Med最新文献

{"title":"Molecular insights into trauma: A framework of epigenetic pathways to resilience through intervention.","authors":"Sarah M Merrill, Chaini Konwar, Zaid Fraihat, Justin Parent, Rana Dajani","doi":"10.1016/j.medj.2024.11.013","DOIUrl":"10.1016/j.medj.2024.11.013","url":null,"abstract":"<p><p>Experiences of complex trauma and adversity, especially for children, are ongoing global crises necessitating adaptation. Bioadaptability to adversity and its health consequences emphasizes the dynamism of adaptation to trauma and the potential for research to inform intervention strategies. Epigenetic variability, particularly DNA methylation, associates with chronic adversity while allowing for resilience and adaptability. Epigenetics, including age- and site-specific changes in DNA methylation, gene-environment interactions, pharmacological responses, and biomarker characterization and evaluation, may aid in understanding trauma responses and promoting well-being by facilitating psychological and biological adaptation. Understanding these molecular processes provides a foundation for a biologically adaptive framework to shift public health strategies from restorative to long-term adaptation and resilience. Psychological, cultural, and biological trauma must be addressed in innovative interventions for vulnerable populations, particularly children and adolescents. Understanding molecular changes may provide a biopsychosocial perspective for culturally sensitive, evidence-based interventions that promote resilience and thriving in new settings.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100560"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of distinct stool metabolites in women with endometriosis for non-invasive diagnosis and potential for microbiota-based therapies.","authors":"Chandni Talwar, Goutham Venkata Naga Davuluri, Abu Hena Mostafa Kamal, Cristian Coarfa, Sang Jun Han, Surabi Veeraragavan, Krishna Parsawar, Nagireddy Putluri, Kristi Hoffman, Patricia Jimenez, Scott Biest, Ramakrishna Kommagani","doi":"10.1016/j.medj.2024.09.006","DOIUrl":"10.1016/j.medj.2024.09.006","url":null,"abstract":"<p><strong>Background: </strong>Endometriosis, a poorly studied gynecological condition, is characterized by the presence of ectopic endometrial lesions resulting in pelvic pain, inflammation, and infertility. These associated symptoms contribute to a significant burden, often exacerbated by delayed diagnosis. Current diagnostic methods involve invasive procedures, and existing treatments provide no cure.</p><p><strong>Methods: </strong>Microbiome-metabolome signatures in stool samples from individuals with and without endometriosis were determined using unbiased metabolomics and 16S bacteria sequencing. Functional studies for selected microbiota-derived metabolites were conducted in vitro using patient-derived cells and in vivo by employing murine and human xenograft pre-clinical disease models.</p><p><strong>Findings: </strong>We discovered a unique bacteria-derived metabolite signature intricately linked to endometriosis. The altered fecal metabolite profile exhibits a strong correlation with that observed in inflammatory bowel disease (IBD), revealing intriguing connections between these two conditions. Notably, we validated 4-hydroxyindole, a gut-bacteria-derived metabolite that is lower in stool samples of endometriosis. Extensive in vivo studies found that 4-hydroxyindole suppressed the initiation and progression of endometriosis-associated inflammation and hyperalgesia in heterologous mouse and in pre-clinical models of the disease.</p><p><strong>Conclusions: </strong>Our findings are the first to provide a distinct stool metabolite signature in women with endometriosis, which could serve as stool-based non-invasive diagnostics. Further, the gut-microbiota-derived 4-hydroxyindole poses as a therapeutic candidate for ameliorating endometriosis.</p><p><strong>Funding: </strong>This work was funded by the NIH/NICHD grants (R01HD102680, R01HD104813) and a Research Scholar Grant from the American Cancer Society to R.K.