Kate Manos

Description:Follicular lymphoma (FL) outcomes are influenced by host immune activity. CD20-directed therapy plus programmed cell death 1 inhibition (PD-1i) increases T-cell tumor killing and natural killer cell antibody-dependent cell cytotoxicity. Mounting evidence supports immune priming using PD-1i before cancer directed agents. Our multicenter, phase 2 1st FLOR study enrolled 39 patients with previously untreated advanced-stage FL to receive 4 cycles of nivolumab (240 mg), then 4 cycles of 2-weekly nivolumab plus rituximab 375 mg/m2 (induction), then 1 year of monthly nivolumab (480 mg) plus 2 years of 2-monthly rituximab maintenance. Participants with complete response (CR) after nivolumab priming continued nivolumab monotherapy. The primary end point was toxicity during induction. Adverse events of 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. Overall response rate was 92% (CR, 59%). Median follow-up was 51 months. Median and 4-year progression-free survival (PFS) were 61 months (95% confidence interval [CI], 2-72) and 58% (95% CI, 34-97); 70% of responders remained in CR. The 4-year overall survival was 95%. High baseline total metabolic tumor volume (TMTV) and total lesion glycolysis conferred inferior PFS (P = .04 and P = .02). Additionally, high baseline tumor CD8A gene expression was associated with improved PFS (P = .03). Nivolumab priming followed by nivolumab-rituximab in treatment-naïve 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. This trial was registered at www.ClinicalTrials.gov as #NCT03245021.

Description:Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are highly radiosensitive with immune-driven abscopal responses reported. PD-1/PD-L1 inhibitors are relatively ineffective in DLBCL/FL but evidence suggests synergy with radiotherapy (RT), yet no clear biomarkers. This phase I study (NCT03610061) examined safety of escalating RT dose and treated volumes with durvalumab (PD-L1i) in thirty-four adult relapsed/refractory (RR)DLBCL and RRFL and the role of immune-cell subsets on outcomes. Patients received external-beam RT (2.5-30 Gray [Gy], five or ten fractions upto 3 target sites) plus durvalumab from RT day two, until progression. Novel Positron Emission Tomography (PET) biodistribution studies of 89Zr-durvalumab and CD8 T-cell minibody-89Zr-Df-cremirlimab were incorporated. RT recommended phase II dose was 10 Gy/5 fractions and 30 Gy/10 fractions to 3 sites for FL and DLBCL respectively. Most common Grade 3-4 toxicities included anaemia (9%), neutropenia (11%), liver dysfunction (5%). Overall response was 60% in FL (3/5; Complete Response [CR] 40% [2/5]), and 14% in DLBCL (4/27; CR 7% (2/27) Distinct peripheral blood and tumour T cell features, including CD8-PET-determined intratumoral CD8 T cells, correlated with response (p<0.05) RT-Durvalumab with 30Gy/10 fractions of radiotherapy to three disease sites is safe and offers promising responses in FL. Intratumoural and peripheral blood CD8 T cell dysregulation correlate with treatment response.

Description:Progression of follicular lymphoma (FL) or transformation (TFL) within 24 months of immunochemotherapy (ICT) represent high-risk defining events (HRDE) with poor overall survival (OS). We examined baseline clinical characteristics, imaging, and outcomes for patients experiencing HRDE with newly diagnosed FL requiring ICT. HRDE groups were: relapse or progression of FL within 24 months (FL24), early TFL (transformation <24 months of ICT), late TFL (transformation >24 months of ICT).433 patients were categorized as reference FL (Ref FL), n = 352 (no HRDE); FL24, n = 43; early TFL, n = 29; late TFL, n = 9. Chemotherapy included bendamustine (63%), CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) (27%), or CVP (cyclophosphamide, vincristine, prednisone) (10%); 85% received rituximab/15% obinutuzumab and 48% received maintenance therapy. Compared with Ref FL group, OS from HRDE was inferior for FL24 (hazard ratio [HR], 3.93; 95% confidence interval [CI], 2.14-7.23), early TFL (HR, 8.16; 95% CI, 4.38-15.2), and late TFL (HR, 8.23; 95% CI, 3.18-21.25). OS from HRDE was inferior for early TFL compared with FL24 (HR, 2.08; 95% CI, 1.02-4.21). In multivariable analysis, performance status, lactate dehydrogenase, beta-2-microglobulin and grade 3A were associated with early TFL. Clinical characteristics did not differentiate early TFL from FL24. Maximum standardized uptake value was higher in early TFL but not FL24 compared to Ref FL. Early TFL and FL24 represent different HRDEs and are associated with inferior OS. Distinguishing early TFL from FL24 is important for biomarker development, management and to develop and interpret trials in this area of unmet need.

Description:Infection and lymphopenia are established bendamustine-related complications. The relationship between lymphopenia severity and infection risk, and the role of antimicrobial prophylaxis, is not well described. This multicentre retrospective study analysed infection characteristics and antimicrobial prophylaxis in 302 bendamustine-treated indolent non-Hodgkin lymphoma patients. Lymphopenia (<1 × 109/L) was near universal and time to lymphocyte recovery correlated with cumulative bendamustine dose. No association between lymphopenia severity and duration with infection was observed. Infections occurred in 44% of patients (50% bacterial) with 27% hospitalised; 32% of infections occurred ≥3 months post bendamustine completion. Infection was associated with obinutuzumab and/or maintenance anti-CD20 therapy, prior therapy and advanced stage. Twenty-four opportunistic infections occurred in 21 patients: ten varicella zoster virus (VZV), seven herpes simplex virus (HSV), one cytomegalovirus, one progressive multifocal leucoencephalopathy, one nocardiosis, one Pneumocystis jiroveci pneumonia (PJP) and three other fungal infections. VZV/HSV and PJP prophylaxis were prescribed to 42% and 54% respectively. Fewer VZV/HSV infections occurred in patients receiving prophylaxis (HR 0.14, p = 0.061) while PJP prophylaxis was associated with reduced risk of bacterial infection (HR 0.48, p = 0.004). Our study demonstrates a significant infection risk regardless of lymphopenia severity and supports prophylaxis to mitigate the risk of early and delayed infections.

Description:Polatuzumab vedotin (Pola) is an approved therapy in combination with rituximab and bendamustine for relapsed or refractory diffuse large B-cell lymphoma (RR-DLBCL) based on positive results of the landmark phase II randomised G029365 trial. However, trial results for many approved novel therapies in RR-DLBCL have not been replicated in routine care cohorts, as RR-DLBCL patient populations are heterogeneous and trial eligibility is increasingly restrictive. We evaluated outcomes from pola ± bendamustine and rituximab in patients with RR-DLBCL enrolled in a compassionate access program with no alternative treatment options identified via the Australasian Lymphoma and Related Diseases Registry according to their eligibility for the original phase II published study. Of 58 eligible patients, 74% met the criteria deeming them ineligible for the G029365 original study at the time of pola's commencement. Median progression-free survival and overall survival in our cohort were 2.3 and 3.5 months, respectively. In contrast to the landmark trial cohort, more of our patients ceased therapy prior to completion, the majority due to progressive disease and only 8/58 received any subsequent treatment. Dismal outcomes in this Australian real-world population demonstrate trial eligibility is challenging to meet, and newer treatments can be difficult to deliver in routine care. Clinically applicable results from therapeutic studies require trial cohorts to reflect representative clinical populations wherever possible, and more research is required to address the benefit of novel agents in the increasing majority who are ineligible for modern studies.