Medicine (RMH) - Research Publications

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    Pretransplant FLT3-ITD MRD assessed by high-sensitivity PCR-NGS determines posttransplant clinical outcome.
    Loo, S ; Dillon, R ; Ivey, A ; Anstee, NS ; Othman, J ; Tiong, IS ; Potter, N ; Jovanovic, J ; Runglall, M ; Chong, CC ; Bajel, A ; Ritchie, D ; Gray, K ; Yeoh, ZH ; McBean, M ; Gilkes, A ; Thomas, I ; Johnson, S ; Russell, NH ; Wei, AH (American Society of Hematology, 2022-12-01)
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    Intratumoural administration of an NKT cell agonist with CpG promotes NKT cell infiltration associated with an enhanced antitumour response and abscopal effect
    Prasit, KK ; Ferrer-Font, L ; Burn, OK ; Anderson, RJ ; Compton, BJ ; Schmidt, AJ ; Mayer, JU ; Chen, C-JJ ; Dasyam, N ; Ritchie, DS ; Godfrey, D ; Mattarollo, SR ; Rod Dundar, P ; Painter, GF ; Hermans, IF (TAYLOR & FRANCIS INC, 2022-12-31)
    Intratumoural administration of unmethylated cytosine-phosphate-guanine motifs (CpG) to stimulate toll-like receptor (TLR)-9 has been shown to induce tumour regression in preclinical studies and some efficacy in the clinic. Because activated natural killer T (NKT) cells can cooperate with pattern-recognition via TLRs to improve adaptive immune responses, we assessed the impact of combining a repeated dosing regimen of intratumoural CpG with a single intratumoural dose of the NKT cell agonist α-galactosylceramide (α-GalCer). The combination was superior to CpG alone at inducing regression of established tumours in several murine tumour models, primarily mediated by CD8+ T cells. An antitumour effect on distant untreated tumours (abscopal effect) was reliant on sustained activity of NKT cells and was associated with infiltration of KLRG1+ NKT cells in tumours and draining lymph nodes at both injected and untreated distant sites. Cytometric analysis pointed to increased exposure to type I interferon (IFN) affecting many immune cell types in the tumour and lymphoid organs. Accordingly, antitumour activity was lost in animals in which dendritic cells (DCs) were incapable of signaling through the type I IFN receptor. Studies in conditional ablation models showed that conventional type 1 DCs and plasmacytoid DCs were required for the response. In tumour models where the combined treatment was less effective, the addition of tumour-antigen derived peptide, preferably conjugated to α-GalCer, significantly enhanced the antitumour response. The combination of TLR ligation, NKT cell agonism, and peptide delivery could therefore be adapted to induce responses to both known and unknown antigens.
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    Exercise in allogeneic bone marrow transplantation: a qualitative representation of the patient perspective
    Abo, S ; Parry, SM ; Ritchie, D ; Sgro, G ; Truong, D ; Denehy, L ; Granger, CL (SPRINGER, 2022-03-16)
    PURPOSE: Exercise is emerging as a vital aspect of care to alleviate the physical and psychosocial symptom burden associated with allogeneic bone marrow transplantation (BMT). Understanding the patient perspective regarding exercise is important to move towards implementation. This study aimed to characterise experiences and views regarding participation in an exercise program in adults receiving treatment for haematological disease with allogeneic BMT. METHODS: Individual semi-structured interviews were conducted with 35 participants from either an early- or late-commencing supervised group-based exercise program. Using an inductive, conventional approach to qualitative content analysis data were independently analysed by two researchers. RESULTS: Six major themes and 33 sub-themes were identified: this encompassed motivation, physical opportunity and capability to exercise; psychosocial effects of group-based exercise; experienced impact of participation in an exercise program; and intervention design considerations. Key barriers to exercise included symptom severity and fluctuating health and distance or difficult access to an exercise facility or equipment, whilst facilitators included encouragement from staff; peer support in the group-based setting; flexibility; education; and ability to measure change. CONCLUSION: This study highlights the importance of a flexible approach to exercise with consideration of individual symptoms and preferences. The perceived psychological impact of exercise should not be underestimated; future exercise programs should be designed in partnership with patients, with consideration of group-based activities to reduce social isolation if this is feasible in the treatment context. Intervention design should also acknowledge the individual's physical and psychological capability, opportunity and automatic and reflective motivation to direct and sustain exercise behaviours following BMT.
