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Background: Diffuse large B-cell lymphoma (DLBCL) is the most common diagnosed aggressive B-cell lymphoma, with poor outcomes in those who experience relapsed or refractory (R/R) disease. Landmark clinical trials have demonstrated the efficacy and safety of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for patients with R/R DLBCL, though further exploration of real-world outcomes (RWOs) and safety data is warranted. Methods: A retrospective chart review was performed to collect patient and disease characteristics from patients with R/R DLBCL receiving CAR T-cell therapy for third-line treatment or beyond at the John Theurer Cancer Center as the standard of care. Results: We report on 82 patients with R/R DLBCL that successfully completed an infusion of an anti-CD19 CAR T-cell product at our institution. Best overall and complete response rates were 74.4% (95% CI, 64.9 to 83.8) and 67.1% (95% CI, 56.9 to 77.2), respectively. From the time of CAR T-cell infusion, median PFS was 26.5 months (95% CI, 8.6 months could not be estimated) and OS was not reached. Subgroup analyses revealed no statistical differences in outcomes by use of bridging therapy, Karnofsky performance status, transformed DLBCL status, and the type of CAR T-cell product used for this study. CAR T-cell therapy was well tolerated, with 58 patients (70.7%) experiencing cytokine-release syndrome and 17 patients (20.7%) experiencing immune effector cell-associated neurotoxicity syndrome. Conclusions: These results of RWOs in third-line patients with R/R DLBCL receiving anti-CD19 CAR T-cell therapy are comparable or superior to prior clinical trials and studies of RWOs, validating the strong efficacy and manageable toxicities of CAR T-cell therapy.

Disease progression is a substantial challenge in patients with non-Hodgkin lymphoma (NHL) undergoing chimeric antigen receptor T cell (CAR-T) therapy. Here we present InflaMix (INFLAmmation MIXture Model), an unsupervised quantitative model integrating 14 pre-CAR-T infusion laboratory and cytokine measures capturing inflammation and end-organ function. Developed using a cohort of 149 patients with NHL, InflaMix revealed an inflammatory signature associated with a high risk of CAR-T treatment failure, including increased hazard of death or relapse (hazard ratio, 2.98; 95% confidence interval, 1.60–4.91; P  < 0.001). Three independent cohorts comprising 688 patients with NHL from diverse treatment centers were used to validate our approach. InflaMix consistently and reproducibly identified patients with a higher likelihood of disease relapse and mortality, and it provided supplementary predictive value beyond established prognostic markers, including tumor burden. Moreover, InflaMix exhibited robust performance in cases with missing data, maintaining accuracy when considering only six readily available laboratory measures. These findings show that InflaMix is a valuable tool for point-of-care clinical decision-making in patients with NHL undergoing CAR-T therapy. A preinfusion circulatory inflammation biomarker-based signature predicts the likelihood of treatment failure in patients with non-Hodgkin lymphoma who were treated with CAR-T cell therapy, with an inflammatory cluster assignment being prognostic of clinical response and survival outcomes.

Background: Disease relapse is a primary cause of treatment failure after hematopoietic stem cell transplantation in the treatment of malignancy. Consolidation therapy early after transplantation may reduce this risk, but it is difficult to administer in the setting of various post-transplant complications. We proposed that testing donor cell chimerism and for persistent minimal residual disease (MRD) with next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA) early after transplantation would identify those patients at higher risk of relapse who would possibly benefit from consolidation therapy. Methods: We enrolled 20 subjects with known tumor-associated somatic mutations into this prospective pilot study, testing plasma samples before and at 28, 56, and 84 days after transplantation. Pre- and post-transplant bone marrow samples were also analyzed. All samples were subjected to an agnostic, commercially available panel covering 302 genes. Results: Significantly more mutations (p < 0.0001) were detected in the plasma cfDNA than in the bone marrow cells in pre-transplant testing (92 versus 61 mutations, respectively), most likely reflecting sampling variation when bone marrow was used. Two subjects were negative for MRD in staging studies immediately before transplants. Most (19/20) subjects had intermittent or sustained MRD detected in post-transplant plasma cfDNA testing, albeit with much lower average variant allele frequencies (VAFs). Six out of 20 subjects suffered relapses within 12 months after transplantation, and all 6 could be identified by adverse-risk driver mutations that persisted after transplantation. No patients who cleared the adverse-risk mutations relapsed. Donor chimerism using cfDNA fell for all relapsed patients and contributed to the identification of patients at early risk for relapse. Conclusions: These data demonstrate that testing plasma cfDNA for persistent leukemia-associated somatic mutations and donor chimerism as early as 28 days after transplantation will identify a subset of patients with high-risk mutations who are at high risk of relapse. This early assessment of relapse risk may facilitate modifications to the treatment plan, reducing the risk of treatment failure.

