A multi-center analysis of the impact of DA-EPOCH-R dose-adjustment on clinical outcomes of patients with double/triple-hit lymphoma.

Patients with double- and triple-hit lymphomas (DHL/THL) have inferior outcomes with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and higher-intensity regimens such as dose-adjusted (DA)-EPOCH-R are standard. Dose-intensification of DA-EPOCH-R is guided by hematologic toxicity, without conclusive benefit for DHL/THL patients. To determine if cumulative doses of DA-EPOCH-R or compliance with dose adjustment impacts survival, we retrospectively evaluated detailed clinical data from 109 adult (age ≥18 years) patients with DHL/THL treated with ≥4 cycles of induction DA-EPOCH-R from 2014 to 2019 at six centers. A comprehensive multivariate analysis was performed. Survival outcomes for the entire cohort were comparable to historical estimates for DHL/THL treated with this regimen (median follow-up 27.9 months). Overall survival (OS) and progression-free survival (PFS) were not significantly associated with cumulative chemotherapy dose, dose escalation, or compliance with dose adjustment. Heterogeneous dosing practices were observed. Prospective investigation is warranted to evaluate the practice of dose adjustment of R-EPOCH for patients with DHL/THL.

Outcomes of Tisagenlecleucel in Lymphoma Patients With Predominant Management in an Ambulatory Setting.

INTRODUCTION: Chimeric antigen receptor T-cell therapy (CAR T) is a revolutionary adoptive immunotherapy approach in lymphoma; however, substantial resources are necessary for administration and care of these patients. Our institution has administered tisagenlecleucel primarily in an outpatient setting, and here we report our clinical outcomes. PATIENTS AND METHODS: We conducted a single institution, retrospective study investigating outcomes of adult lymphoma patients treated with commercial tisagenlecleucel between 10/2017 and 12/2020. We analyzed patient characteristics and outcomes of efficacy and safety including overall response rate, progression-free survival, overall survival and cytokine-release syndrome, neurotoxicity, and hospitalizations. RESULTS: Seventy-two patients with relapsed or refractory non-Hodgkin lymphoma (NHL) who received commercial tisagenlecleucel were identified; 68 (94.4%) patients received outpatient tisagenlecleucel. The overall response rate was 43% with a complete response observed in 25 patients (34.7%). At a median follow-up of 9.1 months, the median progression-free survival was 3.3 months. Grade 3-4 cytokine release syndrome was not observed in the study group and two patients had grade 3-4 neurotoxicity. Twenty-six patients (36.1%) were admitted within 30 days after infusion with a median length of stay of 5 days. Fourteen patients (19.4%) were admitted within 72 hours of infusion. No patient died of CAR T cell-related toxicity. CONCLUSION: Our experience affirms treatment with tisagenlecleucel in the outpatient setting is safe and feasible with close supervision and adequate institutional experience. After infusion, adverse events were manageable and the majority of patients did not require hospitalization.

The 100 Most Mentioned Glaucoma Articles Online With Highest Altmetric Attention Scores.

PRCIS: Characteristics of the most mentioned glaucoma articles on the internet were analyzed, allowing a better understanding of the dissemination of glaucoma research to the general public. PURPOSE: The aim was to determine the 100 most mentioned articles on the internet in the field of glaucoma and analyze their characteristics. MATERIALS AND METHODS: We identified the top 100 glaucoma articles with the highest Altmetric Attention Score (AAS), an automatically calculated metric for monitoring social media. Each article was evaluated for several characteristics including year of publication, title, journal name, journal impact factor (IF), article topic, article type, affiliation, and online mentions (news, blog, policy, Twitter, Facebook, etc.). Correlation analysis was conducted for AAS with these characteristics. RESULTS: The selected 100 articles came from 44 journals with more than half (56%) published in ophthalmology-specific journals. There was no significant correlation between IF and number of articles in a specific journal or AAS (P>0.1), but the number of articles in the top 100 was higher for ophthalmology journals with a higher IF (P<0.05). Original study was the most common study type (87%), of which clinical observation study was the most common subgroup (40%). Epidemiology/risk factor and basic science were the most common article topics (each 24%), followed by medical treatment (13%). Article topics regarding medical treatment had a significantly greater AAS than other topics (P<0.05). Of the top 5 articles, more than half (60%) were related to "Lifestyle choice" topics. CONCLUSIONS: There was no association between journal IF and AAS, consistent with previous studies. 90% of journals that had articles in the top 100 had a Twitter page. "Lifestyle choice" activities and other modifiable risk factors attracted significant online attention regarding glaucoma studies, with two of the top three most mentioned articles related to dietary intake. The present study thus provides a better understanding of online engagement with glaucoma research and the dissemination of this research to the general public.