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    Predictors and outcomes of dose reduction of methotrexate and cyclosporin graft-versus-host disease prophylaxis following allogeneic haemopoietic cell transplantation
    Ramanan, R ; Lim, ABM ; Tan, JLC ; Barmanray, RD ; Mason, K ; Collins, J ; Hillman, M ; Szer, J ; Bajel, A ; Ritchie, D (WILEY, 2022-09-06)
    BACKGROUND: Concern regarding dose-related toxicities of methotrexate (MTX) and cyclosporin (CYA) graft-versus-host disease (GVHD) prophylaxis occasionally leads to dose alterations post allogeneic haemopoietic cell transplant (alloHCT). AIMS: To clarify causes of MTX and CYA dose alteration and assess impact on patient outcomes, including GVHD, relapse, non-relapse mortality (NRM) and overall survival (OS). METHODS: Analysis of retrospective data was performed in a single tertiary centre of patients who underwent alloHCT for any indication and who received GVHD prophylaxis with CYA and MTX between the years 2011 and 2015. Univariate analysis was conducted using the log-rank test for OS and using competing risk regression for NRM, relapse and GVHD. Fisher exact tests were used to determine if an association existed between each of the pre-transplant variables and MTX alteration. Multivariate models for OS and NRM were constructed using Cox proportional hazards modelling and competing risk regression respectively. RESULTS: Fifty-four (28%) of 196 had MTX alterations and 61/187 (33%) had CYA alterations. Reasons for MTX alteration included mucositis, renal or liver impairment, fluid overload and sepsis. Causes of CYA alteration were numerous, but most commonly due to acute kidney impairment. MTX alteration was associated with inferior OS (hazard ratio 2.4; P = <0.001) and higher NRM (odds ratio (OR) 4.6; P < 0.001) at 6 years post-landmark. CYA alteration was associated with greater NRM (OR 2.7; P = 0.0137) at 6 years. GVHD rates were unaffected by dose alteration. CONCLUSIONS: Our findings suggest dose alteration in MTX and CYA GVHD prophylaxis is associated with adverse survival outcomes in alloHCT, without a significant impact on GVHD rates.
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    T Cell Fitness and Autologous CAR T Cell Therapy in Haematologic Malignancy
    Mehta, PH ; Fiorenza, S ; Koldej, RM ; Jaworowski, A ; Ritchie, DS ; Quinn, KM (FRONTIERS MEDIA SA, 2021-11-25)
    A range of emerging therapeutic approaches for the treatment of cancer aim to induce or augment endogenous T cell responses. Chimeric antigen receptor (CAR) T cell therapy (CTT) is one such approach that utilises the patient's own T cells, engineered ex vivo to target cell surface antigens, to eliminate haematological malignancies. Despite mediating high rates of responses in some clinical trials, this approach can be limited by dysfunctional T cells if they are present at high frequencies either in the starting material from the patient or the CAR T cell product. The fitness of an individual's T cells, driven by age, chronic infection, disease burden and cancer treatment, is therefore likely to be a crucial limiting factor of CTT. Currently, T cell dysfunction and its impact on CTT is not specifically quantified when patients are considering the therapy. Here, we review our current understanding of T cell fitness for CTT, how fitness may be impacted by age, chronic infection, malignancy, and treatment. Finally, we explore options to specifically tailor clinical decision-making and the CTT protocol for patients with more extensive dysfunction to improve treatment efficacy. A greater understanding of T cell fitness throughout a patient's treatment course could ultimately be used to identify patients likely to achieve favourable CTT outcomes and improve methods for T cell collection and CTT delivery.
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    Dissection of the bone marrow microenvironment in hairy cell leukaemia identifies prognostic tumour and immune related biomarkers
    Koldej, RM ; Prabahran, A ; Tan, CW ; Ng, AP ; Davis, MJ ; Ritchie, DS (NATURE PORTFOLIO, 2021-09-24)
    Hairy cell leukaemia (HCL) is a rare CD20+ B cell malignancy characterised by rare "hairy" B cells and extensive bone marrow (BM) infiltration. Frontline treatment with the purine analogue cladribine (CDA) results in a highly variable response duration. We hypothesised that analysis of the BM tumour microenvironment would identify prognostic biomarkers of response to CDA. HCL BM immunology pre and post CDA treatment and healthy controls were analysed using Digital Spatial Profiling to assess the expression of 57 proteins using an immunology panel. A bioinformatics pipeline was developed to accommodate the more complex experimental design of a spatially resolved study. Treatment with CDA was associated with the reduction in expression of HCL tumour markers (CD20, CD11c) and increased expression of myeloid markers (CD14, CD68, CD66b, ARG1). Expression of HLA-DR, STING, CTLA4, VISTA, OX40L were dysregulated pre- and post-CDA. Duration of response to treatment was associated with greater reduction in tumour burden and infiltration by CD8 T cells into the BM post-CDA. This is the first study to provide a high multiplex analysis of HCL BM microenvironment demonstrating significant immune dysregulation and identify biomarkers of response to CDA. With validation in future studies, prospective application of these biomarkers could allow early identification and increased monitoring in patients at increased relapse risk post CDA.
