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Abstract: Little is known about the central nervous system (CNS) risk in high-grade B-cell lymphoma, not otherwise specified (HGBL NOS). Hence, we sought to describe the rates of baseline CNS involvement, risk of CNS recurrence after primary therapy, and management strategies in HGBL NOS. In this multicenter retrospective study, we included 160 adults with newly diagnosed HGBL NOS treated between 2016 and 2021 at 20 US institutions. Eleven patients (7%) had baseline CNS involvement at diagnosis (leptomeningeal = 6, parenchymal = 4, and both = 1). Baseline CNS involvement was significantly associated only with MYC rearrangement (OR = 3.5) and testicular (in men) or female pelvic (in women) involvement (OR = 8.1). There was no significant difference in survival outcomes between patients with HGBL NOS with (median PFS = 4 years) or without (median PFS = 2.4 years) baseline CNS involvement (P = 0.45). The cumulative incidence of CNS recurrence at 3 years was 11%. Patients with baseline CNS involvement were at the highest risk (48.5% vs 8% for those without baseline CNS involvement) and were excluded from the risk factors analysis for CNS recurrence. The risk for CNS recurrence was significantly associated with blood or bone marrow involvement, CD5 expression, non-germinal center B-cell subtype, and "dual-expresser lymphoma" phenotype, however, high CNS IPI was not. The prognosis of relapsed HGBL NOS was poor, regardless of whether recurrence was systemic or limited to the CNS, and with currently available salvage strategies, including autologous transplantation and chimeric antigen receptor T-cell modalities, almost all patients with CNS recurrence ultimately succumbed to their disease., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Robust biomarkers and a complete understanding of CAR T-cell function in the postinfusion phase remain limited. Here, we used a 37-color spectral flow cytometry panel to perform high dimensional single-cell analysis of postinfusion samples in 26 patients treated with CD28 costimulatory domain containing commercial CAR T cells for NHL and focused on computationally gated CD8+ CAR T cells. We found that the presence of postinfusion Programmed cell death protein 1 (PD-1)+ CD8+ CAR T cells at the day 14 time point highly correlated with the ability to achieve complete response (CR) by 6 months. Further analysis identified multiple subtypes of CD8+ PD-1+ CAR T cells, including PD-1+ T cell factor 1 (TCF1)+ stem-like CAR T cells and PD-1+ T-cell immunoglobulin and mucin-domain containing-3 (TIM3)+ effector-like CAR T cells that correlated with improved clinical outcomes such as response and progression-free survival. Additionally, we identified a subset of PD-1+ CD8+ CAR+ T cells with effector-like function that was increased in patients who achieved a CR and was associated with grade 3 or higher immune effector cell-associated neurotoxicity syndrome. Here, we identified robust biomarkers of response to CD28 CAR T cells and highlight the importance of PD-1 positivity in CD8+ CAR T cells after infusion in achieving CR., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma. Circulating lymphoma (CL) cells can be seen at diagnosis in some FL patients, however, previous studies evaluating this have shown mixed results. Therefore, we sought to evaluate the impact of CL at diagnosis on outcomes in patients with newly diagnosed FL using data from a single center. Patients were divided into CL+ and CL- based on immunophenotyping via peripheral blood (PB) flow cytometry. CL was defined as detectable clonally restricted B-cells that matched the actual or expected B-cell immunophenotype of FL. The primary endpoint was progression-free survival (PFS) after first-line treatment and secondary endpoints included overall response rate (ORR), overall survival (OS), diagnosis to treatment interval (DTI), progression of disease within 2 years of diagnosis (POD24), and cumulative incidence of transformation between the two groups. Among the 541 patients with FL, 204 had PB flow cytometry performed at diagnosis, and after excluding patients not meeting the eligibility criteria, 147 cases remained with 24 (16%) CL+ at diagnosis. Patients in the CL+ group were younger (53 vs. 58 years, p = 0.02), had more extranodal involvement (83% vs. 44%, p < 0.01), follicular lymphoma international prognostic index 3-5 (55% vs. 31%, p = 0.01), and a higher proportion received first-line immunochemotherapy (75% vs. 43%, p = 0.01) compared to the CL-group. The median PFS was not significantly different between CL+ (6.27 years, 95% CI = 3.61-NR) and CL- (6.61 years, 95% CI = 5.10-9.82) cohorts regardless of the first-line treatment or level of absolute PB CL cells. There was no significant difference in ORR, median OS, DTI, POD24, and cumulative incidence of transformation between the two groups. In our study, we found that the presence of CL cells at diagnosis in FL in the contemporary era did not impact outcomes and survival., (© 2024 John Wiley & Sons Ltd.)