bluuebunny/crossref_metadata_2025 huggingface dataset:
Perimarginal lymph node metastasis in gingivo-buccal complex carcinoma: Is it time to push the limits of neck dissection?.
Authors: Mitra Sandipta , Panda Smriti , Kakkar Aanchal , Sikka Kapil , Thakar Alok , Singh Amit Chirom , Kumar Rajeev
Published: June 2024

6069

Background: Perimarginal nodes (PMN) are a group of perifacial lymph nodes that lie in close relationship with marginal mandibular nerve (MMN). They lie in the lymphatic drainage pathway of gingivo-buccal cancers (GBC), above the lower border of mandible which forms the superior limit of conventional neck dissection and thus remain unaddressed. With reported incidence of metastasis as high as 20.5%, we aimed to explore incidence of PMN metastasis in GBC, its correlation with histopathological tumor and nodal characteristics. Methods: A prospective study was conducted on 112 consecutive treatment naïve patients of GB squamous cell carcinoma. Patients with unresectable nodal disease, distant metastasis and prior radiotherapy or surgery to neck were excluded. PMN dissection was performed in the quadrangle bounded superiorly by the mandibular alveolar ridge, inferiorly by lower border of mandible, anteriorly by mental foramen and posteriorly by anterior border of masseter. On histopathological analysis, serial step sectioning and cytokeratin immunohistochemistry were performed. Prospective clinical characteristics analyzed were subsite, clinical tumor, nodal stage, location of primary and clinical skin involvement. PMN positivity was correlated with demographic, clinical, nodal status. Histopathological characteristics analyzed included tumor grade, pathological tumor, nodal stage, tumor size, skin and/or bone involvement, depth of invasion, Brandwein Gensler histological risk score and lympho-vascular emboli. MMN functional outcome was graded according to House-Brackman (HB) grading recorded at 3 and 6 months post-operatively. Results: Baseline characteristics are summarized in the table. The PMN were identified histologically in 75.89% (85/112) patients. Metastasis in these nodes were identified in 15.2% (17/112) patients. Our study revealed an occult PMN metastasis of 16.67% (13/78). None of the pre-operative clinical factors was found to be significant in predicting incidence of metastasis. Higher nodal burden (p=0.01) and pathological skin involvement (p=0.03) had statistically significant odds of having PMN metastasis on multivariable analysis. At 6 months follow-up, none of the patients had any MMN functional deformity at rest. Conclusions: There is a high incidence of occult PMN metastasis from gingivo-buccal complex cancer. High nodal stage and pathological skin involvement are independent adverse prognostic factors for PMN metastasis. The limits of conventional neck dissection should be expanded to include clearance of PMN in all cases of gingivo-buccal cancers. [Table: see text]
Analysis of PD-L1 expression in locally advanced head and neck squamous cell carcinoma and its correlation with the efficacy of neoadjuvant immunotherapy + chemotherapy: A retrospective real-world study.
Authors: Tan Haolei , Huang Wenxiao , Long Ying , Zhang Hailin , Zhong Waisheng , Tan Pingqing , Han Yaqian , Liu Feng , Jiang Cuihong , Li Jinyun , Zhou Yujuan , Wu Zheng
Published: June 2024

6074

Background: The incidence rate of HNSCC in Hunan China are notably higher than in other regions, likely due to the high prevalence of betel nut chewing. Therefore, we conducted a study to examine the PD-L1 expression in newly diagnosed locally advanced (stage III-IVB) HNSCC patients. Methods: 1. We conducted a retrospective analysis of the PD-L1 expression (represented as CPS) in pre-treatment biopsy tissues from locally advanced HNSCC. 2. 57 patients received neoadjuvant treatment consisting of nab-paclitaxel+ cisplatin+ pembrolizumab. The efficacy of the treatment was evaluated using pathology assessments. Results: 1. A total of 373 patients were included. The top five primary sites of the tumors were the tongue(32.17%), Buccal oris (20.91%), oropharynx (10.19%), hypopharynx(9.92%), and gingiva(7.77%). The proportion of patients with PD-L1 CPS≥20 (55.23%) was significantly higher than the 43.20% reported in the KEYNOTE-048 study. Furthermore, the subgroup was even higher in the buccal oris (70.51%) and gingiva (72.41%). 2. A total of 57 patients were tested for PD-L1 CPS and received neoadjuvant treatment.After surgery, 22/57 (38.60%) achieved pathological complete response (pCR) or major pathological response (MPR), 29/57 (50.88%) achieved partial pathological response (pPR), resulting in an overall response rate (ORR) of 89.47%. In the PD-L1 CPS ≥20 group, the ORR was as high as 91.89% (34/37). 3. Among the 57 patients, 36 patients had lymph node metastasis. After treatment, 15/36 patients (41.67%) achieved pCR/MPR in lymph nodes, 7/36 patients (19.44%) achieved pPR, resulting in an ORR was 61.11% (22/36). Conclusions: 1. The oral cavity is the most common primary in HNSCC in Hunan,China. In the locally advanced , the proportion of PD-L1 CPS ≥20 is higher than reported in other studies. 2. Regardless of PD-L1 expression, neoadjuvant treatment with nab-paclitaxel+ cisplatin+ pembrolizumab has shown a high rate of local disease control in newly diagnosed HNSCC patients. Additionally, the use of neoadjuvant therapy has improved the delineation of surgical safety margins, leading to 100% R0 resections in all 57 patients. 3. The response of the primary lesion in patients treated with neoadjuvant therapy is better than that of the lymph node. Patients with a well-responding primary lesion but multiple lymph node metastases should be closely monitored for the possibility of short-term systemic metastasis. [Table: see text]
Clinical validation of a mesenchymal gene expression signature for prognosis and treatment decision making in early-stage oral cavity squamous cell carcinoma.
Authors: Hayes David N. , Mayhew Gregory , Uronis Joshua M. , Zevallos Jose
Published: June 2024

