bluuebunny/crossref_metadata_2025 huggingface dataset:
Post-ASCT consolidation with EPD or ERD in patients with high-risk multiple myeloma.
Authors: Zolotov Eli , Kabat Maciej , Parmar Harsh , Anand Palka , Zenreich Josh , Aleman Adolfo , Phull Pooja , Vesole David H. , Siegel David Samuel DiCapua , Biran Noa
Published: June 2024

7534

Background: Patients (pts) with high-risk (HR) Multiple Myeloma (MM), characterized by at least two cytogenetic abnormalities often experience rapid disease progression and early relapse post-autologous stem cell transplant (ASCT) with median Progression-Free Survival (PFS) of 24 or 12 months with or without lenalidomide maintenance (Panopoulou et al, Blood 2023). This study assesses the efficacy and safety of EPD (Elotuzumab, Pomalidomide, Dexamethasone) or ERD (Elotuzumab, lenalidomide , Dexamethasone) as consolidation therapy post-ASCT in HR MM pts. Methods: In this single-center retrospective study, we reviewed records of MM pts treated with consolidative ERD or EPD from September 2016 to March 2023. We collected baseline MM characteristics, treatment history, adverse events (AEs), and survival outcomes. HR MM pts were defined by 2 or more cytogenetic abnormalities (del 17p, 1q21 gain or amplification, t(14;16), t(14;20), complex karyotype) and/or high-risk gene expression profiling scores (GEP, SKY92). All patients, aged ≥21, underwent ≥1 full cycle of EPD or ERD post-ASCT, administered for a total of four 28-day cycles, following the standard dosing regimen with a rapid dexamethasone taper over the last two cycles. Results: A total of 78 HR MM pts, median age 64 years with 51.2% males and 71.7% caucasians were included. Of them, 62 pts received ERD and 16 received EPD. FISH revealed 62.7% of pts had 2 or more high risk cytogenetic abnormalities. Other pts expressed a combination of cytogenetic abnormalities and/or high-risk GEP or SKY92 scores. The table shows improvement in MRD negativity rates from 21.7% to 26.9% pre and post consolidation, and in VGPR or better from 78.2% to 85.8%. Median PFS for all pts, defined from the time of ASCT to disease progression, was 26.9 months. Most common adverse effects were anemia (71.7%), fatigue (55.1%) and thrombocytopenia (51.2%). Five patients experienced grade 3 adverse events, including 3 with infectious etiology (3.8%) and 2 with immune-mediated toxicity (2.5%). No treatment-related serious adverse events were reported. Conclusions: Four cycles of EPD or ERD consolidation therapy post-ASCT, demonstrated promising efficacy in HR MM pts. The observed median PFS of 26.9 months was comparable to that seen with chronic lenalidomide maintenance and superior to patients who do not receive lenalidomide maintenance. The improvement in PFS was achieved with a fixed duration rather than continuous therapy and without lenalidomide-associated toxicities such as secondary malignancies, chronic diarrhea, and financial toxicity. Further prospective confirmatory studies are needed. [Table: see text]
Real-world schedule de-escalation of teclistamab in patients with relapsed/refractory multiple myeloma.
Authors: Tan Carlyn Rose Co , Derkach Andriy , Maclachlan Kylee , Hultcrantz Malin , Hassoun Hani , Mailankody Sham , Shah Urvi A , Rajeeve Sridevi , Shah Gunjan L. , Scordo Michael , Chung David J. , Landau Heather Jolie , Giralt Sergio , Lesokhin Alexander M. , Korde Neha , Lin Dee , Wu Bingcao , Fowler Jessica , Fernandez Mariana , Usmani Saad Zafar
Published: June 2024

7536

Background: Teclistamab (Tec) is the first BCMAxCD3 bispecific antibody approved for triple-class-exposed relapsed/refractory multiple myeloma (RRMM). The MajesTEC-1 study demonstrated an overall response rate (ORR) of 63% and a median progression-free survival (mPFS) of 11.3 months (mos). Herein, we examined real-world pt characteristics and outcomes associated with Tec in (1) pts treated within the first 4 mos of Tec approval (early initiators who were expected to have high disease burden) as compared to recent initiators, and (2) any pts who switched to de-escalated dosing schedules. Methods: This is a retrospective study of pts with RRMM treated with Tec at Memorial Sloan Kettering Cancer Center from 11/29/22 to 11/30/23 (analysis cut-off: 12/31/23). Responses were evaluated per IMWG Response Criteria. Pt characteristics were summarized by frequency (%) or median (interquartile range [IQR]). PFS was evaluated using the Kaplan-Meier method. Results: In 77 pts who received ≥1 Tec dose, the median age was 70 (IQR 63-77); 55% male; 14% Black; and 42% had high-risk cytogenetic abnormalities (HRCA). The ORR was 62% for 69 response-evaluable pts, including 42% with ≥very good partial response (VGPR). The median time to first response was 1.9 mos (IQR 1.0-2.4). After a median follow-up (mFU) of 7.6 mos, 6-mo PFS rate was 52.3% (95%CI 41.5-66%). The median duration of response has not been reached. In the cohort of early initiators (n=34), pts had more prior lines of therapy (LOT; median 8 vs 5, P=0.002) and higher proportion of prior BCMA therapy use (62% vs 23%; P=0.002) as compared to recent initiators treated after 3/31/23 (n=43). ORR was 67% and 59%, respectively (P=0.80; Table). Among all pts at data cut-off, 25 (32%) switched from weekly to every-other-week or monthly Tec after a median time of 3.1 mos from Tec initiation (95%CI 1.8-4.6) and based on achieving ≥PR and/or toxicity. At mFU of 5.3 mos since switching, 6-mo PFS rate was 94.1% (95%CI 83.6-100%). Conclusions: In this real-world study, Tec demonstrated comparable ORR to MajesTEC-1. Both early and recent Tec initiators had high baseline risk features. A higher proportion of early initiators had prior BCMA therapy and more LOTs, but both cohorts yielded consistently high treatment response rates. In pts who responded, schedule de-escalation was feasible with a high subsequent 6-mo PFS. Updated multicenter findings will be presented at the meeting. [Table: see text]
Uncontrolled diabetes mellitus and the progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans.
Authors: Liu Lawrence , Sigel Byron , Wang Mei , Grandhi Nikhil , Schoen Martin W. , Sanfilippo Kristen Marie , Janakiram Murali , Thomas Theodore Seth , Chang Su-Hsin
Published: June 2024

