bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of CN201, a novel CD3xCD19 IgG4 bispecific antibody, in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia.
Authors: Wang Ying , Yin Qingsong , Ren Jinhai , Zhou Hongsheng , Gong Tiejun , Zhu Feng , Zhang Xi , Wen Qin , Mei Heng , Huang Wei , Li Haiying , Wang Jianxiang 
Published: June 2024

6505 Background: Patients with relapsed or refractory B-cell acute lymphoblastic leukaemia (B-ALL) still need more and better treatment options. CN201 is a novel CD19-targeting T-cell-engaging IgG4 bispecific antibody. This phase I study is to investigate the safety, tolerability and preliminary efficacy of CN201 in B-ALL (ClinicalTrials.gov identifier: NCT05579132). The data from the dose escalation and expansion of the ongoing study is presented. Methods: The study is enrolling patients with B-ALL who are refractory to primary induction therapy or to salvage therapy, or relapse. Patients with Philadelphia chromosome-positive after two or more tyrosine kinase inhibitors (TKIs) were eligible. Single-agent CN201 was administered intravenously once per week with a step-up dose approach during cycle 1, a priming dose on Day 1 followed by an intermediate dose on Day 8 and the target dose administered on Day 15 and thereafter. The patients will receive 2 cycles of CN201 for induction. Responders will continue to receive a further 3 cycles for consolidation, and up to an additional 7 cycles for maintenance treatment or until PD or unacceptable toxicity. Results: As of January 31, 2024, 42 adult patients received CN201 with full dose from 600 μg to 40mg. 37 patients were evaluable for efficacy (Table1). Maximum tolerated dose has not reached. The most common adverse events (≥20%) of grade 3 or higher were leukopenia (47.6%), lymphopenia (42.9%), neutropenia (38%), thrombopenia (33.3%) , anaemia (26.2%). 6 patients (14.3%) had infections of grade 3 or higher. Cytokine release syndrome occurred in 13 (30.9%) patients, mainly occurred following the first dose, most were low-grade, except for one patient with grade 3. No immune effector cell-associated neurotoxicity syndrome was observed. Overall, 11 (30%) of 37 patients had complete remission (CR), 1 (2.7%) patient had complete remission with incomplete haematological recovery (CRi), 75% of responders had MRD negativity. The CR rate significantly increased with dose descalation, reached 50% (4 of 8 patients) with 10mg target dose, two of those occurred within the first two weeks following CN201 treatment. Among those responders, 100% were MRD negative. The CR rate in patients with higher dose levels are under investigation. Conclusions: Preliminary data show CN201 has a well tolerable safety profile and promising activity in adult patients with relapsed or refractory ALL. Clinical trial information: NCT05579132 . [Table: see text]
Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL): Post hoc analysis of adverse events of interest from AALL1931.