Willingness to Travel for Cellular Therapy: The Influence of Follow-Up Care Location, Oncologist Continuity, and Race.

PURPOSE: Patients weigh competing priorities when deciding whether to travel to a cellular therapy center for treatment. We conducted a choice-based conjoint analysis to determine the relative value they place on clinical factors, oncologist continuity, and travel time under different post-treatment follow-up arrangements. We also evaluated for differences in preferences by sociodemographic factors. METHODS: We administered a survey in which patients with diffuse large B-cell lymphoma selected treatment plans between pairs of hypothetical options that varied in travel time, follow-up arrangement, oncologist continuity, 2-year overall survival, and intensive care unit admission rate. We determined importance weights (which represent attributes' value to participants) using generalized estimating equations. RESULTS: Three hundred and two patients (62%) responded. When all follow-up care was at the center providing treatment, plans requiring longer travel times were less attractive (v 30 minutes, importance weights [95% CI] of -0.54 [-0.80 to -0.27], -0.57 [-0.84 to -0.29], and -0.17 [-0.49 to 0.14] for 60, 90, and 120 minutes). However, the negative impact of travel on treatment plan choice was mitigated by offering shared follow-up (importance weights [95% CI] of 0.63 [0.33 to 0.93], 0.32 [0.08 to 0.57], and 0.26 [0.04 to 0.47] at 60, 90, and 120 minutes). Black participants were less likely to choose plans requiring longer travel, regardless of follow-up arrangement, as indicated by lower value importance weights for longer travel times. CONCLUSION: Reducing travel burden through shared follow-up may increase patients' willingness to travel to receive cellular therapies, but additional measures are required to facilitate equitable access.

Inherited L1 Retrotransposon Insertions Associated With Risk for Schizophrenia and Bipolar Disorder.

Studies of the genetic heritability of schizophrenia and bipolar disorder examining single nucleotide polymorphisms (SNPs) and copy number variations have failed to explain a large portion of the genetic liability, resulting in substantial missing heritability. Long interspersed element 1 (L1) retrotransposons are a type of inherited polymorphic variant that may be associated with risk for schizophrenia and bipolar disorder. We performed REBELseq, a genome wide assay for L1 sequences, on DNA from male and female persons with schizophrenia and controls (n = 63 each) to identify inherited L1 insertions and validated priority insertions. L1 insertions of interest were genotyped in DNA from a replication cohort of persons with schizophrenia, bipolar disorder, and controls (n = 2268 each) to examine differences in carrier frequencies. We identified an inherited L1 insertion in ARHGAP24 and a quadallelic SNP (rs74169643) inside an L1 insertion in SNTG2 that are associated with risk for developing schizophrenia and bipolar disorder (all odds ratios ~1.2). Pathway analysis identified 15 gene ontologies that were differentially affected by L1 burden, including multiple ontologies related to glutamatergic signaling and immune function, which have been previously associated with schizophrenia. These findings provide further evidence supporting the role of inherited repetitive genetic elements in the heritability of psychiatric disorders.

18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Following Chimeric Antigen Receptor T-cell Therapy in Large B-cell Lymphoma.

PURPOSE: 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a well-established imaging modality to assess responses in patients with B-cell neoplasms. However, there is limited information about the utility of FDG PET/CT after chimeric antigen receptor T-cell (CART) therapies for large B-cell lymphomas. In this retrospective analysis, we aimed to evaluate how FDG PET/CT performs in patients receiving commercially available anti-CD19 CART therapies for relapsed/refractory (r/r) large B-cell lymphomas. In addition, we examined the time to repeat scan and the rate of pseudoprogression within this population. Lastly, the rates of radiographic response to CART therapy using FDG PET/CT are reported. PROCEDURES: The pre-treatment and post-treatment scans were analyzed from a selected cohort of 43 patients from a single institution. Patients were stratified by diagnosis of either a first occurrence of diffuse large B-cell lymphoma: de novo diffuse large B-cell lymphoma (DLBCL); or a transformed diffuse large B-cell lymphoma arising from indolent non-Hodgkin lymphoma (t-iNHL). RESULTS: More patients received CART therapy for DLBCL than t-iNHL (65 % vs 35 %). FDG PET/CT had a 99 % sensitivity and 100 % specificity for detecting recurrent disease in this group. The median time to initial response assessment was 86 days (IQR 79-91; full range 24-146) after infusion. There were no biopsy-proven cases of pseudoprogression identified. In this selected group of patients, the overall response rate by Lugano 2014 criteria was 56 %. All patients with a partial response (N = 6) eventually progressed despite additional therapy. CONCLUSIONS: Due to its excellent test characteristics and ability to detect asymptomatic disease, routine surveillance with PET/CT at 3 months after CART infusion is supported by our data. Earlier PET/CT may be of value in select situations as we did not find any cases of pseudoprogression.