7551

Background: Studies have shown that, independent of obesity, the metabolic effects of diabetes mellitus (DM) promote the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). However, it is unclear whether glycemic control is associated with MGUS progression in DM patients. We aimed to evaluate the association between poor glycemic control, measured by HbA1c >6.5%, and progression. Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration (VHA) were identified using a published natural language processing (NLP)-based algorithm. We focused on patients whose MGUS subtype was IgG, IgA, or light chain. We excluded patients lacking body weight measurements from the time of MGUS diagnosis to the end of follow-up to ensure receiving care in the VHA. We further excluded patients with extended gaps >1 year between HbA1c measurements. Time-varying HbA1c measurements during the follow-up, evaluated at 1-day intervals and categorized into uncontrolled (HbA1c >6.5%) or controlled (≤6.5%) DM was the exposure variable. Progression of MGUS to MM was also confirmed by a published NLP algorithm. The association between the time-varying controlled/uncontrolled DM and progression was estimated by multivariable-adjusted hazard ratio (aHR) with death as a competing event. The covariates included sex, race, MGUS subtype as well as age, body mass index, monoclonal protein level, Charlson Comorbidity Index, DM medication, and DM type (type 1, type 2 with insulin-dependency status, type 2 without insulin-dependency status), all at MGUS diagnosis. Same analysis was conducted in a subgroup of patients with non-insulin dependent DM type 2 (NIDDMT2) without insulin use between MGUS diagnosis and the end of follow-up. Results: After applying inclusion and exclusion criteria, we identified 9,682 patients with both DM and MGUS. The multivariable analysis revealed a positive association between poor glycemic control and MM progression (see Table): (aHR 1.27, 95% CI 1.13-1.42). In NIDDMT2 without insulin use (n=3,498), poor glycemic control was associated with MM progression (aHR 1.81; 95% CI 1.57-2.10). Conclusions: For patients with DM and MGUS, the risk of MGUS progression to MM was 27% higher in uncontrolled DM and 81% higher in patients with NIDDMT2. This finding highlights a modifiable risk factor for MM progression in MGUS patients. Future studies should examine if interventions to enhance glycemic control could potentially reduce MGUS progression.
Effect of dose-adjusted melphalan on MRD-negativity to full dose melphalan in patients with multiple myeloma post-autologous stem cell transplant.
Authors: Kort Jeries , Ignatz-Hoover James John , Naleid Nikolas , Oley Frank , Cooper Brenda W.
Published: June 2024

7557

Background: Despite significant therapeutic advancements, Multiple Myeloma (MM) remains an incurable disease. Autologous stem cell transplantation (ASCT) is a standard treatment for eligible patients, with high-dose melphalan (MEL200) as the preferred conditioning regimen. Reduced-dose melphalan (MEL140) is used for older or less fit patients. However, this was not prospectively studied and there has been ongoing debate about the efficacy of reduced dosing. This study aimed to investigate the impact of melphalan dose on minimal residual disease (MRD) negativity rates in MM patients undergoing upfront ASCT. Methods: We conducted a retrospective, single-center study involving 74 MM patients who underwent ASCT between 2018 and 2022 at UHCMC, Cleveland, OH and had MRD testing done after transplant. MRD testing was performed using the ClonoSEQ next generation sequencing platform. Results: Median age was higher in the MEL140 group compared to MEL200 (70.3 vs 59.8 years), both groups were similar in terms of sex and race distribution, BMI and KPS scores. Both groups have comparable ISS staging and high-risk cytogenetics. Similar numbers of lines of treatment prior to transplant were seen, with approximately 64% having only one line. First-line induction therapy included triplet therapy (Lenalidomide, Bortezomib, and Dexamethasone) in 73% of patients. Depth of remission at transplant was comparable between groups. MRD negativity rates at 10-5 and 10-6 were comparable between MEL140 and MEL200 groups (64% and 39% in MEL140; 61% and 41% in MEL200; p=0.8 and 0.7 respectively). Sustained MRD negativity at 10-5 over at least 12 months was also comparable (43% in MEL140; 50% in MEL200, p=0.8). After a median follow-up of 37 months, PFS was not reached for either group (p=0.69). Patients achieving MRD negativity at levels of 10-5 had a not reached median PFS, while those not achieving MRD negativity had a median PFS of 41 months (95%CI 23-NR; p=0.024). There was no significant difference in hospital stay duration, time to neutrophil engraftment, readmission rate, or infections within 100 days post-transplant between the MEL140 and MEL200 groups. Conclusions: Our real-world analysis demonstrates that MEL140 yields similar deep post-transplant remissions as MEL200, translating to improved PFS for patients achieving MRD negativity, regardless of the dose used. This is the first report to our knowledge of MRD negativity rate in patients receiving MEL140. [Table: see text]
Indirect comparison of linvoseltamab versus teclistamab for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM).
Authors: Jagannath Sundar , Lee Hans C. , Richter Joshua Ryan , Zonder Jeffrey A. , Hoffman James E. , Zhou Zheng-Yi , Horton Viviana Garcia , Fillbrunn Mirko , Wang Hongjue , Mattera Matthew , Ma Qiufei , Inocencio Timothy J , Xu Yingxin , Bergrath Evelien , Harnett James , Roccia Tito , Kroog Glenn Scott , Rodriguez-Lorenc Karen , Houvras Yariv , Bumma Naresh
Published: June 2024

