Abstract Comprehensive clinical characteristics of Australian patients with classical Hodgkin Lymphoma (cHL) have not previously been systematically collected and described. We report real‐world data of 498 eligible patients from the first 5 years of the Lymphoma and Related Diseases Registry (LaRDR), including baseline characteristics, histologic subtype, and treatment patterns in first‐line therapy. Patient demographics and distribution of histopathological subtypes of cHL are similar to reported international cohorts. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was the most common therapy for both early and advanced‐stage disease, and 48% of patients with the early‐stage disease received radiotherapy. Treatment patterns are consistent with international guidelines. In comorbid patients ≥60 years of age with advanced‐stage disease, there is greater variation in treatment. In patients with a recorded response, the objective response rate (ORR) was 96% in early‐stage disease, and 88% in advanced‐stage disease. Early progression‐free survival data suggest Australian patients with cHL have good outcomes, similar to other international studies.
Abstract Primary central nervous system lymphoma is a clinicopathological disease entity that accounts for 1% of all non‐Hodgkin lymphoma (NHL). Advanced patient age, adverse disease biology and complexities of diagnosis and treatment render outcomes markedly inferior to systemic NHL. Despite this, an increasing evidence base, including limited randomised controlled clinical trial data, is informing optimal therapeutic strategies with methotrexate‐based induction chemotherapy schedules and intensified consolidation in selected patients. This practice statement represents an evidence‐based review of the literature and has been devised to assist healthcare professionals in the diagnosis and management of this disease.
Introduction: Inter-tumoral T cell dysfunction and efficacy of immune checkpoint inhibitors (ICI) in follicular lymphoma (FL) has been well described. However, few studies have examined peripheral blood immunity at diagnosis or the impact of frontline ICI on circulating immunity in FL. We hypothesised that immune dysregulation in peripheral blood would be present in treatment naïve FL and would correlate to response to frontline ICI. Methods: PBMC samples from 34 untreated FL patients receiving rituximab (R) and nivolumab (nivo) in the 1st FLOR trial (Hawkes JCO 2021) were collected at baseline, post 4 cycles of nivo and after 6 months of nivo±R. Immune profile was assessed using a single-tube 29 antibody FACS panel on a spectral flow cytometer and compared to the profile of 12 age matched healthy donors. Results were correlated with centrally determined PET response (Lugano criteria). Results: Compared to healthy donors, FL patients had increased proportions of TRegs (P < 0.0001) with decreased HLA-DR+ (P < 0.01) and increased PD-1+ (P < 0.01) populations. NK cells were increased (P < 0.05) with a 2-fold increase in TIM3 expression (P < 0.01). While total T cells were unchanged, expression of PD-1, TIM3, HLA-DR and 4-1BB were significantly increased in T cells from FL patients. Treatment with nivo significantly increased the populations of TRegs expressing 41BB, LAG-3, TIM3 or PD-L2 (P < 0.05) with a decreased PD-L1 positive population at PET-CT2. Expression of immune checkpoints on T cells was unchanged by therapy. To assess biomarkers of response, patients were stratified into sustained CR (CR achieved by PET-CT4 and maintained for 6 months without evidence of relapse, n = 15) vs. PR/PD (n = 21). At baseline, sustained CR was associated with a trend for increased proportions of Naïve CD4 and CD8 T cells and decreased TRegs and PD-L2 expressing TRegs. Baseline expression of PD-1 on T and NK cells did not correlate with sustained response. Most strikingly, expression of CD62L was significantly downregulated across total CD4 and CD8 T cells and TRegs at PET-CT2 in PR/PD patients (P < 0.05) and maintained at baseline levels in those patients who achieved a sustained CR. At this early timepoint final patient responses had not been established with most patients having either progressive or stable disease, suggesting that dysfunctional downregulation of CD62L in response to nivo may reflect the inability of patient's T cells to activate and/or migrate to the tumour site and facilitate tumour clearance and long-term treatment responses. Conclusions: Grade 1-3A treatment naïve FL is associated with significant dysregulation of peripheral blood T and NK cells prior to therapy. Early downregulation of CD62L on T cells of patients treated with nivo was associated with the inability to achieve long term complete responses and may indicate aberrant T cell activation and/or function which impacts on long term response to therapy. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Bristol Myers Squibb Keywords: Basic and Translational Science, Diagnostic and Prognostic Biomarkers Conflicts of interests pertinent to the abstract. A. Barraclough Honoraria: Roche, Gilead G. Chong Consultant or advisory role: Bristol Myers Squibb Research funding: Bristol Myers Squibb, Merck Serono, Pharmacyclics, Regeneron, Bayer, Astra Zeneca, Amgen, Hutch Med, Incyte E. A. Hawkes Consultant or advisory role: Roche, Merck Sharpe & Dohme, Astra Zeneca, Gilead, Antigene, Novartis, Regeneron, Janssen, Specialised Therapeutics Research funding: Bristol Myers Squibb, Roche, Merck KgA, Astra Zeneca