Restriction Enzyme Based Enriched L1Hs Sequencing (REBELseq): A Scalable Technique for Detection of Ta Subfamily L1Hs in the Human Genome.

Long interspersed element-1 retrotransposons (LINE-1 or L1) are ∼6 kb mobile DNA elements implicated in the origins of many Mendelian and complex diseases. The actively retrotransposing L1s are mostly limited to the L1 human specific (L1Hs) transcriptional active (Ta) subfamily. In this manuscript, we present REBELseq as a method for the construction of Ta subfamily L1Hs-enriched next-generation sequencing libraries and bioinformatic identification. REBELseq was performed on DNA isolated from NeuN+ neuronal nuclei from postmortem brain samples of 177 individuals and empirically-driven bioinformatic and experimental cutoffs were established. Putative L1Hs insertions passing bioinformatics cutoffs were experimentally validated. REBELseq reliably identified both known and novel Ta subfamily L1Hs insertions distributed throughout the genome. Differences in the proportion of individuals possessing a given reference or non-reference retrotransposon insertion were identified. We conclude that REBELseq is an unbiased, whole genome approach to the amplification and detection of Ta subfamily L1Hs retrotransposons.

Management and outcomes of sinus histiocytosis with massive lymphadenopathy (Rosai Dorfman Disease).

Sinus histiocytosis with massive lymphadenopathy (Rosai Dorfman Disease [RDD]), is a rare, benign but clinically heterogeneous histiocytic disorder. Our aims were to analyze the clinical characteristics of the disease and explore the outcomes of patients with RDD followed at our institution. Between January 2000 and February 2019, there were 15 patients with a pathologically confirmed diagnosis of RDD. Median age at diagnosis was 48 years old (range 26-78). The majority (87%, n = 13) of the patients had extranodal disease. Frontline approaches included surgical intervention/complete excision (n = 5, 33%), rituximab monotherapy (n = 5, 33%), observation (n = 3, 20%), and radiation (n = 2, 13%). Two of the five patients underwent surgical excision and were subsequently treated with rituximab. Of the 7 patients who were given rituximab, 64% remained progression free 24 months after the initial rituximab administration. Our review parallels previous reports and highlights rituximab as a favorable option for therapy if ineligible for surgery or radiation.

Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use.

INTRODUCTION: Venetoclax is a highly effective agent in chronic lymphocytic leukemia and acute myeloid leukemia. Phase I/II clinical trials have shown it to be safe and effective in non-Hodgkin lymphoma (NHL). Adverse events were consistent with package labeling despite escalation to high doses. To the best of our knowledge, venetoclax use outside the setting of a clinical trial of NHL has not been reported. PATIENTS AND METHODS: We conducted a single-center, retrospective study of 34 adult patients who had been treated off-label with venetoclax-containing regimens from 2016 to 2018. RESULTS: Of the 34 patients with NHL treated with venetoclax therapy, 13 had had high-grade B-cell lymphoma/diffuse large B-cell lymphoma, 10 mantle cell lymphoma, 5 transformed follicular lymphoma, 2 Richter transformation, 2 marginal zone lymphoma, 1 follicular lymphoma, and 1 post-transplant lymphoproliferative disorder. The patients had received a median of 4 previous therapies. The overall response rate was 26% (3% with a complete response and 35% with stable disease). The median venetoclax dose achieved was 400 mg. Of those receiving combination therapy, 18% had undergone radiation and 62% had received other systemic antineoplastic therapy. The median progression-free and overall survival for the cohort was 2 and 4.5 months, respectively. Adverse events occurred in 76% of the patients during venetoclax therapy. The adverse events included neutropenia, thrombocytopenia, tumor lysis syndrome, infection, neutropenic fever, diarrhea, and 1 opportunistic infection. CONCLUSION: Venetoclax therapy in a real-world cohort offered modest benefits in heavily pretreated patients. Adverse events were observed at a greater incidence than in the clinical trials. A wide heterogeneity of venetoclax dose escalation, multiagent combinations, and timing of initiation were identified and require investigation in subsequent clinical trials.