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100517"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Responsiveness of different disease activity indices in moderate-to-severe ulcerative colitis.","authors":"Virginia Solitano, Remo Panaccione, Bruce E Sands, Zhongya Wang, Malcolm Hogan, Guangyong Zou, Laurent Peyrin-Biroulet, Silvio Danese, Linda J Cornfield, Brian G Feagan, Siddharth Singh, Vipul Jairath, Christopher Ma","doi":"10.1016/j.medj.2024.09.001","DOIUrl":"10.1016/j.medj.2024.09.001","url":null,"abstract":"<p><strong>Background: </strong>Clinical, endoscopic, histological, and composite instruments are currently used to measure disease activity in patients with ulcerative colitis (UC). We compared the responsiveness of the Mayo Clinic score (MCS), modified MCS (mMS; excluding physician global assessment), partial MCS (pMS; MCS without endoscopic subscore), Robart's Histopathology Index (RHI), and UC-100 score to change after ustekinumab treatment in patients with moderately to severely active UC.</p><p><strong>Methods: </strong>Post hoc analysis of the phase 3 UNIFI induction trial (ClinicalTrials.gov: NCT02407236) was conducted. Participants with moderately to severely active UC were randomized to receive ustekinumab or placebo. Treatment assignment was the criterion to assess responsiveness, which was quantified using the probability of a treated participant having a larger change in score than a placebo participant, termed the win probability (WinP), and estimated using nonparametric methods.</p><p><strong>Findings: </strong>The UC-100 score demonstrated large responsiveness (WinP 0.72 [95% confidence interval: 0.66-0.78]), and the MCS (0.68 [0.62-0.73]), mMS (0.69 [0.63-0.75]), and pMS (0.65 [0.59-0.71]) demonstrated similar effect sizes. Of the component items of the Mayo score, the endoscopic subscore (WinP 0.76 [0.69-0.82]) and the stool frequency subscore (WinP 0.74 [0.69-0.79]) were the most responsive. The Inflammatory Bowel Disease Questionnaire (IBDQ) quality-of-life questionnaire was also responsive (WinP 0.78 [0.72-0.82]).</p><p><strong>Conclusions: </strong>UC disease activity indices are similarly responsive. Depending on the treatment setting, time point of evaluation, and feasibility of measurement, different scores may be used to demonstrate response. These results support the use of mMS as a composite primary endpoint, incorporating both patient-reported and endoscopic outcome measures. The UC-100 score may be more appropriate in settings that also routinely incorporate histological evaluation.</p><p><strong>Funding: </strong>There is no funding for this study.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100512"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors.","authors":"Ángel Bayón-Gil, Inmaculada Hernández, Judith Dalmau, Juan C Nieto, Víctor Urrea, Lidia Garrido-Sanz, Ginevra Caratú, Maria C García-Guerrero, Cristina Gálvez, María Salgado, Itziar Erkizia, Fernando Laguía, Patricia Resa-Infante, Marta Massanella, Raúl Tonda, Jordi Morata, Kai Ying Hong, Jane Koshy, Aaron R Goldman, Leila Giron, Mohamed Abdel-Mohsen, Holger Heyn, Javier Martinez-Picado, Maria C Puertas","doi":"10.1016/j.medj.2024.09.007","DOIUrl":"10.1016/j.medj.2024.09.007","url":null,"abstract":"<p><strong>Background: </strong>Viremic non-progressors (VNPs) represent an exceptional and uncommon subset of people with HIV-1, characterized by the remarkable preservation of normal CD4⁺ T cell counts despite uncontrolled viral replication-a trait reminiscent of natural hosts of simian immunodeficiency virus. The mechanisms orchestrating evasion from HIV-1 pathogenesis in human VNPs remain elusive, primarily due to the absence of integrative studies.</p><p><strong>Methods: </strong>We implemented a novel single-cell and multiomics approach to comprehensively characterize viral, genomic, transcriptomic, and metabolomic factors driving this exceedingly rare disease phenotype in 16 VNPs and 29 HIV+ progressors.</p><p><strong>Findings: </strong>Genetic predisposition to the VNP phenotype was evidenced by a higher prevalence of CCR5Δ32 heterozygosity, which was associated with lower levels of CCR5 expression and a lower frequency of infected cells in peripheral circulation. We also observed reduced levels of plasma markers of intestinal disruption and attenuated interferon responses in VNPs. These factors potentially drive the other phenotypic traits of immune preservation in this population, including the unaltered tryptophan metabolic profile, reduced activation of cytotoxic lymphocytes, and reduced bystander CD4⁺ T cell apoptosis.