration or lifetime cumulative exposure to occupational ELF-MF exposure in the primary or sensitivity analyses. CONCLUSIONS: Our findings do not support an association between occupational ELF-MF exposure and FL risk. Although the inclusion of family members as part of the larger control group may have biased our risk estimates towards the null, findings were similar in sensitivity analyses restricted to cases and unrelated controls. Further research incorporating enhanced exposure assessment to ELF-MF is warranted to inform occupational safety regulations and any potential role in lymphomagenesis.
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    Enhancing our chances of picking a winner in higher-risk myelodysplastic syndromes
    Wei, AH ; Seymour, JF (WILEY, 2022-08)
    Hypomethylating agents remain the current standard of care for patients with higher-risk myelodysplastic syndromes. Adès et al. report outcomes from a randomised 'pick-a-winner' study design that examined the addition of either lenalidomide, valproic acid or idarubicin in combination with azacitidine, compared to azacitidine alone. Commentary on: Adès et al. A randomised phase II study of azacitidine (AZA) alone or with lenalidomide (LEN), valproic acid (VPA) or idarubicin (IDA) in higher-risk MDS: GFM's 'pick a winner' trial, with the impact of somatic mutations. Br J Haematol 2022;198:535-544.
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    Consensus opinion from an international group of experts on measurable residual disease in hairy cell leukemia
    Ravandi, F ; Kreitman, RJ ; Tiacci, E ; Andritsos, L ; Banerji, V ; Barrientos, JC ; Bhat, SA ; Blachly, JS ; Broccoli, A ; Call, T ; Chihara, D ; Dearden, C ; Demeter, J ; Dietrich, S ; Else, M ; Epperla, N ; Falini, B ; Forconi, F ; Gladstone, DE ; Gozzetti, A ; Iyengar, S ; Johnston, JB ; Jorgensen, J ; Juliusson, G ; Lauria, F ; Lozanski, G ; Parikh, SA ; Park, JH ; Polliack, A ; Quest, G ; Robak, T ; Rogers, KA ; Saven, A ; Seymour, JF ; Tadmor, T ; Tallman, MS ; Tam, CS ; Thompson, PA ; Troussard, X ; Zent, CS ; Zenz, T ; Zinzani, PL ; Woermann, B ; Rai, K ; Grever, M (SPRINGERNATURE, 2022-12-13)
    A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.
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    Single-cell multiomics reveal the scale of multilayered adaptations enabling CLL relapse during venetoclax therapy
    Thijssen, R ; Tian, L ; Anderson, MA ; Flensburg, C ; Jarratt, A ; Garnham, AL ; Jabbari, JS ; Peng, H ; Lew, TE ; Teh, CE ; Gouil, Q ; Georgiou, A ; Tan, T ; Djajawi, TM ; Tam, CS ; Seymour, JF ; Blombery, P ; Gray, DHD ; Majewski, IJ ; Ritchie, ME ; Roberts, AW ; Huang, DCS (AMER SOC HEMATOLOGY, 2022-11-17)
    Venetoclax (VEN) inhibits the prosurvival protein BCL2 to induce apoptosis and is a standard therapy for chronic lymphocytic leukemia (CLL), delivering high complete remission rates and prolonged progression-free survival in relapsed CLL but with eventual loss of efficacy. A spectrum of subclonal genetic changes associated with VEN resistance has now been described. To fully understand clinical resistance to VEN, we combined single-cell short- and long-read RNA-sequencing to reveal the previously unappreciated scale of genetic and epigenetic changes underpinning acquired VEN resistance. These appear to be multilayered. One layer comprises changes in the BCL2 family of apoptosis regulators, especially the prosurvival family members. This includes previously described mutations in BCL2 and amplification of the MCL1 gene but is heterogeneous across and within individual patient leukemias. Changes in the proapoptotic genes are notably uncommon, except for single cases with subclonal losses of BAX or NOXA. Much more prominent was universal MCL1 gene upregulation. This was driven by an overlying layer of emergent NF-κB (nuclear factor kappa B) activation, which persisted in circulating cells during VEN therapy. We discovered that MCL1 could be a direct transcriptional target of NF-κB. Both the switch to alternative prosurvival factors and NF-κB activation largely dissipate following VEN discontinuation. Our studies reveal the extent of plasticity of CLL cells in their ability to evade VEN-induced apoptosis. Importantly, these findings pinpoint new approaches to circumvent VEN resistance and provide a specific biological justification for the strategy of VEN discontinuation once a maximal response is achieved rather than maintaining long-term selective pressure with the drug.