6091

Background: Treatment for human papillomavirus (HPV)-negative oral cavity squamous cell carcinoma (OCSCC) includes surgical resection of the primary tumor, usually with elective or therapeutic neck dissection with adjuvant radiation or chemotherapy and radiation based on risk stratification. While therapeutic advances have been modest at best for over a century, the addition of chemotherapy to radiation has demonstrated benefit for the highest risk patient groups, although recurrence rates remain high for advanced-stage patients. Even more concerning, some early-stage patients demonstrate life-threatening relapses in the absence of biomarker guidance. Using retrospective analysis, our group and others have identified gene expression signatures that reveal molecular subtypes (classical, atypical, basal and mesenchymal) that could identify early-stage patients most likely to recur and are likely candidates for therapy escalation, such as chemotherapy plus radiation. We hypothesize that the mesenchymal (MS) gene expression subtype is associated with worse overall survival (OS) in early-stage, node-negative OCSCC compared to non-mesenchymal subtypes. Herein we present further clinical validation of our previously described 88-gene OCSCC classifier (Mayhew et al, 2022; PMID: 36147910). Methods: As part of a prospectively designed retrospective study, residual tumor samples and paired clinical data, including n-stage and survival, were collected for patients with node-negative OCSCC (IRB# 201706088 at Washington University in St. Louis). Using the NanoString nCounter platform, RNA was isolated and counts were generated according to the manufacturer’s specifications. Gene expression data were used to assign molecular subtypes, and associations with overall survival (OS) were investigated using Kaplan-Meier plots and cox models in patients who were pathologically node negative. Results: A total of n=137 patients had node-negative OCSCC and sufficient tumor quantity to generate molecular subtype results. Consistent with our previous findings, the MS subtype was strongly associated with inferior survival in both univariate (HR = 3.24, p = 0.0019) and multivariable (HR = 3.26, p = 0.0026) analyses, confirming a potential role for gene expression-based subtyping as a biomarker for prognostication and informing clinical treatment decisions. Conclusions: These findings confirm that the MS subtype is associated with significantly worse survival in surgically resected, early-stage OCSCC which typically demonstrate favorable outcomes. Also, these findings strongly suggest value in gene expression subtyping for prognostication and treatment decision-making in OCSCC patients and warrant the further development of the 88-gene classifier as a diagnostic test for this clinically actionable patient population.
Extended follow-up results beyond 2.5 years from the pivotal NHL-1 EPCORE trial: Subcutaneous epcoritamab monotherapy in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL).
Authors: Karimi Yasmin , Thieblemont Catherine , Ghesquieres Hervé , Cheah Chan Y , Clausen Michael Roost , Cunningham David , Jurczak Wojciech , Linton Kim M. , Hutchings Martin , Phillips Tycel Jovelle , Farooq Umar , Kim Won Seog , Dinh Minh H , Ghosh Jagannath , Pallai Rajash , Wielgos-Bonvallet Monica , Eskelund Christian , Lugtenburg Pieternella , Vose Julie
Published: June 2024

7039

Background: Epcoritamab induces high complete response (CR) and MRD-negativity rates with manageable safety in patients (pts) with challenging-to-treat R/R LBCL as shown in the pivotal phase 2 study (NCT03625037). Here we present long-term data, an additional efficacy analysis from the expansion cohort, and data from the cycle 1 optimization (C1 OPT) part. Methods: Adults with R/R CD20+ LBCL and ≥2 prior systemic therapies received subcutaneous epcoritamab (2 step-up doses, then 48-mg full doses per label) in 28-d Cs. The primary endpoint of the expansion cohort was IRC-assessed overall response rate (ORR). A subgroup analysis evaluated efficacy outcomes by investigator assessment in complete responders with longer follow-up. C1 OPT assessed CRS incidence and severity with hydration and dexamethasone prophylaxis in C1; hospitalization was not required. Results: Overall, 157 LBCL pts were treated in the expansion cohort; 148 had diffuse LBCL (DLBCL) or high-grade B-cell lymphoma (HGBCL). Baseline characteristics were previously reported. As of April 21, 2023, the median follow-up for LBCL was 25.1 mo (range, 0.3+ to 32.7); ORR/CR rates were 63/40% (LBCL) and 61/39% (DLBCL + HGBCL) by IRC. In a subgroup analysis of complete responders with longer follow-up (median, 31.3 mo), median duration of CR was not reached; efficacy outcomes for complete responders are shown in the Table. Long-term safety was consistent with previous reports. CRS remained the most common AE (51% all grade [G]; 32% G1, 16% G2, 3% G3). In C1 OPT, 36 pts were evaluable for CRS with a median follow-up of 1.7 mo. Overall CRS incidence was 22% and events were low grade (14% G1, 8% G2), mostly occurring following the first full dose. All CRS events resolved; none led to treatment discontinuation. Among 60 total pts in C1 OPT, 1 pt experienced ICANS (G1). Additionally, IL-6 levels were lower with C1 OPT and consistent with the observed lower rate and severity of CRS. Preliminary C1 OPT efficacy data were comparable to data observed in the expansion cohort. Conclusions: Epcoritamab monotherapy continues to demonstrate deep and durable responses, with most complete responders remaining in CR and without new safety signals in these long-term follow-up analyses. Implementing simple measures of adequate hydration and prophylactic dexamethasone in C1 markedly reduced the overall incidence and severity of CRS with no impact on efficacy. The continued benefit beyond 2.5 y underlines the long-term efficacy and value of epcoritamab in R/R LBCL. Clinical trial information: NCT03625037 . [Table: see text]
Real-world risk of bleeding events in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) treated with BTKi.
Authors: Moslehi Javid J. , Wahlstrom Svea K , Teschemaker Anna , Mackey Rachel H , DeVincenzo Diana , Carabuena Leslie A , Thompson Samantha L , Gordon Brittaney , Rosenthal Ning A
Published: June 2024