Authors: Aoki Etsuko , Maese Luke Devon , Loh Mignon , Agarwal Shirali , Chandrasekaran Vijayalakshmi , Liang Yali , Dronamraju Nalina , Iannone Robert , Silverman Lewis B. , Raetz Elizabeth A. , Rau Rachel 
Published: June 2024

6521 Background: The pivotal Children’s Oncology Group Study AALL1931 (NCT04145531) evaluated JZP458, a recombinant Erwinia asparaginase (ASP), in patients with ALL/LBL who developed hypersensitivity/silent inactivation to E. coli-derived ASPs, leading to approval of JZP458 by the FDA and EMA. Primary efficacy and safety data have been reported; here, we report on adverse events of interest (AEIs: allergic reaction, pancreatitis, thrombosis, hepatotoxicity) and nausea/vomiting, and summarize post hoc descriptive analyses of AEIs by timing and known risk factors (eg, age and ethnicity). Methods: Each pegylated E. coli ASP remaining on treatment was replaced by 6 doses of JZP458 administered Monday/Wednesday/Friday (MWF). Three intramuscular (IM) cohorts (1a [25 mg/m2 MWF], n=33; 1b [37.5 mg/m2 MWF], n=83; and 1c [25/25/50 mg/m2 MWF], n=51) and 1 intravenous (IV) cohort (25/25/50 mg/m2 MWF, n=61) were evaluated. Results: Rates of any-grade treatment-related allergic reactions, pancreatitis, thrombosis, increased ALT/AST, and increased bilirubin were 11%, 7%, 1%, 16%, and 7% in the total IM cohort and 26%, 5%, 2%, 18%, and 5% in the IV cohort, respectively. Rates of treatment-related grade ≥2 nausea/vomiting (N/V) were 32% and 64% in the total IM and IV cohorts. Table shows the median number of JZP458 doses on or before the first AEI. Notably, rates of grade ≥2 N/V events were similar after 25 and 50 mg/m2 dosing. Subgroup analyses showed no consistent trends in the rates of any-grade AEIs by age except for pancreatitis where rates were numerically higher in patients aged 12 to <18 (9/62 [15%]) and ≥18 years (4/31 [13%]) than in those aged 6 to <12 (1/71 [1%]) or <6 years (1/64 [2%]). Overall, incidences of any-grade treatment-related allergic reactions, pancreatitis, thrombosis, increased ALT/AST, and increased bilirubin among Hispanic patients (n=74) were 12%, 5% 1%, 19%, and 7% respectively, similar to non-Hispanic patients (n=140). Conclusions: The safety profile of JZP458 is consistent with other ASPs in patients with ALL/LBL and generally similar across age and ethnicity subgroups. Clinical trial information: NCT04145531 . [Table: see text]
Safety and efficacy of olutasidenib treatment in elderly patients with relapsed/refractory mIDH1 acute myeloid leukemia.
Authors: De Botton Stéphane , Jonas Brian Andrew , Ferrell P. Brent , Chao Mwe Mwe , Mims Alice S. 
Published: June 2024

6527 Background: Elderly patients with relapsed/refractory (R/R AML) are a special population that may elevate safety concerns, which must be balanced with clinical benefit. Olutasidenib (OLU), a targeted therapy for m IDH1 AML, was well tolerated in a registrational, Ph2, open-label, multicenter trial and, in the pivotal cohort, demonstrated complete remission (CR) or CR with partial hematologic recovery (CRh) in 35% of patients (age 32-87 years, y) for a median duration of 25.9 months. We evaluated safety and efficacy of OLU in the elderly subgroup (≥75y) with m IDH1 AML. Methods: In the Phase 2 trial, the pivotal cohort enrolled adults with R/R m IDH1AML. OLU was administered at 150 mg BID. Adverse events (AE) and lab values were collected at least monthly and graded based on the NCI CTCAE Version 4.03. Efficacy was based on response criteria of the International Working Group in AML (2003). Results: 153 patients received OLU monotherapy, 147 had centrally-confirmed mIDH1 AML, , and 45 were ≥75y (range 75-87) at study entry. Of the 45 elderly patients, 27 (60%) were male, 51% had ECOG=1, 16% had ECOG =2, 71% were relapsed, 29% had refractory AML, 58% had prior HMA, 11% received prior venetoclax, and none had prior stem cell transplant. Median bone marrow blasts were 43% (5-93). Genetic co-mutations included FLT3 in 9%, NPM1 in 20%, and TP53 in 2%. Grade 3 or 4 adverse events were reported in 45.8% of elderly patients; the most common were decreases in red blood cells (31%), platelets (13%) and neutrophils (10%) as well as febrile neutropenia (15%). AEs were consistent with published pivotal Phase 2 results, with no new safety signals. Deaths occurred in 19 patients due to disease progression (9), pneumonia (2), sepsis (2), GI haemorrhage (1), aortic stenosis (1), atrioventricular block (1), cardiac failure congestive (1), acute kidney injury (1) and other (1). The response to OLU therapy is summarized in the table. 31% of patients ≥75 y achieved CR/CRh; median time to CR/CRh was 1.5 mos (0.9-5.6) and median duration of CR/CRh was 25.9 mos (95%CI 7.4, not reached). Conclusions: Olutasidenib was generally well tolerated in elderly patients with R/R m IDH1AML and induced durable remissions. Despite the challenges of treating elderly patients who had already failed prior AML treatment, the results suggest that elderly patients can benefit from therapy with olutasidenib. Clinical trial information: NCT02719574 . [Table: see text]
Improved survival for myeloid malignancy patients receiving thiotepa/cyclophosphamide (TT/Cy) versus total body irradiation/cyclophosphamide (TBI/Cy) conditioning and allogeneic stem cell transplantation.
