PD-1 expression identifies proliferating malignant CLL B cells and is a potential biomarker of response to BTK inhibitor therapy.

Chronic lymphocytic leukemia (CLL) remains incurable despite treatment advances, and a major challenge is that biomarkers that predict response and resistance to current therapies are lacking. We report that activated and proliferating malignant CLL B cells in circulation express PD-1, a protein normally expressed in T cells. PD-1 expression is absent in circulating B cells from healthy controls and nonmalignant B cells from patients with CLL.

Multi-Institutional Study of ALK-Positive Large B-Cell Lymphoma: Outcomes in the Era of ALK Inhibitors and Biologically Informed Therapies.

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).

Subsets of follicular lymphoma 3B have divergent outcomes: results from the prospective multicenter MER and LEO cohorts.

Follicular lymphoma (FL) 3B is considered an aggressive lymphoma, however recent studies have challenged this paradigm. Additional controversy involves the clinical implication of pure FL3B (FL3Bp) vs FL3B with concurrent diffuse large B cell lymphoma (DLBCL) (FL3Bc). To address these questions, we performed a pooled study of the MER and LEO cohorts comparing 464 newly diagnosed, R-CHOP-treated patients with FL1-2 (n = 216), FL3A (n = 170), FL3B (n = 78) and 739 DLBCL.

Frontline acalabrutinib, lenalidomide and rituximab for advanced stage follicular lymphoma with high tumor burden: phase II trial.

This phase II trial aims to determine the efficacy and safety of frontline acalabrutinib, lenalidomide and rituximab for patients with advanced stage follicular lymphoma (FL) and high tumor burden. The primary endpoint was best complete response (CR) rate; the secondary endpoints were overall response rate (ORR), duration of response measured as CR at 30 months (CR30), progression of disease at 24 months (POD24) rate, progression-free survival (PFS), overall survival and safety. Twenty-four patients with previously untreated FL were included in this phase 2 single arm study (NCT04404088).

A Phase I Trial of Evorpacept, Lenalidomide and Rituximab for Patients with B-cell Non-Hodgkin Lymphoma.

Introduction: SIRPα+ macrophages can mediate resistance to lenalidomide and rituximab (R2) in patients with B-cell non-Hodgkin lymphoma (B-NHL). Evorpacept (ALX148) is a novel CD47 blocker that abrogates interactions between lymphoma cells and SIRPα+ macrophages.

Methods: Adult patients with B-NHL who had received at least 2 prior lines of systemic therapy were included in this single arm phase I study (NCT05025800).

TCA cycle mode switch determines the fate of pirtobrutinib-tolerant persister cells in mantle cell lymphoma.

Bruton's tyrosine kinase inhibitors (BTKi) and cell therapy have successfully been used to treat mantle cell lymphoma (MCL); however, therapy resistance inevitably emerges. Cancer cells can progressively develop stable resistance by traversing through a transient drug-tolerant persister (DTP) state. The mechanisms enabling DTP cells to reversibly adapt to therapies and evolve to acquire heterogeneity remain poorly understood, and characterizing DTP cells in MCL continues to pose a challenge for clinic translation.

Impact of sociodemographic determinants on enrollment into contemporary lymphoma clinical trials: a systematic review.

While the incidence and survival associated with lymphoma have improved in recent years, outcome disparities related to sociodemographic factors such as age, sex, race, ethnicity, socioeconomic status (SES), and other social determinants of health (SDOH) remain prevalent in the modern era. Clinical trials are crucial for further improving outcomes, yet not all sociodemographic groups are equally represented in contemporary lymphoma trials. We conducted a systematic review of the literature evaluating the impact of SDOH on enrollment into clinical trials in the United States and identified 21 relevant studies.

A phase 2 study of obinutuzumab combined with lenalidomide in previously untreated high tumor burden follicular lymphoma.

