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Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study. In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment. From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25–84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3–8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome. This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach. National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association. [ABSTRACT FROM AUTHOR]

This article examines the use of axicabtagene ciloleucel (axi-cel), a CAR T-cell therapy, as a second-line treatment for large B-cell lymphoma (LBCL) in a real-world setting. The study analyzes data from patients who received axi-cel at a single center and evaluates various outcomes such as survival rates, response rates, and side effects. The results indicate that axi-cel is effective and well-tolerated, providing valuable insights for its use in clinical practice. However, larger studies with longer follow-up are needed to further validate its efficacy and practicality. [Extracted from the article]

We report a case of a 65-year-old female who presented with right-sided headaches, blurring of vision in the right eye, cold-induced epistaxis, and facial numbness in the trigeminal nerve distribution. Laboratory studies revealed a significant number of myeloblasts on peripheral smear with granulated cytoplasm, irregular nuclei, and prominent vacuoles. Magnetic resonance imaging (MRI) of the brain demonstrated a T1-enhancing 1.5 cm right-sided dural-based lesion involving the medial sphenoid wing, cavernous sinus, infratemporal fossa, and sphenoid sinus region. An endoscopic biopsy of the lesion within the sphenoid sinus confirmed the diagnosis of myeloid sarcoma, with myeloblasts comprising 30% of cellularity by flow cytometry. A subsequent bone marrow biopsy revealed a hypercellular marrow with 23% blasts by flow cytometry that demonstrated a similar immunophenotypic pattern to those seen in the sinus mass. Fluorescence in situ hybridization (FISH) testing revealed the balanced translocation t(8;21)(q22;q22.1), consistent with a diagnosis of acute myeloid leukemia with RUNX1-RUNX1T1-balanced translocation by WHO 2016 criteria. Myeloid sarcoma represents a rare extramedullary presentation of acute myeloid leukemia (AML), either alone or in conjunction with blood or bone marrow involvement. This case emphasizes the need for a broad differential diagnosis and an aggressive work-up for any unusual paranasal sinus mass. [ABSTRACT FROM AUTHOR]

Introduction: Although polycythemia vera is rarely seen, absolute polycythemia is seen more frequently and can drastically change imagine interpretation when taken out of context of the patient's chief complaint. Case Report: We report the case of a 21-year-old male without any known medical history who presented as a trauma patient initially diagnosed with acute subarachnoid and subdural hemorrhages. Further examination of the imaging and later serum laboratory findings demonstrated a primary diagnosis of absolute polycythemia, which was an incidental diagnosis that resulted in the patient's care team and disposition being changed. Conclusion: Absolute polycythemia is not uncommon, and its causes vary from congenital and myeloproliferative disorders to chronic obstructive pulmonary disease and sleep apnea. It can cause pseudoenhancement in noncontrast computed tomography (CT) scans because of the increased protein level in the blood, and emergency physicians should consider all differential diagnoses of pseudoenhancement. [ABSTRACT FROM AUTHOR]

Hydroxycarbamide therapy has been associated with significant oscillations in peripheral blood counts from myeloid, lymphoid and erythroid lineages in patients with polycythaemia vera and chronic myeloid leukaemia. We retrospectively evaluated serial blood counts over an 8-year period from 44 adult patients with sickle cell disease receiving hydroxycarbamide. Platelet counts, leucocyte counts, haemoglobin values and reticulocyte counts, apportioned by hydroxycarbamide status, were analysed using a Lomb-Scargle periodogram algorithm. Significant periodicities were present in one or more counts in 38 patients receiving hydroxycarbamide for a mean duration of 4·81 years. Platelet and leucocyte counts oscillated in 56·8% and 52·3% of patients, respectively. These oscillations generally became detectable within days of initiating therapy. During hydroxycarbamide therapy, the predominant periods of oscillation were 27 ± 1 d for platelet counts and 15 ± 1 d for leucocyte counts. Despite an absolute decrease in leucocyte and platelet counts during hydroxycarbamide treatment, the amplitudes between nadirs and zeniths remained similar regardless of exposure. Our observations appear consistent with previously proposed models of cyclic haematopoiesis, and document that hydroxycarbamide-induced oscillations in blood counts are innocuous phenomena not limited to myeloproliferative disorders as described previously. We speculate the known cell cycle inhibitory properties of hydroxycarbamide may accentuate otherwise latent constitutive oscillatory haematopoiesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Bridging therapy (BT) in the form of systemic therapy (ST), radiation therapy (RT), or combined-modality therapy (CMT) is increasingly being utilized prior to chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). Prior institutional experiences with BT, and RT in particular, suggest it does not lead to increased toxicity or compromise outcomes. Further investigation of the optimal use of BT is warranted. In this research, we sought to evaluate the impact of BT in a large institutional cohort of patients who received commercial CAR T-cell therapy for LBCL, specifically examining the effect of BT modality and disease burden on outcomes. Here, we report the long-term outcomes of our CAR T cohort. The patients with limited disease treated with RT had favorable outcomes. Prospective studies are warranted to better characterize the optimal management of patients with relapsed/refractory LBCL who are planning to undergo CAR T-cell therapy to optimize treatment. Background: Bridging therapy (BT) with systemic therapy (ST), radiation therapy (RT), or combined-modality therapy (CMT) is increasingly being utilized prior to chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). We report the long-term outcomes of the patients who received commercial CAR T-cell therapy with or without BT. Methods: The patients with LBCL who underwent infusion of a commercial CD19 CAR T product were eligible. The radiation was stratified as comprehensive or focal. The efficacy outcomes and toxicity were analyzed. Results: In total, 156 patients were included and, of them, 52.5% of the patients received BT. The median progression-free survival (PFS) was 0.65 years in the BT cohort compared to 1.45 years in the non-BT cohort. The median overall survival (OS) was 3.16 years in the BT cohort and was not reached in the non-BT cohort. The patients who received comprehensive radiation (versus focal) had significantly improved PFS and OS, achieving a 1-year PFS of 100% vs. 9.1% and 1-year OS of 100% vs. 45.5%. There was no difference in the severe toxicity between any of the nonbridging or BT cohorts. Conclusions: BT did not appear to compromise outcomes with respect to response rates, disease control, survival, and toxicity. The patients with limited disease treated with RT had favorable outcomes. [ABSTRACT FROM AUTHOR]

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches. [Display omitted] • Tumors and CAR T cell effectors can be simultaneously profiled using cell-free DNA • Alterations in multiple classes of genes influence outcomes after CAR19 therapy • Tumor genotype and phenotype influence CAR19 T cell expansion, and vice versa • A multivariable model incorporating tumor and effector features predicts outcomes Sworder et al. develop and apply a tool to simultaneously profile tumor and effector-mediated determinants of resistance to anti-CD19 CAR T cells using cell-free DNA. The authors profile two independent cohorts of patients with relapsed/refractory large B cell lymphoma and identify genomic alterations, molecular thresholds, and microenvironmental changes associated with resistance. [ABSTRACT FROM AUTHOR]