7560

Background: No head-to-head clinical trials have compared effectiveness of anti-BCMA×CD3 bispecific antibodies for TCE RRMM. This analysis compared efficacy of linvoseltamab vs teclistamab via an unanchored matching-adjusted indirect comparison (MAIC). Methods: A MAIC was deemed feasible after excluding 10 patients (pts) with prior BCMA antibody–drug conjugate exposure from LINKER-MM1 (linvoseltamab) to match MajesTEC-1 (teclistamab) criteria. Pt-level data from LINKER-MM1 (107 pts receiving 200 mg in Phase 1/2, data cut-off [DCO] 9/2023, median follow-up 11.1 months [mos]) and published data from MajesTEC-1’s efficacy population (150 pts, DCO 11/2021, median follow-up 9.8 mos) were analyzed. LINKER-MM1 pts were weighted to match key baseline characteristics in MajesTEC-1 (cytogenetic risk, age, refractory status, ISS stage, ECOG score, extramedullary disease/plasmacytoma status) selected via a prespecified algorithm (Kumar et al., 2023). Objective response rate (ORR), very good partial response or better (≥VGPR), complete response or better (≥CR), and minimal residual disease (MRD) negativity (- [at 10-5 threshold]) rates, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were compared. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were reported before and after matching; a sensitivity analysis included all LINKER-MM1 200 mg pts (n=117). Results: Effective sample size for linvoseltamab was 82 after matching and baseline characteristics were balanced with MajesTEC-1. Before and after matching, linvoseltamab exhibited higher ORR, ≥VGPR, ≥CR, and MRD(-) rates, with significant differences in ≥CR. Linvoseltamab had significantly longer PFS and a trend toward longer OS and DOR (Table). Sensitivity analysis results were similar. Conclusions: The results suggest potentially greater efficacy for linvoseltamab vs teclistamab for all outcomes, highlighting its potential as a highly effective treatment option for TCE RRMM. [Table: see text]
Effect of maintenance therapy (MT) on real-world outcomes (RWO) of patients (pts) with newly diagnosed multiple myeloma (NDMM) post stem cell transplant (SCT).
Authors: Parmar Harsh , Barcellos Anna , Biran Noa , Phull Pooja , Vesole David H. , Belli Andrew J. , Fernandes Laura L. , Hansen Eric , Zettler Christina , Wang Ching-Kun , Goran Stefanie , Anderson Courtney , Doucette Kimberley , Gunning Thomas S , Ip Andrew , Siegel David Samuel DiCapua
Published: June 2024

7562

Background: SCT followed by MT is the standard of care for pts with transplant-eligible (TE) NDMM. Five randomized clinical trials (RCTs) comparing lenalidomide MT versus no MT showed improved progression free survival (PFS), but no overall survival (OS) benefit except for one by McCarthy et al. that allowed pt crossover between treatment arms. Use of MT has also been associated with an increased risk of second primary malignancies and an inferior quality of life. We report RWO post SCT with and without MT in TE NDMM. Methods: We performed a multi-center, retrospective, observational study using the de-identified COTA real-world database derived from the EMRs of US centers. Pts with NDMM from 1/1/2012 to 1/1/23 were included in the study. Kaplan-Meier method was used to evaluate time to next treatment (TTNT), OS, follow-up time (reverse OS endpoint), and report log-rank test p-values. TTNT was defined in two ways: time from SCT to the earliest of initiation of next line of therapy (LOT) or death (TTNT1) and the time from 2nd LOT post-SCT to the earliest of initiation of next LOT or death (TTNT2). A propensity score (PS) matched analysis was used to compare study cohorts and report hazard ratios (HRs) using the Cox proportional hazards method. High risk cytogenetic abnormalities (HRCA) were defined as pts with 17p(-), t(4;14), t(14;16), t(14;20) and 1q+. Results: 1928 ptsmet the study criteria: 957 pts received SCT with MT (M) and 971 pts received no MT (NM). Median age at Dx was 61 y, 57% were male, 70% were White, and 31.2% had HRCA with a median follow-up of 64 months (mos) (95% CI: 61.6, 66.7). In the M vs NM arms, 29.6% and 32.7% pts had HRCA, respectively. Median TTNT1 for M vs NM was 51 vs 36 months (mos), (p<0.001), respectively. Median TTNT2 for M vs NM was 11.7 vs 21.6 mos, (p<0.001), respectively. Median OS for M vs NM was 108.8 mos vs 126.3 mos, (p=0.08), respectively. In the PS model, the NM group had significantly lower hazard of TTNT2 and OS events (HRs 0.65 and 0.85, p<0.001 and p=0.08, respectively). Conclusions: Our study demonstrates improved TTNT2 outcomes with the NM approach. M therapy did not have an impact on OS in this cohort. Both results indicate an absence of long-term benefit with the use of M therapy. OS is a difficult primary outcome to achieve in MM RCTs where survival may have to be collected for decades. Thus, our large study of RWO with long-term follow-up is valuable. [Table: see text]
Genome-wide 5-hydroxymethylation mapping and epigenetic pathways in multiple myeloma.
Authors: Zhang Zhou , Wang Bei , Kowitwanich Krissana , Cui Xiaolong , Bhatti Parveen , He Chuan , Chiu Brian , Zhang Wei
Published: June 2024

