Medicine (RMH) - Research Publications

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    Recommendation for TP53 mutation testing in newly diagnosed mantle cell lymphoma: a statement from working groups sponsored by the Victorian Comprehensive Cancer Centre
    Tam, CS ; Gregory, GP ; Ku, M ; Fleming, S ; Handunnetti, SM ; Lee, D ; Walker, P ; Perkins, A ; Lew, TE ; Sirdesai, S ; Chua, CC ; Gilbertson, M ; Lasica, M ; Anderson, MA ; Renwick, W ; Grigg, A ; Patil, S ; Opat, S ; Friebe, A ; Cooke, R ; De Boer, J ; Spencer, A ; Ritchie, D ; Agarwal, R ; Blombery, P (WILEY, 2022-07)
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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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    A multicenter retrospective comparison of induction chemoimmunotherapy regimens on outcomes in transplant-eligible patients with previously untreated mantle cell lymphoma
    Ng, ZY ; Bishton, M ; Ritchie, D ; Campbell, R ; Gilbertson, M ; Hill, K ; Ratnasingam, S ; Schwarer, A ; Manos, K ; Shorten, S ; Ng, M ; Nelson, N ; Xin, L ; De Mel Widanalage, S ; Sunny, T ; Purtill, D ; Poon, M ; Johnston, A ; Cochrane, T ; Lee, H-P ; Hapgood, G ; Tam, C ; Opat, S ; Hawkes, E ; Seymour, J ; Cheah, CY (WILEY, 2019-08)
    Mantle cell lymphoma (MCL) is an uncommon and typically aggressive form of lymphoma. Although often initially chemosensitive, relapse is common. Several induction and conditioning regimens are used in transplant-eligible patients, and the optimal approach remains unknown. We performed an international, retrospective study of transplant-eligible patients to assess impact of induction chemoimmunotherapy and conditioning regimens on clinical outcomes. We identified 228 patients meeting inclusion criteria. Baseline characteristics were similar among the induction groups except for some variation in age. The type of induction chemoimmunotherapy received did not influence overall response rates (ORRs) (0.43), progression-free survival (PFS) (P > .67), or overall survival (OS) (P > .35) on multivariate analysis (PFS and OS). Delivery of autologous stem cell transplant (ASCT) was associated with favorable PFS and OS (0.01) on univariate analysis only; this benefit was not seen on multivariate analysis-PFS (0.36) and OS (0.21). Compared with busulfan and melphalan (BuMel), the use of the carmustine, etoposide, cytarabine, melphalan (BEAM)-conditioning regimen was associated with inferior PFS (HR = 2.0 [95% CI 1.1-3.6], 0.02) but not OS (HR = 1.1 [95% CI 0.5-2.3], 0.81) on univariate analysis only. Within the limits of a retrospective study and modest power for some comparisons, type of induction therapy did not influence ORR, PFS, or OS for transplant-eligible patients with MCL. International efforts are required to perform randomized clinical trials evaluating chemoimmunotherapy induction regimens.