Authors: Nichols Cydney , Ervin Kirsten , Schmidt Caitlin , Schwartz Jennifer E. , Abu Zaid Mohammad Issam , Robertson Michael J. , Abonour Rafat , Grove Meagan , Thakrar Teresa , Farag Sherif 
Published: June 2024

6555 Background: TBI/Cy is a commonly used conditioning regimen prior to allogeneic stem cell transplant (SCT). Chemotherapy only regimens, mostly containing busulfan, have been shown to be effective and less toxic in patients with myeloid malignancies. Here, we present the largest reported experience with a non-busulfan myeloablative chemotherapy regimen of TT/Cy in myeloid malignancy patients undergoing allogeneic SCT and compare outcomes with TBI/Cy. Methods: Patients with myeloid malignancies receiving allogeneic SCT at Indiana University from 2007-2020 were included. TT/Cy consisted of TT 15 mg/kg and Cy 120 mg/kg. TBI/Cy consisted of 13.2 Gy in 8 fractions and Cy 3600 mg/m2. The primary endpoint was overall survival (OS). Secondary endpoints included relapse-free survival (RFS), engraftment, and toxicities within the first 100 days. Median follow up for surviving patients is 2,046 (range 816-5,572) days. Results: 225 patients with AML (n=160), CML (n=45), and MDS (n=30) of median age 44 (range 19-59 years) received conditioning with TT/Cy (n=159) or TBI/Cy (n=66). Baseline characteristics were similar. For TT/Cy patients, the median OS was not reached, and 4-year OS was 57.2% (95% confidence interval [CI], 49.2-65.2%), which was significantly better than with TBI/Cy, with median OS 373 days and 4-year OS 33.9% (95% CI, 22.3-45.5%; p<.001). Similarly, for TT/Cy patients, the median RFS was not reached and 4-year RFS was 59.2% (95% CI, 52-67.2%), significantly better than median RFS of 341 days and 4-year RFS 35.2% (95% CI, 23.7-46.9%; p<.001) for recipients of TBI/Cy. On multivariable analysis adjusting for age, sex, diagnosis, disease risk, comorbidity index (HCI), and degree of stem cell source, TT/Cy had significantly lower risk of death (HR 0.44, 95% CI, 0.30-0.65; p<.001) together with female sex (p=.03) and lower HCI (p=.046). As shown in the Table summarizing secondary endpoints, TBI/Cy was associated with significantly higher rates of mucositis, sinusoidal obstruction syndrome (SOS), TPN usage, multiorgan failure, and length of stay of primary admission. Conclusions: TT/Cy is an efficacious regimen for patients with myeloid malignancies undergoing myeloablative allogeneic SCT with less toxicity and improved RFS and OS compared with TBI/Cy. TT/Cy should be compared to other non-TBI containing busulfan-based regimens. [Table: see text]
Noncanonical RET fusions in Chinese patients with non-small cell lung cancer from DNA-based next-generation sequencing.