Acute graft-versus-host disease (aGvHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). We performed RNA analysis of 1408 candidate genes in bone marrow samples obtained from 167 patients undergoing HSCT. RNA expression data were used in a machine learning algorithm to predict the presence or absence of aGvHD using either random forest or extreme gradient boosting algorithms. Patients were randomly divided into training (2/3 of patients) and validation (1/3 of patients) sets. Using post-HSCT RNA data, the machine learning algorithm selected 92 genes for predicting aGvHD that appear to play a role in PI3/AKT, MAPK, and FOXO signaling, as well as microRNA. The algorithm selected 20 genes for predicting survival included genes involved in MAPK and chemokine signaling. Using pre-HSCT RNA data, the machine learning algorithm selected 400 genes and 700 genes predicting aGvHD and overall survival, but candidate signaling pathways could not be specified in this analysis. These data show that NGS analyses of RNA expression using machine learning algorithms may be useful biomarkers of aGvHD and overall survival for patients undergoing HSCT, allowing for the identification of major signaling pathways associated with HSCT outcomes and helping to dissect the complex steps involved in the development of aGvHD. The analysis of pre-HSCT bone marrow samples may lead to pre-HSCT interventions including choice of remission induction regimens and modifications in patient health before HSCT.

Background/Objectives: Allogeneic hematopoietic stem cell transplantation (alloSCT) is a curative treatment for myeloid diseases, yet relapse remains the major cause of post-transplant mortality. To reduce the risk of recurrence, we evaluated the addition of 400 cGy total body irradiation (TBI) to conditioning with fludarabine-busulfan (Flu/Bu4). Methods: In this prospective study, 46 patients with myeloid diseases were randomized to Flu/Bu4 or Flu/Bu4/TBI conditioning group. The Flu/Bu4 conditioning regimen consisted of fludarabine 40 mg/m2 on days -6 to -3 followed by busulfan 130 mg/m2 on days -6 to -3. Flu/Bu4/TBI conditioning regimen added 400 cGy TBI on day -1 to the FluBu4 regimen. Results: Among 34 acute myeloid leukemia (AML) patients, relapse was numerically lower in those who received Flu/Bu4/TBI (25%) versus Flu/Bu4 (44.4%) at three years (HR = 0.58, 95% CI 0.19 to 1.81, p = 0.35). Flu/Bu4/TBI appeared to increase the risk of non-relapse mortality (NRM) vs. Flu/Bu4 in AML patients at three years (25.0% versus 11.1%; HR = 2.11, 95% CI 0.51 to 8.83, p = 0.65). Overall survival (OS) was similar in AML patients undergoing conditioning with Flu/Bu4 (72.2%) versus Flu/Bu4/TBI (62.5%) at one year (p = 0.4). Conclusions: In conclusion, the addition of 400 cGy TBI to Flu/Bu4 reduced the risk of relapse but did not improve OS as a consequence of higher regimen-related mortality. Clinicaltrials.gov identifier: NCT01366612.