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    Venetoclax or Ruxolitinib in Pre-Transplant Conditioning Lowers the Engraftment Barrier by Different Mechanisms in Allogeneic Stem Cell Transplant Recipients
    Davis, JE ; Du, K ; Ludford-Menting, MJ ; Prabahran, A ; Wong, E ; Huntington, ND ; Koldej, RM ; Ritchie, DS (FRONTIERS MEDIA SA, 2021-09-24)
    Allogeneic stem cell transplantation (alloSCT) is utilised to cure haematological malignancies through a combination of conditioning regimen intensity and immunological disease control via the graft versus tumour (GVT) effect. Currently, conventional myeloablative chemotherapeutic or chemoradiation conditioning regimens are associated with significant side effects including graft versus host disease (GVHD), infection, and organ toxicity. Conversely, more tolerable reduced intensity conditioning (RIC) regimens are associated with unacceptably higher rates of disease relapse, partly through an excess incidence of mixed chimerism. Improvement in post-alloSCT outcomes therefore depends on promotion of the GVT effect whilst simultaneously reducing conditioning-related toxicity. We have previously shown that this could be achieved through BCL-2 inhibition, and in this study, we explored the modulation of JAK1/2 as a strategy to lower the barrier to donor engraftment in the setting of RIC. We investigated the impact of short-term treatment of BCL2 (venetoclax) or JAK1/2 (ruxolitinib) inhibition on recipient natural killer and T cell immunity and the subsequent effect on donor engraftment. We identified striking differences in mechanism of action of these two drugs on immune cell subsets in the bone marrow of recipients, and in the regulation of MHC class-II and interferon-inducible gene expression, leading to different rates of GVHD. This study demonstrates that the repurposed use of ruxolitinib or venetoclax can be utilised as pre-transplant immune-modulators to promote the efficacy of alloSCT, whilst reducing its toxicity.
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    Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence
    Davis, JE ; Sharpe, C ; Mason, K ; Tam, CS ; Koldej, RM ; Ritchie, DS (BMC, 2021-11-22)
    BACKGROUND: The development of Bruton's tyrosine kinase inhibitors (BTKi) for the treatment of chronic lymphocytic leukaemia (CLL) has provided a highly effective and relatively non-toxic alternative to conventional chemotherapy. Some studies have shown that BTKi can also lead to improvements in T cell immunity in patients despite in vitro analyses suggesting an immunosuppressive effect of BTKi on T cell function. METHODS: In this study, we examined both the in vitro effect and long-term in vivo effect of two clinically available BTKi, ibrutinib and zanubrutinib. Additional in vitro assessments were undertaken for a third BTKi, acalabrutinib. Immune subset phenotyping, cytokine secretion, T cell degranulation and proliferation assays were performed on peripheral blood mononuclear cells isolated from untreated CLL patients, and CLL patients on long-term (> 12 months) BTKi treatment. RESULTS: Similar to prior studies we observed that long-term BTKi treatment normalises lymphocyte subset frequency and reduces PD-1 expression on T cells. We also observed that T cells from patients taken prior to BTKi therapy showed an abnormal hyper-proliferation pattern typical of senescent T cells, which was normalised by long-term BTKi treatment. Furthermore, BTKi therapy resulted in reduced expression of the T cell exhaustion markers PD-1, TIM3 and LAG3 in late generations of T cells undergoing proliferation. CONCLUSIONS: Collectively, these findings indicate that there are critical differences between the in vitro effects of BTKi on T cell function and the effects derived from long-term BTKi exposure in vivo. Overall long-term exposure to BTKi, and particularly ibrutinib, resulted in improved T cell fitness in part due to suppressing the abnormal hyper-proliferation of CLL T cells and the associated development of T cell senescence.
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    Clinical features, pathophysiology, and therapy of poor graft function post-allogeneic stem cell transplantation
    Prabahran, A ; Koldej, R ; Chee, L ; Ritchie, D (ELSEVIER, 2022-03-22)
    Poor graft function (PGF), defined by the presence of multilineage cytopenias in the presence of 100% donor chimerism, is a serious complication of allogeneic stem cell transplant (alloSCT). Inducers or potentiators of alloimmunity such as cytomegalovirus reactivation and graft-versus-host disease are associated with the development of PGF, however, more clinical studies are required to establish further risk factors and describe outcomes of PGF. The pathophysiology of PGF can be conceptualized as dysfunction related to the number or productivity of the stem cell compartment, defects in bone marrow microenvironment components such as mesenchymal stromal cells and endothelial cells, or immunological suppression of post-alloSCT hematopoiesis. Treatment strategies focused on improving stem cell number and function and microenvironment support of hematopoiesis have been attempted with variable success. There has been limited use of immune manipulation as a therapeutic strategy, but emerging therapies hold promise. This review details the current understanding of the causes of PGF and methods of treatment to provide a framework for clinicians managing this complex problem.
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    Integrating Shared Survivorship Care into an Allogeneic Bone Marrow Transplant Long Term Follow up Service
    Panek-Hudson, Y ; Ritchie, DS ; Hookey, S ; Wright, T ; Masons, K ; O'Leary, S ; Chard, L (ELSEVIER SCIENCE INC, 2020-03-01)