7052

Background: Bruton tyrosine kinase inhibitors (BTKis) are effective treatments for various B-cell malignancies including CLL/SLL but are known to be associated with increased bleeding risk. Current evidence indicating this association has largely been demonstrated in clinical trial research. However, bleeding risk in real-world CLL/SLL patients, who are often sicker with more comorbidities requiring anticoagulant (AC) or antiplatelet (AP) use is not well described. This study aimed to assess the prevalence of AC/AP use and explore risk factors for bleeding among real-world CLL/SLL patients receiving BTKi therapies. Methods: We conducted a retrospective cohort study using the claims-linked Premier PINC AI Healthcare Database of patients aged ≥18 years with a diagnosis of CLL/SLL from July 1, 2016 to March 31, 2022. Patients were followed from first BTKi prescription fill (index date) to earliest of BTKi discontinuation, death, or end of the study period. Patient comorbidities, treatments, and bleeding events were assessed using diagnosis and procedure codes and prescription claims. Multivariable-adjusted risk for bleeding events was assessed with Cox proportional-hazards regression. Results: Among 2091 patients with CLL/SLL receiving BTKi therapies, mean age was 65.7 years, 61.8% were men, and 77.7% were White. BTKi treatments included ibrutinib (86.3%), acalabrutinib (13.1%), and zanubrutinib (<1%). Overall, 4.3% of patients switched BTKis during follow-up; 615 (29.4%) had AC/AP use at any time during the study period, of whom 411 (66.8%) started after BTKi initiation. Bleeding events occurred in 526 (25.2%) patients during a mean BTKi exposure of 14.2 months, with an incidence of 26.6 per 100 person-years (PYs) overall, and 37.2 and 22.0 per 100 PYs in patients with and without any prescription AC/AP use, respectively. The proportion of patients with fatal bleeding was <0.3%. In adjusted models, risk of first bleeding event was higher for AC use (HR [95% CI] 2.33 [1.83–2.98]), age ≥65 years (1.32 [1.14–1.53]), women (1.28 [1.10–1.48]), and history (during 90 days prior to BTKi start) of bleeding (2.27 [1.87–2.76]), ulcers (2.21 [1.06–4.63]) or myocardial infarction (MI) (1.74 [1.31–2.33]) (all P≤0.05). Prescription AP use, race/ethnicity, and history of chronic kidney disease or thrombocytopenia were not statistically significant. Conclusions: In this large real-world study of bleeding risk in patients receiving BTKis, bleeding events occurred in 26.6 per 100 patients per year, with higher risk in AC users, women, and patients with history of bleeding, ulcers, or MI. However, the risk of fatal bleeding was low.
Frontline brentuximab vedotin and CHP (A+CHP) in patients (pts) with peripheral T-cell lymphoma with less than 10% CD30 expression: Results from the phase 2 SGN35-032 study.
Authors: Iyer Swaminathan Padmanabhan , Jagadeesh Deepa , Domingo-Domenech Eva , Benedetti Fabio , Rodriguez Izquierdo Antonia , Bouabdallah Krimo , Vitolo Umberto , Illidge Tim M. , Liu Jingmin , Shaikh Eeman , Horwitz Steven M.
Published: June 2024

7069

Background: Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, combined with cyclophosphamide, doxorubicin, and prednisone (A+CHP) was evaluated in the phase 3 ECHELON-2 trial in pts with anaplastic large cell lymphoma (ALCL) and other peripheral T-cell lymphoma (PTCL) types with ≥10% CD30 expression. Compared to conventional frontline therapy, pts treated with A+CHP had a 30% risk reduction in progression-free survival (PFS) (stratified HR=0.70 [95% CI: 0.53, 0.91], P=0.0077) and a survival benefit (HR=0.72 [95% CI: 0.53, 0.99], P=0.0424) (Horwitz 2022). Since no correlation between CD30 expression and duration of response (DOR) was found, it was hypothesized that frontline A+CHP may also be active in pts with non-sALCL PTCL with <10% CD30 expression. Methods: SGN35-032 (NCT04569032; EudraCT 2020-002336-74) is an ongoing phase 2 study. Pts with newly diagnosed non-sALCL PTCL with <10% CD30 expression (by local assessment) are enrolled. Pts are assigned to CD30 <1% or CD30 1% to <10% cohorts. All pts receive 21-day cycles of A+CHP (BV 1.8 mg/kg, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2 by IV infusion, and prednisone 100 mg po qd on Days 1-5) for up to 6-8 cycles. The primary endpoint, overall response rate (ORR), is assessed by blinded independent central review (BICR) per Cheson 2007. Secondary endpoints are complete response (CR) rate, PFS, overall survival (OS), DOR, ORR per BICR using modified Lugano, and safety. Results: Seventy pts received ≥1 dose of study drug as of June 30, 2023. Median age was 63.5 years, 57% were male, and 90% had ECOG ≤1. Most had stage IV disease (63%) and were in the CD30 1% to <10% cohort per local CD30 (55%). Median treatment duration was 18 weeks (range, 0-24 weeks). Per BICR, ORR was 77% (95% CI: 65.3%, 86.7%), including 65% (95% CI: 52.4%, 76.5%) with CR among the 66 efficacy evaluable (EE) pts. ORR and CR rate per BICR are listed by cohort in the Table. Grade ≥3 treatment-emergent adverse events (TEAEs) were experienced by 43 pts (61%), most commonly neutropenia (20%), febrile neutropenia (17%), and anemia (10%). Six pts (9%) discontinued treatment due to TEAEs. Nineteen pts (27%) had BV-related serious TEAEs. There were 2 (3%) treatment-related deaths: 1 pt died of decreased appetite and 1 pt died of general physical health deterioration. Conclusions: In pts with non-sALCL PTCL with <10% CD30 expression, A+CHP as frontline therapy appears effective and has a safety profile consistent with label. Clinical trial information: NCT04569032 . [Table: see text]
Impact of renal impairment (RI) on pharmacokinetics (PK) and clinical outcomes with mezigdomide plus dexamethasone (DEX) in relapsed/refractory multiple myeloma (RRMM).
Authors: Trudel Suzanne , Bahlis Nizar J. , Popat Rakesh , Mateos Maria-Victoria , Vangsted Annette J. , Ramasamy Karthik , Martínez-Lopez Joaquín , Quach Hang , Orlowski Robert Z , Burnett Joseph , Gaudy Allison , Chen Wencong , Gong Jing , Hadala Joseph T. , Donahue Cynthia , Koo Phillip , Zhu Yue , Katz Jessica , Richardson Paul G.
Published: June 2024