C/EBPε is a critical transcriptional factor for granulocyte differentiation and function. Individuals with germline mutations of C/EBPε fail to develop normal granulocytes and suffer from repeated infections. In order to gain a global view of the transcriptional machinery regulated by C/EBPε, we performed whole-genome ChIP-Seq using mouse bone marrow cells. To complement the C/EBPε DNA binding analyses, RNA-Sequencing was done in parallel using sorted mature and immature granulocytes from WT and C/EBPε KO bone marrow. This approach led to the identification of several direct targets of C/EBPε, which are potential effectors of its role in granulocytic differentiation and function. Interestingly, Trem1 , a gene critical to granulocyte function, was identified as a direct C/EBPε target gene. Trem1 expression overlaps very closely with expression signature of C/EBPε during hematopoietic development. Luciferase reporter and EMSA assays revealed that C/EBPε binds to the regulatory elements of Trem1 and regulates its expression during granulocytic differentiation. In addition, we provide evidence that inflammatory stimuli (LPS) can also control the expression of Trem1 independent of C/EBPε. Overall, this study provides comprehensive profiling of the transcriptional network controlled by C/EBPε during granulopoiesis and identifies Trem1 as one of its downstream effectors involved in eliciting an immune response.

BackgroundEngineered T cell therapies such as CAR-T cell therapies have transformed the treatment of B-cell but not non-B cell hematologic malignancies. Allogeneic hematopoietic cell transplantation (HCT) remains the best curative option for hematologic malignancies but ~40% of patients relapse post-HCT with up to 90% mortality due to residual disease post-HCT. A key challenge in non-B cell malignancies is identifying the right antigens for T cell targeting. Cancer-associated antigens are heterogenous, enabling rapid escape of malignant cells with low antigens, while targeting lineage-specific antigens without distinct expression in malignant versus normal myeloid cells can cause prolonged neutropenia.A potential solution is targeting minor histocompatibility antigens (MiHAs) that are homogenously expressed on all hematopoietic cells and are genetically mismatched between donors and patients undergoing HCT. These mismatches enable T cells to selectively eliminate residual patient hematopoietic cells, normal or malignant, leaving donor cells untouched. TScan has developed allogeneic donor derived T-cell products TSC-100 and TSC-101, targeting MiHAs HA-1 and HA-2 respectively, both presented on HLA-A*02:01. By choosing HCT patients who are HLA-A*02:01 positive (>98% of whom are either HA-1 or HA-2 positive) and donors who are either HLA-A*02:01 or MiHA negative, TSC-100 or TSC-101 can potentially eliminate all residual patient-derived hematopoietic cells after HCT, sparing donor cells, to prevent disease relapse.MethodsStudy NCT05473910 is a multi-center, multi-arm, non-randomized controlled Phase 1 umbrella study evaluating the feasibility, safety and preliminary efficacy of TSC-100 and TSC-101. Inclusion criteria (figure 1) include adults with AML, MDS or ALL eligible for reduced intensity conditioning-based haploidentical donor transplantation from HLA or MiHA mismatched donors. HLA-A*02:01-positive patients undergo HA-1/HA-2 testing and are assigned to either TSC-100 or TSC-101 treatment arms in addition to HCT. HLA-A*02:01-negative patients in the control arm receive HCT alone. Upon count recovery after HCT, patients in treatment arms receive either TSC-100 or TSC-101, administered as single or two doses. Primary endpoints include adverse event profiles and dose limiting toxicities. Secondary endpoints include relapse rates, disease-free survival and overall survival. Exploratory endpoints include surrogates of efficacy such as minimal residual disease (MRD) rates and donor chimerism rates and kinetics. MRD is measured before and after HCT using flow cytometry, NGS and ddPCR. Donor chimerism is measured by standard STR-based and novel high-sensitivity NGS-based assays to quantify residual patient-derived hematopoietic cells. Together, these assays measure elimination of residual patient hematopoietic cells, malignant or normal, and could provide early evidence of biological activity.Trial RegistrationNCT05473910Ethics ApprovalThe study obtained ethics approval from WCG-IRB (20220488). Participants will give/have given informed consent before taking part.Abstract 682 Figure 1

