Medicine (St Vincent's) - Research Publications
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ItemTargeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas(MDPI, 2022-03)Targeted therapies continue to change the landscape of lymphoma treatment, resulting in improved therapy options and patient outcomes. Numerous agents are now approved for use in the indolent lymphomas and many others under development demonstrate significant promise. In this article, we review the landscape of targeted agents that apply to the indolent lymphomas, predominantly follicular lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinaemia and marginal zone lymphoma. The review covers small molecule inhibitors, immunomodulators and targeted immunotherapies, as well as presenting emerging and promising combination therapies.
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ItemAutologous stem cell transplantation for untreated transformed indolent B-cell lymphoma in first remission: an international, multi-centre propensity-score-matched study(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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ItemA multicentre retrospective comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma(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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ItemCharacterisation of immune checkpoints in Richter syndrome identifies LAG3 as a potential therapeutic target(WILEY, 2021-10)Richter syndrome (RS), an aggressive lymphoma occurring in the context of chronic lymphocytic leukaemia/small lymphocytic lymphoma, is associated with poor prognosis when treated with conventional immunochemotherapy, therefore, improved treatments are required. Immune checkpoint blockade has shown efficacy in some B-cell malignancies and modest responses in early clinical trials for RS. We investigated the immune checkpoint profile of RS as a basis to inform rational therapeutic investigations in RS. Formalin-fixed, paraffin-embedded biopsies of RS (n = 19), de novo diffuse large B-cell lymphoma (DLBCL; n = 58), transformed indolent lymphomas (follicular [tFL], n = 16; marginal zone [tMZL], n = 24) and non-transformed small lymphocytic lymphoma (SLL; n = 15) underwent gene expression profiling using the NanoString Human Immunology panel. Copy number assessment was performed using next-generation sequencing. Immunohistochemistry (IHC) for LAG3 and PD-1 was performed. LAG3 gene expression was higher in RS compared to DLBCL (P = 0·0002, log2FC 1·96), tFL (P < 0·0001, log2FC 2·61), tMZL (P = 0·0004, log2FC 1·79) and SLL (P = 0·0057, log2FC 1·45). LAG3 gene expression correlated with the gene expression of human leukocyte antigen Class I and II, and related immune genes and immune checkpoints. IHC revealed LAG3 protein expression on both malignant RS cells and tumour-infiltrating lymphocytes. Our findings support the investigation of LAG3 inhibition to enhance anti-tumour responses in RS.
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ItemLimited clinical benefit for surveillance PET-CT scanning in patients with histologically transformed lymphoma in complete metabolic remission following primary therapy(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.
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ItemLimited role for surveillance PET-CT scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission following primary therapy(NATURE PUBLISHING GROUP, 2013-07-23)BACKGROUND: The usefulness of positron emission tomography with computed tomography (PET-CT) in the surveillance of patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission after primary therapy is not well studied. METHODS: We performed a retrospective review of our database between 2002 and 2009 for patients with de novo DLBCL who underwent surveillance PET-CT after achieving complete metabolic response (CMR) following primary therapy. RESULTS: Four-hundred and fifty scans were performed in 116 patients, with a median follow-up of 53 (range 8-133) months from completion of therapy. Thirteen patients (11%) relapsed: seven were suspected clinically and six were subclinical (all within first 18 months). The positive predictive value in patients with international prognostic index (IPI) <3 was 56% compared with 80% in patients with IPI ≥3. Including indeterminate scans, PET-CT retained high sensitivity 95% and specificity 97% for relapse. CONCLUSION: Positron emission tomography with computed tomography is not useful in patients for the majority of patients with diffuse large B-cell lymphoma in CMR after primary therapy, with the possible exception of patients with baseline IPI ≥3 in the 18 months following completion of primary therapy. This issue could be addressed by a prospective clinical trial.