No abstract

The tumor necrosis factor family molecule Ox40-ligand (Ox40L) has been identified as a potential costimulatory molecule and also has been implicated in T cell homing and B cell activation. To ascertain the essential functions of Ox40L, we generated and characterized Ox40L-deficient mice. Mice lacking Ox40L exhibit an impaired contact hypersensitivity response, a dendritic cell-dependent T cell-mediated response, due to defects in T cell priming and cytokine production. In contrast, Ox40L-deficient mice do not have defects in T cell homing or humoral immune responses. In vitro, Ox40L-deficient dendritic cells are defective in costimulating T cell cytokine production. Thus, Ox40L has a critical costimulatory function in vitro and in vivo for dendritic cell:T cell interactions.

Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months; interquartile range, 13.8-20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8-78.3) and ORR 86.2% (95% confidence interval, 77.5-92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients.

Key Points Early consolidation with BV improves 5-year PFS vs best supportive care and reduces the need for subsequent therapy. At 5-year follow-up, BV shows long-term tolerability, with peripheral neuropathy continuing to improve and/or resolve.

No abstract

The poor prognosis of diffuse large B-cell lymphoma (DLBCL) patients relapsing within 1-year of initial diagnosis after first-line rituximab-based chemoimmunotherapy has created controversy about the role of autologous transplantation (auto-HCT) in this setting. We compared auto-HCT outcomes of chemosensitive DLBCL patients between 2000 and 2011 in two cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1-year of initial diagnosis. The ERF cohort was compared with those relapsing >1-year after initial diagnosis (Late Rituximab Failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Non-relapse mortality (NRM), progression/relapse, progression-free survival (PFS) and overall survival (OS) of ERF vs. LRF cohorts at 3-years were 9% (95%CI 6–13) vs. 9% (95%CI 5–13), 47% (95%CI 41–52) vs. 39% (95%CI 33–46), 44% (95%CI 38–50) vs. 52% (95%CI 45–59) and 50% (95 CI 44–56) vs. 67% (95%CI 60–74), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk (RR) 1.31, p=0.34). ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR 2.08, p<0.001) and overall mortality (RR 3.75, p<0.001) within the first 9 months post auto-HCT. Beyond this period, PFS and OS were not significantly different between ERF and LRF cohorts. Auto-HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS 44%), and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse.

The peripheral T cell lymphomas (PTCL) carry a worse prognosis compared to B cell non-Hodgkin lymphoma. There is no uniform standard therapy for PTCL, and autologous hematopoietic cell transplant (AHCT) is often offered as consolidation in first remission or at relapse because of the poor outcomes with conventional therapy. We conducted a retrospective review of patients who underwent AHCT for PTCL from 1989 to 2006. Fifty-three cases were identified consisting of systemic anaplastic large cell (n = 18), PTCL unspecified (n = 17), angioimmunoblastic (n = 9), nasal type extranodal NK/T (n = 7), hepatosplenic (n = 2), and adult T cell leukemia/lymphoma (n = 1). Fifteen patients were transplanted in first complete or partial response (CR1/PR1), 32 in second or beyond CR or PR (CR2/PR2+), and 11 with primary refractory disease (REF). With a median follow-up was 5 years (range: 1.0–11.5), the 5-year progression-free survival (PFS) and overall survival (OS) were 25% and 48%, respectively. Disease status at AHCT had a significant impact on PFS and OS. The 5-year PFS for patients in CR1/PR1, CR2/PR2+, and REF was 51%, 12%, and 0%, respectively, and the corresponding figures for OS were 76%, 40%, and 30%, respectively. The pretransplant factors that impacted survival were disease status and the number of prior regimens. Histology, age, sex, stage, B symptoms, bone marrow involvement, and duration of first response did not significantly affect PFS or OS. Based on these results, AHCT as consolidation therapy in first complete or partial response may offer a durable survival benefit. However, AHCT with conventional salvage chemotherapy has minimal durable benefit in patients with relapsed or refractory PTCL, and thus novel strategies and/or allogeneic HCT should be more aggressively explored in lieu of AHCT for relapsed/ refractory PTCL.

No abstract