Authors: Lin Hao , Liu Yujie , Zhou Ruitao , Feng Yutao , Cao Huiya , Suo Peisu , Guo JIA , Chen Shifu 
Published: June 2024

e20000 Background: The FDA has approved selpercatinib and pralsetinib for the treatment of metastatic RET fusion-positive non-small cell lung cancer in adult patients. Although the overall response rate is high and the response is durable, the outcomes may vary due to different fusion types of the same driver gene. Methods: We retrospectively collected and analyzed 14062 samples (tumour tissue or plasma) from Chinese lung cancer patients who underwent tissue-based or ctDNA-based next-generation sequencing (NGS) assays at HaploX Genomic Sequencing Center from May 18, 2020, to January 11, 2024. All samples with a RET gene fusion were included and classified based on the fusion partner gene and breakpoint position. Results: A total of 157 (1.1%) samples with DNA-based NGS harbored a RET gene fusion. Among the samples with a RET gene fusion, the most common RET fusion partners at the DNA level were KIF5B (73.2%) and CCDC6 (21.0%). We categorized RET fusions into canonical fusions and noncanonical fusions based on fusion partner and breakpoint position, and the proportions of canonical fusions and noncanonical fusions were 88.5% (139/157) and 11.5% (18/157) respectively. Among the samples with a noncanonical RET fusion, 5 samples harbored a RET fusion with an uncommon fusion partner, it remains unclear whether these fusions lead to RET activation. Conclusions: In this retrospective study, we identify different types of RET fusions in Chinese lung cancer patients. The majority are canonical fusions, which can benefit from tyrosine kinase inhibitors in clinical, the rest are noncanonical fusions, and their role in precision therapy needs further verification by RNA-based NGS or other assays. All in all, our research helps guide precision therapy in clinical settings. [Table: see text]
PM 2.5 and risk of lung cancer and associated mortality: An umbrella meta-analysis.
Authors: Gupta Ashima , Singh Abhishek , Tarimci Baris , Sindhu Alamjeet Kaur , Bathvar Pinank , Bedi Simranjeet , Theik Nyein Wint Yee , Shah Vedant , Malhotra Saarthak , Khealani Milan , Obulareddy Sri Usha Jeevani , Kukreja Geetika , Kanitkar Amaraja 
Published: June 2024

e20012 Background: PM 2.5, particulate matter with a diameter of 2.5 micrometers or less, is a major contributor to lung cancer and associated mortality. Epidemiological studies reveal a concerning trend, with each 10 micrograms per cubic meter increase in PM 2.5 associated with a 15% higher risk of lung cancer and a 13% increase in mortality rates, underscoring the significant burden it imposes on public health systems globally. We aimed to evaluate the odds of association between environmental exposure to PM 2.5 and the risk of lung cancer and associated mortality. Methods: We performed a systematic review and umbrella meta-analysis using studies containing quantitative data on PM 2.5 and lung cancer. We used PRISMA guidelines and the MOOSE protocol using PubMed and MeSH terms like PM 2.5, non-small cell cancer, lung cancer, pollutants, particulate matter 2.5, and environmental factors. We had excluded non-full-length articles, non-meta-analysis studies, and non-human studies. RavMan 5.4 was used, and generic inverse variance methods with mixed effect models were applied to identify a pooled risk ratio with a 95% confidence interval. Forest plots were obtained, and sensitivity analysis was performed based on funnel plots and I2 (heterogeneity) values. Results: Of the 245,529 articles evaluated for the quality of the data, 99 met the inclusion and exclusion criteria. Out of 99, we used six articles to derive the quantitative data. In umbrella meta-analysis, PM 2.5 exposure was associated with a 1.16 times higher risk (95%CI: 1.1-1.22, p<0.00001, I2=0%) of lung cancer and a 1.22 times higher risk of non-lung cancers (95%CI: 1.15-1.30, p<0.00001, I2=0%). PM 2.5 was associated with non-significant higher mortality (RR: 1.06, 95%CI: 0.99-1.13, p=0.09, I2=97%) with leave-on-out analysis (excluding Chen et al.) significant association between mortality and PM 2.5 (RR: 1.08, 95%CI: 1.06-1.10, p<0.00001, I2=0%). Conclusions: Our umbrella meta-analysis shows a significant risk of lung cancer and mortality from PM 2.5 exposure. Further investigation and increased consciousness are necessary to mitigate the risk of lung cancer associated with this pollutant.