7539

Background: RI is a common complication in MM and may alter drug elimination, leading to increased systemic exposures, risk of adverse events (AEs), and dosing adjustments. The novel CELMoD agent mezigdomide (MEZI) is being investigated alone or with DEX in the CC-92480-MM-001 (NCT03374085) phase 1/2 trial. MEZI has shown dose-dependent linear PK with rapid absorption and is mainly eliminated through hepatic metabolism, with renal elimination playing a smaller role. Here we investigate the impact of RI on the efficacy, safety, and PK of MEZI + DEX in RRMM. Methods: Eligible patients (pts) had RRMM, ≥ 3 prior lines of therapy, triple-class refractoriness, and disease progression ≤ 60 days of last therapy. Pts were stratified by creatinine clearance (CrCl), excluding those with CrCl < 45 mL/min or needing dialysis. Oral MEZI (1 mg) was given on days 1–21 per 28-day cycle + weekly DEX. MEZI doses were not adjusted based on RI. Responses, AEs, and PK were assessed descriptively over the full population and in pts with no RI (CrCl ≥ 90 mL/min), mild RI (CrCl 60–< 90 mL/min), and moderate RI (CrCl 30–< 60 mL/min) at baseline. MEZI clearance and PK exposure were estimated from an integrated population PK model. PK exposure parameters were stratified by chronic kidney disease (CKD) staging. Results: 101 pts received MEZI + DEX in the dose-expansion cohort; 37 had no RI, 41 had mild RI, and 23 had moderate RI. Grade (Gr) 3/4 treatment-emergent AEs (TEAEs) were similar, occurring in 91.1% (overall), 89.2% (no RI), 90.2% (mild RI), and 95.7% (moderate RI) of pts. TEAEs were mostly hematologic, with neutropenia the most common Gr 3/4 TEAE; its occurrence did not differ in no RI (75.7%), mild RI (75.6%), and moderate RI (73.9%) cohorts. Non-hematologic Gr 3/4 TEAEs were low. Eighty-nine (88.1%) and 32 (31.7%) pts had MEZI dose interruptions and reductions, respectively. Overall response rate (ORR) was 40.6% in all pts, 56.8% in no-RI pts, 29.3% in mild-RI pts, and 34.8% in moderate-RI pts (Table). Evaluated as a continuous variable, CrCl showed no apparent relationship with MEZI oral clearance or systemic exposures. This was supported by subgroup evaluation of MEZI exposures by CKD stage. Results showed MEZI exposures in mild or moderate RI are consistent with no RI. Conclusions: Based on renal function, there was no adverse trend between efficacy, safety, and PK of MEZI + DEX. MEZI dose modifications are likely not required for pts with mild to moderate RI. Clinical trial information: NCT03374085 . [Table: see text]
Mortality trends (1999-2022) in patients with multiple myeloma with pneumonia, influenza, and COVID-19.
Authors: Zolotov Eli , Parmar Harsh , Anand Palka , Zenreich Josh , Aleman Adolfo , Phull Pooja , Vesole David H. , Siegel David Samuel DiCapua , Biran Noa
Published: June 2024

7553

Background: Patients (pts) with multiple myeloma (MM) are immunosuppressed either due to the hypogammaglobulinemia and impaired plasma cell function or due to pharmacological management and stem cell transplantations. Consequently, they are at a higher risk of infections. This study aims to evaluate the changes in mortality from COVID-19 (CVD), influenza virus (FLU), and pneumonia (PNA) in MM pts in the era of CVD pandemic. Methods: Using the Wide-ranging Online Data for Epidemiologic Research (WONDER) database from the CDC, we collected mortality data for pts with CVD (U07.1 code), FLU and PNA (J09-J18 codes), and MM (C90.0 code). Using sex and ethnicity-specific stratification, the gathered data made it easier to calculate age-adjusted mortality rates (AAMRs) per 100,000 people. Using the collected data we were able to analyze mortality patterns over the years 1999-2022. Results: Overall, 25,271 MM pts died from CVD, FLU and PNA between 1999 to 2022. The mortality rate remained stable from 1999 to 2019 ranging between 0.4 AAMR per 100,000 to 0.3 AAMR, representing an annual percentage change (APC) of -0.5%. However, the mortality rate increased in 2019, rising from 0.3 AAMR per 100,000 to 0.5 in 2022, with APC of 7%. When evaluating the trends by gender, there was an increase in mortality among male pts, rising from 0.4 AAMR per 100,000 to 0.7 between 2019 and 2020, while the increase among females was minimal, from 0.3 AAMR per 100,000 to 0.4. While Hispanic, White, and African American ethnicities mortality increased in 2020-2022, Asian pts maintained a rate of 0.2 AAMR in 2019, 2020, and 2022 (Table). Conclusions: We showed an increase in mortality among pts with MM combined with CVD, FLU, or PNA between 2020 and 2021. It might be attributable to the CVD pandemic, announced by WHO in March 2020. Despite the FDA's approval of the first CVD vaccine in December 2020, the emergence of new CVD variants and limited vaccine availability could have contributed to a continued increase in mortality in 2021.In 2022, we noticed a drop in mortality. It might be explained by the wider accessibility to CVD vaccination or to diminished virulence. Additionally, increased awareness of the importance of CVD vaccinations in immunocompromised pts could also lead to increased FLU vaccination rates. It might explain the downtrending mortality of pts with MM, FLU and PNA only in 2021. This is the first study presenting the mortality trend of MM pts with FLU, PNA and CVD, and comes to highlight the importance of vaccination in immunocompromised MM pts. [Table: see text]
Smoking and pathogenic germline variants in patients with lung cancer.
Authors: Esplin Ed , Nielsen Young Sarah M. , Russell Emily M. , Ellsworth Rachel , Heald Brandie , Watson Alexander S , Aisner Dara L. , Korn W. Michael
Published: June 2024