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    Autologous stem cell transplantation for untreated transformed indolent B-cell lymphoma in first remission: an international, multi-centre propensity-score-matched study
    Chin, CK ; Lim, KJ ; Lewis, K ; Jain, P ; Qing, Y ; Feng, L ; Cheah, CY ; Seymour, JF ; Ritchie, D ; Burbury, K ; Tam, CS ; Fowler, NH ; Fayad, LE ; Westin, JR ; Neelapu, SS ; Hagemeister, FB ; Samaniego, F ; Flowers, CR ; Nastoupil, LJ ; Dickinson, MJ (WILEY, 2020-12)
    High-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are used as consolidation in first remission (CR1) in some centres for untreated, transformed indolent B-cell lymphoma (Tr-iNHL) but the evidence base is weak. A total of 319 patients with untreated Tr-iNHL meeting prespecified transplant eligibility criteria [age <75, LVEF ≥45%, no severe lung disease, CR by positron emission tomography or computed tomography ≥3 months after at least standard cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) intensity front-line chemotherapy] were retrospectively identified. Non-diffuse large B-cell lymphoma transformations were excluded. About 283 (89%) patients had follicular lymphoma, 30 (9%) marginal-zone lymphoma and six (2%) other subtypes. Forty-nine patients underwent HDC/ASCT in CR1, and a 1:2 propensity-score-matched cohort of 98 patients based on age, stage and high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements (HGBL-DH) was generated. After a median follow-up of 3·7 (range 0·1-18·3) years, ASCT was associated with significantly superior progression-free survival [hazard ratio (HR) 0·51, 0·27-0·98; P = 0·043] with a trend towards inferior overall survival (OS; HR 2·36;0·87-6·42; P = 0·1) due to more deaths from progressive disease (8% vs. 4%). Forty (41%) patients experienced relapse in the non-ASCT cohort - 15 underwent HDC/ASCT with seven (47%) ongoing complete remission (CR); 10 chimeric antigen receptor-modified T-cell (CAR-T) therapy with 6 (60%) ongoing CR; 3 allogeneic SCT with 2 (67%) ongoing CR. Although ASCT in CR1 improves initial duration of disease control in untreated Tr-iNHL, the impact on OS is less clear with effective salvage therapies in this era of CAR-T.
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    Improvement in Non-Relapse Mortality Following Allogeneic Transplantation for Chronic Lymphocytic Leukaemia in Australia and New Zealand: An Australasian Bone Marrow Transplant Recipient Registry Study
    Barge, L ; Tran, S ; Kennedy, G ; Ritchie, DS ; Gottlieb, D ; Milliken, S ; Spencer, A ; Purtill, D ; Perera, T ; Doocey, RT ; Larsen, S ; Butler, A ; Bardy, P ; Greenwood, M ; Durrant, S ; Curley, C ; Stewart, C ; Tam, CS ; Collins, J ; Balendran, S ; Di Ciaccio, PR ; Patil, S ; Han, M-H ; Hamad, N (Elsevier BV, 2021-03)
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    T-Cell Replete Allogeneic Stem Cell Transplant Is an Effective Treatment Option for Patients with TP53 mutated Mantle Cell Lymphoma
    Scheffer Cliff, ER ; Lew, TE ; Blombery, P ; Dickinson, M ; Tam, CS ; Seymour, JF ; Bajel, A ; Ritchie, DS ; Khot, A (Elsevier BV, 2021-03)
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    Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy
    Davis, JE ; Handunnetti, SM ; Ludford-Menting, M ; Sharpe, C ; Blombery, P ; Anderson, MA ; Roberts, AW ; Seymour, JF ; Tam, CS ; Ritchie, DS ; Koldej, RM (AMER SOC HEMATOLOGY, 2020-10-13)
    Combination venetoclax plus ibrutinib for the treatment of mantle cell lymphoma (MCL) has demonstrated efficacy in the relapsed or refractory setting; however, the long-term impact on patient immunology is unknown. In this study, changes in immune subsets of MCL patients treated with combination venetoclax and ibrutinib were assessed over a 4-year period. Multiparameter flow cytometry of peripheral blood mononuclear cells showed that ≥12 months of treatment resulted in alterations in the proportions of multiple immune subsets, most notably CD4+ and CD8+ effector and central memory T cells and natural killer cells, and normalization of T-cell cytokine production in response to T-cell receptor stimulation. Gene expression analysis identified upregulation of multiple myeloid genes (including S100 and cathepsin family members) and inflammatory pathways over 12 months. Four patients with deep responses stopped study drugs, resulting in restoration of normal immune subsets for all study parameters except myeloid gene/pathway expression, suggesting long-term combination venetoclax and ibrutinib irreversibly affects this population. Our findings demonstrate that long-term combination therapy is associated with immune recovery in MCL, which may allow responses to subsequent immunotherapies and suggests that this targeted therapy results in beneficial impacts on immunological recovery. This trial was registered at www.clinicaltrials.gov as #NCT02471391.