Early-stage lung adenocarcinoma with a micropapillary pattern showing a distinct immunogenic tumor microenvironment.
Authors: Han Yun , Yu Yue , Xu Chongyuan , He Qianru , Zhang Qin , Duan Qianqian , Chen Dongsheng 
Published: June 2024

e20016 Background: Lung adenocarcinomas with a micropapillary pattern (MPP) have been suggested to be associated with prognosis. Immune microenvironment plays a critical role in cancer from onset to relapse. However, it is unclear whether MPP can reflect the tumor immune microenvironment (TIME). Methods: A total of 44 stage I lung cancer patients who underwent surgery at Shengjing Hospital of China Medical University were included (with micropapillary pattern, n = 16; without micropapillary pattern, n = 28). Using NanoString nCounter, the gene expression patterns (GEPs) of 289 tumour immune-related genes were examined. Differentially expressed genes(DEGs), estimation of TIME cell infiltration, and TIME signatures between micropapillary and non-micropapillary were assessed. Results: Significant immunological differences were seen between histological subtypes. Differential gene expression analysis showed that KIR2DL3, MAGEA4, MELK, CD244, and 26 other genes were significantly upregulated in the micropapillary group compared with the non-micropapillary group, while PDGFA, RORC, CCL22, and other seven genes were down-regulated in the micropapillary group. These DEGs were mostly enriched in “leukocyte cell-cell adhesion”, “T cell activation”, “cellular response to chemokine”, and “T cell proliferation” pathways according to GO enrichment analysis. The results of the KEGG analysis revealed that genes were significantly enriched in “Cytokine-cytokine receptor interaction”, “Cell adhesion molecules (CAMs)”, “Chemokine signaling pathway”, and so on. Immune analyses revealed that micropapillary group had a better TIME cell infiltration which are associated with increased CD45, CD8+ T cells, Exhausted CD8, and NK CD56dim cells. Furthermore, the immune signature scores for chemokines, total TILs, and GEP scores were higher in the micropapillary group, indicating increased immune cytotoxic activity. Conclusions: Lung adenocarcinomas with micropapillary pattern were identified as a subtype with enhanced immunogenic tumor microenvironment. According to these results, patients with lung adenocarcinomas that have micropapillary pattern may be a prospective select group who will benefit from adjuvant immunotherapy.
A novel strategy for detecting mutations from circulating tumor DNA with blood tissue only.