7566

Background: Multiple myeloma (MM), a B-cell neoplasm characterized by bone marrow infiltration of malignant plasma cells, is the second most common blood malignancy, with an estimated number of ~35,000 new patients annually in the United States. The molecular pathogenesis of MM is complex and involves various genetic and epigenetic alterations. Key molecular mechanisms, including chromosomal abnormalities such as translocations involving the immunoglobulin heavy chain locus and various oncogenes (e.g., MMSET, FGFR3, CCND1, MAF), alterations in epigenetic regulators (e.g., EZH2, DNMT3A), dysregulation of cell cycle control, and aberrant activation of signaling pathways (e.g., NF-kB, PI3K/AKT, and JAK/STAT), play critical roles in MM pathogenesis. However, epigenetic pathways implicated in MM has not been comprehensively investigated, partly due to technical limitations that cannot distinguish major cytosine modification types. Methods: Using the 5hmC-Seal, a highly sensitive chemical labeling technique, we profiled genome-wide 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA (cfDNA) from a population-based case-control study of MM (cases, n = 313; controls, n = 317) conducted in Canada. Results: The 5hmC modification levels were summarized for various genomic features, showing an enrichment in gene bodies and enhancer markers, consistent with the putative role of gene regulation for 5hmC modification. A genome-wide scan of gene bodies identified 771 differential features between cases and controls, adjusting for age, sex, smoking status, education, and first two principal components, at a permutation-based empirical p-value cutoff of 10-4. For instance, IL1RAP, a component of the interleukin-1 signaling cascade, may impact tumor progression and immune system evasion. Furthermore, functional analysis indicated canonical pathways associated with MM pathology and treatment, such as calcium signaling, and synthesis and secretion of cortisol/aldosterone, were enriched in the differential 5hmC features between cases and controls. Notably, the calcium signaling pathway, integral to Ca2+ transport and involved in various physiological and pathological processes, plays a critical role in MM pathogenesis. Within this pathway, the CAMK1D gene, which has been identified as a crucial regulator of tumor-intrinsic immune resistance, showed differential 5hmC level between cases and controls, highlighting a vital connection between epigenetic modifications and immune evasion mechanisms in MM. Conclusions: Leveraging a state-of-the-art technique, we identified novel epigenetic modifications and pathways in the risk of MM. This approach establishes a solid foundation for further investigating etiology of MM, deepening our understanding of the disease, and advancing the discovery of biomarkers, which could potentially guide preventive strategies.
Artificial intelligence-based prediction model of malignant lung nodules for preoperative planning.
Authors: Lu Di , Cai Yupeng , Chen Liuyin , Yuan Xing , Chen Zhiming , Wang Zhizhi , Tong Yu , Cai Kaican
Published: June 2024

8034

Background: The histopathological prediction of malignant lung nodules is crucial for preoperative planning, but it always remains not precise until the detailed pathological evaluation is performed after the surgery. Thus, to define the histology types (in situ adenocarcinoma (AIS), microinvasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA)) of pulmonary adenocarcinoma appearing as lung nodules before the operation and reduce unnecessary invasive diagnosis and treatment operations, we developed a classification model of based on CT images. Methods: Patients who were diagnosed with pulmonary adenocarcinoma (tumor diameter ≤ 3cm) at Nanfang Hospital, Southern Medical University, China, were retrospectively enrolled, including detailed pathology results, computed tomography (CT) images, and basic information. Through training the model proposed in our previous study, we proposed a new model for defining histopathological types. Then, we used this data to train and compare the diagnostic efficacy of our model with another previously reported deep learning (DL) model (that was a segmentation - classification model with the 3D Unet++ - ResNet-50 combined model) and machine learning (ML) model (that was a traditional model Grey Level Co-occurrence Matrices (GLCM) as the feature extractor and the support vector machine (SVM) as the classifier) in the same method. Results: A total of 2061 patients (with 395 of AIS, 334 of MIA and 1332 of IA) were retrospectively enrolled from January 2019 to April 2022. The data from 2/3 of the patients were randomly selected for training and another 1/3 for verifying. Through training and verifying, our model shows much better diagnostic efficacy, with areas under receiver operating characteristic (ROC) curves with 95% confidence interval (CI) of 0.97(0.96, 0.98), comparing with those of the ML model of 0.77(0.73, 0.81) and the DL model of (0.90(0.88, 0.92). The heatmap visualization of the proposed model shows the classification ability with prediction probabilities of our model clearly and understandably. Conclusions: In this study, we developed a novel artificial intelligence multi-task learning model to precisely predict the pathology type of malignant lung nodules with satisfying diagnostic efficacy, which might provide a new and reliable way for preoperative planning of lung nodules. Further external verifying should be done in the future. In addition, prediction of the growth patterns of pulmonary adenocarcinoma could be more helpful in addition to predicting histopathological types.
Clinicopathologic and molecular landscape of invasive mucinous adenocarcinoma of the lung.
Authors: Kim Hye Sung , Dugan Adam Joseph , Godden Jen , Chao Calvin Y. , Chae Young Kwang
Published: June 2024