8040

Background: Few studies have investigated the correlation of smoking history with pathogenic germline variants (PGVs) in patients diagnosed with lung cancer. With emerging opportunities for PGVs in DNA damage-repair (DDR) genes to inform precision therapies, we investigated the prevalence of PGVs in patients with lung cancer, stratified by smoking status. Methods: Germline genetic testing (GGT) (Invitae Corp.) and insurance claims (Komodo Healthcare MapTM) data were reviewed for 14,317 patients with an ICD code for lung cancer from 2015-2023 and hereditary cancer GGT of ≥ 10 genes. PGV rates were assessed overall, in DDR genes and in lung cancer related genes. Smoking history was defined by ICD codes. Number of genes tested varied per ordering clinician preference. Clinically actionable PGVs were defined as those associated with clinical management recommendations or trial eligibility per current standard of care guidelines. Chi-square tests were used with significance set to p < 0.05. Results: The cohort was predominantly female (70.9%), white (65.7%), and over half had a history of smoking (57.1%). PGVs in 73 known cancer-risk genes were identified in 1,804/14,317 (12.6%) patients. Frequencies of PGV were 12.6% (1,026/8,175) in patients with smoking history compared to 12.7% (778/6,142) in those with no reported smoking history. There was no statistically significant difference in DDR gene, TP53, or EGFR PGV rates for patients with or without smoking history (p > 0.05). Mean (SD) age of lung cancer diagnosis was significantly younger for patients with a history of smoking and DDR PGVs (61 (11)) compared to those with negative results (62 (12), p = 0.005). There was no significant difference in age of diagnosis between patients with no smoking history and DDR PGVs (60 (12)) and those with negative results (59 (13), p = 0.888). PGV rates by clinician-reported ancestry: Black/African-American, 9%; Asian or Pacific Islander, 11%; Hispanic, 12%; White, 13%. Among genes with > 1,000 patients tested, PGVs were most common in BRCA2 (2.2%), CHEK2 (2.0%), ATM (1.6%), SPINK1 (1.6%), and BRCA1 (1.2%). Conclusions: In 14,317 patients with lung cancer, 12.6% had PGVs. There was no significant difference in enrichment of PGVs in DDR genes when patients were stratified by reported smoking history, suggesting the enrichment of these genes is independently associated with lung cancer. The age of onset for patients with DDR gene PGVs varied with smoking history, suggesting that risk conferred by these PGVs could be additive to smoking risk. These data reinforce prior studies supporting consideration of GGT for all patients with lung cancer, independent of age or reported smoking history.
Long-term survival, toxicities, and the role of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma treated with intensity-modulated radiation therapy: A retrospective study with a 5-year follow-up.
Authors: Liu Lina , Luo Xunyan , Wu Weili , Li Yuanyuan , Long Jinhua , Luo Xiuling , Chen Xiaoxiao , Gong Xiuyun , Zhao Chaofen , LI Zhuoling , Shang Kai , Xu Xinyu , Jin Feng
Published: June 2024

e18003

Background: This study aimed to evaluate 5-year outcomes and the late toxicity profile of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma (NPC). Methods: Our retrospective analysis included 70 patients with locally advanced NPC stages III and IVB (according to the 2010 American Joint Committee on Cancer staging system). Patients were treated with two cycles of induction chemotherapy (IC) before concurrent chemoradiotherapy (CCRT) at the affiliated cancer hospital of Guizhou medical university. The IC with docetaxel, cisplatin (DDP) and fluorouracil regimen. Patients were divided into two groups during CCRT. Using a “MELODIE” multi-channel programmed pump, DDP (100 mg/m2) was administered for 12 hours from 10:00 am to 10:00 pm and repeated every 3 weeks for 2-3 cycles. DDP was administered at the peak period of 4:00 pm in the sinusoidal chrono-modulated infusion group (Arm A, n = 35). The patients in Arm B received a constant rate of infusion. Both arms received radiotherapy through the same technique and dose fraction. The long-term survival and disease progression were observed. Results: After a median follow-up of 82.8 months, the 5-year progression-free survival rate was 81.3% in Arm A and 79.6% in Arm B (P = 0.85). The 5-year overall survival rate was not significantly different between Arm A and Arm B (79.6% vs 85.3%, P = 0.79). The 5-year distant metastasis-free survival rate was 83.6% in Arm A and 84.6% in Arm B (P = 0.75). The 5-year local recurrence-free survival rate was 88.2% in Arm A and 85.3% in Arm B (P = 0.16). There were no late toxicities of grade 3-4 in either group. Both groups had grade 1-2 late toxicities. Dry mouth was the most common late toxic side effect, followed by hearing loss and difficulty in swallowing. There was no statistically significant difference between Arm A and Arm B in terms of side effects. Conclusions: Long-term analysis confirmed that in CCRT, cisplatin administration with sinusoidal chrono-modulated infusion was not superior to the constant infusion rate in terms of long-term toxicity and prognosis.
Screening failure in clinical trials for patients with head and neck squamous cell carcinoma: A retrospective analysis.
Authors: Jiménez Labaig Pablo , Llop Sandra , Rullan Antonio , O'Leary Ben , Newbold Kate , Wong Kee Howe , Bhide Shreerang , Nutting Christopher , Harrington Kevin Joseph
Published: June 2024