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    A multicentre retrospective comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma
    Cheah, CY ; Herbert, KE ; O'Rourke, K ; Kennedy, GA ; George, A ; Fedele, PL ; Gilbertson, M ; Tan, SY ; Ritchie, DS ; Opat, SS ; Prince, HM ; Dickinson, M ; Burbury, K ; Wolf, M ; Januszewicz, EH ; Tam, CS ; Westerman, DA ; Carney, DA ; Harrison, SJ ; Seymour, JF (NATURE PUBLISHING GROUP, 2014-09-09)
    BACKGROUND: Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a devastating complication; the optimal prophylactic strategy remains unclear. METHODS: We performed a multicentre, retrospective analysis of patients with DLBCL with high risk for CNS relapse as defined by two or more of: multiple extranodal sites, elevated serum LDH and B symptoms or involvement of specific high-risk anatomical sites. We compared three different strategies of CNS-directed therapy: intrathecal (IT) methotrexate (MTX) with (R)-CHOP 'group 1'; R-CHOP with IT MTX and two cycles of high-dose intravenous (IV) MTX 'group 2'; dose-intensive systemic antimetabolite-containing chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX 'group 3'. RESULTS: Overall, 217 patients were identified (49, 125 and 43 in groups 1-3, respectively). With median follow-up of 3.4 (range 0.2-18.6) years, 23 CNS relapses occurred (12, 10 and 1 in groups 1-3 respectively). The 3-year actuarial rates (95% CI) of CNS relapse were 18.4% (9.5-33.1%), 6.9% (3.5-13.4%) and 2.3% (0.4-15.4%) in groups 1-3, respectively (P=0.009). CONCLUSIONS: The addition of high-dose IV MTX and/or cytarabine was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. However, these data are limited by their retrospective nature and warrant confirmation in prospective randomised studies.
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    Limited clinical benefit for surveillance PET-CT scanning in patients with histologically transformed lymphoma in complete metabolic remission following primary therapy
    Cheah, CY ; Dickinson, M ; Hofman, MS ; George, A ; Ritchie, DS ; Prince, HM ; Westerman, D ; Harrison, SJ ; Burbury, K ; Wolf, M ; Januszewicz, H ; Herbert, KE ; Carney, DA ; Tam, C ; Seymour, JF (SPRINGER, 2014-07)
    The optimum follow-up of patients with transformed indolent lymphoma (TrIL) is not well defined. We sought to determine the utility of surveillance positron emission tomography-computed tomography (PET-CT) in patients with TrIL achieving complete metabolic remission (CMR) after primary therapy. We performed a retrospective analysis of patients with TrIL treated at Peter MacCallum Cancer Centre between 2002 and 2012 who achieved CMR after primary therapy who had ≥1 subsequent surveillance PET-CT. Of 55 patients with TrIL, 37 (67 %) received autologous stem cell transplantation as consolidation following chemoimmunotherapy. After a median follow-up of 34 (range 3-101) months, the actuarial 3-year progression-free (PFS) and overall survival (OS) were 77 % (95 %CI 62-86 %) and 88 % (75-94 %), respectively. Of 180 surveillance PET-CT scans, there were 153 true negatives, 4 false positives, 1 false negative, 7 indeterminate and 15 true positives. Considering indeterminate scans as false positives, the specificity of PET-CT for detecting relapse was 94 %, sensitivity was 83 %, positive predictive value was 63 % and negative predictive value was 98 %. All seven subclinical (PET detected) relapses were of low-grade histology; in contrast, all nine relapses with diffuse large B cell lymphoma (DLBCL) were symptomatic. In our cohort of patients with TrIL achieving CMR, PET-CT detected subclinical low-grade relapses but all DLBCL relapses were accompanied by clinical symptoms. Thus, surveillance imaging of patients with TrIL achieving CMR is of limited clinical benefit. PET-CT should be reserved for evaluation of clinically suspected relapse.