8037

Background: Invasive mucinous adenocarcinoma (IMA), accounting for 2–10% of lung adenocarcinomas, often mimics pneumonia with multicentric opacities in multiple lobes and both lungs. Notable for its microscopic skip lesions leading to tumor spread through air spaces (STAS), IMA is still under-researched in terms of its comprehensive clinical and genetic characteristics in large, multicenter studies. Methods: Primary lung cancer cases were obtained from the Tempus database, categorized into either IMA or non-IMA, and compared by patient, clinical, biopsy, and molecular characteristics. The normalization of RNA-seq data involved computing transcripts per million (TPM), performing log2 transformations, and adjusting for assay and batch effects. Significantly up- and down-regulated genes were defined as false discovery rate q-values < 0.05 and |log2(fold change)| > 0.5. Results: The study analyzed 18,857 cases, with 655 (3.5%) in the IMA group and 18,202 (96.5%) in the non-IMA group. The IMA group predominantly consisted of older individuals (median age 70 vs. 68; p<0.001), had fewer smokers (63% vs. 73%; p<0.001), and included more individuals of Hispanic or Latino ethnicity (4.3% vs. 2.7%; p=0.007). This group was more likely to be diagnosed with early-stage cancer and less likely to have stage 4 cancer at diagnosis (stage 1: 23% vs. 14%, stage 2: 18% vs. 7.3%, stage 3: 23% vs. 17%, stage 4: 36% vs. 62%; p<0.001). They exhibited significantly lower tumor mutational and neoantigen burdens (median 3.1 vs. 4.6 mutations/Mb and 6 vs. 9 neoantigens/Mb, respectively; both p<0.001), fewer positive PD-L1 statuses (27% vs. 58%; p<0.001), and different immune cell infiltration patterns (Table). Gene expression analysis revealed 416 upregulated and 258 downregulated genes in the IMA group compared to the non-IMA group. Conclusions: This analysis underscores the unique clinicopathologic and molecular characteristics of IMAs. An improved understanding of IMA’s biological behavior could lead to the development of more effective, personalized treatment strategies. [Table: see text]
Induction therapy with PD-1 antibody combined with platinum-based doublet chemotherapy for locally-advanced non-small cell lung cancer: A randomised controlled, open-label, phase 2 trial.
Authors: Wang Suyu , Zhang Peng
Published: June 2024

8044

Background: Chemoradiotherpay plus immunotherapy is recommended for unresectable locally-advanced non-small cell lung cancer (NSCLC) based on PACIFIC trial. However, it is unclear whether surgery can provide survival benefit for patients with tumors initially unresectable transformed into resectable ones after chemoimmunotherapy. This trial aims to investigate the efficacy and safety of the therapeutic regimen of chemoimmunotherapy plus surgery or radiotherapy. Methods: Patients with unresectable stage IIIB-IIIC NSCLC were enrolled to receive 4 cycles (q21d) of PD-1 antibody (Serplulimab, 4.5mg/kg) and platinum-based doublet chemotherapy. After the induction therapy, those with disease downstaged to IIIA or lower stage and resectable were randomized to receive radical surgery or radiotherapy with a ratio of 1:1, and those with stage IIIB or higher stage or unresectable disease after induction therapy were then treated by oncologists. Primary endpoint was event-free survival (EFS). Secondary endpoints included objective response rate (ORR), major pathologic response (MPR), pathologic complete response (pCR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), R0 rate of resection, severe adverse event (SAE) rate, and health related quality of life (HRQol). Preliminary short-term results were collected. Results: One hundred patients will be enrolled as planned, and a total of 82 patients were enrolled by the data cutoff date (January 6, 2024). Fifty-four and 28 patients were diagnosed with stage IIIB and IIIC disease, respectively. The percentage of squamous carcinomas, adenocarcinomas, and NSCLCs not otherwise specified were 68.3% (56/82), 15.9% (13/82), and 15.9% (13/82), respectively. ORR in 73 evaluable patients was 74.0% (54/73). Twenty-six of them are still in induction therapy phase, and the other 47 and 9 patients received 4 cycles and 1-3 cycles of induction therapy, respectively. Thirty-one patients had downstaged and resectable disease after 4 cycles of induction therapy, and 26 of them were randomized to arm A (n = 13) and arm B (n = 13), and 5 refused randomization (3 received surgery). One patient received surgery after 2 cycles of induction therapy. In 56 patients finished 1-4 cycles of induction therapy, the rate of conversion to resectability was 57.1% (32/56). In total, 17 patients received surgery, and the MPR and pCR rate in 16 evaluable patients were 62.5% (10/16) and 31.3% (5/16), respectively. The grade 3-5 adverse event rate in 56 patients finished induction therapy was 50.0% (28/56). One patient died of immune-related pneumonia. Conclusions: Induction therapy with PD-1 antibody (Serplulimab) and chemotherapy could transform half of unresectable stage IIIB-IIIC NSCLC into resectable, and the efficacy and safety were satisfactory. Clinical trial information: NCT05766800 .
High pre-treatment NLR and PLR predict poor prognosis of patients with recurrent/metastatic head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.
Authors: Anile Giuseppe , Gottardi Chiara , Micheletto Ilaria , Nicolai Piero , El Khouzai Badr , Ferrari Marco , Ghirelli Angelica , Pretto Greta , Guarneri Valentina , Ghi Maria Grazia
Published: June 2024

