bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative effectiveness of linvoseltamab versus standard-of-care (SOC) treatment (tx) in real-world patients (pts) in the United States (US) with triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM).
Authors: Kumar Shaji , Weisel Katja C , Ma Qiufei , Hampp Christian , Humblet Olivier , Shokoohi Mostafa , Bonar Nicolle , Spin Paul , Harnett James , Ge Wenzhen , Jalbert Jessica J , Sobel Rachel E , Kroog Glenn Scott , Rodriguez-Lorenc Karen , Jagannath Sundar
Published: June 2024

7561

Background: Pts with TCE RRMM have poor outcomes and a high unmet need, with no established SOC tx. LINKER-MM1 (NCT03761108) is a single-arm, Phase 1/2 study investigating linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody, in pts with RRMM who were previously treated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody, or were triple-class refractory (TCR) to these tx. The aim of this study was to contextualize LINKER-MM1 by comparing outcomes with linvoseltamab vs a real-world (RW) external control arm (ECA). Methods: A RW ECA was derived from 2 US electronic health record databases (COTA, Guardian Research Network) of pts who started a new line of therapy (LOT) after classification as TCE or TCR and met key eligibility criteria for LINKER-MM1. Eligibility was assessed at the initiation of each new LOT, and all eligible LOTs were included in the ECA. Data in Phase 2 pts who received linvoseltamab 200 mg in LINKER-MM1 were included (data cutoff: Sep 8, 2023). Inverse probability of tx weighting (IPTW) was used to reduce imbalances between the RW and LINKER-MM1 cohorts. Key prognostic factors were identified using a systematic review and rank ordered by an international committee of MM experts (Kumar et al., 2023). Outcomes included overall response rate (ORR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). An independent committee of epidemiology and oncology experts reviewed the comparability of the cohorts and endpoint assessments prior to conducting comparative analyses. Results: Comparative analyses were performed in 105 pts in the linvoseltamab cohort and 101 RW pts (137 LOTs). Following IPTW, the distribution of cytogenetic risk, age, TCR status, Eastern Cooperative Oncology Group Performance Status, and platelet count were balanced between the 2 cohorts (absolute standardized mean difference <0.10). After adjustment, pts receiving linvoseltamab had significantly improved ORR, PFS, TTNT, and OS vs the RW ECA (see table). Conclusions: Linvoseltamab significantly improved outcomes vs RW SOC in the US, highlighting its potential as a highly effective tx in pts with TCE RRMM. [Table: see text]
Predicting response of patients with NSCLC to immunotherapy using innate immune fitness (IIF) profiling.
Authors: Lindley Robyn Alice , Hall Nathan E , Mamrot Jared
Published: June 2024

8038

Background: Aberrant activity of AID/APOBEC deaminase enzymes can cause 'off-target' somatic mutations in cancerous cells. Mutations associated with deaminases and other mechanisms can be quantified using metrics relating to motif usage, strand bias, transitions/transversions, codon context, and amino acid changes. Collectively, these metrics form an Innate Immune Fitness (IIF) profile (US Patent 20200370124). The aim of this project was to conduct IIF profiling on a cohort of Non-Small Cell Lung Cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI), and use the IIF profiles to build and evaluate a predictive model. Methods: Whole exome and progression-free survival (PFS) data was obtained from Rizvi et al. 2015, Hellmann et al. 2018, Miao et al. 2018, Fang et al. 2019, Frigola et al. 2021, and Ravi et al. 2023 (n = 515). IIF profiles were generated using CRIS (v5.0.0; GMDx Genomics Ltd). Patients were classified as a ‘Responder’ (PFS > 12 months or Complete Response; n = 148) or ‘Non-Responder’ (PFS ≤ 12 months; n = 367). Machine learning models were generated using the H2O.ai AutoML platform and evaluated using multiple rounds of cross-validation. Patient response predictions were collated for each patient and a consensus ‘IIF Score’ was calculated. Multivariable analysis of IIF Score, TMB (10mut/Mb) and PD-L1 TPS ( < 1%, 1% - 50%, > 50%) was conducted using a Cox proportional-hazards model. Results: The predictive accuracy of IIF Scores was 76% (Sensitivity = 58%; Specificity = 83% , NPV = 83% , PPV = 58%) with a Hazard Ratio (HR) of 0.39 (0.29-0.53; p < 0.001; corrected for TMB and PD-L1). In comparison, the predictive accuracy of TMB was 67% (Sensitivity = 53%; Specificity = 79% , NPV = 79% , PPV = 44%), HR = 0.77 (0.59-1.00; p = 0.049; corrected for IIF Score and PD-L1). ‘PD-L1 > 50%’ accuracy was 53% and HR = 0.64 (0.44-0.94; p = 0.023; corrected for IIF Score and TMB). The Area Under the Curve (AUC) for IIF Score was significantly higher than TMB (0.77 vs 0.70; DeLong test: p < 0.001). Conclusions: IIF Score was the strongest predictor of patient response to ICI. Despite the inherent limitations of combining data from multiple cohorts, IIF Score outperformed TMB and PD-L1 in predictive accuracy, HR and AUC. With a Negative Predictive Value of 83%, these results support the use of IIF Score as a biomarker for identifying ICI Non-Responders in NSCLC patients. Research Sponsor: GMDx Genomics Ltd.
Signatures of early plasticity in the histological transformation of lung cancer.
Authors: Rakhade Swanand , Chen Monica F , Quintanal-Villalonga Alvaro , Sabet Amin , Manoj Parvathy , Chaudhary Ojasvi , Xu Tianhao , Masilionis Ignas , Falcon Christina J. , Egger Jacklynn V. , Nawy Tal , Mazutis Linas , Chaligne Ronan , Yu Helena Alexandra , Pe'er Dana , Rudin Charles M. , Chan Joseph Minhow
Published: June 2024