Follicular lymphoma (FL) has a clinical course that is often characterized by high response rates to first-line therapy, followed by multiple relapses over a prolonged natural history. Currently, there are multiple possible approaches to frontline therapy for untreated advanced-stage FL, but there is an ongoing debate around what is the preferred approach. Based on the benefits seen with combining lenalidomide, an immunomodulatory agent, with rituximab, an anti-CD20 antibody, we aimed to evaluate the safety and efficacy of lenalidomide in combination with obinuzutumab, an anti-CD20 antibody with enhanced antibody-dependent cellular cytotoxicity.

Clinical outcomes of patients with newly diagnosed large B-cell lymphoma in a safety-net hospital system.

Real-world outcome data for patients with large B-cell lymphomas (LBCLs) who are uninsured or have socioeconomic barriers to care are limited. We performed a retrospective cohort study of patients with newly diagnosed LBCL treated in a large safety-net hospital system. Between January 2011 and June 2022, 496 patients aged >18 years were diagnosed with LBCL at Harris Health System, Houston, Texas.

Patient-Reported Outcome Measures (PROMS) in Lymphoma.

Patient-reported outcome measures (PROMs) are often used to evaluate the impact of treatment and clinical decisions on the patient experience for patients with lymphoma. Regulatory agencies have provided guidance on the use of PROMs for patient-focused drug development. Though PROMs are increasingly utilized, the way in which they are used, analyzed, and reported is heterogeneous.

Clinical Safety and Preliminary Efficacy of Regulatory T Cells for ALS.

Background: Peripheral and neuroinflammation have been previously associated with progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving progressive loss of motor neurons. We hypothesize that regulatory T cell (Treg) therapy can resolve inflammation and preserve function in those patients with ALS.

Methods: Participants with ALS received infusions of a fixed dose (100×10 cells) of umbilical cord blood-derived, allogeneic, nonhuman leukocyte antigen-matched, cryopreserved Treg product (TREG), administered as four weekly infusions followed by six monthly infusions.

Longitudinal analysis of gut microbiome and metabolome correlates of response and toxicity with idecabtagene vicleucel.

Increasing evidence suggests that the gut microbiome may influence the responses and toxicities associated with chimeric antigen receptor T-cell (CAR-T) therapy. We conducted whole-genome shotgun sequencing on stool samples (N = 117) collected at various times from patients with multiple myeloma (n = 33) who underwent idecabtagene vicleucel (ide-cel) anti-B-cell maturation antigen CAR-T therapy. We observed a significant decrease in bacterial diversity after ide-cel infusion, along with significant differences in the bacterial composition linked to therapy response and toxicities.

Cytokine Storms in COVID-19, Hemophagocytic Lymphohistiocytosis, and CAR-T Therapy.

Importance: Cytokine storm (CS) is a hyperinflammatory syndrome causing multiorgan dysfunction and high mortality, especially in patients with malignant hematologic neoplasms. Triggers include malignant neoplasm-associated hemophagocytic lymphohistiocytosis (MN-HLH), cytokine release syndrome from chimeric antigen receptor T-cell therapy (CAR-T CRS), and COVID-19, but the underlying mechanisms of inflammation and their impact on outcomes are poorly understood.

Objective: To delineate the inflammatory patterns characterizing different CS etiologies and their association with clinical outcomes.

Blunted CD40-responsive enhancer activation in CREBBP-mutant lymphomas can be restored by enforced CD4 T-cell engagement.

The CREBBP lysine acetyltransferase (KAT) is frequently mutated in follicular lymphoma and diffuse large B-cell lymphoma and has been studied using gene knockout in murine and human cells. However, most CREBBP mutations encode amino acid substitutions within the catalytic KAT domain (CREBBP KAT-PM) that retain an inactive protein and have not been extensively characterized. Using CRISPR gene editing and extensive epigenomic characterization of lymphoma cell lines, we found that CREBBP KAT-PM lead to unloading of CREBBP from chromatin, loss of enhancer acetylation, and prevention of EP300 compensation.

End points and Outcomes in Follicular Lymphoma: What should we measure, how, and why?