</p><p><strong>Conclusions: </strong>In summary, our comprehensive analysis identified intricate factors collectively associated with the unique immunovirological equilibrium in VNPs, shedding light on potential avenues for therapeutic exploration in managing HIV pathogenesis.</p><p><strong>Funding: </strong>The work was supported by funding from the Spanish Ministry of Science and Innovation and the National Institutes of Health (NIH).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100518"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlation of PSA and survival in metastatic hormone-sensitive prostate cancer treated with rezvilutamide plus ADT in the CHART trial.","authors":"Xiaojie Bian, Weijie Gu, Xuepei Zhang, Liping Xie, Shaogang Wang, Benkang Shi, Ting Sun, Shaozhong Wei, Zhiliang Weng, Shujie Xia, Bangmin Han, Zhuoqun Xu, Jinchun Xing, Dahong Zhang, Danfeng Xu, Chuanjun Du, Chaohong He, Qilin Wang, Xinfeng Yang, Jianpo Lian, Wenliang Wang, Dingwei Ye","doi":"10.1016/j.medj.2024.09.009","DOIUrl":"10.1016/j.medj.2024.09.009","url":null,"abstract":"<p><strong>Background: </strong>This exploratory analysis of the CHART trial (ClinicalTrials.gov: NCT03520478) investigated prostate-specific antigen (PSA) kinetics and the correlation between PSA and survival outcomes in high-volume, metastatic, hormone-sensitive prostate cancer (mHSPC).</p><p><strong>Methods: </strong>A total of 654 patients were randomized 1:1 to receive either rezvilutamide plus androgen deprivation therapy (ADT; n = 326) or bicalutamide plus ADT (n = 328). PSA kinetics were evaluated, and the correlation between survival and the achievement of undetectable PSA (≤0.2 ng/mL) or ≥90% PSA reduction (PSA90) was assessed.</p><p><strong>Findings: </strong>The rezvilutamide group exhibited higher proportions of ≥50% PSA reduction (PSA50; 98.2% vs. 87.5%), PSA90 (88.7% vs. 63.1%), and undetectable PSA (38.3% vs. 17.7%) responses compared to the bicalutamide group by 3 months. The rezvilutamide group demonstrated superior efficacy in delaying PSA progression compared to the bicalutamide group (hazard ratio [HR] 0.21, 95% confidence interval 0.16-0.27). The achievement of undetectable PSA and PSA90 by 6 months in the rezvilutamide group was associated with prolonged overall survival (undetectable PSA, HR = 0.34; PSA90, HR = 0.22), radiographic progression-free survival (HR = 0.36, HR = 0.26), time to PSA progression (HR = 0.25, HR = 0.17), and time to castration resistance (HR = 0.34, HR = 0.23) compared to those who did not achieve these PSA milestones. Stratification by baseline PSA level revealed consistent survival improvements with rezvilutamide plus ADT across quartiles.</p><p><strong>Conclusions: </strong>PSA kinetics is a valuable prognostic factor in mHSPC treated with rezvilutamide plus ADT, and the achievement of undetectable PSA and PSA90 is associated with improved survival. These findings highlight the importance of monitoring PSA kinetics in the management of mHSPC.</p><p><strong>Funding: </strong>This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100520"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV viremic non-progressors: More clues and more questions.","authors":"Julia Hitschfel, Bruce D Walker","doi":"10.1016/j.medj.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.014","url":null,"abstract":"<p><p>Viremic non-progressors are a unique subset of untreated people living with HIV who remarkably maintain high CD4⁺ T cell counts despite continuous high plasma viral loads. To better understand this rare phenotype, Bayón-Gil et al. explored host genetic and immunologic factors distinguishing viremic non-progressors from individuals with progressive disease.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 2","pages":"100537"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reaching the SUMMIT? Benefits and potential risks associated with the use of tirzepatide in heart failure with preserved ejection fraction.","authors":"Kristian Hellenkamp, Ryosuke Sato, Stephan von Haehling","doi":"10.1016/j.medj.