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    Robust SARS-CoV-2 T cell responses with common TCRab motifs toward COVID-19 vaccines in patients with hematological malignancy impacting B cells
    Nguyen, THO ; Rowntree, LC ; Allen, LF ; Chua, BY ; Kedzierski, L ; Lim, C ; Lasica, M ; Tennakoon, GS ; Saunders, NR ; Crane, M ; Chee, L ; Seymour, JF ; Anderson, MA ; Whitechurch, A ; Clemens, EB ; Zhang, W ; Chang, SY ; Habel, JR ; Jia, X ; McQuilten, HA ; Minervina, AA ; Pogorelyy, MV ; Chaurasia, P ; Petersen, J ; Menon, T ; Hensen, L ; Neil, JA ; Mordant, FL ; Tan, H-X ; Cabug, AF ; Wheatley, AK ; Kent, SJ ; Subbarao, K ; Karapanagiotidis, T ; Huang, H ; Vo, LK ; Cain, NL ; Nicholson, S ; Krammer, F ; Gibney, G ; James, F ; Trevillyan, JM ; Trubiano, JA ; Mitchell, J ; Christensen, B ; Bond, KA ; Williamson, DA ; Rossjohn, J ; Crawford, JC ; Thomas, PG ; Thursky, KA ; Slavin, MA ; Tam, CS ; Teh, BW ; Kedzierska, K (CELL PRESS, 2023-04-18)
    Immunocompromised hematology patients are vulnerable to severe COVID-19 and respond poorly to vaccination. Relative deficits in immunity are, however, unclear, especially after 3 vaccine doses. We evaluated immune responses in hematology patients across three COVID-19 vaccination doses. Seropositivity was low after a first dose of BNT162b2 and ChAdOx1 (∼26%), increased to 59%-75% after a second dose, and increased to 85% after a third dose. While prototypical antibody-secreting cells (ASCs) and T follicular helper (Tfh) cell responses were elicited in healthy participants, hematology patients showed prolonged ASCs and skewed Tfh2/17 responses. Importantly, vaccine-induced expansions of spike-specific and peptide-HLA tetramer-specific CD4+/CD8+ T cells, together with their T cell receptor (TCR) repertoires, were robust in hematology patients, irrespective of B cell numbers, and comparable to healthy participants. Vaccinated patients with breakthrough infections developed higher antibody responses, while T cell responses were comparable to healthy groups. COVID-19 vaccination induces robust T cell immunity in hematology patients of varying diseases and treatments irrespective of B cell numbers and antibody response.
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    JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias
    Kim, S-K ; Knight, DA ; Jones, LR ; Vervoort, S ; Ng, AP ; Seymour, JF ; Bradner, JE ; Waibel, M ; Kats, L ; Johnstone, RW (COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2018-06-01)
    Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
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    Dietary intake of animal-based products and likelihood of follicular lymphoma and survival: A population-based family case-control study
    Odutola, MK ; van Leeuwen, MT ; Bassett, JK ; Bruinsma, F ; Turner, J ; Seymour, JF ; Prince, HM ; Milliken, ST ; Hertzberg, M ; Roncolato, F ; Opat, SS ; Lindeman, R ; Tiley, C ; Trotman, J ; Verner, E ; Harvey, M ; Underhill, CR ; Benke, G ; Giles, GG ; Vajdic, CM (FRONTIERS MEDIA SA, 2023-01-04)
    BACKGROUND: The association between dietary intake of foods of animal origin and follicular lymphoma (FL) risk and survival is uncertain. In this study, we examined the relationship between dietary intake of dairy foods and fats, meat, fish and seafoods, and the likelihood of FL and survival. METHODS: We conducted a population-based family case-control study in Australia between 2011 and 2016 and included 710 cases, 303 siblings and 186 spouse/partner controls. We assessed dietary intake of animal products prior to diagnosis (the year before last) using a structured food frequency questionnaire and followed-up cases over a median of 6.9 years using record linkage to national death data. We examined associations with the likelihood of FL using logistic regression and used Cox regression to assess association with all-cause and FL-specific mortality among cases. RESULTS: We observed an increased likelihood of FL with increasing daily quantity of oily fish consumption in the year before last (highest category OR = 1.96, CI = 1.02-3.77; p-trend 0.06) among cases and sibling controls, but no associations with spouse/partner controls. We found no association between the likelihood of FL and the consumption of other types of fish or seafood, meats or dairy foods and fats. In FL cases, we found no association between meat or oily fish intake and all-cause or FL-specific mortality. CONCLUSION: Our study showed suggestive evidence of a positive association between oily fish intake and the likelihood of FL, but findings varied by control type. Further investigation of the potential role of environmental contaminants in oily fish on FL etiology is warranted.