Overall survival (OS) and quality of life (QoL) are clinically relevant outcomes/endpoints during examination of therapies. However, with median OS approaching 20 years for patients with follicular lymphoma (FL), it is often not feasible to use OS as a primary endpoint in clinical studies. While validated tools for assessing QoL in patient with lymphoma exist, QoL data are rarely the sole basis for drug approvals in FL.

Ruxolitinib synergizes with regulatory T cells to improve inflammation but has no added benefits in decreasing albuminuria in SLE.

Background: Umbilical cord blood (UCB)-derived CD4CD25CD127 regulatory T cells (Tregs) can decrease albuminuria and anti-dsDNA IgG in systemic lupus erythematosus (SLE). Ruxolitinib, a JAK/STAT inhibitor, has been shown to improve cutaneous manifestations of SLE. We hypothesize that the addition of ruxolitinib to UCB-Tregs may improve SLE outcomes.

Real-World Effectiveness of Chemoimmunotherapy and Novel Therapies for Patients With Relapsed/Refractory Aggressive Large B-Cell Lymphoma.

Introduction: Clinical trials provide meaningful data regarding the safety and efficacy of novel therapies but there is often a lag between the time of new drug approval and information on posttreatment clinical outcomes in real-world practice. This study evaluated clinical outcomes in a large real-world population of patients with relapsed and/or refractory large B-cell lymphoma (r/r LBCL) treated with chemoimmunotherapy or novel therapies in second or later lines of therapy (2L+).

Materials And Methods: Data from the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real-World Evidence (CReWE) cohort (1/1/2015-2/15/2023) were analyzed.

Outcomes with bridging radiation therapy prior to chimeric antigen receptor T-cell therapy in patients with aggressive large B-cell lymphomas.

Background: Select patients with relapsed/refractory aggressive B cell lymphoma may benefit from bridging radiation (bRT) prior to anti-CD19-directed chimeric antigen receptor T cell therapy (CAR-T). Here, we examined patient and treatment factors associated with outcomes and patterns of failure after bRT and CAR-T.

Methods: We retrospectively reviewed adults with diffuse large B-cell lymphoma (DLBCL) who received bRT prior to axicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel between 11/2017-4/2023.

Outcomes of Relapsed or Refractory Diffuse Large B-Cell Lymphoma Treated With R-GemOx: A Multicenter Cohort Study.

Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is a commonly used chemoimmunotherapy regimen for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but there are limited real-world data. In a multicenter retrospective study from a cohort of eight US academic centers (LEO CReWE), we evaluated 183 patients with R/R DLBCL and high-grade B cell lymphoma treated with R-GemOx, including subgroups treated without intent for consolidation with autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T cell therapy (n = 100), those utilizing R-GemOx as a bridge to ASCT or CAR T (n = 83), and those aged 70 and older (n = 71). Overall response rates (ORRs) for all patients treated with R-GemOx were 45% with a complete response (CR) rate of 29%.

Phase 2 trial of ibrutinib and nivolumab in patients with relapsed CNS lymphomas.

Treatment options are limited for both relapsed/refractory primary and secondary central nervous system (CNS) lymphoma and the prognosis remains poor. Previous studies have shown the activity of Bruton tyrosine kinase inhibitors and programmed death-1-targeted therapies in CNS lymphoma, and studies suggested potential synergy. Therefore, we conducted a phase 2 trial that combined ibrutinib with nivolumab for patients with relapsed/refractory CNS lymphoma.

Addressing Health Disparities in Hematologic Malignancies: from Genes to Outreach.

This review underscores our shared responsibility to champion multidimensional strategies rooted in basic and translational science, community involvement, and societal responsiveness for a meaningful impact. Unifying themes include the need to enhance collaborative infrastructure to engage laboratory researchers, epidemiologists, data scientists, clinicians, patients, community leaders, and policymakers; patient-level support services; outreach, education, and navigation for patients at the community level; recruitment and retention of underrepresented groups in the healthcare and research workforce; and funding for these efforts.