e18001

Background: The treatment landscape of unresectable recurrent and/or metastatic (R/M) Head and Neck Squamous cell Carcinoma (HNSCC) has profoundly changed with the introduction of Immune checkpoint inhibitors (ICIs). High neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been associated with poor outcome in several tumor types. The aim of the present study was to investigate the role of pre-treatment NLR and PLR in predicting overall survival (OS) of patients treated with ICIs. Materials and Methods: We retrospectively reviewed the clinical records of 106 consecutive patients with R/M-HNSCC who received ICIs (single-agent or ICIs-based treatment) between January 2018 and June 2023 at the Istituto Oncologico Veneto of Padua. Patients were grouped into platinum-refractory (patients progressed within 6 months from the last platinum dose) and platinum-sensitive. The cut-off values of pre-treatment NLR and PLR were determined based on percentile distribution (75th percentile). OS was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used to compare survival outcomes. Results: A total of 102 patients were analyzed. Four patients were excluded because of incomplete data. Primary tumor sites were oropharynx (37%), oral cavity (24%), hypopharynx (19%), larynx (15%), nasopharynx (5%) and nasal cavity (1%). 63 patients (62%) with platinum-refractory disease received nivolumab single-agent. All 39 patients (38%) with platinum-sensitive disease were PD-L1 positive (CPS≥1) and received pembrolizumab-based treatment. Median OS was 8.0 months (95% CI 5.8-10.1) in the platinum-refractory cohort and 13.3 months (95% CI 7.3-19.3) in the platinum-sensitive cohort. At the univariate analysis high NLR (≥7) and PLR (≥345) correlated with poor OS in the overall population and in both the platinum-refractory and the platinum-sensitive cohorts (Table1). At the multivariate analysis PLR was an independent predictor of OS. Conclusions: The efficacy results reported in this retrospective series were in line with the literature data. High PLR was an independent predictor of poor outcome regardless of the platinum sensitivity. Prospective studies are needed to better explore the predictive role of easily obtainable blood biomarkers in this poor prognostic population. Univariate analysis for OS [Table: see text]
Comparative efficacy of pembrolizumab with carboplatin and paclitaxel as first-line (1L) therapy in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): A network meta-analysis (NMA) with matching-adjusted indirect comparison (MAIC).
Authors: Zheng Dandan , Mojebi Ali , Black Christopher M. , Giezek Hilde , Naicker Niroshini , Vanetta Chiara , Keeping Sam , Merchant Sanjay , Dzienis Marcin Radoslaw
Published: June 2024

e18006

Background: The single-arm, phase IV, KEYNOTE-B10 (KNB10) trial demonstrated the antitumor effect of the KNB10 regimen for 1L treatment of R/M HNSCC. It is critical to understand the comparative efficacy of the KNB10 regimen versus other recommended interventions in 1L R/M HNSCC, using advanced evidence synthesis methodologies, to inform clinical decision making. Methods: A systematic literature review, conducted on October 31, 2023, identified 25 randomized controlled trials evaluating 1L interventions in R/M HNSCC, of which six evaluated recommended interventions and formed a connected network. Of these, KEYNOTE-048 was determined to be the most similar study to the disconnected, single-arm, KEYNOTE-B10 trial. Therefore, individual patient-level data from KEYNOTE-B10 final analysis were reweighted and matched to KEYNOTE-048 via a MAIC in terms of metastatic disease, PD-L1 Combined Positive Score, ECOG performance status, primary tumor location as well as HPV status, sex, race, age, and smoking status. KEYNOTE-B10 was then considered an additional treatment arm of KEYNOTE-048 and was incorporated in the network. Fixed-effect NMA models in Bayesian framework were then used to estimate odds ratios of objective response rate (ORR), with 95% credible intervals, for comparisons between KNB10 and other interventions recommended for 1L R/M HNSCC. Results: Results from the fixed-effects NMA are summarized in the table. For ORR, the KNB10 regimen was more efficacious compared to pembrolizumab+platinum+5-FU, cetuximab+platinum+5-FU, platinum+5-FU, cisplatin+paclitaxel, cisplatin, 5-FU, and methotrexate ( p < 0.05). There was no statistically significant difference in ORR between the KNB10 regimen and cetuximab+cisplatin+docetaxel. Conclusions: This NMA with MAIC suggests patients treated with the KNB10 regimen had improved or comparable ORR outcomes versus other recommended 1L interventions for R/M HNSCC, which further reinforces the combination therapy of pembrolizumab+platinum+taxane as an acceptable alternative 1L treatment option for R/M HNSCC. Future analyses should additionally compare survival outcomes between the KNB10 regimen and other recognized interventions in this patient population. [Table: see text]
Survival outcomes of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with platinum-based chemotherapy plus paclitaxel after anti-PD-1 monotherapy.
Authors: Burkitt Kyunghee , Fu Pingfu , Margevicius Seunghee
Published: June 2024

e18010

Background: There have been reports of higher than expected objective response rate (ORR) to platinum-based combinations following immunotherapy failure in a number of metastatic solid and hematological malignancies. In light of these intriguing results and the fact that the optimal second line regimen for R/M HNSCC after immunotherapy remains unclear, we conducted a prospective cohort study of patients with R/M HNSCC treated with platinum-based chemotherapy plus paclitaxel after anti-PD-1 monotherapy to investigate survival outcomes. Methods: This is a single institutional prospective cohort study which has a total of 12 patients with R/M HNSCC. Within 2 weeks after confirmation of progression from anti-PD-1 monotherapy (pembrolizumab or nivolumab), platinum-based chemotherapy (cisplatin 80mg/m2 or carboplatin AUC=5) plus paclitaxel 175mg/m2 every 21 day cycle were initiated and continued for a total of 3-9 cycles. The best overall response (BOR) was assessed by RECIST v1.1. ORR was determined based on binomial distribution theory and Wilson’s method. Progressive-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method. The association between ORR and HPV status, PD-L1 score were determined by the chi-square test. Blood samples were collected prior to the start of chemotherapy and also at the time of restaging scans (every 3 cycles of chemotherapy) for RNA sequencing. Results: Patients were treated from May 2021 to June 2023. There were 10 men and 2 women, median age of 63 years (range, 51-73) and ECOG 0-1. Oropharynx (9, 75%) was the most common primary site (oral cavity: 1, larynx: 1). Eleven (92%) had distant metastatic disease. 45% of patients (5 out of 11) had PD-L1 CPS <50. 58% of patients (7 out of 12) had HPV positive HNSCC. The median follow up of the study was 15.6 (range: 4.9-23.9) months. The ORR was 75% with 95% CI: 0.47- 0.91. The median OS was 17.9 months and median PFS was 6.74 months. The median OS for PDL1 >= 50 is longer than 23.9 months vs 15 months in patients with PD-L1 CPS <50. Compared to HPV negative patients, HPV positive patients had a superior median PFS (8.75 vs 3.9 months, p= 0.069). The ORR by HPV status was higher in HPV positive than HPV negative patients (85.7% vs 60%, p=0.311), and the ORR by PDL1 score was higher in PDL1 ≥ 50 than PDL1 <50 (100% vs 66.7%, p=0.154), but neither ORR by HPV status nor PDL1 was significant. Conclusions: Platinum-based chemotherapy plus paclitaxel after anti-PD-1 monotherapy showed dramatically higher ORR and more favorable median OS compared to the historical data from the pre-anti PD-1 era (ORR: 75% vs 26%, median OS: 17.9 vs 8.1 months), which warrants a larger prospective study for validation. Our ongoing analysis of RNA sequencing may reveal mechanism for immunotherapy induced chemosensitization effect.
Impact of tertiary lymphoid structures in response to immune checkpoint blockade in patients with head and neck squamous cell carcinoma.
Authors: Ruiz Torres Daniel A. , Hirayama Shun , Merkin Ross D. , Roberts Thomas J. , Patel Manisha Jayandra , Park Jong Chul , Wirth Lori J. , Sadow Peter , Sade-Feldman Moshe , Stott Shannon , Faden Daniel
Published: June 2024