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.medj.2024.12.004","url":null,"abstract":"<p><p>The SUMMIT trial¹ showed that the dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist tirzepatide improves quality of life and reduces worsening heart failure (HF) events in patients with HF with preserved ejection fraction (HFpEF) and obesity. Some concerns, however, remain.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 2","pages":"100570"},"PeriodicalIF":12.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KRAS mutation status integrated with RNA subtyping improves prognostic modeling in FOLFIRINOX-treated metastatic pancreatic cancer.","authors":"Marjolein F Lansbergen, Mark P G Dings, Jan Koster, Mariette Labots, Emile D Kerver, Anouk Jochems, Marjolein Y V Homs, Judith de Vos-Geelen, Mathijs P Hendriks, Michael W T Tanck, Johanna W Wilmink, Hanneke W M van Laarhoven, Maarten F Bijlsma","doi":"10.1016/j.medj.2025.100601","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100601","url":null,"abstract":"<p><strong>Background: </strong>First-line chemotherapy (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin [FOLFIRINOX]) benefits few patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Prognostic markers for treatment-related survival are needed. This study validated the added benefit of whole-genome sequencing (WGS) to transcriptome-based classification in modeling FOLFIRINOX-related survival.</p><p><strong>Methods: </strong>Patients with mPDAC planning to start FOLFIRINOX were included in a prospective nationwide cohort. Pretreatment biopsies were submitted to WGS and RNA sequencing. Samples of non-FOLFIRINOX-treated patients were included for exploratory analyses.</p><p><strong>Findings: </strong>WGS was performed in biopsies from 108 FOLFIRINOX-treated patients and 51 non-FOLFIRINOX-treated patients. 12% of the tumors were KRAS wild type. These tumors had more targetable alterations (42% vs. 17%) and were associated with a longer median overall survival (mOS) than KRAS mutant tumors (7.8 months in KRAS mutant vs. 17.7 months in wild-type tumors, p = 0.0024). Transcriptome-based clustering revealed a tumor subgroup showing low classical and basal-like gene expression, enriched for KRAS wild-type status (p < 0.0001), a so-called \"classifier-negative\" subtype. The gene expression of these classifier-negative tumors correlated with neural-like signatures. For patients with a homologous recombination-deficient (HRD) tumor, mOS was not increased (8.0 months in homologous recombination-proficient [HRP] vs. 13.3 months in HRD tumors, p = 0.21).</p><p><strong>Conclusions: </strong>KRAS wild-type tumors are a distinct PDAC subgroup with a better prognosis. Consequently, KRAS status assessment before transcriptome-based subtyping can stratify patients into three prognostic molecular subgroups (KRAS wild type, KRAS mutant classical, and KRAS mutant basal like). This integrative way of classification should be validated prior to incorporation in diagnostic practice.</p><p><strong>Funding: </strong>ZonMw \"Good Use of Medicine\" program (848101012).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100601"},"PeriodicalIF":12.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toripalimab plus platinum-doublet chemotherapy as perioperative therapy for initially unresectable NSCLC: An open-label, phase 2 trial.","authors":"Liang Zeng, Huan Yan, Wenjuan Jiang, Haoyue Qin, Jiacheng Dai, Yuda Zhang, Shiyou Wei, Shanmei Chen, Li Liu, Yi Xiong, Haiyan Yang, Yizhi Li, Zhan Wang, Li Deng, Qinqin Xu, Ling Peng, Ruiguang Zhang, Chao Fang, Xue Chen, Jun Deng, Jing Wang, Ting Li, Hong Liu, Gao Zhang, Nong Yang, Yongchang Zhang","doi":"10.1016/j.medj.2025.100574","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100574","url":null,"abstract":"<p><strong>Background: </strong>Perioperative treatment with toripalimab combined with chemotherapy was efficacious and safe in resectable stage II-IIIA non-small cell lung cancer (NSCLC); however, little is known about whether this treatment regimen could convert unresectable NSCLC to resectable.