8042

Background: Tumor plasticity, especially histological transformation, is an emergent mechanism of therapeutic resistance. Lung adenocarcinoma (LUAD) can transform to small cell lung cancer (SCLC), a more aggressive tumor type of neuroendocrine (NE) histology, leading to EGFR inhibitor resistance and a more aggressive disease phenotype. TP53 and RB1 loss are enriched but insufficient for NE transformation, and it remains unknown what additional molecular changes underlie plasticity. We use single-cell RNA sequencing (scRNA-seq) to profile the intratumoral transcriptional heterogeneity of NE transformation across multiple time points. Methods: We performed 10X scRNA-seq in patient samples to create an atlas of NE plasticity (47 transformed and admixed LUAD-SCLC, 10 EGFR/RB1/TP53 mut LUAD, 17 de novo SCLC, 4 normal lung). Our pipeline performed ambient RNA removal, outlier filtering, normalization, and batch correction. Tumor cells from transformed and admixed LUAD-SCLC tumors were divided into the LUAD compartment prior to transformation (pre-transformed LUAD) and the transformed SCLC compartment based on acquisition of NE marker expression. We performed copy-number inference, pseudotime analysis, and estimation of differentiation potential to establish dynamic changes in phenotypic and subclonal architecture across longitudinal timepoints. Results: We captured 12,105 (9%) pre-transformed LUAD cells from transformed and admixed LUAD-SCLC tumors. Canonical squamous cell carcinoma genes (KRT5, KRT6A, TP63, SERPINB4) were found to be enriched in this pre-transformed LUAD compartment. By projecting a force-directed layout of cells from these samples, we modeled the transition between LUAD, LUSC, and SCLC cell types. Genetic pathways promoting angiogenesis, inflammatory signaling, epithelial-to-mesenchymal transition, and RAS/RAF signaling were highly overexpressed during LUAD-LUSC transformation. Furthermore, we show that macrophages from transforming LUAD-LUSC tumors exhibit a pro-fibrotic phenotype. CNV inference revealed distinct subclonal populations in pre-transformed LUAD tumors. Subclones with high CNV burden and high differentiation potential represented early plastic cells whose lineage could be traced to matched longitudinal post-transformation samples. Conclusions: There is remarkable intratumoral heterogeneity within transforming LUAD. Squamous transformation, mediated by early RAS/RAF signaling, may represent a precursor to SCLC transformation. Identifying early hallmarks of plasticity can help stratify patients at high risk for transformation and reveal therapeutic vulnerabilities.
Nuclear receptor subfamily 4A2: Novel role and a potential therapeutic lead in cancers.
Authors: Kumar Mudasir Ahmad , Basit Aga , Masoodi Tariq , Chaudhary Sanjib , Assad Assif , Bhat Muzafar Rasool , Shah Zubair A. , Al-Shabeeb Akil Ammira S. , Bhat Ajaz Ahmad , Batra Surinder K. , Macha Muzafar Ahmad
Published: June 2024

e18017

Background: Perineural invasion (PNI) is a pathological process where cancer cells infiltrate surrounding nerve tissues, markedly increasing the risk of cancer recurrence, metastasis, post-surgical complications, and associated pain. Alarmingly, PNI is prevalent in 80 - 100% of Head and Neck Squamous Carcinoma (HNSCC) and Pancreatic Ductal Adenocarcinoma (PDAC) cases. In these tumors, nerve invasion often occurs as a distinct route of metastasis, bypassing the usual lymphatic or vascular routes. Despite the rigor of surgical interventions and post-operative radiation, PNI-associated tumors recurrently manifest, emphasizing an urgent need to elucidate the underlying molecular interplay between tumor cells and nerves. Methods: Our study focuses on the Nuclear receptor subfamily 4A2 (NR4A2) transcription factor, known for its pivotal roles in cellular homeostasis and response to pathological conditions. Results: Comprehensive analyses employing tissue microarrays, curated public datasets, and cell lines unveiled a consistent overexpression of NR4A2 in HNSCC and PDAC tumor cells compared to their normal counterparts. Intriguingly, genome-wide chromatin immunoprecipitation (ChIP) sequencing with an NR4A2-specific antibody highlighted an enrichment of genes linked to neuronal guidance, suggesting a probable NR4A2-mediated mechanism underpinning PNI. Further, an in-depth analysis of these ChIP-enriched neuronal genes using The Cancer Genome Atlas (TCGA) confirmed their heightened expression in HNSCC and PDAC tumor tissues relative to healthy tissues. Advancing our research with graph neural networks and sophisticated bioinformatics, we identified two potent lead compounds targeting NR4A2. Preliminary Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) assessments of these compounds indicate favorable safety and efficacy profiles for clinical application. We are currently conducting comprehensive evaluations of these compounds, deciphering their molecular mode of action and therapeutic potential in cell culture and animal models. Conclusions: To sum up, our findings reveal a yet unknown role of NR4A2 in the landscape of PNI in HNSCC and PDAC. The AI-driven discovery and ensuing validation of NR4A2-centric inhibitors present a novel therapeutic avenue to curb cancer progression, prevent metastasis, and potentially improve patient outcomes.
Clinical utility of circulating tumor tissue-modified viral HPV DNA testing in HPV-driven oropharyngeal cancer arising in women.
Authors: Russial Olga , Raben Adam , Shah Sophia , Kegelman Timothy
Published: June 2024