C/EBPε is a critical transcriptional factor for granulocyte differentiation and function. Individuals with germline mutations of C/EBPε fail to develop normal granulocytes and suffer from repeated infections. In order to gain a global view of the transcriptional machinery regulated by C/EBPε, we performed whole-genome ChIP-Seq using mouse bone marrow cells. To complement the C/EBPε DNA binding analyses, RNA-Sequencing was done in parallel using sorted mature and immature granulocytes from WT and C/EBPε KO bone marrow. This approach led to the identification of several direct targets of C/EBPε, which are potential effectors of its role in granulocytic differentiation and function. Interestingly, Trem1, a gene critical to granulocyte function, was identified as a direct C/EBPε target gene. Trem1 expression overlaps very closely with expression signature of C/EBPε during hematopoietic development. Luciferase reporter and EMSA assays revealed that C/EBPε binds to the regulatory elements of Trem1 and regulates its expression during granulocytic differentiation. In addition, we provide evidence that inflammatory stimuli (LPS) can also control the expression of Trem1 independent of C/EBPε. Overall, this study provides comprehensive profiling of the transcriptional network controlled by C/EBPε during granulopoiesis and identifies Trem1 as one of its downstream effectors involved in eliciting an immune response.

This study aimed to compare and evaluate the efficacy of the blood pressure (BP) control and cholesterol‐lowering effects and safety of combination therapy with telmisartan, rosuvastatin, and ezetimibe versus rosuvastatin and ezetimibe double therapy or telmisartan single therapy in dyslipidemia patients with hypertension. After a wash‐out/therapeutic lifestyle change period of ≥4 weeks, a total of 100 eligible patients were randomized and received one of three treatments for 8 weeks: (1) telmisartan 80 mg/rosuvastatin 20 mg/ezetimibe 10 mg (TRE), (2) rosuvastatin 20 mg/ezetimibe 10 mg (RE), or (3) telmisartan 80 mg (T). The primary endpoint was the efficacy evaluation of TRE by comparing changes in mean sitting systolic blood pressure (msSBP) and mean percentage change in low‐density lipoprotein‐C (LDL‐C) from baseline after 8 weeks of treatment. The least square (LS) mean (SE) changes in msSBP at 8 weeks compared with baseline were −23.02 (3.04) versus −7.18 (3.09) mmHg in the TRE and RE groups, respectively (p < .0001), and −25.80 (2.74) versus −14.92 (2.65) mmHg in the TRE and T groups, respectively (p = .0005). The percentage changes in the mean (SD) LDL‐C at 8 weeks compared with baseline were −54.97% (3.49%) versus −0.17% (3.23%) in the TRE and T groups, respectively (p < .0001). No serious adverse events occurred, and no statistically significant differences in the incidence of overall AEs and adverse drug reactions occurred among the three groups. TRE therapy significantly decreased msSBP and LDL‐C compared to RE or T therapy with comparable safety and tolerability profiles.

Late-life depression (LLD) may increase the risk of Alzheimer’s dementia (AD). While amyloidopathy accelerates AD progression, its role in such patients has not yet been elucidated. We hypothesized that cerebral amyloidopathy distinctly affects the alteration of brain network topology and may be associated with distinct cognitive symptoms. We recruited 26 and 27 depressed mild cognitive impairment (MCI) patients with (LLD-MCI-A(+)) and without amyloid accumulation (LLD-MCI-A(−)), respectively, and 21 normal controls. We extracted structural brain networks using their diffusion-weighted images. We aimed to compare the distinct network deterioration in LLD-MCI with and without amyloid accumulation and the relationship with their distinct cognitive decline. Thus, we performed a group comparison of the network topological measures and investigated any correlations with neurocognitive testing scores. Topological features of brain networks were different according to the presence of amyloid accumulation. Disrupted network connectivity was highly associated with impaired recall and recognition in LLD-MCI-A(+) patients. Inattention and dysexecutive function were more influenced by the altered networks involved in fronto-limbic circuitry dysfunction in LLD-MCI-A(−) patients. Our results show that alterations in brain network topology may reflect different cognitive dysfunction depending on amyloid accumulation in depressed older adults with MCI.