e18009

Background: Clinical trials drive improvements in patient care with head and neck squamous cell carcinoma (HNSCC), presenting opportunities for optimizing clinical outcomes. However, a significant number of patients (pts) miss out on new therapeutic opportunities due to screen failure (SF) after signing the informed consent form. Understanding the circumstances leading to SF might improve enrollment processes. Methods: Retrospective cohort analysis of pts with HNSCC intended for treatment within a clinical trial at the Royal Marsden Cancer Centre but who experienced SF between Jan 2016 and Jan 2024. Demographic and cancer-related characteristics, comorbidities, consent and SF dates, SF causes, and subsequent outcomes after SF were analyzed. Results: 76 pts who experienced SF were identified across 33 different trials. Cohort characteristics and type of trials offered are described in the table. The largest number of SFs was due to exclusion criteria being met in screening tests in 37 pts (49%): Pathology sample did not meet the quality standards in 11 pts (14%); abnormal laboratory tests in 5pts (6%); abnormal echocardiogram/reduced ejection fraction in 5 pts (6%); vessel invasion/ encasement in 4 pts (5%); non-measurable disease in 2 pts (3%); abnormal audiometry in 1pt (1%) among other reasons. The next commonest cause of SF was rapid progression during screening in 28 pts (37%): 11% compromised airway; 11% active bleeding; 5% central nervous system progression and 7% other rapid progression causes. Other causes of SF included: withdrawn consent in 7 pts (9%), comorbidity-related complication in 3 pts (5%) and study termination by sponsor in 2 pts (3%). The median time between consenting and SF was 20 days (range 4-42). After SF, 8% reconsented for the same trial, 56% received standard therapy, and 36% received best supportive care. Conclusions: This study reveals abnormal screening tests and rapid progression as primary causes for SF in patients with HNSCC. Timely referral , airway assessments and improved tissue acquisition could improve enrollment and minimize SF. [Table: see text]
Weekly paclitaxel (P), carboplatin (CP) plus pembrolizumab (PMB) as first-line treatment of recurrent or metastatic (R/M) or locally very advanced (LVA) head and neck squamous cell carcinoma (HNSCC): A retrospective study in 39 patients (pts).
Authors: Borel Christian , Carinato Hélène , Pflumio Carole , Poprawa Elodie , Brahimi Youssef , Oriel Marine , Vacheret Clara , Ravily Delphine , Coliat Pierre , Petit Thierry , Burgy Mickael
Published: June 2024

e18018

Background: Since the results of the KN-048 trial, the combination of platinum/5FU plus PMB has become the standard of care (SOC) for R/M HNSCC pts. The KN-B10 study shows that 5FU can be replaced by P with a favorable response rate and toxicity profile. Weekly use of P reduces hematologic toxicity and increases dose-intensity. Methods: We retrospectively reviewed all records of patients with R/M or LVA (T4b and/or N3b) HNSCC, ECOG-PS 0 to 2, PDL1 CPS ≥ 1, treated in first-line with weekly P (80 mg/m2) and CP (AUC 2: maximum total dose of 250 mg and systematic G-CSF at D3 and D4) for up to 12 infusions plus PMB every 3 weeks for up to 35 administrations. Results: From July 2020 to April 2023, 39 pts (median age 63 years, 74% male, 18% PS2) were treated. Primary tumors: oropharynx 44%, larynx 23%, hypopharynx 18% and oral cavity 15%. Disease setting: LVA 20%, local recurrence in irradiated area 54%, local recurrence and distant metastases 10% distant metastases only15%. With a median follow-up of 19 months (m), median Overall Survival (mOS) was 17.2 m (95%CI: 10.8-NR). 31/39 (79%) pts achieved an objective response (OR): 7 CR and 24 PR. For the 8 LVA pts, all achieved an OR, with a median Event Free Survival of 10 m (95%CI: 6.27-NR): the 4 progression-free pts (8.6 m+ to 25 m+) were treated with radiotherapy after neoadjuvant immuno-chemotherapy. For the 31 R/M pts, ECOG-PS was a significant prognostic factor of OS, mOS: 19.3 m (95%CI: 14.4-NR) for ECOG-PS 0-1 pts vs. 10.3 m (95%CI: 5.4-13.9) for ECOG-PS 2 pts (p = 0.02). For R/M pts, median Progression Free survival was 6.9 m (95%CI: 4.4-8.6) and the ORR was 74%, with a median duration of response of 6.5 m (95%CI: 3.13-8.56). Toxicity was manageable, with 20 (51%) pts experiencing at least one grade 3-4 adverse event: hematologic 18% (including one febrile neutropenia), infection 5%, neuropathy 8%, diarrhea 8%, infusion reaction 8%, electrolyte disturbances 8%, renal failure 3% and no toxic deaths. Conclusions: The combination of weekly P and CP plus PMB produces a high ORR and increased OS consistent with the results of the Frail-Immune study (J. Fayette ASCO 2023). This regimen deserves further consideration not only in the R/M setting, but also in the neoadjuvant setting for locally advanced patients.
Precision medicine for papillary thyroid carcinoma (PTC) variants: A machine learning approach to prognosis and treatment guidance.
Authors: Alshwayyat Sakhr Abdulsalam , Alenezy Abdalwahab , Asha Wafa , Alshwayyat Mustafa , Kamal Haya , Ghammaz Owais , Alshwayyat Tala Abdulsalam
Published: June 2024