e18032

Background: HPV+OPSCC is rare in womenand may indicate a different biology. The purpose of this study was to evaluate the clinical utility of circulating tumor tissue modified viral (TTMV)-HPV DNA testing in women with HPV+ OPSCC, and to compare the results to our male cohort. Methods: A total of 88 TTMV-HPV DNA tests were collected on 23 women with OPSCC, treated with curative intent. 87% pts (20/23) had pre-treatment TTMV testing. Initial HPV status was assessed by p16 marker IHC and then by TTMV-HPV DNA assay. There were 22/23 pts with p16+ by IHC. One pt with p16- IHC had a positive pre-Tx TTMV score of 185. Post treatment TTMV testing was performed at 3-month intervals. The pre-Tx TTMV median score was 1047 normalized frags/ml. (range: 7-16909). Median number of surveillances TTMV tests were 2.5 (range 1-7). Test results were correlated with imaging to assess clinical utility. Results: 23 women were included. Median age 65.9 (Range: 49-79). Median follow-up was 25.6 months (Range 1.4-52.7). There were 20 pre-treatment tests, 19/20 pts were p16+ IHC. 14 TTMV tests were true positive, with a per-test and per-patient sensitivity of 76.5% (95% CI: 56.3 – 96.6%). For p16+ males, the per-test sensitivity was 54/59, 91.5%, (95% CI: 84.4 – 98.6%) and the per-pt sensitivity is 50/55, 90.9% (95% CI: 83.8 – 98.5%). Fisher’s exact test was used to determine if there is a relationship between biological sex and pre-treatment sensitivity. The per-test p-value was 0.0575, and the per-pt p-value was 0.1119. 5 pts with p16+ IHC had negative baseline TTMV tests, one of which had TTMV-HPV16 DNA subsequently confirmed by FFPE. Clinical staging included T1-T2 (N=19; 82.6%), T3-T4 (N=4, 17.4%), N0-N1 (65.2%: N0=3, N1=12), N2-N3 (34.8%: N2=7, N3=1). There was no correlation between pre-treatment TTMV score and T stage. There was a significant difference in pre-treatment score for pts with N0 vs N+ (Mann-Whitney U test, p = 0.0392). However, the N0 group only had 3 tests, compared to 15 tests in the N1/N2/N3 group. The median score of the N0 group was 7 and the median score of the N1/N2/N3 group was 371. All TTMV tests resolved to zero after treatment completion. 9/14 (64.3%) TTMV scores resolved within 3 months after treatment completion. These pts had post treatment imaging and clinical examination without evidence of disease. We have not observed to date any rise in TTMV-HPV ctDNA in this cohort. Conclusions: This is the first single institutional report evaluating the clinical utility of TTMV-HPV DNA in a female cohort treated for HPV+ OPSCC. Utilization of this testing in a female population appears feasible in a community-based hospital setting. All pts had TTMV resolution after treatment and remained undetectable without recurrence. Despite the apparent trend toward lower sensitivity in females, the difference was not statistically significant and warrant further investigation in a larger multi-institutional study.
Immunotherapy for local/regional control of locally advanced orbital and periocular squamous cell carcinoma.
Authors: Esmaeli Bita , Fan Janet , Goldberg Hila , Lu Tracy , Akhave Neal , Guimaraes de Sousa Luana , Ferrarotto Renata
Published: June 2024

e18034

Background: Periocular squamous cell carcinoma can be of eyelid skin, ocular surface (bulbar) or palpebral conjunctival, or of lacrimal sac/nasolacrimal duct mucosal origin, is relatively rare, and presents unique anatomic considerations due to proximity to the eye and inherent risk to ocular structures associated with high dose radiation therapy. We herein report on 17 patients with orbital or periocular SCC who were treated with immunotherapy (IO) to decrease surgical morbidity or to avoid high dose radiation therapy. Methods: Retrospective review of all previously unreported patients with orbital, conjunctival, or periocular SCC who were treated with IO either in the neoadjuvant setting prior to surgery or for treatment of periocular SCC with perineural spread into the orbit and skull base. Results: 17 patients, 12 men and 5 women (Age range: 44-92; median=70 years old) with orbital (n=6), conjunctival (n=5), or lacrimal sac/duct (n=2) squamous cell carcinoma (SCC), or periocular SCC with perineural spread into the orbit and skull base (n=4) who were treated with IO either as single drug (n= 11) or in combination with chemotherapy (n= 6 ). In all patients either cemiplimab or pembolizumab was used. In 13 patients IO was used in the neoadjuvant setting prior to planned surgery. In 4 patients with perineural spread as they had non surgically resectable disease, IO was used to avoid high dose radiation therapy with its inherent significant risk of ocular toxicity. Overall, 3 patients achieved complete response, 10 patients achieved partial response, and 4 patients had stable disease, using RECIST criteria. One of 5 patients with conjunctival SCC also had nodal metastasis at presentation and achieved a dramatic complete response of both the conjunctival tumor and the nodal metastasis and managed to avoid surgery altogether. This patient had a very high tumor mutation burden (TMB). One patient developed diabetic ketoacidosis as a side effect of IO; otherwise the adverse effects were low grade. Conclusions: IO either as single drug or in combination with chemotherapy has a fairly high response rate in patients with ocular adnexal, conjunctival or orbital SCC and in patients with periocular SCC with perineural spread in the orbit and skull base. Future prospective trails using IO for orbital and ocular adnexal SCC should be planned and should aim to correlate molecular data such as TMB with response.
Differential sensitivities of primary tumor and lymph nodes to induction chemotherapy and definitive radiotherapy in nasopharyngeal carcinoma.
Authors: Wang Juan , Cheng Yanshuang , Sun Ji , Zhong Yahua , Wu Qiuji
Published: June 2024