</p><p><strong>Methods: </strong>This study enrolled 40 treatment-naive patients with initially unresectable stage IIIA-IIIB NSCLC. Toripalimab (240 mg) and platinum-doublet chemotherapy were administered every 3 weeks for 2-4 cycles. Surgical resection was decided after assessing the efficacy of induction therapy. The primary outcome was the R0 resection rate. The secondary outcomes included safety, overall survival, disease-free survival, event-free survival, objective response rate, major pathological response (MPR), and pathological complete response (pCR). Available baseline tumor biopsy samples were used for molecular biomarker analyses, including bulk RNA sequencing and multiplex immunostaining. This study was registered at ClinicalTrials.gov: NCT04144608.</p><p><strong>Findings: </strong>Of the 40 patients who received induction toripalimab plus chemotherapy, 29 (72.5%) patients received surgery, and all achieved R0 resection (100% R0 rate). Of these patients, 17 (58.6%) achieved MPR, with 10 (34.5%) patients evaluated as pCR. With a median follow-up of 31.8 months (95% confidence interval [CI]: 24.2-39.4), the median event-free survival and overall survival were not reached. Molecular analyses revealed highly expressed gene sets for germinal center B cells (signatures of tertiary lymphoid structure [TLS]) at baseline among patients with pCR compared to patients with non-pCR, suggesting that the TLS status of the patients was associated with the induction of immunotherapy responses.</p><p><strong>Conclusions: </strong>Toripalimab-based induction treatment of initially unresectable NSCLC yielded a high R0 rate and MPR rate, with a good safety profile and encouraging survival outcomes.</p><p><strong>Funding: </strong>This work was funded by the National Natural Science Foundation of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100574"},"PeriodicalIF":12.8,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMPL-306 in relapsed or refractory IDH1- and/or IDH2-mutated acute myeloid leukemia: A phase 1 study.","authors":"Lijuan Hu, Xudong Wei, Weili Zhao, Yu Hu, Juan Li, Yugang Dong, Tiejun Gong, Xuhan Zhang, Yajing Xu, Yu Zhang, Chongyuan Xu, Cheng Zhang, Zhen Cai, Hongmei Jing, Ruihua Mi, Wen Wu, Wenjuan He, Hehua Wang, Qinghua Tang, Zhiping Jiang, Hui Liu, Guo Chen, Jie Sun, Jian Chen, Sai Yan, Huan Yan, Jiaxuan Wangwu, Zeyu Zhong, Linfang Wang, Songhua Fan, Michael Shi, Weiguo Su, Xiaojun Huang","doi":"10.1016/j.medj.2025.100575","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100575","url":null,"abstract":"<p><strong>Background: </strong>HMPL-306 has equally high inhibitory activity against mutated isocitrate dehydrogenases 1 and 2 (mIDH1/2).</p><p><strong>Methods: </strong>This first-in-human, phase 1 dose-escalation/dose-expansion study (this study was registered at ClinicalTrials.gov: NCT04272957) enrolled patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) harboring mIDH1 and/or mIDH2. Patients received 25-250 mg of HMPL-306 orally once daily (QD) in a 28-day treatment cycle. Primary objectives were safety, tolerability, and recommended phase 2 dose (RP2D), and the secondary objective was preliminary efficacy.</p><p><strong>Findings: </strong>A total of 76 patients were enrolled. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. RP2D was 250 mg QD for cycle 1 and 150 mg QD from cycle 2 onward. Common (≥10%) grade ≥3 treatment-related adverse events included platelet count decreased, anemia, neutrophil count decreased, and white blood cell count decreased. In patients who received 150 mg, 250 mg, or the RP2D (N = 59), rates of complete remission (CR)+CR with partial hematologic recovery were 34.6% and 36.4% in the mIDH1 (n = 26) and mIDH2 (n = 33) subgroups, respectively, and among these, CR with minimal residual disease negative rates were 77.8% and 50.0%, respectively. The median overall survival was 13.4 months in patients with mIDH1 and 13.1 months in patients with mIDH2.</p><p><strong>Conclusions: </strong>HMPL-306 showed an acceptable safety profile and promising preliminary efficacy. A phase 3, randomized study of HMPL-306 in R/R AML (this study was registered at ClinicalTrials.gov: NCT06387069) has been initiated.</p><p><strong>Funding: </strong>HUTCHMED Limited, National Key Research and Development Program of China, National Natural Science Foundation of China, and Peking University Medicine Fund for world's leading discipline or discipline cluster development.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100575"},"PeriodicalIF":12.8,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}