Citations

Abstract Background In the current Canadian treatment landscape for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), eligibility for autologous stem cell transplantation (ASCT) guides the choice of salvage treatment. CD19 chimeric antigen receptor T-cell (CAR-T) therapies have improved outcomes in patients with chemorefractory DLBCL, but access is limited to eligible patients. This subanalysis of the RE-MIND2 observational retrospective cohort study investigated treatment patterns for R/R DLBCL in Canada. Patients and methods Data from patients enrolled in RE-MIND2 treated between 2010 and 2020 at 2 Canadian centers were retrospectively collected from health records. Descriptive statistics were used to analyze baseline characteristics, treatment initiated, and duration of treatment by line of therapy. Results One hundred and nine patients were included; 74.2% of patients were eligible for ASCT as 2L therapy, and 45.4% received transplants. ASCT eligibility for third- (3L) and fourth-line (4L) therapy declined to 17.1% and 5.9%, respectively. Patients received a wide variety of treatments in 3 and 4L. CAR-T therapy became available in 3 and 4L by the end of 2019. Median durations of treatment were <2.6 months in all lines of therapy; median time to next treatment ranged from 3.4 months in 4L to 5.3 months in 2L. Conclusion Results of our study support that ASCT-ineligible patients have a poor prognosis with conventional salvage chemotherapy. Before the availability of novel immunotherapies, no apparent standard of care was observed for Canadian patients with R/R DLBCL who were ineligible for or did not receive ASCT, especially after 2L treatment.

ABSTRACT Anaplastic lymphoma kinase‐positive large B‐cell lymphoma (ALK+ LBCL) is a rare, aggressive subtype of diffuse large B‐cell lymphoma with poor outcomes using standard chemotherapy. In this multi‐institutional retrospective study, we analyzed 39 cases of ALK+ LBCL identified at six US academic centers from 2002 to 2024, with treatment including conventional cytotoxic regimens in frontline and biologically informed and nonchemotherapy‐based strategies in the relapsed setting. Ninety‐two percent of patients received frontline anthracycline‐based chemotherapy; 43% received intensified regimens, and 15% underwent upfront autologous stem cell transplantation (ASCT). Despite these approaches, outcomes remained poor. At a median follow‐up of 5.4 years, median event‐free survival (EFS) was 0.6 years (95% CI, 0.4–0.9), and median overall survival (OS) was 1.5 years (95% CI, 1.3–NR). One‐ and five‐year EFS rates were 28% and 17%, while corresponding OS rates were 72% and 42%, respectively. Advanced stage and high IPI scores were associated with inferior outcomes. Twelve patients received ALK inhibitors, with alectinib showing more durable responses than crizotinib. Lenalidomide and immune checkpoint inhibitors also demonstrated activity, including durable complete responses. Five patients underwent allogeneic stem cell transplantation, with three achieving sustained remission. In conclusion, our findings highlight the limited benefit of chemotherapy, even when intensified or followed by ASCT, and support the integration of biologically targeted therapies, which may have contributed to improved OS in our cohort compared to historical outcomes. Prospective, collaborative studies are needed to better understand disease biology and define optimal use of modern therapies in this rare lymphoma.

Abstract Twenty percent of patients with follicular lymphoma relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multiomic approach, we show that patients with follicular lymphoma with elevated IRF4 expression (IRF4hi) have increased transformation risk, dysregulated immune signaling, and a suppressive tumor microenvironment. Loss- and gain-of-function experiments in IRF4hi lymphoma cells, along with chromatin profiling, demonstrate that IRF4 impairs their interaction with T cells by repressing antigen presentation and co-receptor gene modules while promoting the expression of cytokines that antagonize T-follicular helper cell and regulatory T-cell functions. Additionally, IRF4 rewires tumor metabolism and restricts glucose availability to immune cells. Silencing of IRF4 inhibits tumor cell growth and restores immune surveillance mechanisms, thus representing a promising target for therapy. Our data suggest that IRF4hi lymphoma cells co-opt a developmental mechanism used to exit the germinal center response in promoting a more aggressive cancer via engagement of multiple immune-evasive mechanisms. Significance: We show that IRF4 controls immune and metabolic signaling with functional effects on the cross-talk between B and T cells, resulting in a suppressive immune microenvironment when IRF4 is overexpressed in lymphoma. This underscores the importance of IRF4 as a pivotal therapeutic target to restore antitumor immunosurveillance for IRF4-associated lymphomas.