e18037

Background: Risk factors associated with differential sensitivities of primary tumors and lymph nodes to induction chemotherapy and their impact on clinical outcome in nasopharyngeal carcinoma (NPC) patients are undetermined. Methods: During June 2017 to June 2022, 105 NPC patients treated with comprehensive induction chemotherapy and concurrent chemoradiotherapy in our institute were eligible for analysis. Logistic regression analysis was used to identify factors associated with differential sensitivities of primary tumors and lymph nodes to induction chemotherapy (IC). Correlation and regression analysis were used to investigate whether there was a linear relationship between the sensitivity to induction chemotherapy and the efficacy of chemoradiotherapy. COX regression models were used to find prognostic factors, and Kaplan-Meier survival analysis was used to compare prognostic differences among groups with different induction chemotherapy sensitivities. Results: The median patient follow-up time was 26.0 (95%CI: 23.0-34.0) months. Grouped according to the response of the tumor primary site and lymph nodes to induction chemotherapy, we identified potential risk factors associated with different response patterns: primary tumor non-responsive and lymph node non-responsive, performance status (PS) score (OR: 3.824, 95% CI: 1.005-14.558, p = 0.030) ; primary tumor non-responsive but lymph node responsive, hemoglobin level (OR: 1.033, 95% CI: 1-1.067, p = 0.039) ; primary tumor responsive but lymph node non-responsive, N stage (OR: 2.297, 95% CI: 0.103-0.857, p = 0.014), white blood cell count (OR: 1.32, 95% CI: 1.025-1.699, p = 0.030); lymphocyte count (OR: 3.499, 95% CI: 1.196-10.241, p = 0.018) and blood urea nitrogen (OR: 1.416, 95% CI: 1.055-1.901, p = 0.021); primary tumor responsive and lymph node responsive, N stage (OR: 2.02, 95% CI: 1.044-3.907, p = 0.033), red blood cell count (OR: 0.369, 95% CI: 0.157-0.865, p=0.018) and lymphocyte count (OR: 0.359, 95% CI: 0.151-0.856, p = 0.015). Tumor response 6 months after chemoradiotherapy was significantly associated with tumor response after induction chemotherapy (p = 0.037). Similarly, lymph node response 3 months after chemoradiotherapy was significantly associated with lymph node response after induction chemotherapy (p = 0.043). White blood cell count (HR: 1.327, 95% CI: 1.035-1.701, p = 0.026) and neutrophil count (HR: 1.405, 95% CI: 1.049-1.882, p = 0.022) was risk factors associated with progression free survival. Conclusions: In this study, we identified PS score and hemoglobin as potential factors associated with differential sensitivities of primary tumors and lymph nodes to induction chemotherapy in NPC. However, our study found the efficacy of induction chemotherapy could predict the efficacy of chemoradiotherapy or progression free survival.
Health disparities in acute myeloid leukemia: A decade-long analysis of Afro-Caribbean patients in a safety net New York City hospital.
Authors: Thida Aye Mon , Erdinc Burak , Homsy Sylvester , Jafri Firas Muhammad , Chiu Edwin , Gonsky Jason Parker
Published: June 2024

e18515

Background: Acute Myeloid Leukemia (AML) in the Afro-Caribbean population is associated with poor outcomes due to disparities in health insurance and access to healthcare resources, among other factors, when compared to survival data in the national SEER database. This study reviews clinical characteristics and treatment outcomes of a cohort of 51 Afro-Caribbean patients who were diagnosed with AML and treated in the past 10 years in a urban safety net hospital in Brooklyn, New York. Methods: This is a retrospective review of patients diagnosed and treated for AML at New York City Health and Hospitals/Kings County from 2012 to 2022. Electronic Health Data was reviewed for clinicopathologic data and treatment outcomes. Analysis was performed through descriptive statistics with specific focus on insurance status and survival outcomes. Results: Our AML patient cohort had a mean age of 66, with 84% of patients identifying as Afro-Caribbean, and 51% being female. In this cohort, the AML risk stratification distribution based on 2022 European LeukemiaNet Risk classification includes 21 (41%) patients in the adverse-risk group, 23 (45%) patients in the intermediate-risk group, and 7 (14%) patients in the favorable-risk group. Of the 36 patients with molecular analysis data, 9 (25%) harbored a mutation in FLT3-ITD. Healthcare disparities are evident in insurance coverage, as 58% of patients lacked medical insurance, 19% had Medicare/Medicaid, and 23% had private insurance. At the time of this retrospective chart review, 35% of patients lacked any follow-up information, including appointments or status updates regarding their condition, vital status, or engagement with healthcare, possibly due to missed appointments, transfers, mortality, or other reasons. Of the 27 patients who were deemed transplant eligible, three (11%) successfully completed allogeneic bone marrow transplant. Reasons for non-transplantation include lack of a compatible donor, inadequate social support, insurance-related challenges, or patient refusal. Patients who completed induction and consolidation treatment with documented follow-up had a 23% survival rate at the five-year mark, compared to 31.7% overall survival rate reported in SEER data from 2013 to 2019. Conclusions: Our study highlights persistent healthcare disparities in Afro-Caribbean AML patients leading to poor survival outcomes. Despite treatment advancements, challenges related to insurance coverage, social support, follow-up care, and access to restricted, advanced care remain. Addressing these disparities calls for targeted interventions to enhance access and support systems for this vulnerable population.
Risk of new-onset hypertension in patients (pts) with newly diagnosed chronic lymphocytic leukemia (CLL) treated with Bruton tyrosine kinase inhibitors (BTKi): A real-world data study using the Symphony Health Solution database.
Authors: Kou Tzuyung Douglas , Zhou Lili , Zhou Jinzhi , Cohen Aileen , Aldairy Wassim , White William B
Published: June 2024