e18072

Background: PTC is a common endocrine cancer with a good prognosis, but aggressive subtypes, such as Hürthle cell (HCC) and columnar cell variants (CCV), pose challenges due to their higher recurrence and metastasis rates. To provide personalized care, we applied machine learning to evaluate the treatment effectiveness and develop precise prognostic models for PTC variants. Methods: The Surveillance, Epidemiology, and End Results (SEER) database provided the data used for this study’s analysis (2000–2019). Patients who met any of the following criteria were excluded: diagnosis not confirmed by histology, previous history of cancer or with other concurrent malignancies, and unknown data. To identify prognostic variables, we conducted Cox regression analysis and constructed prognostic models using machine learning (ML) algorithms to predict the 5-year survival. Patient records were randomly divided into training (70 %) and validation (30 %) sets. A validation method incorporating the area under the curve (AUC) of the receiver operating characteristic curve was used to validate the accuracy and reliability of the ML models. Results: The study population comprised 3690 patients. Among them 3180 patients with CCV and 510 patients with HCC, respectively. Most patients (62.8%) were 45 years or older, with a median age of 52 years. A total of 56.9% of patients had a tumor size greater than 2 cm, with a median tumor size of 3.1 cm. The largest racial group was white, comprising 83.8% of the cases, and 11.8% of the cases were Asian. Most cases were regional (53.4%, n=1969), followed by localized (38.3%, n= 1413). Multivariate Cox regression analysis revealed that N1 negatively affected the survival of HCC patients. CCV has a favorable prognosis after surgery, radiotherapy, or total thyroidectomy. Poor prognosis in CCV is associated with black race, large tumor size, and T4 stage. Improved survival in the localized/regional stage and decreased survival with male sex, older age, distant metastasis, and advanced AJCC stage in both PTC subtypes. ML models revealed that the random forest classifier (RFC) and K-Nearest Neighbors (KNN) accurately predicted outcomes, followed by Logistic Regression (LR) models. The highest contributing factors were AJCC staging, tumor size, and T aspect of TNM staging. Conclusions: Our study offers a method for evaluating and treating patients with PTC variants. The machine learning model that we created serves as a useful and personalized resource to aid in clinical decision-making processes.[Table: see text]
Cytogenetic and molecular features of mixed-phenotype acute leukemia in US veterans and its potential impact on therapy.
Authors: McKinnell Zoe , Degann Seta , Karel Daniel , Antonio Martha , Nassereddine Samah , Neppalli Amarendra Kumar , Jain Maneesh Rajiv
Published: June 2024

e18535

Background: Mixed phenotype acute leukemia (MPAL) is a rare and heterogeneous subtype of acute leukemia. Per the 2022 WHO criteria, it is categorized based on its predominant immunophenotypic lineage (B vs. T) and the presence of a Philadelphia chromosome (Ph+) or a KMT2A rearrangement. While many other cytogenetic and molecular abnormalities have been described, due to the rarity of this disease, neither their incidence nor the role of targeted therapies has been well defined. We conducted a retrospective study of all veterans with MPAL diagnosed between 2000-2023 to examine the impact of different clinical, immunophenotypic, cytogenetic, molecular, and treatment strategies on overall survival (OS). Methods: Electronic medical record data from the Veterans Affairs Informatics and Computing Infrastructure database were used to identify 320 patients diagnosed with MPAL between 2000-2023 using the text utilization integration feature to query all notes. All patient charts were reviewed manually. Pathology reports and clinical notes were reviewed to collect data on diagnosis, treatment, and outcome. To date, 74 patients have been identified and included in this preliminary analysis. Cox regression analyses were used to compare OS between patients with different MPAL subtypes, cytogenetic, and molecular features as well as different treatment approaches. Multivariate analysis was performed with controls for age, race, and BMI. Results: In line with prior research, decreases in OS were seen among older patients > 65 yo compared to patients <30 yo and those who received an AML induction over ALL induction regimen with HR of 8.28 (p 0.04) and 2.02 (p 0.03) respectively. Patients who had a transplant had significantly improved OS with a HR of 0.19 (p <0.001). Of the 32 patients who had potentially targetable mutations, 14 received targeted maintenance therapy with either Ph+ or FLT3 inhibitors. Patients who got targeted maintenance therapy (including FLT3 inhibitors) had an OS of 55 months compared to 17 months for those who did not. 50% of those patients who did not get maintenance therapy went to transplant and 31% of patients who did get maintenance therapy went to transplant yet these patients still had improved OS. Conclusions: This preliminary data demonstrate that while MPAL is a complex and heterogeneous disease, a significant portion of patients have targetable mutations. Further studies evaluating targeted therapies such as FLT3, IDH, and menin inhibitors in MPAL patients may be warranted. [Table: see text]
CD19 expression in diffuse large B-cell lymphoma (DLBCL) patient biopsies after treatment with tafasitamab.
Authors: Volgina Alla , Rumberger Beth , Johannsdottir Hrefna , Larsen Thomas Stauffer , Alvarez Arias Diana
Published: June 2024