Authors: Wen Jiale , Zheng Zhi 
Published: June 2024

e20031 Background: Molecular Residual Disease (MRD) test detects tumor-specific mutations in circulating tumor DNA (ctDNA), which can indicate the risk of tumor recurrence. However, without tumor-specific mutations, detecting mutations in blood tissue alone is extremely challenging due to the low concentration of ctDNA in blood. To address this challenge, we proposed an innovative mutation filtering and calling strategy by simulating noise’s distribution and quality assessment to greatly boost the performance. Methods: We performed 406 pairs of MRD tests on both tumor and blood tissue of postoperative patients with mixed cancer types, including lung, gastrointestinal (GI), hepatobiliary, and pancreatic. Patients that possess one or more tumor-specific mutations in their blood tissue were classified as recurrence high-risk (n = 66), others were classified as recurrence low-risk (n = 340). All sequence data were analyzed using both traditional and proposed method. In the traditional method, VAF threshold, end-reads, multiple-align reads and population frequencies were used as filtering criteria. While in the proposed method, VAF threshold was excluded and two new parameters were introduced: The distribution of variant allele frequency (VAF) of sequencing noise, which simulated 42 healthy individuals’ background noise with conf > 0.995; The normalized proportion of supported unique and total variants, to assess the likelihood of mutations originated from ctDNA. Results: Among 406 patients of mixed tumor types, the traditional approach barely reached a sensitivity of 39.4% and a specificity of 89.1%, while our strategy achieved a sensitivity of 71.2% and a specificity of 80.9%. Particularly among the 92 patients with gastrointestinal tumor, by filtering specific noise caused by the MRD panel (e.g. multi-alignment error of MUC gene family), we further boost the sensitivity from 47.1% to 82.4% with a loss of specificity from 93.3% to 90.7%. Moreover, among 248 patients with lung tumors, the sensitivity and specificity between traditional approach and proposed method were 15.8%, 93.9%, and 52.6%, 90.0% respectively, which might be caused by the low recurrence rate in the patient cohort (19 out of 248). Conclusions: The novel strategy based on simulated noise distribution and read quality assessment surpasses the traditional threshold-based approaches in mutation detection, especially in deep sequencing like MRD tests. The findings of the study indicate that the recurrence monitoring strategy is applicable across various tumor types and exhibits superior performance in GI tumor, albeit with certain limitations. In conclusion, this study boosts the feasibility of MRD as a non-invasive alternative for tissue biopsy by providing a novel mutation filtering strategy, which further strengthen the potential of MRD testing in enhancing cancer patients’ long-term prognosis and treatment.
ViTR-SP: A CT-based vision transformer model for prediction of pneumonitis in patients with non-small cell lung cancer who received thoracic radiotherapy and immunotherapy.
Authors: Yang Linlin , Li Butuo , Dong Taotao , Wang Linlin 
Published: June 2024

e20034 Background: The combination of thoracic radiotherapy (TRT) and immunotherapy accompanied by the accumulation of pulmonary toxicity. This study aimed to construct a deep radiomics model based on sequential computed tomography (CT) images for radioimmune-associated pneumonitis prediction in non-small cell lung cancer (NSCLC) patients treated with TRT and immune checkpoint inhibitors (ICIs). Methods: Three models were constructed based on a vision transformer (ViT) network using sequential chest CT images, tumor-mask and lung-mask as inputs, respectively. NSCLC patients treated with TRT and ICIs at Shandong Cancer Hospital and Qilu Hospital were included for model training and external validation, respectively. The image-level model was trained based on ViT to identify predictive images, and the image-level probability distribution were performed. Then, a ViT-Recursive Neural Network (ViT-RNN) model framework was constructed at the patient-level to integrate the image-level information to derive the final prediction, which was evaluated in an independent validation cohort. Results: A total of 230 NSCLC patients from Shandong Cancer Hospital were randomly assigned in a 7:3 ratio for model training and validation, respectively. Another 42 patients from Qilu Hospital were used as an independent external validation cohort. The ViT-RNN model for symptomatic pneumonitis (ViTR-SP) based on sequential CT images achieved better area under curve (AUC), sensitivity, and specificity of 0.725, 0.750, and 0.886 than lung-mask based model (0.575, 0.625, and 0.705) and tumor-mask based model (0.658, 0.667, and 0.773) in the internal validation set. In the external validation set, the proposed model achieved the AUC, sensitivity, and specificity of 0.654, 0.818, 0.727, while the lung-mask and tumor-mask based models had the AUC, sensitivity, and specificity of 0.540, 0.545, 0.677, and 0.630, 0.545, 0.742, respectively. The performance of the model was improved after integrating clinical features, with internal and external validation AUC of 0.782 and 0.672, respectively. Conclusions: In conclusion, the clinical combined ViTR-SP neural network risk prediction model based on sequential chest CT images can be used for predicting the risk of developing radioimmune-associated pneumonitis in NSCLC patients.