e19014

Background: BTKis provide an important therapeutic option for pts diagnosed with CLL. Concerns have arisen about a potential association with the risk of cardiovascular events with BTKi. Using the Symphony Health Solutions database, this study describes the risk of new-onset hypertension in CLL pts treated with and without BTKis. Methods: Newly diagnosed CLL pts who started ibrutinib or acalabrutinib and those not treated with an approved BTKi between 2019 and 2022 were included in the analysis. The prevalence of hypertension prior to and risk of new-onset hypertension after treatment initiation were defined by use of antihypertensive medication. Pt demographics and comorbidities were described. Multivariate regression and inverse probability treatment weight based on propensity score were used to account for bias due to differences in pt characteristics between groups. Results: In CLL pts treated with (n=7,114) and without BTKis (n=34,571), demographics and clinical characteristics included age at the index date (mean: 70.2 yrs, BTKi; 69.0 yrs, without BTKi), sex (male: 59.8%, BTKi; 55.7%, without BTKi), and Charlson comorbidity scores (mean: 3.3, BTKi; 3.1, without BTKi). At baseline, the prevalence of hypertension defined by the use of antihypertensive medication was 67.8% with BTKi and 67.6% without BTKi. Among pts without any antihypertensive medication use at baseline, the rates of new-onset hypertension within 1 yr after treatment initiation were greater in pts with BTKis than without BTKis (Table). Conclusions: In this real-world analysis, CLL pts treated with BTKis had a higher burden of comorbidities, and use of antihypertensive medication was common. The risk of new-onset hypertension was higher in pts initiated on BTKis than those on non-BTKi treatments. These data suggest that development of hypertension is an important consideration in the long-term management of CLL pts undergoing BTKi treatment. [Table: see text]
Incidence of any infections and SARS-CoV-2 infections in patients receiving treatment for follicular lymphoma and diffuse large B-cell lymphoma: Real-world evidence from a large US national claims database.
Authors: Omofuma Omonefe O. , Breskin Alexander , Shao Ping , Asubonteng Julius , Archambault Alexi N. , Hampp Christian , Shariff Saleem , Hearnden Claire , Ambati Srikanth R. , Mohamed Hesham
Published: June 2024

e19061

Background: Non-Hodgkin’s lymphoma is a heterogeneous group of conditions, including the indolent subtype follicular lymphoma (FL) and the aggressive subtype diffuse large B-cell lymphoma (DLBCL). Infections associated with NHL are a major concern due to effects of the underlying disease and its treatment and have been reported to increase with increasing lines of therapy (LoT). However, the risk of infections overall and SARS-COV-2 infections specifically is not well characterized in patients who have received multiple LoTs. The goal of the study was to estimate the exposure-adjusted incidence rates (EAIR) of infections during the COVID-19 pandemic by type, severity and LoT received in patients treated for FL or DLBCL in the real-world setting. Methods: We identified patients in the Optum Clinformatics claims data from October 1, 2015, to June 30, 2023. Patients were aged ≥18 years, enrolled continuously for 365 days before index (start of LoT), and had ≥2 ICD-10 diagnosis codes for FL or DLBCL in the 365 days before index. The EAIR (per 100 person-years, PY) was estimated for infections by type (any infections and SARS-COV-2 [after 1/1/2020]), severity (hospitalized or fatal hospitalizations), and number of LoTs received. Results: A total of 4,799, 989 and 249 FL patients were included in the 1L (1 LoT), 2L, and 3L+ cohorts, respectively. The EAIR of infections resulting in hospitalization in 1L, 2L, and 3L+ cohorts were 20.4 (95% confidence interval (CI): 18.9-22.1), 32.5 (27.4-38.5), and 56.7 (44.3-72.5) per 100-PY for any infection; and 9.7 (8.1-11.5), 8.5 (4.4-13.4) and 11.6 (6.2-21.5) per 100-PY for SARS-COV-2 infections, respectively. The EAIR of fatal hospitalizations were 4.1 (3.5-4.8), 9.3 (7.0-12.4), and 14.9 (9.8-22.8) per 100-PY for any infection; and 2.7 (2.0-3.8), 3.1 (1.5-6.5), and 3.1 (1.1-10.5) per 100-PY for SARS-COV-2 infections. A total of 8,058, 2,114 and 682 DLBCL patients were included in 1L, 2L, and 3L+ cohorts, respectively. The EAIR of infections resulting in hospitalization in 1L, 2L, and 3L+ cohorts were 64.2 (60.7-67.8), 85.2 (76.9-94.3), and 113.4 (98.4-130.7) per 100-PY for any infection; and 13.1 (11.4-15.1), 14.4 (10.9-19.0), and 22.8 (16.7-31.0) per 100-PY for SARS-COV-2 infections respectively. The EAIR of fatal hospitalizations were 12.0 (10.8-13.3), 23.0 (19.5-27.1), and 27.8 (22.1-34.9) per 100-PY for any infection; and 3.1 (2.3-4.1), 5.5 (3.5-8.6), and 7.0 (4.1-12.0) per 100-PY for SARS-COV-2 infections in 1L, 2L and 3L+ cohorts, respectively. Conclusions: This real-world analysis demonstrated substantial morbidity and mortality associated with overall and SARS-COV-2 infections among NHL patients, with a higher incidence in DLBCL compared to FL, and with increasing LoTs.
Impact of military deployment on non-Hodgkin lymphoma subtype.
Authors: Sgrignoli Robert , Rendo Matthew , Fenderson Joshua L. , Morris Michael , Kou Chung-ting Jimmy , Aden James , DeStefano Christin
Published: June 2024