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    Development of a distributed international patient data registry for hairy cell leukemia
    Andritsos, LA ; Anghelina, M ; Neal, J ; Blachly, JS ; Mathur, P ; Lele, O ; Dearden, C ; Iyengar, S ; Cross, M ; Zent, CS ; Rogers, KA ; Epperla, N ; Lozanski, G ; Oakes, CC ; Kraut, E ; Ruppert, AS ; Zhao, Q ; Bhat, SA ; Forconi, F ; Banerji, V ; Handunnetti, S ; Tam, CS ; Seymour, JF ; Else, M ; Kreitman, RJ ; Saven, A ; Call, T ; Parikh, SA ; Ravandi, F ; Johnston, JB ; Tiacci, E ; Troussard, X ; Tallman, MS ; Dietrich, S ; Tadmor, T ; Gozzetti, A ; Zinzani, PL ; Robak, T ; Quest, G ; Demeter, J ; Rai, K ; Fernandez, SA ; Grever, M (TAYLOR & FRANCIS LTD, 2022-11-10)
    Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder, comprising only 2% of all leukemias. The Hairy Cell Leukemia Foundation (HCLF) has developed a patient data registry to enable investigators to better study the clinical features, treatment outcomes, and complications of patients with HCL. This system utilizes a centralized registry architecture. Patients are enrolled at HCL Centers of Excellence (COE) or via a web-based portal. All data are de-identified, which reduces regulatory burden and increases opportunities for data access and re-use. To date, 579 patients have been enrolled in the registry. Efforts are underway to engage additional COE's to expand access to patients across the globe. This international PDR will enable researchers to study outcomes in HCL in ways not previously possible due to the rarity of the disease and will serve as a platform for future prospective research.
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    Utility of measurable residual disease for predicting treatment outcomes with BCR- and BCL2-Targeted therapies in patients with CLL
    Wierda, WG ; Kipps, TJ ; Al-Sawaf, O ; Chyla, B ; Biondo, JML ; Mun, Y ; Jiang, Y ; Seymour, JF (TAYLOR & FRANCIS LTD, 2022-10-15)
    Inhibitors targeting B-cell receptor (BCR) signaling pathway proteins and B-cell lymphoma-2 (BCL2) in chronic lymphocytic leukemia (CLL) are recommended in the first-line and relapsed/refractory disease settings. Measurable residual disease (MRD) is an important prognostic tool in patients treated with the BCL2-targeted agent, venetoclax. We explored the relationship between MRD status and progression-free (PFS)/overall survival (OS) in patients with CLL, following treatment with novel BCR- and BCL2-targeted agents. Compared with chemoimmunotherapy, higher rates of undetectable (u)MRD were achieved with BCL2-targeted therapies; achieving uMRD status was associated with longer PFS and OS than MRD-positivity. Continuous treatment with BCR-targeted agents did not achieve uMRD status in many patients, and outcomes were not correlated with uMRD status. Future clinical trials of targeted treatment combinations could be designed to demonstrate uMRD as a treatment objective, and allow a response-driven, personalized strategy to optimize treatment and improve OS outcomes.