e18021

Background: Immune checkpoint blockade (ICB) is the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), yetefficacy remains low. Current assessment for tumor response relies on a single proportional biomarker expressed in immune and tumor cells (Combined Positive Score, CPS) without differentiation by cell type, potentially explaining its limited predictive value. Tertiary Lymphoid Structures (TLS) have shown a stronger association with improved ICB response than PD-L1. However, their exact composition, size, and spatial biology in HNSCC remain understudied, and there is a need for a deeper examination of TLS biology in HNSCC and its link with clinical response to ICB. Methods: Pre-ICB tumor tissue sections (formalin-fixed, paraffin-embedded) were obtained from 10 responders (complete response, partial response, or stable disease) and 10 non-responders to ICB (progressive disease). A custom multi-immunofluorescence (mIF) staining assay was designed, optimized, and applied to characterize tumor cells (pan-cytokeratin), T cells (CD4, CD8), B cells (CD19, CD20), myeloid cells (CD16, CD56, CD163), dendritic cells (LAMP3), fibroblast (alpha Smooth Muscle Actin), proliferative status (Ki67) and immunoregulatory molecules (PD1). Following imaging and tissue classification using machine learning techniques, spatial profiling was performed, including proximity, density, and infiltration analysis. Response status was assessed via RECIST 1.1. Spatial metrics were compared among groups based on response to ICB. An unpaired t-test was used to compare mean densities. Multivariable logistic regression was used to measure the effect of TLS size on achieving response to ICB (CR, PR or SD). Results: A higher density of dendritic cells (LAMP3) was found in responders compared to non-responders to ICB (p=0.0415). A positive correlation was observed between mIF and pathologist identification of TLS (r2=0.51; p=0.0039). TLS trended toward more prevalent in responders to ICB (p=0.0906). There was no association of high CPS (>20) with improved PFS (HR=0.91; p-value=0.8538 C.I.= 0.3538-2.369). Multivariate logistic regression analysis showed that total TLS area > 5.8 (mm²) (mean TLS size in this cohort) in pretreatment tissue biopsies was associated with 2.4 increased odds of achieving objective response (OR= 2.4, p=0.05, 95% C.I.=1.2-275.1) independent of CPS score. Conclusions: Tertiary Lymphoid Structures play a critical role in the immune response to HNSCC, are quantifiable through histopathologic assessment by a pathologist, and may potentially outperform CPS as a predictor of ICB response.
Role of induction chemotherapy in locally advanced oropharyngeal carcinoma in Indian population.
Authors: Moorthy Vijay , Naik Radheshyam , Bj Srinivasa , Patil Shekar , Thungappa Satheesh Chiradoni , Kumar Delvin , T P Sharafudheen , Adadi Srinivasa Naidu
Published: June 2024

e18026

Background: Head and neck cancer is the third most frequent cancer in Indian men, it is a growing public health problem. Given the numerous disparities in head and neck cancer biology, etiologic and demography between the developing world and the developed world, management guidelines should be based on Indian literature rather than western data. This study aims to define role of Induction chemotherapy in locally advanced oropharyngeal cancer In Indian population by comparing the outcomes which are Overall response rate (O.R.R), Progression free survival (P.F.S), overall survival (O.S) between patients who received Induction chemotherapy followed by CTRT vs CTRT. Methods: Patients who were registered for treatment between jan-2018 to dec-2022 who met the selection criteria were included for the study. Selection criteria: Patients who were diagnosed with Stage III OR IV (a & b, non-metastatic) oropharyngeal squamous cell carcinoma from age group of 20 to 70 who were HPV negative or unknown status were included for study. Total of 50 patients were chosen for the study after stringent selection criteria. Out of 50 ,23 patients received Induction chemotherapy and 27 patients received only CTRT. Results: Overall response rate was analysed using Interim PET CT after Induction chemotherapy and PET CT after 3 to 6 months of CTRT. Complete response and partial response is considered as ORR. It was observed that ORR in sequential therapy arm is 42% and only CTRT arm is 36%, however this is not statistically significant with p value of 0.54. Median PFS for CTRT arm is 8 months and median PFS for IC +CTRT arm is 12 months with p value = 0.97(>0.05) (Log rank test) which is not statistically significant. Median OS for CTRT is 60 months and IC+ CTRT is 18 months. The log rank test has been used for comparing the overall survival outcomes of both the groups , and thus the p-value obtained is 0.56(>0.05), which shows that there is no statistically significant difference in the survival outcome of the two groups. Conclusions: In conclusion, our study on induction chemotherapy in locally advanced head and neck cancer did not identify statistically significant differences in O.R.R, PFS and OS between the two treatment arms which is concordant with MACH- NC updated 2021 data. Several factors, including patient heterogeneity, sample size, treatment protocol, follow-up, duration, may have contributed to these results, it is essential to interpret these results in the context of the study's limitations. [Table: see text]
Beyond margins: TIME-infused insights into recurrence in surgically treated oral squamous cell carcinoma (OSCC).
Authors: Reghunadhan Parvathy , Rao Vishal Uchila Shishir , Thakur Shalini , Subash Anand , George Abhijith , Sharma Anamika
Published: June 2024