e19070

Background: Approximately 3.5 million activity duty service members (ADSM) have deployed to Afghanistan or Iraq from 2001-2022. During deployments, ADSMs are potentially exposed to deployment-related toxins and carcinogens, which could theoretically alter cancer biology. In terms of non-Hodgkin lymphoma (NHL), it is unclear whether deployment affects NHL subtype or cancer-specific survival. Methods: Deployment and occupation data from the Defense Manpower Data Center was merged with data from the Department of Defense Tumor Registry. Documented cases of NHL diagnosed from 2001-2022 were identified. ADSMs and retirees were included; dependents and those under the age of 18 were excluded. Differences in NHL subtype (aggressive B-cell, indolent B-cell, T-cell) and cancer-specific survival were assessed by deployment status (previously deployed vs. never deployed). Occupation was assessed among those who deployed. Propensity score matching (2:1) for age at diagnosis, year of diagnosis, and gender was performed to minimize confounding. All data were carried out using SAS and Jump statistical software. This study was approved by the IRB. Results: There were 2,599 ADSMs and retirees diagnosed with NHL between 2001-2022. Approximately 15% had previously deployed (n=398). Compared with never deployed, military personnel who had previously deployed were more likely to have aggressive B-cell NHL (45% vs. 34%) and less likely to have indolent B-cell NHL (50% vs. 54%) or T-cell NHL (6% vs. 12%), p<0.001. Deployment to Iraq or Afghanistan did not impact NHL subtype. During deployment, occupations of Infantry, Engineering and Healthcare did not impact NHL subtype, whereas occupations of Pilot/Aircrew and Intelligence did, with less T-cell lymphoma diagnosed (0 vs. 7%, and 3% vs. 8%, respectively). When evaluating NHL subtype by race, it was noted that in comparison to White, Asian, Pacific Islander and Other Race, Black Race was associated with more T-cell NHL (21%), largely comprised of cutaneous T-cell lymphoma. Conclusions: After propensity score matching, prior deployment was associated with more aggressive B-cell lymphoma than military personnel who had never deployed. Deployment occupation affected NHL subtype diagnosed, with Pilots/Aircrew and Intelligence personnel being less likely to have T-cell lymphoma, whereas Black Race was associated with a higher likelihood of having T-cell lymphoma. This study sheds insights into the impact of deployment on cancer subtype. Ongoing investigations are assessing mortality differences by deployment as well as causes of death.
Survival outcomes in primary cutaneous diffuse large B-cell lymphoma, leg type.
Authors: Baidoun Firas , Hoppe Bradford S. , Tun Han W. , Alhaj Moustafa Muhamad
Published: June 2024

e19074

Background: Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL-LT) is an uncommon type of lymphoma predominantly affects elderly patients and is associated with poor outcome. Large-scale studies describing and evaluating the effect of different type of treatments on survival outcome are lacking. Methods: The National Cancer Database (NCDB) was queried for patients diagnosed with PCDLBCL-LT between 2004 and 2020. All patients aged ≥18 years diagnosed with PCDLBL-LT were included. We excluded patients with unknown chemotherapy and radiation therapy status or lost to follow-up (unknown vital status of last contact). Kaplan-Meier and multivariate Cox regression were used in the analyses. Results: The total cohort consisted of 967 patients with PCDLBCL-LT. Out of whom 516 (53%) were females, 841 (87%) were White non-Hispanic, 41 (4%) were White Hispanic and 37 (4%) were African Americans. 276 (29%) received chemotherapy, 203 (21%) received radiation only, 293 (30%) received chemoradiation, 147 (15%) did not receive any treatment and 48 (5%) had unknown treatment status. The median age at diagnosis was 78 years (range 23-90). The median follow-up time was 87 months (95% CI 74-99), the median overall survival (mOS) for the whole cohort was 42 months (95%CI 37-47). Among patients with known treatment status and vital status of last contact (N=841), patient who received chemoradiation had significantly better mOS compared to patients who received chemotherapy only, radiation only and no treatment (64 vs 41, 39 and 9 months, respectively P<0.001). Patient who received chemotherapy only and radiation only as first line therapy had significantly better mOS compared to patients who received no treatment (41 and 39 vs 9 months, respectively P<0.001), but there was no statistically significant difference in the mOS between chemotherapy only and radiation only (41 vs 39 months, P=0.359). On multivariate analysis, older age, male gender, and Charlson-Deyo score 2 and ≥3 were associated with worse OS (HR 1.061 95%CI 1.050-1.072; P<0.001, HR 1.241 95%CI 1.093-1.482; P=0.017, HR 1.396 95%CI 1.004-1.941; P=0.047 and HR 2.454 95%CI 1.619-3.719; P<0.001 respectively), all type of treatments including chemotherapy only, chemoradiation, and radiation only were associated with better OS (HR 0.576 95% CI 0.443-0.749; P<0.001, HR 0.379 95%CI 0.290-0.495; P<0.001 and HR 0.443 95%CI 0.339-0.578; P<0.001, respectively). Conclusions: This large real-world analysis shows a survival benefit with combined treatment of chemoradiation in this uncommon type of lymphoma compared to single treatment modality.
Racial disparities in major adverse cardiovascular and cerebrovascular events in patients with non-Hodgkin lymphoma.
Authors: Raval Maharshi , Uttam Chandani Kanishka , Agrawal Siddharth Pravin , Eldimllawi Ahmed Medhat , Siddiq Sajid , Nadeem Ahmed , Chintakuntlawar Ashish V. , Hashmi Shahrukh K.
Published: June 2024

e19076

Background: Non-Hodgkin Lymphoma (NHL) is the seventh most prevalent cancer and has sixth highest malignancy mortality in United States. Owing to the advances in treatment of NHL including targeted therapies, the survival of NHL patients has increased over the past decades. However, inequalities may exist in the access to advanced care, clinical trials, and subspecialist appointments in certain patient populations. We aim to study the racial disparities in major cardiovascular and cerebrovascular events (MACCE) in NHL patients. Methods: Using ICD-10 codes, patients with NHL were identified from National Inpatient Sample 2019 database. We included all-cause in-hospital mortality (ACIHM), acute myocardial infarction (AMI), atrial fibrillation (AF), cerebrovascular accident (CVA), and sudden cardiac death (SCD) as MACCE for the outcomes. Baseline characteristics including demographics, comorbidities; and MACCE outcomes were studied using chi-square for categorical or ANOVA for continuous data (statistical significance determined as p-value <0.05) and results were stratified based on patient’s races. Results: Out of the total sample size of 205220 patients admitted with a diagnosis of NHL, 74.94% (153785) were White, 8.95% (18370) were Black, 9.46% (19415) were Hispanic, 3.48% (7140) were Asian/Pacific Islander, 0.42% (875) were Native American, while 2.75% (5635) belonged to other races. When compared to White patients, ACIHM was significantly higher in Black patients with adjusted odds ratio (aOR) of 1.294 (95% CI 1.099-1.523, p=0.002) and Asian/Pacific Islander patients (aOR 1.279, 95% CI 1.005-1.628, p=0.045). Risk of AMI was lower in Black patients (aOR 0.751, 95% CI 0.587-0.96, p=0.023) as compared to White patients. AF risk was significantly lower in Black, Hispanic, and Other race patients compared to White patients. The odds of developing CVA are higher in Asian/Pacific Islander patients (aOR 1.285, 95% CI 1.002-1.649, p=0.048) and of having SCD are higher in Black patients (aOR 2.052, 95% CI 1.5-2.806, p<0.001) when compared to White patients. Conclusions: In patients with NHL, Black patients had higher ACIHM and SCD while Asian/Pacific Islander patients had higher ACIHM and CVA when compared to White patients. Although the reason of disparity is likely multifactorial, the findings of this study highlight the need for development of healthcare strategies stratified by race which may aid to mitigate the increased risk of MACCE in certain races. Further research involving possible genetic influences and social determinants of health contributing to poorer outcomes in Black and Asian/Pacific Islander patients with NHL becomes imperative.
Incidence, characteristics and outcomes in relapsed and refractory CD20+ PTLD: An institutional retrospective cohort study.
Authors: El-amir Zain , McLane Michael Joseph , Kaminski Mark S. , Phillips Tycel Jovelle , Wilcox Ryan A. , Sano Dahlia , Karimi Yasmin , Carty Shannon
Published: June 2024