e19050

Background: Tafasitamab (tafa) is a CD19-targeting immunotherapy that induces enhanced antibody dependent cellular cytotoxicity and phagocytosis. Tafa received accelerated FDA approval in 2020 for treating relapsed or refractory DLBCL in combination with lenalidomide in patients ineligible for autologous stem cell transplant, based on results from L-MIND, a multicenter, open-label, single-arm, phase 2 trial. FirmMIND (NCT05429268) is an ongoing identical study, further evaluating efficacy and safety of tafa in this setting. Several other CD19 targeting agents are available; however, CD19 antigen loss following treatment with chimeric antigen receptor T-cell therapy targeting CD19 (CART19) has raised concerns over CD19-targeted therapy sequencing. Loss of CD19 has not been observed to date in tafa clinical trials or practice. Methods: To evaluate CD19 expression at screening and after disease progression in firmMIND, we developed an immunohistochemistry (IHC) assay using a mAb that binds to an intracellular epitope of CD19 clone LE-CD19. To validate that CD19 expression is detectable after tafa treatment, we treated cultured SU-DHL-4 or Jurkat cells with tafa at a saturating concentration for 24 hours. After washing out unbound tafa, cells were harvested at specific timepoints. Resulting cell line blocks were assessed for CD19 expression by IHC. We also monitored CD19 trafficking in response to fluorescently labeled tafa by confocal microscopy. Results: By IHC, CD19 expression was comparable between treatment conditions, suggesting the assay can effectively measure CD19 expression in lymphoma biopsy samples post-tafa. Confocal microscopy showed a fraction of tafa-bound CD19 internalized and colocalized with a CD19 intracellular pool labeled with anti-CD19 mAb clone EPR5906; this mAb also detected CD19 that remained localized on the cell surface. The data demonstrated that CD19 persists on tumor cells after tafa treatment at levels that could be bound by other CD19-targeting therapies. As of the January 25, 2024 data cutoff, we received 6 end-of-treatment (EOT) samples from patients in firmMIND. Biopsies were collected 14-26 days after the last tafa dose; 5 of 6 samples were biopsies from lymph nodes or liver and showed ≥80% of tumor cells staining CD19+ on membranes with 3+ intensity by IHC, except 1 that was collected only 6 days after last dose and showed 50% positivity. The sixth biopsy (extranodal subcutaneous lesion) showed no CD19 expression at baseline or EOT. Conclusions: Patient biopsy analysis and preclinical data suggest that following tafa treatment, CD19 antigen is preserved on the surface of tumor cells after short and transient internalization and could be targeted by other CD19 agents, such as CART therapy. This conclusion is supported by sequential treatment with tafa followed by CART in vivo (Sakemura, 2024). Analyses are ongoing to confirm these findings.
Health-related quality of life (HRQoL), functioning, and symptoms with odronextamab monotherapy in patients (pts) with relapsed or refractory follicular lymphoma (R/R FL) by POD24 status in the ELM-2 study.
Authors: Villasboas Jose Caetano , Mayer Laura Magnano , Tessoulin Benoît , Cho Seok-Goo , Taszner Michal , Novelli Silvana , Luminari Stefano , Merli Michele , Ubieto Ana Jiménez , Poon Michelle , Tucker David , Walewski Jan Andrzej , Ivanescu Cristina , Chaudhry Aafia , Mohamed Hesham , Ambati Srikanth R. , Harnett James , Kamat Siddhesh , Kim Tae Min ,   ELM-2 Investigators
Published: June 2024

e19057

Background: In ELM-2 (NCT03888105), a Ph 2, single arm, open label trial, odronextamab demonstrated robust efficacy, generally manageable safety, and overall maintenance of patient-reported outcomes (PROs) in R/R FL pts (Villasboas et al. ASH 2023). In FL, pts with disease progression within 2 yrs of frontline chemoimmunotherapy (POD24) are hard to treat with poor clinical outcomes, representing an unmet need. We report PROs by POD24 status in pts with Grade 1–3a R/R FL from ELM-2. Methods: Pts received IV odronextamab in 21-day cycles (C): 80 mg QW in C1–4, with C1 dose step up to mitigate cytokine release syndrome, then 160 mg Q2W (Q4W if complete response ≥9 mo) until progression. PROs were collected at baseline (BL), Wks 2–4, 10, then Q8W in Yr 1, and Q12W in Yr 2. Post-hoc POD24 subgroup analyses were performed on six EORTC QLQ-C30 scales, the EQ-5D-3L VAS, and FACT-Lym LymS. Estimated mean change from BL (CFB) was analyzed using mixed models for repeated measures (MMRM) through Wk 42 (≥10 pts at last assessment). Published meaningful CFB thresholds were used to define deterioration/improvement in responder analyses. Results: By Jan 31, 2023, 140 pts with R/R FL had received odronextamab. Pts with POD24 (n=70) were younger than pts without POD24 (n=70; median age 57.5 vs 62.0 y), had fewer prior Tx lines (median 2 vs 3), and a higher proportion double refractory to anti-CD20 Ab + alkylator (53% vs 29%). Objective response rate was similar in evaluable pts with (n=63; 79%) and without (n=65; 80%) POD24. PRO questionnaire completion ranged from 52–95% through Wk 42 across groups. Descriptive analyses suggest BL PRO scores were similar by POD24 status, showing good HRQoL/functioning and low symptom burden, and were generally maintained through Wk 42 with minimal between-group differences (overlapping 95% CIs for LS mean CFB [Table]). In both groups, more pts reported PRO maintenance or improvement vs deterioration across visits, except for fatigue at Wk 10 in pts without POD24. Conclusions: In pts with heavily pretreated R/R FL, odronextamab Tx maintained HRQoL, functioning, and symptoms irrespective of POD24 status. Clinical trial information: NCT03888105 . [Table: see text]