e18036

Background: Surgical margins are considered negative if the tumor is 3-5mm away from margins. At times patients with clear margins report back with a recurrence. There are factors beyond the margins that needs to be analyzed. The tumor immune microenvironment (TIME) plays a critical role in cancer development, progression, & control. Aim: To assess the TIME at different surgical margins and derive scoring criteria for the prognostication of recurrence in OSCC. Objective: 1) Derive a TIME score that prognosticates the recurrence-free survival (RFS) and overall survival (OS) of the patients 2) Determine the most significant margin at which TIME score can be estimated. Methods: A retrospective cohort study between 2016 to 2023. Slides of the OSCC patients who had local recurrence were evaluated for TIME parameters: a) Tumor infiltrating lymphocytes (TILS)-(CD3, CD4, CD8, FOXP3, CD57) b) Tumor associated macrophages (TAMS)-(CD68, CD163) c) Programmed death Ligand(PDL-1) d) P53 and d) Desmoplasia at - Interphase, 1mm, 3mm, 5mm, & periphery of the surgical specimen. 30 patients were included. Logistic Regression Equation (LRE) was derived for all the variables of TIME at 5 different margins. Significant margin and average RFS & OS obtained. TIME score was derived. A standard equation for RFS & OS was obtained using the TIME score. Results: Total = 30 patients. 19 were 40-60 years. Tongue was common site(36.66%). The predicted RFS = 23+/- 7 Months (M). OS = 47+/-8M. Regression model with the highest accuracy was found at 3mm margins (83.33%) for all the variables. LRE were fitted for all the variables to find the RFS & OS. LRE for RFS for each parameter at 3mm: TILS:12.4211-0.0190*CD3-0.1222*CD4-0.0979*CD8-0.0744*FXOP3-0.1809*CD57 TAMS: -0.6635+0.0768*CD68 +0.0241*CD163 PDL1: -0.4055+0.5878*PDL1+TC +2.1972*PDL1+2.1972*PDL1 DESMOPLASIA: 0.4055+0.4418* DESMOPLASIA GRADE P53: 0.4700+0.4055*P53 LRE for OS for each parameter at 3mm: TILS:0.5784+0.0262*CD3-0.0233*CD4-0.0132*CD8-0.0233*FXOP3-0.0036*CD57 TAMS: -2.8158+0.1307*CD68 + 0.0451*CD163 PDL-1: -1.3860+1.9460*PDL1 + 1.0990*PDL1 + 0.4700*PDL1 DESMOPLASIA: -0.4055* DESMOPLASIA P53: -0.8109+0.9287*P53 Value (V) From the above equations substituted in : Probability=1/1+exp(-V)), >0.5 the score is 0 : RFS (< 23+/-7 M), OS (<47+/-8 M) <0.5 the score is 1 : RFS (>23+/-7 M), OS (>47+/-8 M) Summing the score from each equation= TIME score (Max. score =5) RFS = 15.621+3.030*TIME score (p Value significant) OS = 11.481+10.699*TIME score(p Value significant) Conclusions: The TIME score can be the real-time estimator of the recurrence in surgically treated OSCC. 3mm margins have best accuracy in evaluating the RFS and OS. Average RFS & OS are 23+/-6 & 47+/-8 M respectively.
Quantifying the financial impact of treatment intolerance in chronic myeloid leukemia on oncology clinical practices: A mixed methods study.
Authors: Shafrin Jason , Jadhav Kehal , Warren Cheryl , Quddus Sabiha , Zawadzki Nadine , Yang Daisy , Damon Andrea , Spurrier Kathryn , Batt Katharine , Wei David
Published: June 2024

e18520

Background: Tyrosine kinase inhibitors (TKIs) have changed the prognosis for patients with chronic myeloid leukemia (CML) to a chronic disease. However, adverse events related to TKI treatment intolerance frequently occur. While the impact of CML treatment intolerance on patient quality of life and cost to health insurers has previously been measured, the time and cost impact to oncology practices is unknown. This mixed methods study aimed to estimate the average time and cost to oncology practices per CML treatment intolerance episode. Methods: The study combined interviews of oncology practice staff with economic modeling. A convenience sample of oncology practice managers was interviewed between October 2023 - January 2024. Interviews aimed to identify and quantify the cost dimensions of addressing treatment intolerance in CML patients. Time impacts reported by respondents were converted into monetary terms using hourly compensation rates of staff needed to complete the identified task. Results: A total of 10 academic oncology practice managers participated in the study. Eight cost dimensions were identified including time spent on prior authorization for medication switch, patient communication, follow-up visits, and care coordination after inpatient stays. Estimated practice time and cost per treatment intolerance episode requiring hospitalization were 34 hours and $3,413 (Table), which were largely attributable to navigating payer prior authorization for medication switch (10 hours, $871), additional follow-up visits (8 hours, $858) and care coordination with inpatient team (9 hours, $782). Activities that could be coded for reimbursement represented only 31.9% of incurred cost. The time and cost per treatment intolerance episode requiring no hospitalization were 17 hours and $1,772. Other burdens not explicitly quantified included negative impact on patient satisfaction, staff morale and care continuity. Conclusions: CML treatment intolerance imposes additional resource and economic burden on oncology practices, and most of these activities are not reimbursed in the current healthcare system. [Table: see text]