e19078

Background: Post-transplant lymphoproliferative disorder (PTLD) is a malignancy with significant morbidity and mortality after solid organ transplant (SOT). Frontline treatment of CD20+ PTLD is well established; however, there is a lack of data on the treatment of relapsed/refractory (R/R) PTLD, especially in the era of novel therapies approved since 2017 for diffuse large B-cell lymphoma. Methods: We conducted a single institution retrospective study of adult SOT patients with CD20+ PTLD. Inclusion criteria were age ≥18 and use of an adult regimen that included rituximab for frontline therapy. Baseline and pathologic characteristics, frontline and subsequent treatments, response rates, and toxicities were collected. Results: 71 cases of CD20+ PTLD were diagnosed between 01/01/2012 to 12/31/2022. The median age at diagnosis was 46. SOTs included kidney (46.5%), liver (21.1%), lung (16.9%), heart (14.1%), and pancreas (1.4%). Pathologically, 47 cases were monomorphic (12 germinal center B-cell-like [GCB] subtype, 26 non-GCB subtype, 9 cases indeterminate), 12 were polymorphic, 2 were non-destructive, and 10 were unclassified. 38 cases (53.5%) were Epstein-Barr virus positive. Frontline treatments included rituximab followed by R-CHOP (38.0%), rituximab monotherapy (16.9%), R-EPOCH (4.2%), and R-miniCHOP (2.8%). Toxicities included acute kidney injury (21.1%) and perforation (9.8%) and rejection (7%). The median overall survival (OS) was 62 months. 21 (29.6%) patients relapsed (N = 13) or were refractory (N = 8) to frontline treatment. Median time to relapse was 12.0 months. Systemic treatments included RCHOP, R-miniCHOP, RICE, R-Gemcitabine and oxaliplatin (R-GemOx), lenalidomide/tafasitamab (len/tafa), and R-ibrutinib with an overall response rate (ORR) of 72.2% in the second line setting; 50% of patients required dose reductions. Median OS was 17 months. Progression-free survival (PFS) was 4.5 months. The. ORR, median PFS and OS among those who received novel therapy (N=3) was 100%, 4.4 months, and not reached compared to 66.7%, 8 months, and 4.6 months with traditional cytotoxic therapy (N=15), respectively. 6 patients received a third line of therapy, which included polatuzumab-BR, CAR-T cell therapy, R-GemOx, len/tafa, and loncastuximab. ORR was 80%. 33% of patients required dose reductions. At data cutoff, 2 patients who received a third line of therapy were alive with stable disease on therapy. Causes of death in third line treatment included perforation (N=1), COVID (N = 1), fungemia (N=1), and cardiac arrest likely unrelated to PTLD (N = 1). 3 patients who died had active PTLD at time of death. No patients experienced graft rejection during treatment for R/R PTLD. Conclusions: R/R CD20+ PTLD after SOT remains a therapeutic challenge. Better understanding of cytotoxic versus novel therapies can help guide clinical decision making.
CSF proteomics for predicting response to treatment in patients with primary and secondary central nervous system lymphoma.
Authors: Wilding Hannah E. , Aastha Aastha , Mikolajewicz Nicholas , Macedo Filho Leonardo , Bhanja Debarati , Heebner Madison , Khan Shahbaz , Ignatchenko Vladimir , Ozair Ahmad , Ahluwalia Manmeet Singh , Glantz Michael J. , Kislinger Thomas , Mansouri Alireza
Published: June 2024