There are limited data on post-transplant lymphoproliferative disorder (PTLD) in the era of positron emission tomography (PET) and rituximab (R). Furthermore, there is limited data on the risk of graft rejection with modern practices in reduction in immunosuppression (RIS). We studied 91 patients with monomorphic diffuse large B-cell lymphoma PTLD at 11 Australian centers: median age 52 years, diagnosed between 2004 and 2017, median follow-up 4.7 years (range, 0.5-14.5 y). RIS occurred in 88% of patients. For patients initially treated with R-monotherapy, 45% achieved complete remission, rising to 71% with the addition of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) for those not in complete remission. For patients initially treated with R-CHOP, the complete remission rate was 76%. There was no difference in overall survival (OS) between R-monotherapy and R-chemotherapy patients. There was no difference in OS for patients with systemic lymphoma (n = 68) versus central nervous system (CNS) involvement (n = 23) (3-y OS 72% versus 73%; P = 0.78). Treatment-related mortality was 7%. End of treatment PET was prognostic for patients with systemic lymphoma with longer OS in the PET negative group (3-y OS 91% versus 57%; P = 0.01). Graft rejection occurred in 9% (n = 4 biopsy-proven; n = 4 suspected) during the entire follow-up period with no cases of graft loss. RIS and R-based treatments are safe and effective with a low likelihood of graft rejection and high cure rate for patients achieving complete remission with CNS or systemic PTLD.
Summary Grade 3B follicular lymphoma (G3BFL) is a rare lymphoma thought to sit on a continuum between low‐grade FL and diffuse large B‐cell lymphoma (DLBCL). The prognostic impact of quantitative positron emission tomography (PET) metrics such as total metabolic tumour volume (TMTV), total lesion glycolysis (TLG), and maximum standard uptake value (SUVmax) have been extensively analysed in FL and DLBCL, but G3BFL data are lacking. Here, we describe PET outcomes and radiomic characteristics in 46 G3BFL cases uniformly treated with R‐CHOP (like) chemotherapy. Central semi‐automated PET TMTV, TLG, and SUVmax analyses, using MIM software, were correlated with clinical outcomes and compared with published results in low‐grade FL and DLBCL. In G3BFL, the end‐of‐treatment complete metabolic response was associated with improved progression‐free survival (PFS; p = 0.002) and overall survival (OS; p = 0.04). G3BFL median TLG (1455) and SUVmax (16.50) sit between published values for low‐grade FL (TLG: 1112, SUVmax: 11.3) and DLBCL (TLG: 3004, SUVmax: 24.35). No association between TMTV (>350 cm 3 ) and survival was seen (PFS: p = 0.24; OS: p = 0.40). High SUVmax (>19.2) and TLG (>2760) both conferred inferior PFS but not OS (PFS: SUVmax p = 0.004; TLG p = 0.05). These data support the routine incorporation of PET radiomics at baseline and treatment response for G3BFL.
Follicular lymphoma (FL) outcomes are heavily influenced by host immune activity with immune anti-tumor activity mitigated by PD-1/PD-L1 pathway engagement. Combination CD20-directed therapy plus PD-1 inhibition (PD-1i) increases T-cell tumor killing and NK-cell antibody-dependent cell cytotoxicity (ADCC). Mounting evidence supports immune-priming using PD-1i before cancer-directed agents. Our multicentre, open-label, phase II 1st FLOR study (NCT03245021) enrolled 39 previously-untreated advanced-stage FL patients to receive 4 cycles of nivolumab (240mg) then 4 cycles of 2-weekly nivolumab plus rituximab 375mg/m2 (induction) then 1 year of monthly nivolumab (480mg) plus 2 years of 2-monthly rituximab maintenance. Participants with complete response (CR) after nivolumab priming continued nivolumab monotherapy. The primary endpoint was toxicity during induction. Adverse events (AEs) ≥ grade 3 during induction occurred in 33% (n=13); most commonly elevated amylase/lipase (15%), liver enzyme derangement (11%) and infection (10%). Three patients discontinued nivolumab secondary to toxicity; two pancreatitis, one acute kidney injury. Overall response rate (ORR) was 92% (CR 59%). Median follow-up was 51 months. Median and 4-year progression-free survival (PFS) were 61 months (95%CI 2-72) and 58% (95%CI 34-97); 70% of responders remained in CR. 4-year overall survival was 95%. High baseline total metabolic tumor volume and total lesion glycolysis conferred inferior PFS (p=0.04 and p=0.02). Additionally, high baseline tumor CD8A gene expression was associated with improved PFS (p=0.03). Nivolumab priming followed by nivolumab-rituximab in treatment-naive FL is associated with favorable toxicity and high response rates potentially providing an alternative to chemotherapy. TMTV and high tumor CD8A expression are promising immunotherapy biomarkers for FL.
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