e19083

Background: Despite exquisite responses to initial therapy in patients with CNS lymphoma (CNSL), relapse is common and overall responses are disappointing compared to other non-CNS diffuse large B-cell lymphomas. Incorporation of multi-agent intraventricular chemotherapy (MAIVC) alongside systemic therapy is a novel strategy. To maximize MAIVC benefit, identification of minimally-invasive biomarkers for guiding patient management is necessary. This study sought to identify cerebrospinal fluid (CSF)-based proteomic predictive biomarkers for MAIVC treatment response at baseline and for longitudinal monitoring of tumor burden in CNSL. Methods: A retrospective study of patients with primary or secondary CNSL that were treated with MAIVC at Penn State Health (2015-2021) was conducted and reported following REMARK guidelines. Each MAIVC cycle was administered via Ommaya reservoir and included a 2-drug combination comprised of methotrexate, rituximab, cytarabine, etoposide, topotecan, gemcitabine, or thiotepa. Patient-matched CSF was sampled at pre- and post-therapeutic endpoints and profiled using shotgun proteomics. Patients were grouped by treatment response status. Early responders were defined as patients achieving malignant-cell-free CSF within 6 MAIVC cycles, whereas never responders were those patients that i) did not achieve malignant-cell-free CSF by endpoint or ii) required salvage surgery or radiation during MAIVC. Results: 59 patients were included (21 primary; 38 secondary CNSL) with a median age of 66 years (range 25-90) and median number of MAIVC cycles of 8 (range 2-23). Only 1 required Ommaya removal secondary to infection. A proteomic-based classifier, comprised of SGCE, LCP1 and AGRN, discriminated between early and never responders with AUROC of 0.95. Comparison of CSF at baseline (<3 cycles MAIVC) vs. post-treatment (>12 cycles MAIVC) identified H3F3A, YWHAE, LCP1, CA1 and GAPDH as tumor burden biomarkers. Conclusions: Here we developed a proteomic signature capable of predicting CNSL patient response to MAIVC, with potential to improve clinical decision making. Furthermore, the biomarkers associated with tumor burden represent important indicators of treatment response. Ongoing efforts are underway to evaluate these candidates in independent validation cohorts.
Efficacy and safety of GPRC5D-based monotherapies for relapsed/refractory multiple myeloma: A systematic review and meta-analysis.
Authors: Shrestha Asis , Adhikari Ayush , Rayamajhi Sandesh , Gouli Sugam , Shrestha Jasmine , Niraula Sujan , Neupane Niraj , Al Hadidi Samer
Published: June 2024

e19503

Background: G protein-coupled receptor family C group 5 member D (GPRC5D), a highly expressed receptor in myeloma cells, is one of the novel emerging targets for relapsed/ refractory (R/R) multiple myeloma (MM). Among the GRPC5D therapies, currently one agent talquetamab has been approved while CAR-T therapies are under development. Methods: A literature search using electronic databases Pubmed, Embase, Scopus, Web of Science and Cochrane, including major conference abstracts was conducted from inception to December 31, 2023 focusing on GPRC5D therapies in MM. For multiple reports of the same study, the latest available report of the study describing the efficacy or safety was selected. Only GPRC5D based monotherapies were included, and combination regimens were excluded for this review. Data on safety and efficacy were extracted, evaluated and systematically analyzed using Comprehensive Meta-analysis 3.3. The study protocol was registered with PROSPERO (CRD42024497933). Results: After screening 562 articles, and removing duplicates, total seven studies with 581 patients were included (5 GPRC5D-CAR T studies with 137 patients and 2 GPRC5D-BsAb studies with 444 patients). The pooled overall response rate (ORR) for GRPC5D therapies in this cohort was 77.4%, with best response rate [very good partial response (VGPR) or better] of 59.2%. The pooled incidence rate of cytokine release syndrome (CRS), any grade and Immune effector cell-associated neurotoxicity syndrome (ICANS), any grade, was 78.8% and 9.6% respectively. Grade 3/4 hematological adverse events included neutropenia being the most common (69.6%), followed by thrombocytopenia (36.8%) and anemia (34.2 %). Subgroup analysis was performed for GPRC5D therapies- CAR T and BsAb as shown in the table. Conclusions: GPRC5D based therapies showed high response rates in R/R MM with distinct side effect profile including CRS and cytopenias. Further studies along with follow up of the ongoing trials is needed to understand the long-term outcomes. [Table: see text]
Risk of gastrointestinal adverse events associated with chimeric antigen receptor T-cell therapy (CAR-T): A nationwide analysis.
Authors: Khan Shahryar , Asif Samia , Khan Mashal Alam , Khan Muhammad Atif , Amin Muhammad Kashif
Published: June 2024

e19505

Background: Chimeric antigen receptor T-cell therapy (CAR-T) has been successfully used and has improved outcomes in the treatment of B-cell hematological malignancies and multiple myeloma. There is evidence that unique serious adverse events like cytokine release syndrome (CRS) and Immune effector cell associated neurotoxicity syndrome (ICANS) are associated with CAR-T. Gastrointestinal adverse events (GI-AE) are commonly observed after CAR-T, although they are not well characterized. In the analysis, we summarized the incidence of gastrointestinal adverse events (GI-AE) and mortality associated with CAR-T with or without CRS. Methods: We conducted a retrospective cohort study using the 2020 Nationwide Inpatient Sample database, which is the largest nationally representative inpatient database in the United States. The dataset is weighted to obtain national estimates, and ICD-10 was utilized to identify admissions for CAR-T. The primary outcome is in-hospital mortality, and secondary outcomes are GI-AE associated with CAR-T with or without CRS and length of stay (LOS). Odds ratio (OR) and Mean difference (MD) were adjusted for confounders like comorbidities and sociodemographics using multivariate regression analysis. Results: There were 32 million weighted discharges in the 2020 NIS database; a total of 1950 cases were identified receiving CAR-T therapy with a mean age of 56.53, male 60.51%, and white race 74.8%. In our study, 40.25% had GI-AE, 15.38% had CRS and 13.8% had ICANS. The most common GI-AE was nausea and vomiting (23.84%). Other GI-AE were diarrhea (9.5%), colitis (8.2%), peptic ulcer disease (2.9%), hepatic failure (1.28%), and pancreatitis (2.2%). 68 (3.85%) patients died after receiving CAR-T. The results revealed that CAR-T with GI-AE was not significantly associated with in-hospital mortality (adjusted OR = 1.12, 95% CI: 0.29-4.24), and LOS (adjusted mean difference = 3.38, 95% CI: -0.91-7.67) compared to CAR-T without GI-AE. Liver failure is significantly associated with the highest mortality after CAR-T (OR = 46.62, 95% CI: 6.9-315). Conclusions: The national survey reveals that predominantly GI-AE are mild including nausea, vomiting, and diarrhea. GI-AE related with CAR-T had similar outcomes including mortality and LOS compared to CAR-T without GI-AE. The risk of mortality becomes higher when CAR-T complicated by hepatic failure. [Table: see text]